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POTENTIAL PREDICTORS OF SUDDEN CARDIAC DEATH
IN AORTIC VALVE DISEASE
Abdullah Amer Sultan Al-Riyami M.B., B .C h ., M.R.C.P. (U.K.)
Thesis submitted for the degree of Ph.D.
T o :
Faculty of Medicine
University of Glasgow
The Research described in
this thesis was carried out
at the University Department
of Medical Cardiology, Royal
Infirmary, Glasgow, G31 2ER.
A.A.S. Al-Riyaipi
Signed:
Dat e : I ° H ' ° \ !
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2
TABLE OF CONTENTS
PAGE
TABLE OF CONTENTS 2
LIST OF TABLES 6
LIST OF ILLUSTRATIONS 10
DECLARATION 13
DEDICATION 14
ACKNOWLEDGEMENTS 15
SUMMARY 17
CHAPTER ONE: LITERATURE REVIEW 21
1.1 NATURAL HISTORY OF AORTIC 22VALVE DISEASE
1.2 SUDDEN DEATH IN AORTICVALVE DISEASE 2 7
1.3 VENRTRICULAR ARRHYTHMIAS ASPREDICTORS OF SUDDEN DEATH 2 9
1.4 PREVALENCE OF VENTRICULAR ARRHYTHMIAS IN LEFTVENTRICULAR HYPERTROPHY 3 3
1.5 EFFECTS OF LEFT VENTRICULAR DYSFUNCTION ON VENTRICULARARRHYTHMIAS 39
1.6 EFFECTS OF AORTIC VALVE REPLACEMENT ON CARDIAC ARRHYTHMIAS
1.7 DETECTION OF VENTRICULAR LATE POTENTIALS FOR THE IDENTIFICATION OF PATIENTS WITH VENTRICULAR TACHYARRHYTHMIAS
3
PAGE
1.8 AUTONOMIC DYSFUNCTION AS APOTENTIAL MECHANISM FOR THE DEVELOPMENT OF VENTRICULAR TACHYARRHYTHMIAS AND SUDDEN DEATH 5 6
CHAPTER TWO: AIMS OF THE THESIS 6 7
CHAPTER THREE: PATIENTS AND METHODS 7 2
3.1 PATIENT SELECTION ANDRECRUITMENT 7 3
3.2 STUDY PROTOCOL 7 4
3.3 ECHOCARDIOGRAPHY 7 6
3.4 DOPPLER ECHOCARDIOGRAPHY 7 9
3.5 AMBULATORY ELECTROCARDIOGRAPHIC MONITORING 81
3.6 SIGNAL-AVERAGED ELECTROCARDIOGRAPHY 84
3.7 AUTONOMIC FUNCTION TESTS 86
3.8 CARDIAC CATHETERISATION 90
3.9 STATISTICAL METHODS 92
3.10 ETHICAL APPROVAL 93
CHAPTER FOUR: CLINICAL, ECHOCARDIOGRAPHICAND ANGIOGRAPHIC CHARACTERISTICS OF PATIENTS 94
4.1 CLINICAL PARTICULARS 95
4.2 ECHOCARDIOGRAPHY 108
4.3 EXTENT OF LEFT VENTRICULARHYPERTROPHY 121
4.4 LEFT VENTRICULAR FUNCTION 126
4.5 ANGINA PECTORIS AND CORONARY ARTERY DISEASE IN PATIENTSWITH AORTIC VALVE DISEASE 128
4
PAGE
CHAPTER FIVE: PREVALENCE AND SIGNIFICANCEOF VENTRICULAR ARRHYTHMIAS IN PATIENTS WITH AORTICVALVE DISEASE 137
5.1 INTRODUCTION 138
5.2 PATIENTS AND METHODS 1415.3 RESULTS 141
5.4 DISCUSSION 161
5.5 SUMMARY 166
CHAPTER SIX: CLINICAL OUTCOME OF PATIENTS 167
CHAPTER SEVEN: PREVALENCE OF VENTRICULARARRHYTHMIAS IN THE EARLYPOST-OPERATIVE PERIOD 175
7.1 INTRODUCTION 176
7.2 PATIENTS AND METHODS 176
7.3 RESULTS 177
7.4 DISCUSSION 182
7.5 SUMMARY 185
CHAPTER EIGHT: EFFECT OF AORTIC VALVE REPLACEMENT ON ECHOCARDIOGRAPHIC LEFT VENTRICULAR HYPERTROPHY AND CARDIAC ARRHYTHMIAS 186
8.1 INTRODUCTION 187
8.2 METHODS 188
8.2.1 STUDY PATIENTS 188
8.2.2 STUDY PROTOCOL 191
8.3 RESULTS 192
8.3.1 CLINICAL CHARACTERISTICSOF PATIENTS 192
8.3.2 ECHOCARDIOGRAPHY 194
8.3.3 AMBULATORY MONITORING 197
5
PAGE
8.3.4 PREVALENCE OF VENTRICULAR ARRHYTHMIAS 197
8.3.5 FREQUENCY OF ARRHYTHMIAS IN THE3 STUDY PERIODS 201
8.3.6 SIGNAL-AVERAGED ELECTROCARDIOGRAPHY 207
8.3.7 SIGNAL-AVERAGED ELECTROCARDIOGRAPHY BEFORE AND LATE AFTERAORTIC VALVE REPLACEMENT 2 09
8.4 DISCUSSION 209
8.4.1 REGRESSION OF LEFTVENTRICULAR HYPERTROPHY 213
8.4.2 PREVALENCE OF VENTRICULARARRHYTHMIAS 215
8.4.3 SIGNIFICANCE OF NONSUSTAINEDVENTRICULAR TACHYCARDIA 217
8.4.4 EFFECT OF AORTIC VALVEREPLACEMENT ON VENTRICULAR ARRHYTHMIAS AND SIGNAL-AVERAGED ELECTROCARDIOGRAPHY 218
8.5 SUMMARY 218
CHAPTER NINE: IMPAIRED CARDIOVASCULARAUTONOMIC FUNCTION IN AORTICVALVE DISEASE 220
9.1 INTRODUCTION 2219.2 STUDY POPULATION 22 3
9.3 METHODS 223
9.4 RESULTS 224
9.5 DISCUSSION 235
9.6 SUMMARY 2 40
CHAPTER 10: SUMMARY OF THE MAIN FINDINGSAND CONCLUSIONS 242
REFERENCES 246
96
97
99
100
102
104
105
106
107
109
111
114
117
119
122
6
LIST OF TABLES
CHARACTERISTICS OF STUDY PATIENTS
CLINICAL CHARACTERISTICS OF PATIENTS
BLOOD RESULTS
DISTRIBUTION OF CLINICAL CHARACTERISTICS OF PATIENTS ACCORDING TO THE NYHA FUNCTIONAL CLASS
DISTRIBUTION OF CLINICAL CHARACTERISTICS OF PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF ANGINA
DISTRIBUTION OF PATIENTS ACCORDING TO THE NUMBER OF STENOSED CORONARY ARTERIES
DISTRIBUTION OF CLINICAL CHARACTERISTICS OF PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF CORONARY ARTERY DISEASE
DISTRIBUTION OF CLINICAL CHARACTERISTICS OF PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF PALPITATIONS
DISTRIBUTION OF CLINICAL CHARACTERISTICS OF PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF SYNCOPEECHOCARDIOGRAPHIC DATA OF PATIENTS ACCORDING TO SEXECHOCARDIOGRAPHIC DATA OF PATIENTS ACCORDING TO THE AORTIC VALVE LESION TYPE
DISTRIBUTION OF ECHOCARDIOGRAPHIC DATA OF PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF ANGINADISTRIBUTION OF ECHOCARDIOGRAPHIC DATA OF PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF CORONARY ARTERY DISEASE
DISTRIBUTION OF ECHOCARDIOGRAPHIC DATA OF PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF PALPITATIONSDISTRIBUTION OF ECHOCARDIOGRAPHIC DATA OF PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF SYNCOPE
7
TABLE:
4 .16
4 .17 4 . 18
4 . 19
5.1
5.2
5.3
5 . 4
5 . 5
5 . 6
5 . 7
5.8
5 . 9
5 . 10
5.11
LEFT VENTRICULAR SYSTOLIC AND DIASTOLIC DYSFUNCTION IN THE STUDY PATIENTSOPERATIVE MORTALITY RATESCHEST PAIN IN RELATION TO CORONARY ARTERY DISEASE IN PATIENTS WITH AORTIC VALVE DISEASE (PRESENT AND PREVIOUS STUDIES)
CHEST PAIN AND INCIDENCE OF CORONARY ARTERY DISEASE RELATIVE TO AORTIC PRESSURE GRADIENT IN PATIENTS WITH PREDOMINANT AORTIC STENOSIS
PREVALENCE OF VENTRICULAR ARRHYTHMIAS
EPISODES OF NONSUSTAINED VENTRICULAR TACHYCARDIA AND THEIR RELATION TO OTHER FORMS OF VENTRICULAR ARRHYTHMIASSUMMARY OF CLINICAL AND ECHOCARDIOGRAPHIC FINDINGS IN 9 PATIENTS WITH NONSUSTAINED VENTRICULAR TACHYCARDIA
DISTRIBUTION OF VENTRICULAR ARRHYTHMIAS ACCORDING TO THE L O W N 'S GRADING
CLINICAL AND ECHOCARDIOGRAPHIC CHARACTERISTICS OF PATIENTS ACCORDING TO THE FREQUENCY OF VENTRICULAR ARRHYTHMIAS
CLINICAL AND ECHOCARDIOGRAPHIC CHARACTERISTICS OF PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF MULTIPLE VENTRICULAR EXTRASYSTOLESCLINICAL AND ECHOCARDIOGRAPHIC CHARACTERISTICS OF PATIENTS ACCORDING TO THE FREQUENCY OF VENTRICULAR COUPLETS
CLINICAL AND ECHOCARDIOGRAPHIC CHARACTERISTICS OF PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF NONSUSTAINED VENTRICULAR TACHYCARDIA
RELATIONSHIP BETWEEN NUMBER OF VES PER 24 HOURS AND CLINICAL AND ECHOCARDIOGRAPHIC FINDINGS OF THE STUDY PATIENTSPREVALENCE OF ABNORMAL SIGNAL-AVERAGED ELECTROCARDIOGRAMSSUMMARY OF CLINICAL, ECHOCARDIOGRAPHIC AND AMBULATORY ECG FINDINGS IN 6 PATIENTS WITH ABNORMAL SAECGS
PAGE
127130
132
134
143
144
145
147
148
150
151
152
154
156
157
8
TABLE:
5 . 12
5 . 13
5 . 14
6 . 1
6.2
6.3
7 . 1
7.2
7 . 3
8.1
8.2
8 . 3
8.4
8 . 5
8 . 6
8 . 7
SIGNAL-AVERAGED ELECTROCARDIOGRAPHIC FINDINGS OF PATIENTS IN RELATION TO THEIR CLINICAL CHARACTERISTICSSIGNAL-AVERAGED ELECTROCARDIOGRAPHIC FINDINGS OF PATIENTS IN RELATION TO VENTRICULAR ARRHYTHMIASINCIDENCE OF COMPLEX VENTRICULAR ARRHYTHMIAS IN PATIENTS WITH AORTIC VALVE DISEASE (PRESENT AND PREVIOUS STUDIES)
TYPE OF SURGERY PERFORMED IN THE STUDY PATIENTS
SUMMARY OF CLINICAL AND ECHOCARDIOGRAPHIC FINDINGS IN 7 PATIENTS WHO HAVE DIED DURING THE STUDY PERIODAMBULATORY ELECTROCARDIOGRAPHIC AND SIGNAL- AVERAGED ELECTROCARDIOGRAPHIC FINDINGS IN 7 PATIENTS WHO HAVE DIED DURING THE STUDY
PREVALENCE OF VENTRICULAR ARRHYTHMIAS IN THE EARLY POST-OPERATIVE PERIOD
EPISODES OF NONSUSTAINED VENTRICULAR TACHYCARDIA AND THEIR RELATIONSHIP TO OTHER FORMS OF VENTRICULAR ARRHYTHMIAS
DISTRIBUTION OF VENTRICULAR ARRHYTHMIAS ACCORDING TO THE L O W N 'S GRADING
OPERATIVE DATA OF PATIENTS
CLINICAL CHARACTERISTICS OF PATIENTS BEFORE AND AFTER SURGERY
ECHOCARDIOGRAPHIC DATA IN PATIENTS STUDIED BEFORE AND AFTER SURGERY - DATA PRESENTED ACCORDING TO THE PREDOMINANT AORTIC VALVE LESION
PREVALENCE OF VENTRICULAR ARRHYTHMIAS IN THE LATE POST-OPERATIVE PERIOD
RELATIONSHIP BETWEEN NUMBER OF VES PER 2 4 HOURS AND ECHOCARDIOGRAPHIC DATA OF THE PATIENTS
EPISODES OF NONSUSTAINED VENTRICULAR TACHYCARDIA AND THEIR RELATIONSHIP TO OTHER FORMS OF VENTRICULAR ARRHYTHMIAS
SUMMARY OF OPERATIVE DATA AND ECHOCARDIOGRAPHIC FINDINGS IN 4 PATIENTS WITH NONSUSTAINED VENTRICULAR TACHYCARDIA
PAGE
158
160
163
169
172
173
178
180
181
189
193
195
198
199
200
202
203
204
206
208
210
211
225
226
227
229
230
232
233
234
236
9
DISTRIBUTION OF VENTRICULAR ARRHYTHMIAS ACCORDING TO THE L O W N 'S GRADING
PREVALENCE OF ARRHYTHMIAS DURING THE 3 STUDY PERIODS IN 21 PATIENTS
PREVALENCE OF ARRHYTHMIAS IN 21 PATIENTS STUDIED BEFORE, EARLY AND LATE AFTER AORTIC VALVE REPLACEMENT
PREVALENCE OF ABNORMAL SIGNAL-AVERAGED ELECTROCARDIOGRAMS IN THE LATE POSTOPERATIVE PERIOD
SUMMARY OF OPERATIVE, ECHOCARDIOGRAPHIC AND AMBULATORY ELECTROCARDIOGRAPHIC DATA IN 2 PATIENTS WITH ABNORMAL SAECGS
SAECGS IN 29 PATIENTS STUDIED BEFORE AND LATE AFTER AORTIC VALVE REPLACEMENT
CARDIOVASCULAR AUTONOMIC FUNCTION TEST RESULTS IN THE STUDY PATIENTS ACCORDING TO THE PREDOMINANT AORTIC VALVE LESIONCARDIOVASCULAR AUTONOMIC FUNCTION TEST RESULTS IN THE STUDY PATIENTS
CARDIOVASCULAR AUTONOMIC FUNCTION TEST RESULTS IN 2 0 NORMAL CONTROLSCARDIOVASCULAR AUTONOMIC FUNCTION TEST DATA IN HEALTHY CONTROLS AND PATIENTS WITH AORTIC VALVE DISEASE
CARDIOVASCULAR AUTONOMIC FUNCTION TEST RESULTS IN THE STUDY PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF SYNCOPE
CARDIOVASCULAR AUTONOMIC FUNCTION TEST RESULTS IN THE STUDY PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF PALPITATIONSCARDIOVASCULAR AUTONOMIC FUNCTION TEST RESULTS IN THE STUDY PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF ANGINA
CARDIOVASCULAR AUTONOMIC FUNCTION TEST RESULTS IN THE STUDY PATIENTS ACCORDING TO THE PRESENCE OR ABSENCE OF CADCARDIOVASCULAR AUTONOMIC FUNCTION TEST RESULTS IN 10 PATIENTS BEFORE AND AFTER AORTIC VALVE REPLACEMENT
10
FIGURE :
3 . 1
3.2
3 . 3
4 . 1 4 . 2
4.3
4 .4
4 . 5
4 . 6
4 . 7
4 . 8
4.9
4 . 10
5 . 1
5 . 2
5 . 3
6 . 17 . 1
8.1
8 . 2
LIST OF ILLUSTRATIONS
AN ELECTROCARDIOGRAM SHOWING LEFT VENTRICULAR HYPERTROPHY AND STRAIN
MEASUREMENTS OF LEFT VENTRICULAR DIMENSIONS ACCORDING TO THE PENN CONVENTION
NORMAL DOPPLER MITRAL FLOW PATTERN
AGE DISTRIBUTION OF THE STUDY PATIENTSDISTRIBUTION OF WEIGHT IN THE STUDY PATIENTS
DISTRIBUTION OF BODY SURFACE AREA IN THE STUDY PATIENTS
PREVALENCE OF ANGINA PECTORIS ACCORDING TO THE PREDOMINANT AV LESION
PREVALENCE OF CORONARY ARTERY DISEASE ACCORDING TO THE PREDOMINANT AV LESION
DISTRUBUTION OF IVSTd IN THE STUDY PATIENTSDISTRIBUTION OF LVIDd IN THE STUDY PATIENTSDISTRIBUTION OF PWTd IN THE STUDY PATIENTSDISTRIBUTION OF LVMI IN THE STUDY PATIENTSABNORMAL DOPPLER MITRAL FLOW PATTERN
AN EPISODE OF NSVT COMPRISING 10 VES
NORMAL SAECG
ABNORMAL SAECG
CARDIAC SURGICAL WAITING LIST
AN EPISODE OF NSVT COMPRISING 10 VES
AN EPISODE OF NSVT COMPRISING 9 VES
PRESENCE OF COMPLEX VES BEFORE, EARLY AFTER AND LATE AFTER AORTIC VALVE REPLACEMENT
FOLLOWINGPAGE
73
77
79
95
95
95
101
103
108
108
108
108
128
145
156156
173
180
200
207
11
FIGURE:
9 . 1
9.2
9 . 3
9.4
9.5
9 . 6
9 . 7
9.8
9 . 9
9 . 10
9 .11
9 . 12
9 . 13
FOLLOWINGPAGE
HEART-RATE RESPONSE TO VALSALVAMANOEUVRE IN 46 PATIENTS WITH AORTICVALVE DISEASE AND 2 0 HEALTHY CONTROLS 228HEART-RATE VARIATION DURING DEEPBREATHING IN 47 PATIENTS WITH AORTICVALVE DISEASE AND 2 0 HEALTHY CONTROLS 22 8
ELECTROCARDIOGRAPHIC STRIPS SHOWING NORMAL HEART-RATE RESPONSE TO VALSALVA MANOEUVRE 229
ELECTROCARDIOGRAPHIC STRIPS SHOWINGAN ABNORMAL HEART-RATE RESPONSE TOVALSALVA MANOEUVRE 22 9
ELECTROCARDIOGRAPHIC STRIPS SHOWING NORMAL AND ABNORMAL HEART-RATEVARIATION TO DEEP BREATHING 229
ELECTROCARDIOGRAPHIC STRIPS SHOWINGNORMAL IMMEDIATE HEART-RATE RESPONSETO STANDING 229
ELECTROCARDIOGRAPHIC STRIPS SHOWING AN ABNORMAL IMMEDIATE HEART-RATERESPONSE TO STANDING 229
PLOT OF RELATION BETWEEN AGE AND HEART-RATE VARIATION DURING DEEP BREATHINGIN PATIENTS WITH AS 234
PLOT OF RELATION BETWEEN PWTd AND HEART-RATE VARIATION DURING DEEPBREATHING IN PATIENTS WITH AS 234
PLOT OF RELATION BETWEEN IVSTd AND HEART- RATE VARIATION DURING DEEP BREATHING IN PATIENTS WITH AS 234PLOT OF RELATION BETWEEN SBP AND HEART- RATE VARIATION DURING DEEP BREATHING IN PATIENTS WITH AS 234
PLOT OF RELATION BETWEEN LVSP AND HEART-RATE VARIATION DURING DEEPBREATHING IN PATIENTS WITH AS 234
PLOT OF RELATION BETWEEN PSLVWS (REICHEK'S METHOD) AND VALSALVARATIO IN PATIENTS WITH AR 234
PLOT OF RELATION BETWEEN E/A RATIO AND HEART-RATE VARIATION DURINGDEEP BREATHING IN PATIENTS WITH AR 2 34
12
FIGURE:
9 . 15
9 . 16
9 . 17
9 . 18
9 . 19
FOLLOWINGPAGE
PLOT OF RELATION BETWEEN IVSTd AND30:15 RATIO IN PATIENTS WITH AR 234
PLOT OF RELATION BETWEEN SBP AND30:15 RATIO IN PATIENTS WITH AR 235
PLOT OF RELATION BETWEEN LVSP AND30:15 RATIO IN PATIENTS WITH AR 235
PLOT OF RELATION BETWEEN PSLVWS (REICHEK'S METHOD) AND HEART-RATE VARIATION DURING DEEP BREATHING IN PATIENTS WITH COMBINED AS AND AR 2 35
PLOT OF RELATION BETWEEN PSLVWS(QUINONES' METHOD) AND HEART-RATEVARIATION DURING DEEP BREATHING INPATIENTS WITH COMBINED AS AND AR 235
13
DECLARATION
I hereby certify that this thesis had been designed, composed and written entirely by myself and has not been
submitted previously for any degree.
Signed:
D a t e : i O V ’ ° [ I
14
DEDICATION
To my
Khadija
SalmaWael and Ayham
Dania
MotherWife
Sons
Little daughter
15
ACKNOWLEDGEMENTS
I wish to offer my deepest appreciation to Professor S.M.
Cobbe for his helpful advice and criticisms in his
capacity as my research Supervisor and for giving me the
opportunity to benefit from his invaluable experience and
special skills in clinical cardiology. I wish to thank Dr. A.R. Lorimer for his unfailing encouragement and
support throughout my stay in Glasgow. My special thanks
to all the Consultants who have allowed me to recruit
their patients into the study. However, this thesis could
not have become a reality were it not for these patients
to whom I am deeply indebted.
I cannot acknowledge everyone who has helped me in this
enterprise, but would wish to cite in particular Dr. P.W.
Macfarlane for his invaluable expert advice, Julie Kennedy
and her colleagues for their technical assistance, Janice
Watson, David Shoat and Brian Devine for their computing expertise, Stephanie McLaughlin for her statistical
advice, Randall Hendriks for reading the manuscript and to
all my medical colleagues and secretarial staff in the
department for assisting me in different ways.
Dr. A.M. Al-Riyami deserves special mention for his
untiring support, encouragement and inspiration. I had
been exceptionally fortunate to work under him during my
early days of clinical apprenticeship.
16
This work however, would not have seen the light of day
had it not been for the assistance and support of the
Ministry of Health, Oman.
Finally, my special thanks to Mrs. Margaret Stirrat for undertaking the difficult task of typing this manuscript.
17
S U M M A R Y
18
Although sudden death continues to claim 15 to 20% of
patients with aortic valve disease, the exact cause still
remains speculative. It has been the assumption of many
workers that these deaths result from ventricular
tachyarrhythmias. The major aim of this thesis was there
fore to assess the prevalence of ventricular arrhythmias
in patients with aortic valve disease and to evaluate
their significance by signal-averaged electrocardiography (SAECG).
A total of 100 patients, 55 with predominant aortic
stenosis (AS) with a mean transaortic gradient of 81 ± 27
mmHg, 16 with predominant aortic regurgitation (AR) and 29
with combined AS and AR were studied prior to aortic valve
replacement (AVR). Substantial left ventricular hyper
trophy was present with a mean echocardiographic left
ventricular mass index of 210 ± 72 g / m 2 . Left ventricular
systolic and diastolic function were normal in 94% and 61%
of patients respectively.
Coronary angiography was performed in 89 patients of whom
50 (56%) had chest pain typical of angina pectoris and 21
(24%) had significant coronary artery disease. Angina was
present in 20 of these 21 patients (95%). Thus angina
could predict the presence of significant coronary artery
disease with 95% sensitivity and 54% specificity.
In agreement with previous work, this study has shown a high prevalence of complex ventricular arrhythmias.
Nonsustained ventricular tachycardia (NSVT) was detected
by ambulatory electrocardiographic monitoring in 9 (9%)
19
patients of whom only one had late potentials on SAECG.
The frequency of ventricular arrhythmias was not related
to the degree of left ventricular hypertrophy or the
severity of aortic valve disease. Left ventricular
function did not have any effect on ventricular arrhythmias.
A high prevalence of complex ventricular arrhythmias was also seen in the early (5 to 7 days post AVR) and late
(121 + 24 days post AVR) post-operative periods. The
frequency of ventricular arrhythmias was not affected by
AVR. In the late post-operative period, 4 patients had
NSVT, but none of them had late potentials on SAECG. As with the pre-operative results, there was little to
suggest the presence of an arrhythmogenic substrate in
these patients in view of the absence of late potentials
on SAECG. Furthermore, no sustained ventricular
arrhythmias were detected in the 3 study periods.
Aortic valve replacement was accompanied by a significant
regression in echocardiographic left ventricular
hypertrophy in patients with predominant AS and those with
combined AS and AR.
Of the total 100 patients in this study, 75 were on the
cardiac surgical waiting list of whom 60 have already
undergone operation. There have been 7 deaths (7%) during
the study period, 3 of them occurring suddenly in patients
awaiting surgery. Thus, the incidence of sudden death
while awaiting operation was 4%.
20
It has been suggested that patients with decreased heart-
rate variability have decreased vagal tone, increased
sympathetic activity or both and hence are at a higher risk of developing ventricular fibrillation and sudden
death. Cardiovascular autonomic function was assessed in
47 patients prior to AVR and repeated in 10 patients 3
months following AVR. Abnormal heart-rate variation
during deep breathing was detected in 18 (38%) patients.AVR was not accompanied by any improvement in
cardiovascular autonomic function at least in the shortterm .
Thus, despite a high prevalence of ventricular arrhythmias
in aortic valve disease patients with substantial left
ventricular hypertrophy, there was little to suggest the presence of an arrhythmogenic substrate. The potential
mechanism of sudden death in these patients could be speculated on the basis of impaired cardiovascular
autonomic function.
21
C H A P T E R O N E
L I T E R A T U R E R E V I E W
22
1•1 Natural History of Aortic Valve Patients
An understanding of the natural history of aortic valve
disease is very important because of the significant
incidence of sudden death associated with this disease and
the grave prognosis that appears to accompany the onset of
certain symptoms (Contratto and Levine, 1937; Mitchell et al, 1954; Chizner, Pearle and de Leon, 1980). However, evaluation of the natural history of aortic valve disease has recently been difficult because of the development of
objective means for assessment of its severity and the
advent of corrective operations resulting in the
interruption of the course of the disease. Thus the
resultant lack of sufficient prospective information
concerning the outlook of aortic valve patients has
necessitated a largely retrospective view of the natural history.
About 100 years ago the diagnosis of aortic valve disease
and in particular aortic stenosis was made solely on the
basis of hearing a systolic murmur over the aortic area.
This resulted in the dismissal of many army recruits
during the first world war who were subsequently
considered to have innocent murmurs. It was therefore felt by many workers that stringent diagnostic criteria
should be developed in the diagnosis of aortic stenosis.
In an excellent paper by Contratto and Levine (1937), 180
definite cases of aortic stenosis were studied. Definite
evidence of aortic stenosis was based on the presence of a
systolic thrill at the base of the heart, the detection of
calcification in the aortic valve on fluoroscopic examin
23
ation and post-mortem findings. In these 180 cases, the commonest aetiology was rheumatic fever and the male sex
predominated. Angina pectoris was guite common, occurring in 22.7% of the cases, and of 9 sudden deaths that occurred, 5 of these cases had angina pectoris.
Palpitation was an early complaint and survival after its
onset was 8 years compared to 23 months for dyspnoea and
only 9.1 months for syncope.
A total of 533 cases of aortic stenosis, half of which
were diagnosed at post-mortem, were studied by Mitchell et
al (1954). Mean survival in 159 cases with angina was 4.1
years after its onset. Sixty-seven patients had syncope
and their mean survival after its onset was 3.3 years.
The mean survival after the onset of congestive cardiac
failure was 2.3 years. Sudden death occurred in 40
patients. There were only three cases of syncope in the
sudden death group, while on the other hand 12 of these
patients had a definite history of angina pectoris. It would follow from this series that angina pectoris is a
fairly common precursor of sudden death in aortic valve
patients and occurs not infrequently in the absence of
significant coronary sclerosis as evident from postmortems .
In a retrospective study involving 100 cases of pure
aortic stenosis, life expectancy was markedly reduced with
the onset of either cardiac pain, syncope or symptoms of
congestive cardiac failure in isolation or in various
combinations (Bergeron et al, 1954).
24
With the development of effective prosthetic devices for
replacement of the aortic valve, the need for a greater
understanding of the natural history of patients with aortic valve disease became even more important. However, the natural history of the patients is freguently
interrupted by surgical intervention. In a follow-up study of 15 cases with pure aortic stenosis in whom
surgery was not performed due to a variety of reasons, the average life expectancy was dependant upon the presence or absence of symptoms, notably angina pectoris, syncope and
congestive cardiac failure (Frank, Johnson and Ross, 1973 ) .
Chizner and his colleagues studied 42 adults with haemo-
dynamically documented valvular aortic stenosis who did not undergo early surgical intervention due to various
reasons (Chizner, Pearle and de Leon, 1980). Aortic
stenosis was categorised into mild, moderate and severe
stenosis according to the valve area or systolic peak-to-
peak gradient. Not surprisingly, mortality was guite high in 23 symptomatic patients with moderate to severe aortic stenosis. Twenty-six percent were dead at one year, 48%
at 2 years and 57% at 3 years. Fifty-six percent of all
deaths were sudden. This high mortality was not seen in
asymptomatic patients with moderate or severe stenosis.
It was striking to note that the mortality was also high
in symptomatic patients with mild stenosis. Four of 9
(44%) of these patients were dead by the end of the
follow-up period.
25
Unlike aortic stenosis, patients with pure aortic
regurgitation have been shown to remain asymptomatic for
many years, sometimes decades, following the clinical
diagnosis, and the progression of the disease is insidious
(Goldschlager et al, 1973). Dyspnoea and fatigue are the
common presenting symptoms, while chest pain and syncope occur less frequently. Sudden death is also not as common as in patients with aortic stenosis. However, progression of the natural course of aortic regurgitation becomes very
rapid with a fatal outcome with the appearance of either
angina or congestive heart failure (Bland and Wheeler,
1957; Massell, Amezcua and Czoniczer, 1966; Spagnuolo et
al, 1971; Smith et al, 1976). In these excellent studies involving a total of 764 patients with pure aortic
regurgitation who were followed up for up to 20 years, prognosis was found to be poor following the appearance of
angina or congestive heart failure. In one series, 13 of
14 patients with congestive heart failure died within 2
years. Aortic valve replacement is therefore strongly
indicated in such symptomatic patients. Other factors that led to a poor prognosis were an enlarged heart on chest radiography, the presence of extreme electrocardio
graphic left ventricular hypertrophy and cardiac
arrhythmias.
It must be emphasised that the pattern of aortic valve
disease in developed countries has been changing recently
in view of the rapid decline in the incidence of rheumatic
heart disease, increasing age of the patient population
and the increase in the frequency of coronary artery
disease. Aortic stenosis is now most commonly due to a
26
bicuspid valve. Rheumatic aortic stenosis has become much less common and calcific stenosis of valves in the elderly is a rapidly increasing cause. As a result of these
changes, the natural history of the disease has altered to
some extent. It would therefore be logical to base our
understanding of the disease progression on the result of
recent studies. In a recent study by Turina et al (1987), 190 adults with aortic valve disease who had undergone haemodynamic studies and in whom operation was not carried
out due to a variety of reasons, were followed up for
several years. Survival was poor in haemodynamically
severe disease and patients with aortic stenosis fared
worse than those with aortic regurgitation. In mild
disease, the first year survival was 100% in both groups,
while moderate disease showed an intermediate prognosis.
Prevalence of symptoms was related to the degree of
severity of the disease. In a prospective study reported
by Kelly et al (1988), 90 patients with haemodynamically
significant aortic stenosis, 39 with and 51 without
symptoms, were followed up until the occurrence of either
death or aortic valve replacement. Fifteen deaths (38%), all cardiac in origin occurred in the symptomatic group
while only 8 deaths, 6 of which were non-cardiac, occurred
in the asymptomatic group. In another long-term follow-up
study involving 142 patients with aortic stenosis, prognosis was related to the occurrence of symptoms
(Torstkotte and Loogen, 1988). Mean survival after the
occurrence of angina pectoris was 45 ± 13 months, after
syncope 27 ± 15 months and after the first occurrence of
left heart failure 11 + 10 months.
27
It would be reasonable to conclude from the above studies
that the prognosis of patients with aortic valve disease
can be largely determined by their symptoms and therefore the decision and timing of valve replacement should in
most cases be based on the knowledge of the severity of symptoms.
1•2 Sudden Death in Aortic Valve Patients
Prior to aortic valve replacement, patients with severe
aortic stenosis often died suddenly. In most cases, sudden death is usually preceded by angina, congestive heart failure or syncope (Contratto, and Levine, 1937; Mitchell et al, 1954; Chizner, Pearle, and de Leon, 1980).
In a minority of cases, however, it may be the first and
only symptom of severe aortic valve disease (Ross and
Braunwald, 1968; Wagner et al, 1977). The association of
aortic stenosis and sudden death was first noted by Cabot
(1926). From a study of post-mortem records attention was
drawn to the fact that in 6 of 28 cases of aortic stenosis, death was noted to be sudden and unexpected.
The paucity of reports in the medical literature and the
failure of textbooks to mention either sudden death or
syncope in connection with aortic stenosis, and by the
occurrence of sudden and unexpected death in two of their
patients with aortic stenosis within a week, prompted
Martin and Sullivan (1935) to pioneer one of the earliest
and most extensive reviews of the medical literature on sudden death in aortic stenosis. In this excellent review
they gave detailed case histories of 11 patients with
28
aortic valve disease in 9 of whom death was witnessed and
occurred suddenly. It is worth noting that all 11
patients had severe symptoms and in nearly half of them
syncope was a common occurrence. Reynolds et al (1960)
described the occurrence of sudden death in a four and a half year old child with congenital aortic stenosis with severe symptoms. In their paper they quoted from reported
series an incidence of sudden death in aortic stenosis of
between 4 and 18%. Glew et al ( 1969 ) reported from
published data nearly the same incidence of sudden death
in congenital aortic stenosis as that quoted by Reynolds
et al. However, sudden death occurred in only 8 patients with congenital aortic stenosis in a 20 year period in
their own practice, an incidence of 1%.
Schwartz et al (1969) studied the electrocardiograms of 9
adult patients with aortic stenosis and a history of
syncopal attacks during and after development of syncopal
seizures. They concluded that sudden death in such
patients was due to ventricular standstill, flutter or
fibrillation, or a combination of the three. They also
reported 12 sudden deaths in patients with aortic stenosis
that occurred in their hospital. Johnson (1971) reported
quite a high incidence of death in his own series of 204
adult patients with aortic stenosis. Twenty-seven of 130
patients with severe aortic stenosis died suddenly, an
incidence of 21%. In agreement with Johnson's findings,
Chizner and his colleagues reported a high incidence of
sudden death in those of their patients who had moderate
to severe aortic stenosis (Chizner, Pearle and de Leon, 1980 ). In a recent study, Von Olshausen et al ( 1983 )
29
reported the occurrence of sudden death in 2 of their patients with aortic valve disease while awaiting aortic valve replacement.
1•3 Ventricular Arrhythmias as Predictors of Sudden Death
Sudden death claims an estimated 350,000 lives per year in the United States and between 50,000 and 100,000 lives a
year in the United Kingdom (Braunwald, 1988). When death
occurs within one hour of the onset of symptoms, the majority are the result of ventricular tachyarrhythmias
(Kremers, Black and Wells, 1989). Two of the commonly
employed methods for detecting ventricular arrhythmias and
hence predict to a certain extent sudden death, are
electrophysiological studies and ambulatory recording of
the electrocardiogram. The first is an invasive technigue where arrhythmias are artificially induced thus detecting
the potential substrate which may ultimately lead to
lethal arrhythmias. This of course assumes that the
lethal arrhythmias thus reproduced will occur as the final
event leading to sudden death. The second is the more
favoured method as it has the advantages of being both
non-invasive and needing less expertise.
Previous reports of recorded sudden death involving 74
patients from 24 centres while on ambulatory electro
cardiographic monitoring, indicated that 66 to 75% of deaths were related to ventricular tachyarrhythmias
(Coumel, Leclercq and Leenhardt 1987). Several other
examples of sudden death during ambulatory monitoring
further confirm that the terminal event in the majority
30
was related to a tachyarrhythmia. In a case report by
Gradman and his associates, an increase in the premature ventricular contraction frequency with couplets was noted one and a half hours before death, finally degenerating into ventricular fibrillation (Gradman, Bell and De Busk, 1977). Pool and his colleagues reported 2 cases of sudden
death during ambulatory monitoring that showed an increase
in complex premature ventricular contractions culminating
into a tachyarrhythmia as a final event (Pool, Kurst and Van Wermeskerken, 1978). Lahiri's group reported 3 cases dying suddenly during ambulatory monitoring (Lahiri,
Balasubramanian and Raftery, 1979). In 2, ventricular
fibrillation was the terminal arrhythmia while in the
third, the terminal event was slow, bizarre ventricular
complexes at 30 to 40 beats per minute ending in asystole.
In a 71 year old man who died suddenly, analysis of the
ambulatory recording showed an increased frequency of
complex premature ventricular contractions with short runs of ventricular tachycardia in the last hour prior to death
(Salerno et al, 1981). In 6 instances of sudden cardiac
death during ambulatory electrocardiographic monitoring
reported by Nikolic and his colleagues, the terminal event
was ventricular fibrillation in 5 of them (Nikolic, Bishop
and Singh, 1982). Coincidentally, all the 6 patients had cardiac enlargement or left ventricular hypertrophy on
objective grounds. In 15 cases of spontaneous ventricular
fibrillation preceded by ventricular tachycardia during ambulatory electrocardiographic monitoring, 8 died and 7
survived cardiopulmonary resuscitation (Pratt et al, 1983). Again, left ventricular hypertrophy was present in
7 patients by electrocardiographic and 3 patients by
31
echocardiographic criteria. In a recent analysis of data from 5 patients who died suddenly during ambulatory
electrocardiographic monitoring, an increased density of
ventricular ectopic activity was noted in the hour before the final event (Martin et al, 1987). The final
arrhythmia in all the 5 cases was ventricular tachycardia
degenerating into ventricular fibrillation.
It is evident from these reports that in the majority of cases of sudden death as recorded by electrocardiographic monitoring, the final lethal event was a ventricular
tachyarrhythmia. Another interesting finding was the
occurrence of an increased density of ventricular ectopic
activity including both isolated ventricular premature
contractions and bouts of repetitive firing during the
hour before the terminal dysrrhythmia. The R - on - T
phenomenon in addition, was implicated in the onset of
ventricular fibrillation in roughly half of the cases.
These experiences provide a valuable glimpse at the terminal electrical event. It would therefore appear
logical to search for these "warning arrhythmias" for the
purpose of identifying those patients who may be at a high
risk of sudden death.
There are very few cases of recorded sudden death in
patients with aortic valve disease reported in the
literature, despite the high incidence of sudden death in
this disease. Von Olshausen et al (1982) reported a case
of severe aortic stenosis with impaired left ventricular
function who died suddenly while on an ambulatory
electrocardiographic recording. This showed ventricular
32
tachycardia as the terminal event with no ventricular arrhythmias recorded in the last hour prior to death. In a recent case report, sudden cardiac death was documented
on a Holter monitor electrocardiogram in a 71 year old man with calcific aortic stenosis where the terminal
arrhythmia was ventricular fibrillation preceded by sinus
tachycardia with broad QRS complexes (Siostrzonek et al, 1987). To further emphasize the role of ventricular
arrhythmias as a major cause of sudden death in patients with aortic valve disease, Von Olshausen and his
associates reported 4 patients with aortic valve disease
who had died suddenly while being monitored on an
ambulatory electrocardiogram (Von Olshausen et al, 1987).
Three of the 4 patients had nonsustained ventricular tachycardia in the hour before death. In all the 3
patients, the ventricular tachycardia ended in ventricular fibrillation. In the fourth patient, the recording time
was only 40 minutes and therefore not sufficient for any
conclusions to be formed. Nevertheless, the final rhythm
in this patient was ventricular fibrillation.
In a recent study reported by Luu and his colleagues, 21
cardiac arrests occurred in 216 patients with advanced heart failure while being monitored by telemetry electro
cardiography (Luu et al, 1989). It is of interest to note
that the final rhythm at the time of arrest was brady
cardia or electromechanical dissociation in 13 (62%)
arrests while ventricular tachycardia or fibrillation
occurred in only 8 (38%) arrests. It should be noted that
none of these patients had aortic valve disease.
33
1•4 Prevalence of Ventricular Arrhythmias in Left Ventricular Hypertrophy
Ventricular tachyarrhythmias have been implicated as the terminal event in the majority of cases of sudden death,
and the studies described above indicate that many of the
cases of sudden death occur in patients with left
ventricular hypertrophy. It would obviously be of
interest and importance to know the prevalence of ventricular arrhythmias in this group of patients.
In the Framingham Heart Study, both electrocardiographic
and echocardiographic left ventricular hypertrophy have
been shown to be associated with an increased risk of all
grades of ventricular arrhythmias (Levy et al, 1987).
Echocardiographic left ventricular hypertrophy, however, was more prevalent and sensitive for ventricular arrhythmias than electrocardiographic left ventricular
hypertrophy. The association of echocardiographic left
ventricular hypertrophy with arrhythmias persisted after
controlling for confounding variables, thus acting as an
independent contributing factor. Electrocardiographic
left ventricular hypertrophy may result from various forms
of cardiovascular diseases. By far the most common cause of left ventricular hypertrophy in the general population
is hypertension (Messerli et al, 1984; Dunn et al, 1977; Savage et al, 1979). In a study by Messerli et al (1984) hypertensive patients with left ventricular hypertrophy
had significantly more premature ventricular contractions
than those without left ventricular hypertrophy or than
normotensive subjects. McLenachan et al (1987)
34
investigated by 48 hour ambulatory monitoring, 100 hypertensive patients of whom 50 had electrocardiographic left ventricular hypertrophy. Salvoes of nonsustainedventricular tachycardia occurred in 28% of the patients with compared to 8% in those without electrocardiographic
left ventricular hypertrophy. However, nonsustained
ventricular tachycardia occurred in only 2% of 50
normotensive controls matched for age, sex and smoking
habits. Pringle et al (1987) performed 24 hour electro
cardiographic monitoring on 16 hypertensive patients with
and 23 without electrocardiographic left ventricular
hypertrophy. Nonsustained ventricular tachycardiaoccurred in 2 of the 16 patients with and in none of the 23 patients without electrocardiographic left ventricular
hypertrophy.
In a study of 100 patients with hypertrophic cardio
myopathy investigated by 24 hour ambulatory electrocardio
graphic monitoring, more than 50% of the patients had
multiform or repetitive ventricular premature
contractions, including 19% who had ventricular tachycardia (Savage et al, 1979). McKenna et al (1980), studied 30 patients with hypertrophic cardiomyopathy by 48
hour ambulatory electrocardiographic monitoring. Multi
form or paired ventricular extrasystoles were present in
43% and ventricular tachycardia occurred in 26% of the
patients. Canedo and his colleagues studied the
prevalence of arrhythmias in 33 patients with hypertrophic
obstructive cardiomyopathy by 24 hour ambulatory electro
cardiographic monitoring (Canedo, Frank and Abdulla,
1980). Eighty-two percent of their patients had
35
ventricular premature contractions with 39% of patientsshowing "potentially life-threatening rhythm dis
turbances". Short runs of ventricular tachycardia
occurred in 15% and frequent couplets in 18% of the
patients. In a study involving 50 patients with hypertrophic obstructive cardiomyopathy by periodic 24 hour Holter monitoring, the incidence of "potentially lethal arrhythmias" was 32% at 5 years and 81% at 10 years of follow-up (Frank et al, 1984). Kowly and his associates
reported the occurrence of nonsustained ventricular
tachycardia on ambulatory electrocardiographic monitoring
in 4 out of 7 patients with hypertrophic cardiomyopathy
that he investigated (Kowly, Eisenberg and Engel, 1984).
In a large series involving 86 unselected patients with hypertrophic cardiomyopathy studied by 72 hour ambulatory electrocardiographic monitoring, 24 patients had
ventricular tachycardia of whom 10 had more than 3
episodes (McKenna et al, 1981). Seven patients died
suddenly during a follow-up period of one to 4 years, 5 of
these patients belonging to the group that showed ventricular tachycardia as well as a combination of multi
form and paired ventricular extrasystoles on the previous
Holter recordings. In addition, they also had a
significantly higher maximum ventricular extrasystolic
count than the survivors, thus showing an association
between arrhythmias and subsequent prognosis.
Few studies using ambulatory electrocardiography for
detecting ventricular arrhythmias have been carried out in
patients with idiopathic dilated cardiomyopathy. Huang
and his colleagues studied 35 patients with idiopathic
36
dilated cardiomyopathy by 24 hour Holter monitoring (Huang, Messer and Denes, 1983). Freguent ventricular premature contractions were seen in 83%, of whom 93% had
complex ventricular premature contractions. Nonsustained
ventricular tachycardia occurred in 60% of the patients. In a similar study involving 74 patients with idiopathic
dilated cardiomyopathy, frequent ventricular premature contractions were seen in 35%, complex ventricularpremature contractions in 87% and nonsustained ventricular
tachycardia in 49% of the patients (Meinertz et al, 1984). In both studies, the severity of ventricular arrhythmias
was not related to the severity of clinical symptoms or to
the impairment of left ventricular function. Further
evidence for the high prevalence of ventricular
arrhythmias in patients with idiopathic dilated
cardiomyopathy is illustrated in a study involving 60 patients (Von Olshausen et al, 1984). Multiform
extrasystoles were recorded by a Holter monitor in 95%,
paired ventricular extrasystoles in 78% and nonsustained
ventricular tachycardia in 42% of the patients.
There is scanty information about the incidence of
ventricular arrhythmias in patients with aortic stenosis
or aortic regurgitation despite the fact that sudden
cardiac death is a well known complication in this group
of patients (Ross and Braunwald 1968; Von Olshausen et al
1982; Von Olshausen et al, 1987 ). Von Olshausen et al
(1983) investigated the incidence and severity of
ventricular arrhythmias in 93 patients with isolated
aortic valve disease (without coronary artery disease) by
24 hour ambulatory electrocardiographic monitoring.
37
Frequent and complex ventricular ectopic activity was noted in 55% of the patients out of whom 18% had
ventricular tachycardia. It is interesting to note that 2
out of the 17 patients with ventricular tachycardia diedsuddenly, and in one of them who died while beingmonitored, the terminal arrhythmia was ventricular tachycardia. There are a few preliminary studies on pre
operative ventricular arrhythmias in patients with aortic
valve disease. Kennedy et al (1975) studied 8 patients
with aortic valve stenosis and 7 with combined aortic
stenosis/aortic regurgitation by 24 hour Holter recordings. Complex ventricular premature contractions were exhibited in 93% of the patients of whom 47% had
ventricular tachycardia. In another preliminary study, Schilling et al (1982) investigated 38 aortic valve
disease patients by 24 hour Holter monitoring. High grade
ventricular arrhythmias occurred in 26 of the 38 patients.
Hochreiter et al (1982) studied 28 patients with severe aortic regurgitation. Complex ventricular arrhythmias
were detected in 10 out of the 28 patients (36%). Twenty- eight patients with aortic stenosis without significant
coronary artery disease or aortic regurgitation were
studied by 24 hour ambulatory electrocardiogram (Kostis et
al, 1984). Ventricular ectopic activity was present in 27
of the 28 patients. Nineteen patients had complex
premature ventricular contractions of whom 4 exhibited
ventricular tachycardia. Klein (1984) performed 24 hour
electrocardiographic monitoring in 52 patients with aortic stenosis and 50 patients with haemodynamically significant
aortic regurgitation. The occurrence of ventricular
arrhythmias in these patients was compared with that in
38
matched controlled subjects without aortic valve disease.
Complex ventricular extrasystoles were detected in 46% of
patients with aortic stenosis and 30% of patients with
aortic regurgitation. There was no difference in the
incidence of complex ectopy between aortic valve disease patients with normal coronary arteries and those with coexisting coronary artery disease. The incidence of
complex arrhythmias in aortic valve disease patients with
normal coronary arteries was significantly greater than
control subjects. However, the incidence of complex ectopy in aortic valve disease patients with co-existing
obstructive coronary artery disease was similar to that of patients with the same degree of coronary artery disease
and normal aortic valves.
There do not appear to be many studies that have directly examined the relationship between ventricular arrhythmias
and the degree of left ventricular mass. McLenachan et al
(1987) have shown a more freguent occurrence of
ventricular tachycardia as well as ventricular couplets in
those hypertensive patients who had left ventricular hypertrophy. Although this relationship is even more
marked with respect to echocardiographic left ventricular
hypertrophy than to electrocardiographic left ventricular
hypertrophy (Levy et al, 1987 ), they did not attempt to
correlate the arrhythmias with the degree of left
ventricular mass. In a study involving 554 elderly
persons, complex ventricular arrhythmias occurred in 75%
and paroxysmal ventricular tachycardia in 15% of the subjects with echocardiographic left ventricular hyper
trophy, compared to 44% and 6% respectively in those with-
39
out hypertrophy (Aronow et al, 1987 ). However, as in the previous study, the authors did not examine the occurrence
of complex ventricular arrhythmias in relation to the
degree of left ventricular mass. In a follow-up study of
patients with hypertrophic cardiomyopathy, ventricular septa were thicker in patients who died compared to those in the survivors (Kowly, Eisenberg and Engel, 1984).
Seventy-one percent of the patients who died had
ventricular tachycardia on their previous ambulatory electrocardiographic recordings. Spirito and hiscolleagues compared the extent of echocardiographic left
ventricular hypertrophy in 30 patients with hypertrophic
cardiomyopathy in whom ventricular tachycardia had been
documented on 24 hour ambulatory electrocardiographic
monitoring, to a control group of 61 patients with hyper
trophic cardiomyopathy who had normal ambulatory electro
cardiographic recordings (Spirito, Walson and Maron,
1987). Severe left ventricular hypertrophy was
significantly more common in patients with documented
ventricular tachycardia than in those with normal
ambulatory electrocardiographic recordings.
1.5 Effects of Left Ventricular Dysfunction on Ventricular Arrhythmias
The relationship between ventricular arrhythmias and left
ventricular dysfunction can ideally be studied in patients following an acute myocardial infarction. About 30 years
ago, the in-hospital mortality of patients with acute
myocardial infarction was as high as 40% (Brown et al,
1963 ). The exact cause for this high mortality was
40
unclear at the time despite the treatment of patients with
anticoagulant drugs, as this mode of therapy had been shown earlier by some workers to improve patient survival (Hilden et al, 1961).
It was with the introduction of the first coronary care
units that the relationship between ventricular ectopic
activity and sudden death in acute myocardial infarction
patients was recognised (Brown et al, 1963). A few years later, Lown et al ( 1967 ) showed for the first time a
reduction in mortality from arrhythmias in hospitalised patients with acute myocardial infarction. This was attributed to the improved organisation of the coronary
care unit, thus providing continuous electrocardiographic
monitoring under the supervision of highly trained nurses
who could detect dangerous arrhythmias and promptly
institute the appropriate therapy.
Sudden death however, continued to claim lives in survivors of acute myocardial infarction in the late post
infarction period. The exact prevalence and prognostic
significance of ventricular arrhythmias during this period
had not been adeguately studied previously. Kotler et al
(1973), studied 160 patients who had survived a recent
infarct by at least 3 months. Repeated ambulatory
electrocardiographic recordings were performed at 8
monthly intervals and the patients were followed up for up to 54 months. Eighty percent of the patients had ventricular ectopic activity on their recordings and
sudden death was significantly more common in this group
compared to those without ventricular ectopics. Four more
41
studies involving a total of 3,675 patients, further lend
support to the prognostic significance of ventricular
arrhythmias detected in the late post-infarction period (Ruberman et al, 1977; Anderson, De Camilla and Moss, 1978; Moss et al, 1979; Schulze, Strauss and Pitt, 1977).
Weaver et al ( 1976 ) were among the first workers who
recognised the relationship between life threatening arrhythmias and left ventricular dysfunction. They
studied 64 patients with coronary artery disease who had
been resuscitated from out of hospital cardiac arrest. Cardiac catheterisation and coronary angiography were performed and patients were followed up for an average of 20.4 months. Recurrent ventricular fibrillation and/or death occurred in those patients with triple vessel
disease and lower left ventricular ejection fraction.
This study however did not look at the prevalence and
severity of ventricular arrhythmias during the ambulatory
state in these patients and therefore no firm conclusions can be drawn pertaining to the relationship of ventricular
arrhythmias and left ventricular dysfunction. Two large studies have shown an independent effect of ventricular
arrhythmias on mortality after adjustment is made for left
ventricular dysfunction (Ruberman et al, 1977 and Moss et
al, 1979). However, both studies used a short period of
ambulatory electrocardiographic recording and clinical
heart failure served as an indicator of left ventricular
dysfunction. In contradiction to the above two studies,
Calvert, Lown and Gorlin ( 1977 ) as well as Califf et al
(1978) have shown a direct relationship between the
freguency and complexity of ventricular arrhythmias and
42
the extent of left ventricular dysfunction. In the study by Califf et al, the relationship of ventricular
arrhythmias to the extent of left ventricular dysfunction
was shown to be independent to the number and/or severity
of diseased vessels. Schulze, Strauss and Pitt (1977),
studied 81 patients following an acute myocardial infarction by 24 hour ambulatory electrocardiographic
monitoring and gated cardiac blood pool scan.
Approximately 90% of their patients with complex
ventricular arrhythmias had a left ventricular ejection
fraction of less than 0.40. Forty-five patients had an
ejection fraction of less than 0.40 and 26 of these 45patients had complex ventricular arrhythmias. Sudden
death occurred in 8 of these 26 patients while no sudden
deaths were reported in the remaining 19 patients with a
low ejection fraction, but with non-complex ventricular arrhythmias. They also showed a low prevalence of complex
ventricular arrhythmias in the patients with an ejection fraction of more than 0.40, and none of these patients
died suddenly.
In the multicentre post-infarction research group study,
both left ventricular dysfunction defined as a radio-
nucleide ejection fraction of less than 0.40 and
ventricular ectopy of 10 or more per hour identified a
group of patients with a higher two year mortality
(Multicentre Post Infarction Research Group, 1983). A
further analysis of the data from this study showed an
independent contribution to mortality of ventricular
arrhythmias and left ventricular dysfunction (Bigger et
al, 1984). Thus these findings from a study that involved
43
866 patients do not support the presence of a direct effect of left ventricular dysfunction on ventricular
arrhythmias. Although it is known that patients with left ventricular dysfunction can either die of heart failure,
myocardial infarction or arrhythmia, it is of interest to
note that a low left ventricular ejection fraction in this
study was more strongly associated with arrhythmic than
heart failure death. The same conclusion was reached in
another large multicentre study involving 533 patients who survived 10 days after myocardial infarction (Mukharji et al, 1984). In a major U.K. study of patients with chronic
ischaemic cardiac failure, mortality was very high in those patients with a combination of poor left ventricular
function and high grade ventricular arrhythmias (Glover
and Littler, 1987). Furthermore, they showed an inverse
relationship between left ventricular ejection fraction and grade of ventricular arrhythmias. They thus came to the conclusion that the presence of severe ventricular arrhythmias acts as a marker of severe left ventricular
impairment and that therapy should be aimed at both
improving left ventricular function and abolishing complex
ventricular arrhythmias.
In a study looking at factors responsible for high
mortality in patients with severe cardiac failure due to
ischaemic and non-ischaemic dilated cardiomyopathy, Chakko
and Gheorghiade (1985) showed an association between high grade ventricular arrhythmias and in particular,
nonsustained ventricular tachycardia, with more severe
resting left ventricular dysfunction. The left
ventricular ejection fraction among the patients with
45
complications were even more pronounced when left
ventricular ejection fraction was less than 30%.
There are few studies that have looked at the relationship
between ventricular arrhythmias and left ventricular function in patients with aortic valve disease. Von
Olshausen et al (1983) showed a highly significant inverse correlation between left ventricular ejection fraction and frequency of ventricular premature contractions in their
study involving 93 patients with aortic valve disease. Klein (1984), noted a significantly lower left ventricular
ejection fraction in patients with aortic regurgitation
who had complex ventricular arrhythmias compared to the ejection fraction of those with simple ventricular
arrhythmias. In an elegant study, Von Olshausen et al(1984) looked at the influence of aortic valve replacement
on the incidence of ventricular arrhythmias. Prior to
surgery, frequent and complex ventricular arrhythmias were
more prevalent in patients with impaired left ventricular
function. Interestingly, following aortic valve replacement, the grade of ventricular arrhythmias improved
significantly only in those patients who obtained an
improvement in their left ventricular function which was assessed non-invasively. In a recent study involving 68
patients with mitral and 92 with aortic valve disease, the
incidence and severity of ventricular arrhythmias showed a
negative correlation to left ventricular ejection fraction
(Meinertz et al, 1987). In addition, there was a positive
correlation between the grade of ventricular arrhythmias
and left ventricular end systolic volume index, as well as
46
to peak systolic left ventricular wall stress in the patients with aortic valve disease.
1•6 Effects of Aortic Valve Replacement on Cardiac Arrhythmias
In a number of long-term follow-up studies of patients
following aortic valve replacement, sudden death was not an uncommon occurrence (Duvoisin et al, 1968; Shean et al, 1971; Lee et al, 1975; Barrat-Boyes, Roche and Whitlock, 1977; Samuels et al, 1979). However, the exact mechanism of sudden death remains speculative and is presumed to be
secondary to an arrhythmic event. There are scant data
available on the effect of aortic valve replacement on
cardiac arrhythmias. Three studies involving a total of 55 patients with aortic valve disease, reported a low
incidence of ventricular arrhythmias following aortic
valve replacement (Smith et al, 1972; Angelini et al,
1974; Michelson, Morganroth and McVaugh, 1979). In all
these three studies arrhythmia monitoring was performed
within the first week following operation. In
contradiction to these findings, other workers have
reported a very high incidence of ventricular arrhythmias
in studies involving a total of 141 aortic valve disease patients following valve replacement (Schilling et al, 1982; Gradman et al, 1981; Kostis et al, 1984; Von
Olshausen et al, 1984 ). In 3 of these studies, the
incidence of ventricular arrhythmias was assessed
immediately before and following aortic valve replacement
(Schilling et al, 1982; Kostis et al, 1984; Von Olshausen et al 1984). Schilling and his colleagues showed a high
47
incidence of complex ventricular arrhythmias in their patients with a further increase 2 weeks and one year after aortic valve replacement (Schilling et al, 1982).
In contrast, Kostis et al (1984) although showing a high
incidence of ventricular arrhythmias in their patients,
did not observe significant effect of aortic valve
replacement on the frequency or complexity of ventricular
ectopic activity. An interesting but not surprising
observation was noted by Von Olshausen and his colleagues when they studied the influence of aortic valve replacement on the incidence of ventricular arrhythmias (Von Olshausen et al, 1984). Following aortic valve replacement, the grade of ventricular arrhythmias improved
significantly only in those patients who obtained an
improvement in their left ventricular function.
1.7 Detection of Ventricular Late Potentials for the Identification of Patients with Ventricular Tachyarrhythmias
Reentry plays a major role in the genesis of ventricular
tachyarrhythmias (El-Sherif et al, 1977; El-Sherif et al, 1977; El-Sherif et al, 1977; Williams et al, 1974; and
Zipes, 1975). The prerequisites for reentry are
unidirectional block, slow conduction and recovery of the
tissue ahead of the wave front of excitation (Zipes,
1975). One of the most significant findings attributed to slow conduction was the detection of delayed fractionated
electrical activity in regions of experimental infarction (El-Sherif et al, 1977) and since these potentials occur
at and after the end of the QRS complex they have been called "late potentials". They are characterised by
48
multiple high frequency low amplitude spikes and it has been suggested that the presence of such signals indicate sites for potential reentrant circuits. It has recently
been possible to record late potentials by signal- averaging of the surface electrocardiogram and this
technique which is simple and non-invasive has gained
popularity for identifying those patients who are prone to develop ventricular tachyarrhythmias. This technique is
performed by feeding a number of electrocardiographic
complexes through a high gain amplifier (X 1,000) and
after dividing by the number of cycles, an average value
of the electrocardiogram for each discrete point in time is obtained. The averaged electrocardiogram is then passed through a high pass filter which permits high frequency signals to pass without a loss of amplitude. By this method, ventricular late potentials can be
identified. These potentials would not be expected to be
recorded in the standard electrocardiogram since they are
in the microvolt range.
Berbari et al (1978), demonstrated for the first time
ventricular late potentials in the experimental animal, and Fontaine et al, in patients with idiopathic
ventricular tachycardia (Breithardt and Borggrefe 1986).
This has been confirmed by a growing number of further
reports (Breithardt, Becker and Seipel, 1980; Simson et
al, 1980; Rozanski et al, 1981; Simson, 1981; Denes et al,
1983; Denes, Uretz and Santarella, 1984). Eight patients
with ventricular aneurysm and chronic recurrent
ventricular tachycardia showed late potentials on signal-
averaged electrocardiograms (Rozanski et al, 1981).
49
Disappearance of both ventricular tachycardia and late potentials was noted following aneurysmectomy thus
suggesting that late potentials are related to the
tendency to develop recurrent sustained ventricular tachycardia. Simson (1981) performed signal-averaging of the
electrocardiogram on 66 patients who had a previous myocardial infarction. Ventricular late potentials were detected in 92% of 39 patients who had repeated episodes
of symptomatic ventricular tachycardia and in only 7% of the remaining 27 patients without complex ventricular
arrhythmias. All the ventricular tachycardia patients had
sustained inducible ventricular tachycardia on electro-
physiological studies. Denes et al (1983) by performing signal-averaging of the electrocardiogram could distinguish patients with documented ventricular tachycardia from normal subjects. All the ventricular tachycardia patients had a history of myocardial infarction and
ventricular tachycardia was inducible by programmed
electrical stimulation. In another larger study reported
by Denes and colleagues on patients with coronary artery
disease, 66% of patients with documented VT/VF had late potentials compared to 25% in those without VT/VF (Denes,
Uretz and Santarelli, 1984). In a study involving 236
patients, ventricular late potentials were recorded in 45
of 63 patients (71%) with documented ventricular tachy
cardia or fibrillation while in 27 control subjects, no
late potentials were recorded (Breithardt et al, 1982).
Several studies have shown a high incidence of life
threatening ventricular arrhythmias in patients with
dilated congestive cardiomyopathy (Huang, Messer and
50
Denes, 1983; Meinertz et al, 1984; and Von Olshausen et al, 1984). To assess whether signal-averaged electrocardiography could identify patients who are at a high risk of an arrhythmic death i.e. those with previously documented episodes of sustained ventricular tachycardia
or fibrillation, Poll et al (1985) studied 41 patients with dilated congestive cardiomyopathy. Abnormal signal-
averaged electrocardiograms occurred in 83% of the patients with previously documented sustained ventricular
tachycardia/ventricular fibrillation, and in only 14% of the patients with no ventricular tachycardia/ventricular
fibrillation. In a control group of 55 healthyindividuals, abnormal signal-averaged electrocardiogram
was detected in only 2%.
In addition to the above studies, several other
investigators have shown a strong correlation between
ventricular tachycardia inducible on electrophysiologic study and the presence of an abnormal signal-averaged
electrocardiogram (Simson et al, 1983; Freedman et al, 1985; Lindsay et al, 1986; Dennis et al, 1987; Winters et
al, 1988; Turitto et al, 1988; Borbola, Ezri and Denes,
1988; and Nalos et al, 1988). Simson et al (1983) studied
102 patients with prior Q wave myocardial infarction and
reported a 78% agreement between inducible ventricular
tachycardia and the presence of late potentials on the signal-averaged electrocardiogram. Freedman et al (1985)
studied patients with a history of spontaneous ventricular
fibrillation or spontaneous sustained ventricular tachy
cardia. Ventricular late potentials were present in 58%
of those patients with inducible ventricular tachycardia
51
or ventricular fibrillation by electrophysiologic study.
By performing signal-averaging of the electrocardiogram,
Lindsay et al (1986) could correctly identify 88% of
patients with inducible ventricular tachycardia on subsequent electrophysiologic study. A year later, Denniss et al (1987) showed a strong correlation between the ability to induce sustained ventricular tachycardia at
programmed ventricular stimulation and the presence of abnormal signal-averaged electrocardiograms in patients
following an acute myocardial infarction. The usefulness
of signal-averaging of the electrocardiogram for selecting
patients with nonsustained ventricular arrhythmias to undergo electrophysiological study was assessed by Winters and his colleagues (Winters et al, 1988). An abnormal
signal-averaged electrocardiogram had a 91% sensitivity
and a 56% specificity with respect to subsequent induction
of tachycardia by programmed ventricular stimulation.
Turitto et al (1988) studied 105 patients with
nonsustained ventricular tachycardia detected by Holter
monitoring and assessed the predictive accuracy of signal- averaged electrocardiogram for the induction of sustained monomorphic ventricular tachycardia by programmed
ventricular stimulation. Signal-averaged electrocardio
gram showed a sensitivity of 64%, specificity of 89% and
predictive accuracy of 84% in predicting inducibility of
sustained ventricular tachycardia. In 50 patients with
coronary artery disease and documented spontaneous
ventricular tachycardia or ventricular fibrillation, late
potentials were present in 71% of those patients with
inducible sustained monomorphic ventricular tachycardia at
electrophysiological studies (Borbola, Ezri and Denes,
52
1988). In a study by Nalos et al (1988), signal-averaged
electrocardiography could correctly identify those
patients in whom sustained monomorphic ventricular tachy
cardia was induced by programmed ventricular stimulation
with a sensitivity of 80% and a specificity of 92%.
The prognostic significance of late potentials in patients with coronary artery disease has been evaluated in a few prospective studies (Zimmermann et al, 1985; Denniss et
al, 1983; Kuchar, Thorburn and Sammel, 1986). Zimmermann et al (1985) followed up 90 patients with coronary artery disease for a period of one to 22 months. There were 9 deaths (10%), 6 of them resulting from sustained
ventricular arrhythmias. All these 6 patients had
ventricular late potentials at the beginning of the study.
Thus ventricular late potentials had a 100% sensitivity in
predicting sudden arrhythmic death. Denniss et al (1983)
had previously reported a similar positive prognostic
value of late potentials in identifying patients with
sustained ventricular tachycardia. In another study involving 165 patients who survived acute myocardial
infarction signal-averaged electrocardiography predicted
arrhythmic events with a 92% sensitivity and 62%
specificity (Kuchar, Thorburn and Sammel, 1986).
The clinical setting of an acute myocardial infarction
provides fertile ground for research in signal-averaged
electrocardiography with the view of identifying patients with poor prognosis. McGuire et al (1988) performed
signal-averaged electrocardiograms in 50 patients within
the first 24 hours following acute myocardial infarction.
53
The presence of late potentials could predict the develop
ment of subsequent fatal ventricular arrhythmias with a
sensitivity of 80% and specificity of 72%. Although this study was performed in a small group of patients, it nonetheless suggests that signal-averaged electrocardio
graphy may well have an important role in identifying high risk patients prior to hospital discharge. These findings
are further supported by data of Kienzle, Falcone and
Simson (1988). They showed a significant decrease in voltage over the first 80 milliseconds of the signal- averaged QRS complex in patients with acute myocardial infarction compared with signal-averaged electrocardio
grams of healthy volunteers. Interestingly, they found a
further decline in voltage when comparing patients with
previous myocardial infarction and sustained ventricular tachycardia with the patients with acute myocardial
infarction without ventricular tachycardia.
Syncope is a commonly encountered clinical problem that
frequently defies ready explanation. Signal-averaged
electrocardiography provides a non-invasive tool in the
initial evaluation of patients with unexplained syncope,
particularly in the presence of organic heart disease before subjecting them to invasive electrophysiological
studies. Kuchar and his colleagues studied 150 patients with recurrent syncope by signal-averaged electrocardio
graphy in order to determine its role in identifying patients with ventricular tachycardia and hence determine
their prognosis (Kuchar, Thorburn and Sammel, 1986). They
found late potentials to have a predictive accuracy of 82%
for identifying ventricular tachycardia in patients with
54
ischaemic heart disease and 54% in those with other forms
of structural heart disease. It is interesting to note
that patients without heart disease in whom late potentials were detected did not have ventricular tachycardia. This is because myocardial disease is a prerequisite for reentrant ventricular arrhythmias and in
addition late potentials do not identify patients in whom
ventricular tachycardia results from an automatic or
triggered mechanism. In another smaller study involving
24 patients with unexplained syncope, signal-averaged electrocardiography provided an 89% sensitivity in detecting those patients with sustained ventricular tachycardia induced on subsequent electrophysiological studies (Gang
et al, 1986). Winters and his colleagues studied 40
patients with unexplained syncope by signal-averaged
electrocardiography followed by electrophysiologic studies
(Winters, Stewart and Gomes, 1987). An abnormal signal-
averaged electrocardiogram had a sensitivity of 82% and
specificity of 91% in predicting the induction of sustained ventricular tachycardia at electrophysiologic
testing.
A reduced incidence of ventricular tachyarrhythmias and
sudden death has been observed in patients who receive
thrombolytic therapy following an acute myocardial
infarction. This observation prompted Gang et al (1989) to perform signal-averaged electrocardiograms in 106
patients within 48 hours of hospital admission following a first myocardial infarction. They noted a significant difference in the incidence of late potentials in patients
who had, compared to those who had not received tissue
55
plasminogen activator (t - PA). Furthermore, in the only
2 patients with late potentials in the t - PA group,
coronary angiography demonstrated continued occlusion of the infarct related artery in both of them.
In another interesting study involving 40 patients with
chronic coronary artery disease, signal-averaged electro
cardiography was performed immediately before and repeated
within a mean of 10 days following coronary artery bypass grafting (Borbola et al, 1988). In 2 of 7 patients with
previous myocardial infarctions and positive for late
potentials before coronary artery bypass grafting, signal-
averaged electrocardiograms became normal following
surgery. In the 5 remaining patients with persistent late potentials, the mean values of the signal-averaged electrocardiographic variables improved after revascular
isation .
As far as I am aware, there are no studies on signal-
averaged electrocardiography in patients with aortic valve
disease. However, in the only study on hypertensive
patients with electrocardiographic left ventricular hyper
trophy, 11 out of a total of 90 patients had nonsustained ventricular tachycardia on ambulatory electrocardiographic
monitoring. Of these 90 patients, only one had
ventricular late potentials on signal-averaged electro
cardiography (Pringle et al, 1989).
56
1•8 Autonomic Dysfunction as a Potential Mechanism for the Development of Ventricular Tachyarrhythmias and Sudden Death
The importance of the autonomic nervous system has been
relatively neglected until recent years simply by the fact
that this system lies in the borderlands between
cardiology, general medicine, neurology and endocrinology. Autonomic neuropathy and its resultant clinical manifest
ations may occur in a long list of diseases, andstructural disturbances may affect different systems. However, I shall restrict myself here in reviewing some of
the work that looks at the effects of autonomic failure on
the cardiovascular system.
The first historical contribution on cardiovascular autonomic failure was pioneered by Bradbury and Eggleston (1925), when they reported three cases with orthostatic
hypotension. However, it was in 1955 that one of thefirst large studies on cardiovascular autonomic
disturbances was presented in the medical literature
(Sharpey-Schafer, 1955). Sharpey-Schafer, who was then
the Professor of Medicine at St. Thomas' Hospital,
performed valsalva manoeuvre in 63 patients with heart
failure resulting from a variety of cardiac conditions
including aortic valve disease, and in 62 normal
volunteers. He showed a marked difference in continuous
arterial pressure records between normal subjects and
patients with heart failure. The classical heart rate
changes occurring in normal subjects were observed to be
absent in the heart failure patients.
57
Diabetes mellitus is by far the commonest cause of
autonomic neuropathy and its appearance is closely associated with peripheral neuropathy. Autonomic impairment can present in a variety of symptoms, but in some patients it may cause no symptoms. The first review on
autonomic neuropathy in diabetes mellitus was contributed
by Rundles (1945). Since then, several syndromes have
been described, but it was in the early sixties that
reports on abnormal circulatory reflexes began to appear in the literature. Sharpey-Schafer and Taylor (1960)
studied 337 patients attending a diabetic clinic, for
evidence of neuropathy. Sixty-nine patients (20%) showed evidence of neuropathy and all had an abnormal response to
valsalva manoeuvre. Ewing et al (1973) studied 37
diabetics with symptoms or signs of autonomic neuropathy. The heart rate and blood pressure response to valsalva
manoeuvre was abnormal in 62% of the patients and this
showed a significant correlation with a fall in systolic
blood pressure on standing. Beat to beat (R-R interval) variation in heart rate which is a sensitive test of
autonomic cardiovascular reflexes, was studied in 42 young
asymptomatic male diabetics (Murray et al, 1975). The mean R-R interval was significantly shorter in the
diabetics compared to 25 age matched healthy controls. This was the first study to document abnormal autonomic
cardiovascular reflexes in diabetics without any clinical features of autonomic neuropathy thus demonstrating that damage to the autonomic pathways controlling heart rate
can occur without any accompanying symptoms. This is
further supported by evidence from a study on 11 diabetics
in whom abnormal autonomic functions were present in 7,
58
being more severe in 3 of them (Bennett et al, 1976 ).
Despite the severity of cardiovascular autonomic dysfunction, no patient reported troublesome symptoms.
Rubier, Chu and Bruzzone (1985), studied 25 adults with diabetes mellitus, but free from heart disease and with no symptoms of peripheral or autonomic nervous dysfunction. Heart-rate variation to deep breathing was abnormal in 52% of the diabetics compared to 23% in 13 healthy volunteers.
On 24 hour ambulatory monitoring, the mean heart rate was
significantly higher in the diabetics with abnormal,
compared to those with normal, heart-rate variation to deep breathing. In addition, the mean of the 5 highest 24
hour systolic blood pressures was also greater in the
diabetics with abnormal heart-rate variation to deep
breathing than in healthy volunteers.
In a recent study, Hornung and his colleagues performed 24
hour ambulatory heart rate and blood pressure recordings
in 42 patients with diabetes mellitus and 22 normal
subjects (Hornung, Mahler and Raftery, 1989). There was little heart-rate variation in the diabetic patients thus giving a somewhat "flat curve" in the 24 hour profile. The smallest diurnal change in heart rate was observed in
6 of the 42 diabetics who had autonomic neuropathy.
The increased prevalence of myocardial infarction in
diabetic patients has been attributed to autonomic
neuropathy and it has been suggested that abnormal
autonomic reflexes may account for some of the deaths, especially those occurring suddenly in these patients
(Clarke, Ewing and Campbell, 1979). In a study by Niakan
59
et al, (1986) unrecognised myocardial infarction i.e. silent, was present in 20% of diabetic patients with
documented cardiovascular autonomic neuropathy as opposed
to 4.2% of patients with normal autonomic function. This
lends further support to the hypotheses that sudden death
which is common in diabetics, may be resulting from unrecognised myocardial infarction and simple bedside autonomic function tests may identify this high risk group of patients. Thirty-seven patients with diabetes mellitus and clinical features suggestive of autonomic neuropathy
were followed up for 33 months (Ewing, Campbell and
Clarke, 1976). There were 10 deaths (27%), all occurring
in patients with previously documented abnormal autonomic
function tests. In another larger study on patients with diabetes mellitus, 26 deaths occurred during a follow-up
period of up to 5 years (Ewing, Campbell and Clarke, 1980 ). There were 21 deaths (53%) in 40 patients with
initially abnormal autonomic function tests compared to
only 5 deaths (15%) in 33 patients with initially normal
tests. Two of these 5 patients had abnormal autonomic
function tests on subseguent testing during the follow-up period. The mean duration of survival in those withinitially abnormal autonomic function tests was 18.6months compared to 28.6 months in the 5 patients with
initially normal tests.
In a study to determine the predictors of intra-operative
cardiovascular morbidity in diabetics, autonomic function
tests were performed in 17 diabetic patients and 21 non
diabetic patients before undergoing elective ophthalmo
logic surgery (Burgos et al, 1989). A significantly
60
greater impairment in autonomic function was noted in diabetics needing intra-operative blood pressure support, thus indicating the usefulness of autonomic screening in
identifying a subset of diabetics who are at an increased
risk of intra-operative cardiovascular instability.
Ventricular fibrillation is regarded as the underlying mechanism of sudden death (Lown and Wolf, 1971). Neural inputs may play a role in the pathogenesis of ventricular
fibrillation. Verrier and his associates provokedventricular fibrillation in 60% of mongrel dogs following stimulation of the stellate ganglia, which are way
stations for sympathetic neural discharge from the brain
to the heart (Verrier, Thompson and Lown, 1974). The
incidence of ventricular fibrillation and the time of its onset were comparable for left and right-sided stimulation. However, when stellate ganglia were
sectioned or when the dog was pre-treated with reserpine, the changes in cardiac vulnerability were prevented.
Brown (1967) demonstrated an increase in sympathetic
discharge with the onset of acute myocardial infarction
following occlusion of the left main coronary artery in
anaesthetised cats. In a similar type of experiment,
coronary occlusion was followed by increased firing from
sympathetic fibres (Malliani, Schwartz and Zanchetti, 1969). If sympathetic neural discharge is a determining factor in cardiac susceptibility to ventricular
fibrillation, pharmacologic adrenergic blockade would be expected to prevent the reduction in threshold for
ventricular fibrillation that attends coronary occlusion.
This is well established in patients following an acute
61
myocardial infarction (Wilhelmsson et al, 1974; The
Norwegian Multicenter Study Group, 1981). Both these
studies showed a significant reduction in sudden cardiac death presumably by preventing lethal arrhythmias in
patients who received a beta-blocker.
Does the vagus nerve play any role in control of the
threshold for ventricular fibrillation? This question was
first addressed by Einbrodt in 1859, when he concluded
from his experiments on dogs, that the vagus protected the
heart against ventricular fibrillation (Bleich and Boro, 1976 ). More than a hundred years later, Kent et al, (1973), in agreement with Einbrodt's findings, demonstrated that a reduction in vagal tone led to an
increase in the electrical instability of the heart.
However, several other studies have indicated that vagal
stimulation has indirect effects that are expressed by
opposing the influence of heightened adrenergic tone on
ventricular vulnerability (Kolman, Verrier and Lown, 1975; Bleich and Boro, 1976). This is further supported by the
failure of vagal stimulation to influence the fibrillation threshold in dogs following beta-adrenergic blockade with
propranolol (Bleich and Boro, 1976).
Schwartz and his co-workers have performed a number of
animal experiments to explore the relationship between the
autonomic nervous system, myocardial ischaemia and ventricular arrhythmias (Billman, Schwartz and Stone,
1982; Schwartz et al, 1988). In these series ofexperiments, dogs were experimentally infarcted by
occluding the left anterior descending coronary artery and
62
after recovering from the acute myocardial infarction,
baroreceptor reflex testing was performed. The baro-
receptor slope was then constructed by plotting the R-R
interval as measured from a continuous electrocardiogram,
against systolic blood pressure that was either lowered or raised by 30 to 50 mmHg by injecting sodium nitroprusside or phenylephrine intravenously. Baroreflex sensitivity was measured as the slope of the ARR/ABP relationship.
Malignant arrhythmias were then induced by a combination
of exercise so as to physiologically elicit a high
sympathetic tone, and a brief episode of myocardial
ischaemia induced by occluding the circumflex artery. The
baroreceptor slope could identify those dogs that were likely to develop ventricular fibrillation and thus at risk of sudden death. Their slopes were noted to be significantly reduced when compared to the slopes in dogs
that did not develop ventricular fibrillation.
It was in 1971 that the first study looking at the
parasympathetic control of the human heart was reported (Eckburg, Drabinsky and Braunwald, 1971). They
constructed baroreceptor slopes by plotting the R-R
interval against systolic blood pressure after injecting
phenylephrine in 22 patients with a variety of cardiac
conditions and in 23 subjects free of heart disease. The
heart rate response to autonomic agents was also tested by
injecting propranolol and atropine intravenously. There
was no difference in heart rate between the patients and
controls after propranolol, while a significant increment
in heart rate was noted after atropine injection in only
the controls, thus indicating a marked disturbance of
63
parasympathetic function in patients with heart disease.
The baroreceptor slope was also significantly diminished in heart disease patients.
The work by Webb and his associates represents another
clinical milestone (Webb, Adgey and Pantridge, 1972).
They studied 74 patients within the first 30 minutes of the onset of acute myocardial infarction and found a vast majority of them to have signs of autonomic disturbances.
Signs of excessive sympathetic activity were more frequent in cases of anterior infarction, whereas signs of vagal
overactivity were more frequent in inferior infarctions.
Correction of these disturbances by pharmocologic means was followed by a noticeable reduction in the in-hospital
mortality. About 12 years later, in agreement with these findings, Imaizumi et al (1984) reported an impairment in
baroreflex control of heart rate in patients following an
acute myocardial infarction. Interestingly, the baroreceptor slope assessed by plotting the R-R interval
against systolic blood pressure was appreciably depressed
in the acute convalescent phase becoming steeper when the
test was repeated in the late convalescent phase. A few
years earlier, Kirby had also reported abnormal blood
pressure responses to the Valsalva manoeuvre in patients
with acute myocardial infarction (Kirby, 1977). A number
of recent studies have lended more support to the
occurrence of significant autonomic dysfunction in
patients following acute myocardial infarction (Bigger et al, 1988; McAreavey et al, 1989; Bhatnagar, Al-Yusuf and
Al-Asfoor, 1987). Bigger et al (1988) and McAreavey et al (1989), used a more sophisticated technique and
64
demonstrated low cardiac parasympathetic activity in
patients with acute myocardial infarction. This was done using 24 hour ambulatory electrocardiographic recordings,
measuring the changes in R-R intervals and monitoring variations throughout the day and night. This technigue was previously shown to provide a good measure of cardiac
parasympathetic activity (Ewing, Neilson and Travis,
1984). In a study in patients with chronic coronary
artery disease, significant impairment of cardiac para
sympathetic function was demonstrated in the patients compared to healthy volunteers (Airaksinen et al, 1987).
The prognostic importance of cardiac autonomic dysfunction has been assessed by several workers (Kleiger et al, 1987;
Martin et al, 1987; La Rovere et al 1988). In an elegant
piece of work Kleiger et al (1987) studied the heart rate
variability by performing 24 hour ambulatory electro
cardiographic recording in 808 patients from 9 hospitals
at an average of 11 days following an acute myocardial infarction. They showed the relative risk of mortality after a mean follow-up period of 31 months to be 5.3 times
higher in patients with lower heart rate variability. The
heart rate variability remained a powerful predictor of
mortality after adjusting for other variables known toaffect survival in patients following acute myocardial
infarction. Martin et al (1987) reported a significantly
lower heart rate variability in 3 patients who diedsuddenly during ambulatory electrocardiographic monitoring
when compared to heart rate variability in normal
subjects.
65
La Rovere et al (1988) studied baroreflex sensitivity in
78 patients following a first acute myocardial infarction
by plotting R-R intervals against systolic blood pressure
following an injection of phenylephrine. Six cardiovascular deaths, 4 of them sudden, occurred during a mean follow-up period of 24 months. Baroreflex sensitivity was remarkably lower in the patients who died than those of the survivors. Mortality significantly increased from 2.9% in patients with satisfactory baroreflex sensitivity
to 40% in those with a markedly depressed baroreflex sensitivity.
An interesting study reported by Ellenbogen and his
associates showed a striking improvement in baroreflex
sensitivity in severe heart failure patients as early as 2
weeks after orthotopic cardiac transplantation (Ellenbogen
et al, 1989). Baroreflex sensitivity was evaluated by
plotting arterial pressure measurments against AA
intervals in the recipient atrial intracavitary
electrogram after intravenous phenylephrine bolus. This
led to the speculation that neurohumoral rather than structural abnormalities of the baroreceptors account for
depressed baroreflex sensitivity in patients with severe
heart failure.
As sudden death is not an uncommon occurrence in aortic
valve patients (Ross and Braunwald, 1968; Chizner, Pearle
and de Leon, 1980; Lombard and Selzer, 1987) and as known
from previous studies, the increased risk of sudden
cardiac death associated with impaired autonomic function
(Billman, Schwartz and Stone, 1982; Schwartz, Billman and
66
Stone, 1984; Kleiger et al, 1987; Martin et al, 1987; La Rovere et al, 1988), it would be interesting to assess the state of the autonomic nervous system in patients with
aortic valve disease. However, I am aware of only one
study that has systematically addressed this question
(Airaksinen et al, 1988). These workers investigated heart rate responses to deep breathing and to standing up
in 24 patients with aortic stenosis and 24 age-matched healthy controls. Heart-rate variation to deep breathing
was significantly lower in patients with aortic stenosis
than in healthy controls. This led to the suggestion that
high left ventricular pressures seen in these patients may
blunt the baroreceptors within the ventricle. However,
aortic valve replacement which is expected to normalise the left ventricular pressure was not followed by improve
ment in the heart rate variability when the tests were
repeated 6 weeks after surgery in 6 patients.
67
C H A P T E R T W O
A I M S 0 F T H E T H E S I S
68
Sudden cardiac death is a well known complication of patients with aortic valve disease (Ross and Braunwald, 1968; Von Olshausen et al, 1982; Von Olshausen et al,
1987). The exact mechanism responsible for this fatal
outcome has remained speculative. However, many workers
have presumed sudden death to occur secondary to an
arrhythmic event in view of the high prevalence of complex ventricular arrhythmias in this group of patients
(Schilling et al, 1982; Von Olshausen et al, 1983; Kostis et al, 1984; Klein, 1984). Electrocardiographic left
ventricular hypertrophy which is found in 85% of patients with severe aortic valve disease (Braunwald, 1988) is
associated with an eight-fold increase in cardiovascular mortality and a six-fold increase in coronary mortality.
This cardiovascular risk is doubled when left ventricular hypertrophy is accompanied by repolarisation abnormalities
(Kannel, 1983). The probability of dying within 8 years after developing this electrocardiographic pattern is more
than half, which is at least 3 times the average mortality for this age-sex group. The mortality is in fact greater in persons with definite electrocardiographic left
ventricular hypertrophy than in persons surviving an acute
myocardial infarction (Kannel, Gordon and Offutt, 1969).
Two explanations have been offered for the increased
incidence of sudden death in this group of patients. One, is the increased incidence of ventricular arrhythmias as
reported in a number of studies (Levy et al, 1987;
Messerli et al, 1984; McLenachan et al, 1987 ), and the
other is the decrease in coronary reserve, well recognised
in patients with pressure induced left ventricular
69
hypertrophy thus leading to myocardial ischaemia (Borhani, 1987 ) .
Most of the above studies have not looked at the relationship between left ventricular dysfunction and ventricular arrhythmias, as the presence of severe
ventricular arrhythmias may merely act as a marker of
severe left ventricular impairment. This fact is
supported by a number of studies (see Chapter One).
The term "complex ventricular arrhythmias" quoted in most studies refers to a modified Lown grading system for ventricular arrhythmias described by Ryan et al, (1975) which also includes short runs of nonsustained ventricular
tachycardia. However, there are no reports of sustained
ventricular tachycardia, and therefore it cannot be
assumed that these complex ventricular arrhythmias are a
direct cause of death in these patients. It would therefore be worthwhile to verify their significance by the use of signal-averaged electrocardiography to detect
ventricular late potentials. The presence of these late
potentials has been shown to identify patients who are
prone to develop sustained ventricular tachycardia either
spontaneously or inducible by programmed ventricular
stimulation (see Chapter One).
Other processes may be involved in the mechanisms leading to sudden death in patients with aortic valve disease.
Several studies have reported an increased risk of sudden cardiac death associated with impaired cardiac autonomic
function (see Chapter One). And in a study by Airaksinen
70
et al, (1988), patients with aortic valve disease were
shown to have significantly impaired parasympathetic
heart-rate control. Animal experiments had earlier shown that a reduction in vagal tone led to an increase in the electrical instability of the heart thus leading to a reduction in the ventricular fibrillation threshold.
In order to examine the various potential factors
responsible for sudden death in aortic valve disease
patients, this thesis was designed to address a number of points:-
1. What is the prevalence of ventricular
arrhythmias in patients with aortic valve disease?
2. Is there a relationship between ventricular
arrhythmias and the degree of left ventricular
mass, the severity of aortic valve disease and the presence or absence of coexisting coronary
artery disease?
3. What is the effect of left ventricular
dysfunction on ventricular arrhythmias?
4. To assess the effect of aortic valve
replacement on ventricular arrhythmias.
5. To evaluate the significance of ventricular
arrhythmias detected by Holter monitoring by the use of signal-averaged electrocardiography.
71
6. To assess the status of cardiac autonomic
nervous function in patients with aortic valve disease.
72
C H A P T E R T H R E E
P A T I E N T S A N D M E T H O D S
73
3•1 Patient Selection and Recruitment
The University Department of Cardiology of the Glasgow Royal Infirmary is a referral centre for invasive cardiological investigations and has a wide catchment area.
Patients with significant aortic valve disease were
identified from the cardiac catheterisation waiting list.
The other main source of patient identification was the surgical waiting list. The majority of the patients enrolled into the study had left ventricular hypertrophy and strain on the 12 lead electrocardiogram. This was
defined as the sum of the amplitudes of the R-wave in V 5
or Vg and S-wave in egual to or exceeding 3.5 mV in the
presence of T-wave inversion of 0.1 mV or more in leads Vg
or Vg (Sokolow and Lyon, 1949; Kannel 1983) (Figure 3.1). The only exclusion criteria for entering the study was
either patient's refusal due to personal reasons or if the
investigating Cardiologist felt that the patient was too
unwell to be able to participate in the study. The
distance of the patient's residence from the hospital was
also taken into consideration before recruitment. Having
identified the patients in this way, the patient was
either interviewed in the hospital while awaiting cardiac catheterisation or an explanatory letter was sent asking the patient to attend a special out-patient clinic. In
either case, an informed consent was obtained. A total of 100 patients with significant aortic valve disease were
studied before surgery.
>
w
Figu
re
3.1:
An el
ectr
ocar
diog
ram
show
ing
left
vent
ricu
lar
hype
rtro
phy
and
stra
in.
74
3.2 Study Protocol
Day 1
On the first day of the study a detailed history was obtained with particular reference t o :-
Past history of rheumatic fever, hypertension, angina, myocardial infarction and diabetes mellitus.
Present medical history, especially exertional chest
pain, breathlessness, palpitations, syncope, blackouts or dizziness and intermittent claudication.
Cigarette smoking and alcohol intake.Current and past drug therapy.
Physical examination was carried out with particular
reference t o :-
Height and weight.
Cardiac failure.Added heart sounds and murmurs.
Investigations
Haematology: haemoglobin and haematocrit.Biochemistry: urea and electrolytes, urate,
gamma GT and total cholesterol.
12 Lead electrocardiogram.
75
Signal-averaging of the electrocardiogram was performed and finally an Oxford Medilog II freguency-modulated tape
recorder was fitted. The patient was then asked to return to the hospital after 48 hours.
Day 3
The Oxford Medilog II frequency-modulated tape recorder was removed and a detailed cardiac ultrasound examination was performed. In 47 of the hundred patients, bedside
autonomic function tests were also carried out.
Early post-operative study
The prevalence of arrhythmias during the immediate post operative period was assessed in 38 patients. Twenty-four
and, whenever feasible, 48 hour ambulatory electro
cardiographic recordings were made between the 5th and 7th
post-operative days using the same equipment as that for
the pre-operative study. Details of the operative procedure were obtained with particular emphasis on the
type of aortic prosthetic valve inserted as well as any other additional surgical procedure e.g. mitral valve
replacement or coronary artery bypass grafting. Haemato-
logical and biochemical results of the patients during the period of ambulatory electrocardiographic monitoring were
also obtained.
76
Late post-operative study
The full study protocol as that for the pre-operative
study was repeated about 3 to 6 months post-operatively in
30 patients. Once again an informed consent was obtained
and after a detailed history with particular emphasis on
the presence or absence of the cardinal symptoms i.e. exertional chest pain, palpitations, syncope and breathlessness, a thorough physical examination was carried out.
Blood was obtained for haematological and biochemical
investigations. Signal-averaging of the electrocardiogram
was then performed and finally the patient was fitted with
the ambulatory electrocardiographic recorder and asked to
return to the hospital 48 hours later. On the return appointment, the patient underwent a detailed cardiac ultrasound examination and in 10 of the 30 patients
bedside autonomic function tests were performed.
3.3 Echocardiography
Echocardiograms were recorded using an Advanced Technology Laboratory Ultramark 8 system with a 3.0 mHz transducer at
a paper speed of 50 mm/s. The patients were studied in the supine or left lateral position with the transducer
placed in the third to fifth left intercostal space to
demonstrate the long axis view. Whenever necessary, the
transducer was manipulated laterally until both the mitral
valve leaflets could be visualised with the transducer
perpendicular to the chest wall and adequate echoes of the
interventricular septum and left ventricular posterior
77
wall were simultaneously visualised. M-mode recordings
were obtained under 2-D guidance. Left ventricular dimensions were measured at or slightly below the tips of the mitral valve leaflets at the peak of the R-wave of the
simultaneously recorded electrocardiogram. Measurements
of the interventricular septum (IVST), left ventricular
internal dimension (LVID) and posterior wall thickness
(PWT) were made according to the Penn convention (Figure
3.2) (Devereux and Reichek, 1977 ). By this method, the thickness of both the septal and left ventricular posterior wall endocardial echoes are included in the left ventricular internal dimension measurement and excludes these echoes from the septal and left ventricular
posterior wall thickness measurements. By this method,
echocardiographic left ventricular mass was shown to correlate well with anatomic left ventricular mass
(Devereux and Reichek, 1977). Left ventricular mass (L V M )
was calculated using an anatomically validated formula:-
LVM = 1.04([LVID+PWT+IVST]3 - [LVID]3 ) - 13.6; where 1.04 is the specific gravity of the myocardium. Left
ventricular mass index was then calculated by dividing the LVM with body surface area derived by using the formula of
Dubois and Dubois (1916). Left ventricular hypertrophy
was considered to be present when the LVMI exceeded 134
g/m2 in males and 110 g/m2 in females (Devereux et al,
1984) .
Left ventricular systolic wall stress was determined non- invasively in all patients using echocardiographic para
meters. Two previously validated methods for the
calculation of wall stress were employed:-
-P 0 dm d d0 0 0r—1•H03d 00 xi0 e +j•H
TJ03 0.. 4-> P -P •CM d 0 d. 0 i-1 Cn Oro E d d •H
0 U •H -P0 p •H X5 d5-1 d P P 0d 03 -P 0 >tr 0 d U d•H 0 0 u 0S > 0 u
78
1• Reichek et al's method (1982^
By this method LV wall stress was determined by using the
angiographically validated method of Grossman and his colleagues (Grossman, Jones and McLaurin, 1975):- (0.334 P (LVID)/PWT [I+PWT/LVID]) where P = LV systolic pressure, LVID = LV diameter in endsystole and PWT = LV posterior wall thickness in endsystole.
2. Quinones et al's method (198CH
P (r/WT)
Where P = LV systolic pressure, r = intracavitary radius in cm, taken as half the echocardiographic left
ventricular diameter in endsystole (LVID/2) and WT = the
average of septal and posterior wall thicknesses in end
systole (IVST + PWT/2, where IVST = interventricular
septal thickness).
In both the above methods, LV systolic pressure was estimated by adding cuff systolic blood pressure and
doppler derived peak systolic gradient across the aortic
valve, both done during the echocardiographic examination.
Endsystole was identified as the time of smallest LVID.
Fractional shortening was calculated using the equation:-
FS = LVIDd - LVDS (McDonald, Feigenbaum and Chang, 1972).
Left atrial dimension was measured as the maximal distance
between the posterior aortic root wall and the posterior
left atrial wall.
79
All measurements were averaged from three consecutive sinus beats by the use of a tracker-ball manipulated
cursor. In addition to the measurements made by the use
of a digitizer contained in the image system, manual measurements were also made from hard copy.
3.4 Doppler Echocardiography
Doppler echocardiographic studies were performed using the same eguipment as that for the echocardiographic studies.
Continuous wave doppler examinations were performed using
a 2.25 mHz transducer. The subjects were examined supine
or in the left lateral position during guiet respiration.
The transducer was placed at or slightly medial to the apex and its position altered until the highest peak flow velocities in early and late diastole and the best
possible graphic quality of the doppler wave forms were
obtained. Tracings of the four cardiac cycles with the
highest velocity profile of early diastolic left ventricular filling were analysed and an average was taken
for the peak velocity of early left ventricular filling (peak E) and peak velocity of late ventricular filling due
to atrial contraction (peak A) (Figure 3.3). The ratio of
peak E/peak A was calculated as was the pressure half time, which is the time required during diastole for the
pressure difference across the mitral valve to fall to one half of its initial value at the onset of diastole (Hatle,
Angelson and Tramsdal, 1979). To record aortic flow
velocity, the transducer was placed at or slightly medial
to the apex with the patient lying in the supine or left
lateral position. Whenever necessary, other transducer
FIGURE 3.3: Normal Doppler mitral flow pattern.The maximal early diastolic flow velocity (E) is high relative to maximal late diastolic flow velocity (A) giving an E/A ratio of >1.
80
positions were sought e.g. the first or second right
intercostal space with the patient turned over to the
right side or the suprasternal notch. Measurement of the
maximum velocity was made after obtaining the optimal aortic flow recording from the ascending aorta. The recordings were considered optimal only after systematic
examination to locate the signal of highest audible
frequency, maximal velocity, and most clearly defined
spectral velocity envelope. Optimal signals were assumed
to be in a near-parallel orientation to the direction of maximal blood flow across the stenosis. The systolic pressure gradient across the aortic valve was then
calculated automatically using the software contained in the system which applied the modified Bernoulli equation
(Hatle, 1980) as follows:- Gradient = 4V^, where =
maximum velocity squared (in m/sec). In several recent studies, a general and close correlation between the
continuous-wave doppler derived pressure gradient and the
catheterisation gradient has well been established (Hatle,
1981; Stamm and Martin, 1983; Currie et al, 1985).
The degree of aortic regurgitation was estimated from the
maximum and clearest diastolic velocity profile. This was
accomplished by estimating the shape of the deceleration
slope which is defined as the line joining the peak
diastolic velocity to the end-diastolic velocity, the
slope being steepest in patients with severe
regurgitation. Previous studies have shown a good correlation between the severity of aortic regurgitation
obtained by continuous-wave doppler and that obtained by
supravalvular aortography (Masuyama et al, 1986; Grayburn
81
et al, 1987; Beyer et al, 1987). Any other coexisting valvular lesions were also documented.
The predominant aortic valve lesion of the patients was determined from doppler ultrasound and when available
cardiac catheterisation studies. Patients with atransvalvular gradient of more than 25 mmHg and aortic
regurgitation of less than grade 2+ of 4+ grades were
classified as having aortic stenosis (AS). Patients with aortic regurgitation of ± 2 + and a transvalvular gradient of <25 mmHg, were classified as having predominant aortic regurgitation (AR). Those who did not meet these criteria were classified as having combined AS and AR.
3.5 Ambulatory Electrocardiographic Monitoring
Ambulatory electrocardiographic recordings were made on
TDK acoustic dynamic cassettes over two consecutive 24 hour periods using calibrated Oxford medilog II frequency-
modulated tape recorders where channel I recorded lead CM5
and channel II recorded lead V 2 . After careful skin preparation the patients were connected to the tape
recorders using standard disposable silver-silver chloride
electrodes. The electrodes were placed over bony
prominences to avoid muscular artifacts. These sites were
the manubrium sternum, right sixth rib over the anterior axillary line, the left subclavicular space, the left
sixth rib in the anterior axillary line (lead C M 5 ) and a
modified V 2 .
82
The patients were then provided with a diary and instructed to note down any significant cardiac symptom,
e.g. chest pain or discomfort, breathlessness, palpitations or dizziness. The complete 48 hour records were analysed by the author by replaying at 60 times
normal speed on an Oxford unit to the high speed analyser
(Pathfinder) produced by Reynolds Medical Electronics.
The outputs from the pathfinder were interfaced to a PDP8A mini computer (MacFarlane, 1979) which prints a detailed
report. By this method, a tabulation of the heart rate,
incidence of ventricular extrasystoles as well as episodes of ST - segment depression were automatically produced for
both the 24 hour periods. Further verification was achieved by visual inspection of the monitor during play back of the tapes and examination of hard copy printouts of areas of interest. In cases of doubt, the hard copy printouts were interpreted by two experienced Cardiolo
gists and a consensus of opinion was taken as the final
result. The use of a manual back up has been shown to
improve the reproducibility of the computer assisted
technigue (Khurmi and Raftery, 1987).
The arrhythmias were classified into the different
categories:
less than 10 ventricular extrasystoles per hour.
10 to 30 ventricular extrasystoles per hour.
More than 30 ventricular extrasystoles per hour.
The presence or absence of couplets.The presence or absence of ventricular tachycardia.
83
Ventricular tachycardia was defined as 3 or more consecutive uniform or multiform ventricular beats at a rate of more than 120 beats per minute, with nonsustained
ventricular tachycardia lasting less than 30 seconds.
In order to allow comparisons to be made with previous
work, arrhythmias were also analysed using the L o w n 's grading (Lown and Wolf, 1971).
Grade 0 No ventricular ectopic beats.
Grade 1 Infreguent ventricular ectopic beats
(less than 30 per hour).
Grade 2 Frequent ventricular ectopic beats (more than 30 per hour).
Grade 3 Multiform ventricular ectopic beats
Grade 4a Couplets(two consecutive ectopic beats).
Grade 4b Salvos of nonsustained ventricular
tachycardia (three or more consecutive
ventricular beats occurring at a rate of greater than 120 per minute and
lasting for not more than 30 seconds).
84
Grade 5 - Early ectopic beats
(when the R - wave of the ectopic beat
commenced before the end of the preceding T - wave).
3•6 Signal-Averaged Electrocardiography
Recordings were carried out with a commercially available
machine (Arrhythmia Research Technology 1200 EP X high
resolution electrocardiogram). This system uses the method described by Simson for the detection of late
potentials (Simson, 1981). After preparation of skin with an alcohol swab and careful abrasion, pre-gelled
electrodes were applied in the orthogonal lead configur
ation using the bipolar X,Y,Z leads. The X lead was
between the right and left mid axillary lines at the
fourth intercostal space. The Y electrodes were placed at the superior aspect of the manubrium and the proximal left leg. The anterior Z electrode was at the V2 position and the other was at the identical position on the posterior
chest. Positive electrodes were left, inferior and
anterior. Recordings were made while the patient was
fully relaxed and lying flat in the supine position. The
whole process of signal-averaging of the electrocardiogram
took approximately 5 minutes. The electrocardiogram was
recorded during basic rhythm and about 300 beats were
averaged to achieve a noise level of less than 1.0 u V .
The signals were amplified, averaged and filtered with a
bidirectional filter at freguencies of 25 to 250 Hz. The filtered leads were then combined into a vector magnitude
( X + Y + Z ), a measure that sums the high frequency
85
information contained in all leads (Simson, 1981). A
computer programme algorithm determined the onset and
offset of the QRS complex and calculated the total
filtered QRS duration, the root mean square voltage of the
signals in the last 40 milliseconds of the filtered QRS (RMSV 40) and the duration of low amplitude signals of less than 40 uV (LAS 40).
Signal-averaged electrocardiogram was considered to be
abnormal in the presence of 2 or more of the following:-
a) Filtered QRS duration of more than or equal
to 120 milli-seconds.
b) Root mean square voltage of the signals in
the last 40 milliseconds. (RMSV40) of
less than or equal to 25 u V .
c) Low amplitude signals under 40 uV (LAS 40)
of more than or equal to 38 milliseconds.
These normal ranges were derived by combining the most
discriminatory features from previous studies (Simson, 1981; Winters, Stewart and Gomes, 1987; Turitto et al,
1988; Borbola, Ezri and Denes, 1988; Nalos et al, 1988;
Cripps et al, 1988). Recordings with a noise level > 1 uV
were rejected. Patients with left bundle branch block on
the 12 lead electrocardiogram were excluded from analysis
of the filtered QRS duration.
86
3.7 Autonomic Function Tests
1• Heart-rate response to valsalva manoeuvre
The valsalva manoeuvre was first described by Antonio
Valsalva, an Italian surgeon from Bologna, who originally
used the technigue to help inflate the middle ear. It consists of a forced expiration against resistance. This
is accompanied by circulatory responses provided the forced expiration is maintained for at least 7 seconds.
Hamilton, Woodbury and Harper (1936), described the
physiological changes and defined the phases of the
valsalva manoeuvre
Phase 1
Following the onset of straining, there is an initial
increase of blood pressure resulting from an increase in
the intrathoracic pressure. This results in a reflex fall
in the heart rate.
Phase 2
As a result of the continuous strain, there is a
progressive fall in blood pressure due to a reduction in
the venous return producing a fall in cardiac output. This in turn causes a progressive increase in heart rate.
87
Phase 3
After release of the strain, there is an initial fall in blood pressure for about 2 - 3 seconds caused by the release of intrathoracic pressure and consequent rise in
pulmonary venous capacitance resulting in a momentary fall in cardiac output. This is accompanied by an increase in heart rate.
Phase 4
This is the phase of a rebound hypertension normally
referred to as the "overshoot", which is caused by an
increase of a raised systemic vascular resistance in
response to the baroreflex stimulation produced by the fall in blood pressure during Phase 2. This is
accompanied by a marked bradycardia.
In the sitting position, the patient is instructed to blow
into a 10 ml syringe connected to a mercury sphygmo
manometer and is asked to hold a pressure of 40 mmHg for 15 seconds while a continuous electrocardiogram is
recorded. The manoeuvre is performed three times with one
minute intervals between.
The result is expressed as a "valsalva ratio" first
described by Levin, (1966), which is a ratio of the longest R - R interval after the manoeuvre to the shortest
R - R interval during the manoeuvre. In normal subjects, the R - R interval shortens during the strain thus
reflecting the tachycardia that occurs and lengthens after
88
release reflecting the bradycardia resulting in a ratio of greater than 1.00.
The valsalva ratio has been shown to be reproducible in normal subjects and to decline very slightly with age in a
number of studies (Levin, 1966; Baldwa and Ewing, 1977; Kalbfleisch, Stowe and Smith, 1978).
2. Heart-rate (R - R interval!variation during deep breathing
In the sitting position, the patient is asked to breathe
deeply at 6 breaths a minute, i.e. 5 seconds of deep inspiration followed by 5 seconds of forced expiration. This technique of breathing at 6 beats a minute has been shown by Ewing et al (1981) to be most convenient and
reproducible. An electrocardiogram is continuously
recorded during the test with a marker used to indicate
the onset of each inspiration and expiration. The maximum
and minimum R - R interval during each breathing cycle are measured with a ruler and converted to beats per minute.
The result is then expressed as the mean of the difference between maximum and minimum heart rates for the 6 cycles
in beats per minute.
This technique in measuring heart-rate variation on deep
breathing was first performed by Wheeler and Watkins (1973) on diabetics by using an instantaneous rate-meter.
They suggested that impaired beat to beat variation in heart rate may be due to loss of cardiac parasympathetic
function that is mediated by the vagus nerve. They showed
89
a diminution in heart rate variation with age and that sympathetic blockade by propranolol did not affect the
beat to beat variation in a normal subject, thus lending
further support to the suggestion that it is the vagus
nerve which is responsible for this physiological effect. The reproducibility of this method was shown by Hilsted and Jensen (1979). In normal subjects the heart rate difference is almost invariably more than 15 beats per minute (MacKay et al, 1980).
3. Immediate heart rate response to standing
This test is performed by asking the subject to lie down for 2 minutes and then stand up unaided and remain standing for about 2 minutes while a continuous electrocardiogram is being recorded. The point at starting to stand is marked on the electrocardiogram. The shortest R
- R interval around the 15th beat and the longest R - R
interval around the 30th beat after starting to stand are
measured using a ruler and the response is expressed by
the 30:15 ratio.
A number of cardiovascular reflexes occur on standing up.
Blood tends to pool in the legs with a consequent
momentary fall in blood pressure. But with normally
functioning baroreflexes, this fall in blood pressure is
rapidly corrected by peripheral and splanchnic vaso
constriction as well as tachycardia (Ewing, 1978 ). This
reflex tachycardia is maximal at around the 15th beat
after standing which is followed by a relative overshoot
90
bradycardia maximal at around the 30th beat, and normally the 30:15 ratio will be 1.04 or more (Ewing et al, 1978).
4. Blood pressure response to standing
The test is performed by measuring the patient's blood
pressure with a sphygmomanometer after 10 minutes of lying down quietly and repeated after a minute of standing up. The postural fall in blood pressure is taken as the difference between the lying and standing systolic
pressures. This test can be performed simultaneously with
the heart rate response to standing thus making it more
convenient for the patient.
3.8 Cardiac Catheterisation
Diagnostic left heart catheterisation and coronary angio
graphy was performed in 89 patients by their respective treating Cardiologists. The films were then reviewed by
the author and an independent observer for the assessment
of left ventricular function and the presence of coronary
artery disease. Significant coronary artery disease was
defined as 70% or more reduction in luminal diameter seen
in at least one angiographic view. Contrast left
ventriculography in a single plane right anterior oblique view (RAO) was utilised for the calculation of ejection
fraction (EF). End-systolic and end-diastolic volumes of
the left ventricle were calculated by Dodge et al's method
(1960) utilising the area length measurements of RAO views. After projecting the ventriculograms frame by
frame onto the screen of the Cipro projector, suitable
91
end-systolic and end-diastolic frames were identified for
analysis. Only sinus beats were included taking care to
exclude enhanced post-ectopic beats. The end-systolic and end-diastolic outlines of the left ventricle and aortic
root were drawn by hand onto tracing paper clipped in position on the projector screen. The longitudinal axis and the surface area of the end-systolic and end-diastolic
frames were then measured from the tracings by a Cherry
digitising tablet interfaced to a Commodore personal
computer for analysis with reference to the external diameter of the catheter that was simultaneously traced during the projection of the film. The short axis was then calculated from the following formula:-
D = 4 A
3 . 14 L
where D is the short axis
A is the surface area
L is the long axis
The volumes of the end-systolic and end-diastolic frames
were respectively calculated from the RAO view from the
following eguation (Rackley, 1976):
V = 3.14 L -D2 cm3
6
where V is the volumeL is the long axis D is the short axis
92
The ejection fraction was finally derived by using the following formula:-
Ejection fraction (%) = end-diast vol - end-syst vol__________________________________xlOO
end-dast vol
It is the policy of our catheter laboratory not to try too hard to cross the aortic valve if there was clinical,
echocardiographic and Doppler evidence of severe AS. Thus 30 left ventriculograms were performed but only 23 were
suitable for assessment of left ventricular function.
Coronary angiograms were evaluated from all the 89 patients.
3.9 Statistical Methods
After estimating the distributions by constructing
histograms, group values were expressed as means ± one
standard deviation or as freguencies. Differences between
two groups were examined by paired or unpaired t - test or
Mann-Whitney test as appropriate. A chi-sguare test was performed when comparing proportions. In cases of small
numbers where the chi-sguare test is not valid, Fisher's exact test was performed.
Comparisons between more than two groups were made by
either a one-way analysis of variance or Kruskall-Wallis
test as appropriate. Correlation between two variables
was assessed by Pearson's product moment correlation if
the data were normally distributed and Spearman's rank
correlation if they were skewed.
93
Statistical significance was defined as a p-value of less
than 0.05.
3.10 Ethical Approval
The study was approved by the ethical committee of the
Glasgow Royal Infirmary. Patients provided verbal consent
for the investigations, which were all non-invasive.
94
C H A P T E R F O U R
C L I N I C A L , E C H O C A R D I O G R A P H I C A N D A N G I O G R A P H I C C H A R A C T E R I S T I C S
O F P A T I E N T S
95
4 . 1 Clinical Particulars
A total of 100 patients with haemodynamically significant
aortic valve disease was studied before aortic valve
replacement. Their age, weight and body surface area (BSA) distributions are shown in figures 4.1 to 4.3. Fifty-three of the patients were males with an average age of 58 ± 11 years (range 32 - 78 years) and 47 females with an average age of 62 ± 10 years (range 32 - 77 years).
The mean age of the whole group was 60 ± 11 years (range 32 - 78 years) (Table 4.1).
Using the criteria defined in Chapter 3, 55 patients were
classified as having predominant AS with a mean transvalvular gradient of 81 ± 27 mmHg (range 38 - 178mmHg), 16 predominant AR and 2 9 combined AS and AR.
Eleven patients had mitral valve disease in addition to
the aortic valve lesion. Of these 11 patients, the
predominant aortic valve lesion was AS in 4, AR in 3 and
combined AS and AR in 4 patients.
The clinical characteristics of patients are outlined in
table 4.2. The mean age of the patients with AS was 61 ±
12 years, of those with AR was 58 ± 10 years and of those
with combined AS and AR was 60 ± 9 years. These
differences in age were insignificant. Diastolic blood
pressure was significantly higher in patients with AS than
in those with AR (83 ± 11 mmHg Vs 69 ± 18 mmHg; p<0.03). Mean systolic blood pressure tended to be lower in AS
patients compared to that in AR and combined AS and AR
patients, but this did not reach statistical significance.
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Smoking was more prevalent in AR patients when compared to
AS and combined AS and AR patients, but this did not reach
statistical significance.
The basic rhythm was sinus in 82 patients and atrialfibrillation (AF) in 18, 11 of whom had concomitant mitralvalve disease. Twenty-three patients were on digoxin with
no significant differences in the three groups and while
diuretics were prescribed to proportionally more patients
with AR compared to those with AS or combined AS and AR,
but this did not reach statistical significance. As would be expected, the plasma potassium of patients taking
diuretics was significantly lower than that of patients
not on diuretics (4.11 ± 0.37 mmols/L Vs 4.26 ± 0.33
mmols/L; p <0.05).
There were no significant differences noted in the haema-
tological and biochemical parameters between the 3 groups
although the total blood cholesterol tended to be higher
in patients with AS than in patients with AR or combined
AS and AR (Table 4.3).
The functional class of the patients was determined
according to the New York Heart Association Classification
(1979). Accordingly 22 patients were determined to be in
Class I, 64 in Class II, 14 in Class III and none in Class
IV (Table 4.4). Patients in NYHA Class III were
significantly older than those in Class I ( 6 6 + 9 years Vs 56 + 10 years; p <0.03). There was no significant
difference in weight, body surface area (BSA) or systolic
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s
100
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101
and diastolic blood pressure between the 3 functional Classes.
Chest pain typical of angina pectoris, defined as sub- sternal left precordial pain, tightness or discomfortprecipitated by effort, emotional stress or exposure tocold and promptly relieved by rest or nitrates, was
present in 51 patients, 31 with AS, 8 with AR and 12 with
combined AS and AR (Figure 4.4). There was no significant
difference in age, weight, BS A , systolic and diastolic
blood pressure, total blood cholesterol and smoking status in patients with compared to those without angina pectoris (Table 4.5).
A total of 89 coronary angiograms was available for
analysis. Eleven patients did not undergo cardiac
catheterisation. In 7 patients, cardiac catheterisation
was not indicated due to the presence of mild asymptomatic aortic valve disease. In 3 patients, cardiac catheter
isation was not performed due to a variety of reasonsincluding one patient who had other medical conditions
that influenced the investigating Cardiologist's decision
in not investigating the patient invasively. None of
these 3 patients had angina pectoris. The remaining
patient who was a 65 year old woman with haemodynamically
severe AR and exertional angina, refused to give consent
for cardiac catheterisation. Significant coronary artery
disease defined as 70% or more reduction in luminaldiameter seen in at least one angiographic view was
present in 21 of the 89 patients who had undergone cardiac
catheterisation; 11 (20%) with AS, 5 (31%) with AR and 5
DC<+
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103
(17%) with combined AS and AR (Table 4.2, Figure 4.5). Of
those 21 patients with significant coronary artery disease 9 had one vessel disease, 5 had 2 vessel disease and 7 had
3 vessel disease (Table 4.6). Angina pectoris was present in all but one patient with significant coronary artery
disease. There was no significant difference in age,
weight, BSA, systolic and diastolic blood pressure, total
blood cholesterol and smoking status of patients with
compared to those without significant coronary artery
disease (Table 4.7).
A total of 53 patients had palpitations; 31 with AS, 11
with AR and 11 with combined AS and AR (Table 4.2). There
was no significant difference in age, weight, BSA,
systolic and diastolic blood pressure, plasma potassium,
total blood cholesterol and haemoglobin of patients with compared to those without palpitations. Coronary artery
disease was egually prevalent in the 2 groups. However,
angina was significantly more common in patients with
palpitations (p <0.05) (Table 4.8).
Syncope occurred in 23 patients; 15 with AS, 3 with AR and 5 with combined AS and AR (Table 4.2). There was no
significant difference in the age, weight, BSA, systolic and diastolic blood pressure, plasma potassium and total
blood cholesterol of patients with compared to those
without a history of syncope. Although angina and
coronary artery disease tended to be marginally more
prevalent in patients with syncope, these differences
failed to attain statistical significance (Table 4.9).
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of the
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48
had
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and
41 had
no
palp
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Dist
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of
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Ch
arac
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s of
Pati
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. Ac
cord
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to the
Pr
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or Ab
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107
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68 had
no sy
ncop
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108
4.2 Echocardiography
Ninety-eight of the 100 study patients had technically
adequate echocardiograms. The distribution of interventricular septal thickness (IVSTd), left ventricular
internal dimension (LVIDd) and posterior left ventricular
wall thickness (PWTd) in diastole, as well as left
ventricular mass index (LVMI) in the study population, are
shown in Figures 4.6 to 4.9. Table 4.10 presents
echocardiographic and doppler ultrasound data of patients
distributed according to sex and predominant aortic valve
lesion. There was no difference between the sexes in
echocardiographic and doppler ultrasound variables in patients with predominant AS. However, in patients with predominant AR, significant differences were noted between
males and females in LVIDd (7.43 ± 1.18 cm Vs 5.01 ± 0.91
cm; p <0.001), LVMI (310 ± 7 2 g/m2 Vs 17 3 ± 4 8 g/m2 ;
p <0.001), EF (44 ± 10% Vs 58 ± 12%; p <0.04), FS (23 ± 7
Vs 31 + 8; p <0.05), aortic gradient (10 ± 7 mmHg Vs 21 ±
3 mmHg; p <0.004), PSLVWS by Reichek's method (158 ± 61
dyn/cm2 Vs 88 ± 34 dyn/cm2 ; p <0.02) and EDV (325 ± 47 cm3
Vs 119 + 50 cm3; p <0.0001) respectively. In patients
with combined AS and AR, EDV was the only variable that
was significantly larger in males compared to females (186
± 58 cm3 Vs 123 ± 28 cm3 ; p <0.002)
Table 4.11 outlines echocardiographic and doppler ultra
sound results of patients distributed according to the
predominant aortic valve lesion. As expected, LVIDd was
significantly smaller in AS (5.10 ± 0.82 cm) than in AR (6.22 + 1.61 cm; p <0.03) and combined AS and AR patients
Dis
trib
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4.9:
Dist
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LVMI
(gm/m
) ca
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Penn
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pati
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wi
th
adeq
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ec
hoca
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s.
Echo
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Acco
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Sex
(n=9
8)109
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w — E U — CO U S N 0TJ TJ U <X> •H s ■— - E E PQ U H h — —— •P > u ut—i H M S JH 00 t-J > — V-r rtj> X > t> < &H C/3 0 > CO Q \
W W < W
LVIDd
= left
vent
ricu
lar
inte
rnal
di
mens
ion
in di
asto
le.
PWTd
= po
ster
ior
left
vent
ricu
lar
wall
thic
knes
s in
dias
tole
. IVSTd
= in
terv
entr
icul
ar
sept
al
thic
knes
s in
dias
tole
. LVMI
= le
ftve
ntri
cula
r ma
ss
inde
x.
LA =
left
atri
um.
EF =
ejec
tion
fr
acti
on.
FS =
frac
tion
al
shor
teni
ng.
LVSP
= left
vent
ricu
lar
syst
olic
pr
essu
re.
PSLV
WS
= peak sy
stol
ic
left
vent
ricu
lar
wall
st
ress
.
112
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OiCuaacuouDuOuaaa.
* * * * -K ■K< < <
113
(5.63 ± 0.90 cm; p <0.03), while IVSTd was significantly
thicker in AS (1.39 ± 0.42 cm) than in AR patients (1.15 ±
0.29 cm; p <0.03). Combined AS and AR patients also had
thicker IVSTd (1.42 ± 0.48 cm) when compared to AR
patients but this did not attain statistical significance.
Left ventricular mass index was significantly lower in AS
patients (190 ± 64 g/m2 ) than in combined AS and ARpatients (230 ± 65 g/m2 ; p <0.03) but insignificantly so
when compared to LVMI of patients with AR. Ejection fraction was significantly higher in patients with AS when
compared to that of patients with AR (63 ± 14% Vs 51 ±
13%; p <0.03). The same was true when comparing FS of
patients with AS to that of patients with AR (33 ± 10 Vs
27 + 8; p < 0.05). As expected peak systolic aortic
gradient and hence left ventricular systolic pressure
(LVSP) of patients with AR was significantly lower than
that of patients with AS and combined AS and AR (p <0.03).
On the other hand, the EDV of patients with AR was
significantly larger (222 ± 117 c m ^ ) than that of patients
with AS ( 128 + 48 cm^; p <0.03) and insignificantly so
when compared to that of patients with combined AS and A R .
The peak systolic left ventricular wall stress (PSLVWS)
tended to be lower in AS patients compared to that in the
other 2 groups by using Reichek's and Quinones' methods.
However, these differences did not attain statistical
significance. There were no significant differences in
the E velocity, A velocity and E/A ratio between the 3 groups.
Table 4.12 presents echocardiographic and doppler ultra
sound data of patients distributed according to the
Dist
ribu
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of
Echo
card
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of Pa
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(n
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CONT
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115
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116
prevalence of angina and predominant aortic valve lesion.
In patients with combined AS and AR fractional shortening
was the only variable that was significantly better in
patients with compared to that of patients without angina
pectoris ( 3 6 + 8 Vs 2 8 + 9 ; p <0.03). In patients with
predominant AR, PSLVWS by Reichek's method was
significantly lower in patients with compared to that of
patients without angina pectoris (90 + 37 dyn/cm^ Vs 156 ±
63 dyn/cm^; p <0.03).
Echocardiographic and doppler ultrasound data distributed
according to the prevalence of coronary artery disease and
predominant aortic valve lesion are shown in table 4.13.
In patients with predominant AS, the aortic gradient was
significantly lower in patients with compared to that of
patients without coronary artery disease (71 ± 16 mmHg Vs
86 + 29 mmHg; p <0.05). In patients with predominant AR,
LVIDd, LVMI, PSLVWS, by both Reichek's and Quinones'
methods and EDV were significantly better in patients with
coronary artery disease. There were no differences in
echocardiographic and doppler variables between the 2
groups in patients with combined AS and AR.
Table 4.14 outlines echocardiographic and doppler ultra
sound data distributed according to the predominant aortic
valve lesion and to the presence or absence of
Palpitations. Posterior left ventricular wall thickness
m diastole was significantly thinner in patients with
compared to that of patients without palpitations (1.16 ±
°-18 cm Vs 1.45 ± 0.22 cm; p <0.05) and LVSP was
significantly lower in patients with compared to that of
117
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inte
rnal
di
mens
ion
in di
asto
le.
PWTd
= po
ster
ior
left
vent
ricu
lar
wall
thic
knes
s in
dias
tole
. IV
STd
= in
terv
entr
icul
ar
sept
al
thic
knes
s in
dias
tole
. LV
MI
= le
ftve
ntri
cula
r ma
ss
inde
x.
LA =
left
atri
um.
EF =
ejec
tion
fr
acti
on.
FS =
frac
tion
al
shor
teni
ng.
LVSP
= left
vent
ricu
lar
syst
olic
pr
essu
re.
PSLV
WS
= peak
syst
olic
left
vent
ricu
lar
wall
st
ress
.
120
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COin Oo Oo OV V
04 Oi
121
patients without palpitations in the subgroup of patients
with predominant AR (160 ± 20 mmHg Vs 189 ± 14 mmHg; p
<0.006). There were no differences noted in
echocardiographic and doppler ultrasound variables between
patients with and those without palpitations in the
subgroups with predominant AS and combined AS and AR.
Table 4.15 presents echocardiographic and doppler ultra
sound data according to the predominant aortic valve
lesion and prevalence of syncope. In patients with
combined AS and AR, EF, FS and LVSP were significantly
higher and PSLVWS by Reichek's method was significantly
lower in those with syncope. There were no differences
noted in echocardiographic and doppler ultrasound
variables between patients with and without syncope in the
subgroups with predominant AS and predominant AR.
4 •3 Extent of Left Ventricular Hypertrophy
Left ventricular dimensions and in particular left
ventricular mass (LVM) has been shown to be related
significantly to body surface area and that when LVM is
corrected for body surface area, the resultant left
ventricular mass index (LVMI) has been shown to be 20%
less in women than in men (Devereux et al, 1984). These
workers have also shown that the range of variability in
LVM in normal individuals can be greatly narrowed by
indexation of the LVM and this results in clinically
useful criteria of left ventricular hypertrophy (LVH).
Thus LVH according to their well validated criteria which
roughly corresponds to the 97th percentile in their normal
Dist
ribu
tion
of
Echo
card
iogr
aphi
c Data
of Pa
tien
ts
Acco
rdin
g:
to the
Pres
ence
or
Abse
nce
of Sy
ncop
e (n
= 98)_
122
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124
subjects, was defined as a LVMI greater than 134 g/m2 in
men and 110 g/m in women.
In the present study 98 of the 100 patients had
technically adequate echocardiograms and LVMI was normal
in only 4 males (<134 g / m 2 ) and 5 females (<110 g/m2 ).
Substantial LVH was present with a mean LVMI of the study
patients of 210 ± 72 g / m 2 (range 63 - 403). Left
ventricular mass index was higher in AR patients (242 ± 92
g/m ) and significantly so in combined AS and AR patients
(230 + 65 g/m2 ; p <0.03) when compared to that in AS
patients (190 ± 64 g/m2 ) (Table 4.11). In agreement with
Devereux et al's observations, the mean LVMI in females
(189 + 69 g/m )was approximately 17% less than that in
males (229 + 69 g/m2 ). Also in keeping with these workers
findings, LVM showed a direct relationship with body
surface area (r = 0.47, p <0.002). There was no
relationship observed between LVMI and age (r = 0.16, p
<0.2), FS (r = "0.11, p <0.2), EF (r = "0.16, p <0.2), E/A
ratio (r = 0.08, p <0.2), peak systolic left ventricular
wall stress as determined by Reichek (r = 0.02, p <0.2)
and Quinones' methods (r = 0.03, p <0.2); and peak aortic
systolic gradient (r = 0.10, p<0.2) and peak left
ventricular systolic pressure (r = 0.20, p <0.1) in the
patients with predominant aortic stenosis. On the other
hand, a direct relationship existed between LVMI and left
ventricular internal dimension in diastole (r = 0.53, p <
0.002) and left ventricular end diastolic volume (r =
°-51, p <0.002) .
summary, the present study has shown a high prevalence
125
(91%) of echocardiographic left ventricular hypertrophy in
patients with aortic valve disease, normal LVMI being seen
in only 9 of the 98 patients with technically adequate
echocardiograms. Left ventricular mass index was
significantly higher in patients with predominant aortic
regurgitation and this is probably due to a preponderance
of these patients having more dilated left ventricles due
to volume overload and consequently larger left
ventricular end-diastolic volumes. This is suggested by
the presence of a direct relationship between LVMI and
left ventricular internal dimension during diastole as
well as to left ventricular end diastolic volume. Most
interestingly and contrary to expectation is the lack of a
relationship between LVMI and the severity of aortic
stenosis as assessed by the pressure gradient across the
aortic valve. This would suggest that factors other than
pressure overload of the left ventricle secondary to
outlet obstruction play a role in the aetiology of left
ventricular hypertrophy in this group of patients.
Alternatively, it may be that a single measurement of
pressure gradient at one point in time is an inadequate
index of long-term left ventricular pressure overload.
This finding of substantial echocardiographic left
ventricular hypertrophy in our study patients has
important prognostic implications. In a follow up study
°f 3200 subjects in the Framingham Heart Study, an
increase in left ventricular mass was associated with a
higher incidence of clinical events including cardio
vascular deaths (Levy et al, 1990).
126
4 . 4 Left Ventricular Function
Left ventricular systolic function was assessed by
echocardiographic EF in 97 patients and by echocardio
graphic FS in 98 patients. In 23 patients with suitable
left ventriculograms, EF was calculated by using a well
established method (see Chapter 3). Left ventricular
function was considered to be impaired when the EF was
less than 40% and severely impaired when EF was less than
30%. Corresponding figures for FS were 25 and 20
respectively. Left ventricular diastolic function was
assessed in 79 patients by the doppler derived E/A ratio
which is the ratio between early (E) and late (A) left
ventricular diastolic filling velocities. An E/A ratio of
less than 0.85 was considered to indicate abnormal left
ventricular diastolic function. This figure was derived
by considering the normal range as lying within two
standard deviations from the mean of recordings in 90
normal subjects studied in our institution (0.85 - 1.65).
Thus using the above criteria 91 of the 97 patients
studied (94%) had normal left ventricular systolic
function by EF, while 6 (6%) had impaired systolic
function of whom only 1 (1%) had severely impaired
function (EF <30%) (Table 4.16). The mean EF of the
entire study group was 60 ± 15%. Aortic regurgitation
patients had lower EF (51 ± 13%) than those of patients
with combined AS and AR (61 ± 15%) but significantly so
than those of patients with predominant AS (63 ± 14%; p
<0.03) (Table 4.11). Systolic function as assessed by FS
was impaired in 27 (28%) patients and severely impaired in
Left
Vent
ricu
lar
Syst
olic
and
Dias
toli
c Dy
sfun
ctio
n in
the
Study
Pati
ents
127
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1128
9 (9%) patients. Fractional shortening of the whole group
was 32 + 10. As with EF, FS was significantly lower in
patients with AR (27 ± 8) when compared to that of
patients with AS (33 + 10; p <0.05) but insignificantly so
when compared to that of patients with combined AS and AR
(32 ± 10; p <0.1) (Table 4.11).
Left ventricular diastolic function was abnormal (E/A
ratio <0.85) in 31 (39%) of a total of 79 patients with
technically adequate doppler studies. Figure 4.10
illustrates an abnormal mitral flow pattern showing a
reversal of E/A ratio. The mean E/A ratio of the study
group was 1.03 ± 0.43 with no differences noted between
the 3 sub-groups (Table 4.11).
Impairment in both systolic (EF <40%) and diastolic (E/A
ratio <0.85) function was seen in only 2 patients.
The mean EF of the 23 patients with technically adequate
left ventriculograms was 65 ± 14%.
Impaired systolic function was present in only one (EF =
35%) of the 23 patients. This patient also had a marked
impairment in systolic function as assessed by echocardio
graphic EF (32%) and FS (16).
4 • 5 Angina Pectoris and Coronary Artery Disease in Patients with Aortic Valve Disease
With the longer survival of the population, the pattern of
a°rtic valve disease in the developed countries has
4.1 0 ; Abnormal Doppler mitral flow pattern.The maximal early diastolic flow velocity (E) is lo.w relative to maximal late diastolic flow velocity (A) giving an E/A ratio of <0.85.
129
changed with the decline in the incidence of rheumatic
heart disease and an increased incidence of calcific
aortic valve disease (Selzer and Lombard, 1988).
Increasing age of the patient population also leads to the
increase in the frequency of coronary artery disease.
Thus the presence of significant coronary artery disease
in patients with aortic valve disease is not an uncommon
finding. In adults with aortic valve disease, aortic
valve replacement is nowadays typically performed in the
sixth or seventh decade of life when the prevalence of
coronary artery disease in the general population is 10%
to 15% among men and 5% to 10% among women (Diamond and
Forrester, 1979). Several studies have also shown an
increase in the operative mortality of aortic valve
replacement in the presence of coexisting coronary artery
disease (Table 4.17). In these series, concomitant
coronary artery bypass grafting had been shown to modulate
surgical mortality. Long-term survival also improves
following myocardial revascularisation (Mullany et al,
1987; Jones et al, 1989; Lytle et al, 1983). To
complicate the issue further, angina pectoris is a common
symptom of both aortic valve disease and coronary artery
disease (Contratto and Levine, 1937; Mitchell et al, 1954;
Wood, 1958). Does the presence of angina therefore
necessitate coronary angiography before aortic valve
replacement, or should the absence of angina in patients
with significant aortic valve disease alleviate the need
to perform a pre-operative coronary angiography? On the
other hand, coronary angiography is associated with a
small but definite risk and therefore should not be
Oper
ativ
e Mo
rtal
ity
Rate
s130
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131
performed unnecessarily (Green, McKinnon and Rosch, 1972;
Adams, Fraser and Abrams, 1973).
Of the major studies in the literature that have addressed
this question, the majority (Paquay et al, 1976; Graboys
and Cohn, 1977; Exadactylos, Sugrue and Oakley, 1984;
Basta et al, 1975) favour the view that coronary angio
graphy should only be performed in those patients with
chest pain typical of angina pectoris as it is less likely
to find significant coronary artery disease in patients
free from chest pain, while other workers (Hancock, 1977;
Hakki et al, 1980) stress the necessity of performing
coronary angiography in all patients (see Table 4.18).
In the present study 89 of the 100 patients had undergone
coronary angiography before aortic valve replacement. Of
these 89 patients, chest pain typical of angina pectoris
was present in 51 patients (57%), and a total of 21 (24%)
had significant coronary artery disease. Angina pectoris
was present in 20 of these 21 patients (95%). One patient
with significant coronary artery disease was free of chest
pain. This patient had predominant aortic regurgitation
and 90% proximal stenosis of the left anterior descending
coronary artery but with good collateral supply from a
dominant right coronary artery. The prevalence of angina
pectoris and coronary artery disease according to the
predominant aortic valve lesion are shown in figures 4.4 and 4.5.
132
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u0Pu<
u0C0U0
cn0•HVppU)
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I'dc0Pc0cn0uPh
0KC•Hc•H0PU
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oN*CN
VO 00CN
cnro
cnCN roCN
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00CN
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cnoo
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00cncn i—i
inooocn
cn
cnC/3
U*
133
Thus angina pectoris could predict the presence of
significant coronary artery disease with a 95% sensitivity
and a 54% specificity.
In the 55 patients with predominant aortic stenosis in
this study, 31 (56%) had angina pectoris while 24 (44%)
were free of chest pain. Aortic gradients were available
in 54 patients and these patients were then divided into 3
groups according to their gradients: 20 to 50, 51 to 100
and >100 mmHg, which were considered mild, moderate and
severe aortic stenosis respectively (Table 4.19).
Approximately 97% of the patients with angina pectoris had
moderate and severe aortic stenosis while, on the other
hand, the majority of patients free from chest pain (83%)
had mild to moderate aortic stenosis. This finding is in
contradiction with that reported by Chobadi et al (1989).
They showed a lower frequency of angina pectoris in the
patients with severe aortic stenosis. Ninety-one percent
of the patients with significant coronary artery disease
in this study had moderate aortic stenosis and in only one
(9%) patient was aortic stenosis severe. This is in
agreement with Chobadi et al's finding of a higher
incidence of coronary artery disease in patients with mild
aortic stenosis and complete absence of coronary artery
disease in 20 of their patients in whom aortic gradient
was >110 mmHg. It must also be emphasised from the
results of the present study that in 10 patients in whom
the transaortic gradient was greater than lOOmmHg only one
had significant coronary artery disease (Table 4.19).
Ches
t Pain
and
Inci
denc
e of
CAD*
Rela
tive
to
Aort
ic
Pres
sure
Gr
adie
nt
in Pa
tien
ts
with
Pr
edom
inan
t Ao
rtic
St
enos
is134
o'— f—1 oo CT\ o\ rHg 1— 1 wQ o o rH rH< iH rHu
<*>—g ✓—.. — *—
fd vo 00 O H 4g 00 CO ■N4•HtT>g vo "Vj* H4fd iH CN0£
<#>—GG•H CN O VO(d rH VO VO inO. —rH rH CO vo ofd CN COc•HG<
Gcn■PG0 t"* ["• o•H CO 1—1 in4-)fd04
CnW| o o-— ■ O o o
in iH rH PIP <G i 1 A Eh0 O•H o i—1 EhXJ CN m0Uo
135
These findings draw our attention to two important
observations. Firstly, angina pectoris is very rare in
patients with mild aortic stenosis occurring in only one
out of 30 patients with chest pain (0.3%). Secondly,
angina becomes more prevalent with increasing severity of
aortic stenosis while the opposite is true for coronary
artery disease as significant coronary artery disease was
present in only one of the 10 patients with severe aortic
stenosis. This patient was a 7 3 year old lady with a
transaortic gradient of 101 mmHg which is at the
borderline between the moderate and severe groups.
Therefore, our study has shown a reverse relationship
between aortic pressure gradient and frequency of coronary
artery disease. In the groups with a lower pressure
gradient, angina is more likely to be due to coronary
artery disease, while in the groups with a higher pressure
gradient it is more likely to be due to uncomplicated
aortic stenosis. Furthermore, in patients with
predominant AS, aortic gradient was significantly lower in
the patients with compared to that of patients without
coronary artery disease (71 ± 16mmHg Vs 86 + 29mmHg;
P <0.05). in patients with predominant AR, those with
coronary artery disease had less severe indices of AR
compared to those with normal coronary arteries (Table
4.13). Thus, patients with less severe aortic valve
disease are presumed to have come to early cardiac
referral as a result of angina secondary to coronary
artery disease. Hence, the occurrence of angina in
patients with mild aortic stenosis should caution the
investigating Cardiologist to the possible presence of
concomitant coronary artery disease. Therefore all
136
workers agree without any reservation the necessity of
performing coronary angiography in patients with aortic
valve disease and chest pain. However it remains less
clear whether coronary angiography should be performed in
patients with aortic valve disease free from chest pain.
Our results revealing only a 2% prevalence of coronary
artery disease in patients without angina supports the
view of those who favour the practice of not performing
coronary angiography before operation in aortic valve
disease patients free from chest pain (Paquay et al, 1976;
Graboys and Cohn, 1977; Exadactylos, Sugrue and Oakley,
1984; Basta et al, 1975).
137
C H A P T E R F I V E
P R E V A L E N C E A N D S I G N I F I C A N C E O F V E N T R I C U L A R A R R H Y T H M I A S
I N P A T I E N T S W I T H A 0 R T I CV A L V E D I S E A S E
138
5.1 Introduction
Sudden death is a known complication of patients with
aortic valve disease (Ross and Braunwald, 1968) but in
most cases this is usually preceded by angina, congestive
heart failure or syncope (Contratto and Levine, 1937;
Mitchell et al, 1954; Chizner, Pearle and de Leon, 1980).
In a few cases however, sudden death may be the first and
only symptom of severe aortic valve disease (Ross and
Braunwald, 1968; Wagner et al, 1977). Reynold et al
(1960) have quoted from reported series an incidence of
sudden death in these patients of between 4 and 18%.
Johnson (1971) reported a higher incidence (21%) of sudden
death in his series comprising of 204 adult patients with
aortic stenosis. With the advances in surgical
techniques, aortic valve replacement is nowadays carried
out with <5 % mortality and hence surgical relief to
patients with severe aortic valve disease is offered
before the occurrence of left ventricular failure. There
fore left ventricular failure may now be regarded as an
accidental occurrence in a patient with significant aortic
valve disease. With the outlook after operation so much
better than the natural history of aortic valve disease,
the incidence of sudden death has assumed more importance.
The exact cause of sudden death still remains speculative,
but it has been partly attributed to ventricular
arrhythmias. This speculation has been entertained by
several workers who have shown an association between
electrocardiographic as well as echocardiographic left
ventricular hypertrophy and complex ventricular
139
arrhythmias in hypertension and hypertrophic cardiomyo
pathy (Levy et al, 1987 ; Messerli et al, 1984; McLenachan
et al, 1987; Pringle et al, 1987; Savage et al, 1979;
McKenna et al, 1980; McKenna et al, 1981). Furthermore,
electrocardiographic left ventricular hypertrophy is found
in 85% of patients with severe aortic valve disease
(Braunwald, 1988). Several studies on patients with
significant aortic valve disease have also shown a high
incidence of complex ventricular arrhythmias (Von
Olshausen et al, 1983; Kennedy et al, 1975; Schilling et
al, 1982; Kostis et al, 1984; Klein, 1984).
In most of the above quoted studies however, ambulatory
electrocardiographic monitoring had been used as a tool for predicting subsequent sudden death. Does the presence
of these spontaneously occurring ventricular arrhythmias
recorded during a limited ambulatory period necessarily
indicate an ominous prognosis? In other words, do they
indicate the presence of an underlying arrhythmogenic
substrate that could support the genesis of fatal
ventricular arrhythmias?
Several studies have shown the major role played by
reentry in the genesis of ventricular tachyarrhythmias
(El-Sherif et al, 1977; Williams et al, 1974; Zipes,
1975). The prerequisites for reentry are unidirectional
block, slow conduction and recovery of the tissue ahead of
the wavefront of excitation (Zipes, 1975). One of the
most significant findings attributed to slow conduction
was the detection of delayed fractional electrical
activity in regions of experimental infarction (El-Sherif
140
et al, 1977) and since these potentials most frequently
occur in the ST segment after the end of the QRS complex,
they have been called "late potentials". They are
characterised by multiple low-amplitude spikes, and it has
been suggested that the presence of such electro
cardiograms indicate sites for potential reentrant
circuits. It has recently been possible to record late
potentials by signal-averaging of the electrocardiogram
and this technique which is simple and non-invasive has
gained popularity for identifying those patients who are
prone to develop ventricular tachyarrhythmias. We can
therefore verify the significance of complex ventricular
arrhythmias detected by ambulatory electrocardiographic
recording by performing signal-averaging of the
electrocardiogram to detect the presence of any late
potentials. Furthermore, several studies have shown a
strong correlation between ventricular tachycardia
inducible on electrophysiologic study and the presence of
an abnormal signal-averaged electrocardiogram (Simson et
al, 1983; Freedman et al, 1985; Lindsay et al, 1986;
Dennis et al, 1987; Winters et al, 1988; Turitto et al,
1988; Borbola, Ezri and Denes, 1988; Nalos et al, 1988).
This part of the study therefore investigates the
incidence and significance of ventricular arrhythmias in
patients with aortic valve disease before undergoing
aortic valve replacement. These findings were related to
clinical, echocardiographic and to some extent cardiac
catheterisation data of the patients.
141
5 . 2 Patients and Methods
The clinical characteristics of the study patients and
methods are described in detail in Chapters 3 and 4. In
brief, 1 0 0 patients with clinically significant aortic
valve disease were studied. All patients underwent a
thorough physical examination after obtaining a detailed
history. Appropriate blood investigations were done and
signal-averaged electrocardiograms were then performed.
The patients were then fitted with an Oxford Medilog II
frequency modulated recorder to wear for a period of 48
hours. During this period all patients were fully
ambulatory and none was receiving anti-arrhythmic
medications. On the return appointment, i.e. 48 hours
later, detailed echocardiographic and doppler ultrasound
examinations were performed. The data were analysed as
described in Chapter 3.
5 . 3 Res u 1ts
Ambulatory Monitoring
Technical problems with the recordings were encountered in
9 patients. Recordings were successfully repeated in 8 of
them while it was not possible in the last patient as he
had already undergone aortic valve replacement. There
fore, ambulatory electrocardiographic results of 99
patients are presented in this study.
142
Prevalence of Ventricular Arrhythmias (VA) (Table 5 . 1 )
Eighty seven (8 8 %) patients had infrequent ventricular
extrasystoles (VES) (<10 VES/h). Of these 87 patients, 9
(9%) had no VES detected during the entire 48 hour period.
Eight (8 %) patients had 10-30 VES/h, while frequent VA
(>30 VES/h) occurred in only 4 (4%) patients. Infrequent
couplets (<10/24hrs) were seen more commonly, occurring in
21 (21%) patients. Nonsustained ventricular tachycardia
(NSVT) was recorded in 9 (9%) patients.
Nonsustained Ventricular Tachycardia fTables 5.2 and 5.3^
A total of 13 episodes of NSVT occurred in the 9 patients.
A single episode of NSVT was recorded in 6 , 2 episodes in
2 and 3 episodes in one patient. Eight of the episodes
were triplets, 2 comprised 4 VES, one comprised 5 VES, one
comprised 7 VES and the longest run comprised 10 VES
(Figure 5.1). Nonsustained ventricular tachycardia was
recorded in the first 24 hours in 6 patients while in the
remaining 3 patients NSVT occurred in the second 24 hour
period. These episodes were not associated with symptoms.
However, a history of palpitations was volunteered in 4
patients while syncope was a symptom in 3. Frequent
couplets as well as frequent VES occurred in only one
patient with NSVT. It is noteworthy that 8 of the 9
patients with NSVT had aortic stenosis as their
predominant lesion while in the remaining patient, the
predominant lesion was aortic regurgitation. Two patients
were in NYHA functional Class 1, 5 in Class 2 and only 2
were in Class 3. Angina pectoris occurred in 5 patients
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while significant coronary artery disease was present in
only 2 patients, angina being a symptom of both. Left
ventricular systolic function was satisfactory in all
except one patient who had an EF of 30% while diastolic
function showed some impairment in the majority of the
patients. Substantial left ventricular hypertrophy was
present in most of the p a t i e n t s . None of the patients had
a normal L V M I . Peak systolic left ventricular wall stress
was elevated in most of the patients while end diastolic
volume was not surprisingly markedly increased in the
patient with predominant A .R .
Table 5.4 presents the distribution of VA by their maximum
Lown Grade. Eight (8 %) patients were in Grade 0, 18 (18%)
in Grade 1, none in Grade 2, 5 (5%) in Grade 3, 4 (4%) in
Grade 4A, 3 (3%) in Grade 4B and 61 (62%) in Grade 5. If
for the purpose of analysis, we consider Lown Grades 0 to
2 as simple and Grade 3 to 5 as complex VES, the majority
of the study patients (74%) had complex VES.
Table 5.5 presents clinical characteristics and echo
cardiographic findings of patients according to the
frequency of VA. Patients with infrequent VA (<10 VES/h)
were significantly younger than those with frequent VA
(>30 VES/h) (59 ± 11 years Vs 6 8 ± 3 years; p <0.03). The
end diastolic volume of patients with <10 VES/h was
significantly smaller than that of patients with 10-30
VES/h (144 ± 69 cm 3 Vs 248 ± 70 cm3 ; p <0.03) but
insignificantly so when compared to that of patients with
'30 VES/h.
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149
The E/A ratio of patients with <10 VES/h was significantly
higher than that of patients with >30 VES/h (1.05 ± 0.44
Vs 0.81 ± 0.08; p <0.03). Left ventricular systolic
function as assessed by both ejection fraction and
fractional shortening appeared to be marginally better in
patients with <10 VES/h when compared to that in the other
2 groups. However, this did not reach statistical
significance. There was no difference in serum potassium
levels of the 3 groups. Left ventricular mass index was
also not statistically different in the 3 groups.
Table 5.6 compares clinical and echocardiographic data of
patients with and without multifocal VES. Patients with
multifocal VES had significantly larger left atria (4.33 ±
1.07 cm Vs 3.68 ± 0.89 cm; p <0.01), more impairment of
left ventricular function by fractional shortening ( 3 0 + 9
Vs 34 + 10; p <0.05) and increased peak systolic left
ventricular wall stress assessed by Reichek's method (129
± 76 dyn/cm 2 Vs 94 ± 43 dyn/cm2 ; p <0.02).
Patients with freguent couplets ( > 1 0 couplets/24hrs) had
significantly lower serum potassium than those with
infrequent couplets (<10 couplets/24hrs) (3.73 ± 0.32
mmols/L Vs 4.30 ± 0.44 mmols/L; p <0.05) (Table 5.7).
Table 5.8 presents clinical and echocardiographic data of
patients according to the prevalence of nonsustained
ventricular tachycardia (NSVT). Although patients with
NSVT tended to be older, had higher systolic blood
Pressure and total cholesterol, poorer left ventricular
systolic function, slightly more dilated left ventricles
150
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153
(LVIDd) and left atria, increased end diastolic volume,
left ventricular mass index and peak systolic left
ventricular wall stress by both Reichek's and Quinones'
methods and decreased E/A ratio, these findings did not
reach statistical significance. Left ventricular systolic
pressure was the only variable which was significantly
higher in patients with NSVT than that of patients with no
episodes of NSVT (241 ± 38 mmHg Vs 213 ± 40 mmHg;
p <0.05). This is not surprising in view of the fact that
8 of the 9 patients with NSVT had aortic stenosis as their
predominant lesion. However, in the patients with
predominant AS, there was no difference in the mean
systolic gradient across the aortic valve between the
group with compared to that without NSVT (91 ± 21 mmHg Vs
7 9 + 28 m m H g ; p <0.19)
The total number of VES per 24 hours was correlated with
clinical and echocardiographic findings in the study
patients (Table 5.9). Left atrial size was the only
variable that showed a weak but highly significant
relationship with total number of VES per 24 hours (r =
0.357; p <0.002) .
Signal-Averaged Electrocardiography (SAECG5
Signal-averaged electrocardiography was technically satis
factory in 99 of the 100 patients. QRS duration was
Prolonged in 16 (16%) out of 9 7 patients, 2 patients being
excluded due to the presence of left bundle branch block
°n their surface electrocardiograms. Five (5%) patients
had prolonged low amplitude signals under 40 microvolts
154
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155
(LAS40) while root mean square voltage of the signals in
the terminal 40 milliseconds (RMSV40) was abnormally
decreased in 6 (6 %) patients. Late potentials were
present according to the criteria previously described in
Chapter 3, in 6 (6 %) patients. Two of these 6 patients
had all the 3 criteria positive on their SAECG's (Table
5.10). Figures 5.2 and 5.3 illustrate examples of a
normal and an abnormal SAECG respectively.
Table 5.11 presents some clinical, echocardiographic and
ambulatory electrocardiographic findings in the 6 patients
with abnormal SA E C G S . The predominant lesion was AR in 3 ,
AS in 2 and combined AS and AR in one patient.
Palpitations were reported in 2 , syncope in one and angina
pectoris in 3 patients. Significant coronary artery
disease was present in 2 patients. None of the patients
had a previous myocardial infarction. Left ventricular
systolic function assessed by echocardiographic EF was
satisfactory in all patients while diastolic function
(E/A) was markedly abnormal in 2 of the 3 patients
assessed. The remaining 3 patients were in atrial
fibrillation. Ambulatory electrocardiographic monitoring
showed frequent VES (4894 VES/24hrs), frequent couplets
(19 couplets/24hrs) and the occurrence of nonsustained
ventricular tachycardia (NSVT) in only one patient (Case
17). Thus, NSVT occurred in only one patient with an
abnormal SAECG.
Signal-averaged electrocardiographic findings of patients
m relation to their clinical characteristics are depicted
fa Table 5.12. Patients with predominant AS had a
Prev
alen
ce
of Ab
norm
al
Sign
al-A
vera
ged
Elec
troc
ardi
ogra
ms.
156
10 in<#>
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in
10 cn
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Figu
re
5.2:
No
rmal
SAECG
reco
rded
in
a 44
year
old
woma
nwith
pred
omin
ant
AS.
CydM
I
Figu
re
5.3:
Abno
rmal
SAECG
reco
rded
in
a 54
year
old
man
with
pred
omin
ant
AR.
It sh
ows
a pr
omin
ent
late
po
tent
ial.
Am
bula
tory
el
ectr
ocar
diog
raph
ic
moni
tori
ng
show
ed
infr
eque
nt
VES
with
abse
nce
of
coup
lets
and
NSVT
.
Summ
ary
of the
Clin
ical
, Ec
hoca
rdio
grap
hic
and
Ambu
lato
ry
ECG
Find
ings
in
6 Pa
tien
ts
with
Ab
norm
al
SAEC
GS
157
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odes
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159
significantly shorter QRS duration (101 ± 10 ms) than that
of patients with AR (122 ± 21 ms; p <0.03) and patients
with combined AS and AR (112 ± 16 ms; p <0.03). Low
amplitude signals under 40 uV were also significantly
shorter in AS patients ( 1 5 + 8 ms) compared to that of AR
patients (30 ± 20 ms; p <0.03) and that of patients with
combined AS and AR (20 + 9 ms; p <0.05). Root mean square
voltage of the signals in the terminal 40 milliseconds in
AS patients (130 ± 87 uV) was significantly higher than
that of patients with AR (64 ± 43 uV; p <0.03) and
combined AS and AR (84 ± 63 uV; p <0.03). Filtered QRS
duration was significantly longer in patients with
compared to that of patients without coronary artery
disease (114 + 18 ms Vs 105 ± 16 ms; p <0.05). Likewise
RMSV40 of patients with coronary artery disease was
significantly lower than that of patients without coronary
artery disease (75 ± 64 uV Vs 117 ± 79 uV; p <0.02).
Although LAS40 in patients with coronary artery disease
was longer than that of patients without coronary artery
disease, this did not reach statistical significance.
There were no significant differences noted in the SAECG
variables between patients with compared to those without
symptoms of angina, palpitations or syncope. Signal-
averaged electrocardiographic variables were also not
significantly affected by NYHA functional classes of the
patients.
Table 5.13 presents SAECG findings of patients in relation
to the results of ambulatory electrocardiographic monitor
ing. There were no differences observed in the SAECG
variables in relation to the frequency of VES or couplets,
160
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plit
ude
sign
als
unde
r 40
uV.
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= root
mean
sq
uare
vo
ltag
e in
last
40ms
. VE
S ve
ntri
cula
r ex
tras
ysto
les.
VT
= ve
ntri
cula
r ta
chyc
ardi
a (n
onsu
stai
ned)
.
161
and in relation to the presence or absence of nonsustained
ventricular tachycardia or multifocal VES.
5 .4 Discussion
Although sudden death claims 15 to 20% of patients with
acquired aortic valve disease (Contratto and Levine, 1937;
Dry and Willius, 1939; Mitchell et al, 1954), the exact
cause of this remains unclear. However, these deaths have
been assumed to result mainly from ventricular
tachyarrhythmias. This is supported by studies that have
demonstrated ventricular tachyarrhythmias as the terminal
event in the majority of cases of recorded sudden deaths
(see Chapter One, Section 1.3). Furthermore, the
Framingham Heart Study has reported an association between
both electrocardiographic and echocardiographic left
ventricular hypertrophy and an increased risk of
ventricular arrhythmias (Levy et al, 1987). It is also
known from studies on hypertensive patients that
significantly more complex ventricular arrhythmias occur
in those patients with left ventricular hypertrophy
(Messerli et al, 1984; McLenachan et al, 1987; Pringle et
si/ 1987). Several other studies have also reported an
association between electrocardiographic and echocardio
graphic left ventricular hypertrophy which occur in the
majority of patients with aortic valve disease (Braunwald,
1988) and the prevalence of complex ventricular
arrhythmias (Savage et al, 1979; McKenna et al, 1981).
In the present study electrocardiographic and echocardio
graphic left ventricular hypertrophy were present in 90%
162
and 91% of patients respectively. Ventricular ectopic
activity was present in 91% of patients. The majority
(8 8 %) of patients had infrequent VA (<10 VES/h) while
frequent VA (>30 VES/h) occurred in only 4 (4%) patients
(Table 5.1). In terms of complexity, 74% of patients had
complex VA (Lown grades 3 to 5). The reported incidence
of complex VA in patients with aortic valve disease varies
between 36 to 93% (Table 5.14). These differing
incidences in the complexity of VA reported by different
studies may be explained by several factors. Firstly, the
patients were not comparable in terms of their age, type
of aortic valve disease, prevalence of concomitant
coronary artery disease and the degree of impairment of
left ventricular function amongst other factors.
Secondly, the methods used for arrhythmia detection and
quantification were not uniform. Thirdly, there was a
marked variability in the size of the study population in
the different studies. Furthermore, a spontaneous and
marked variability in the frequency and complexity of VA
of individual patients has been well documented
(Morganroth et al, 1978; Michelson and Morganroth, 1980).
Prognostic Significance of Complex Ventricular Arrhythmias including Nonsustained Ventricular Tachycardia (NSVT)
Nonsustained ventricular tachycardia may be detected
during ambulatory electrocardiographic monitoring in
patients with heart disease and occasionally in those with
structurally normal hearts (Kennedy et al, 1985). Does
the presence of this arrhythmia indicate an increased risk
°f subsequent sudden death? The significance of this
arrhythmia has been determined by electrophysiological
Inci
denc
e of
Comp
lex
Vent
ricu
lar
Arrh
ythm
ias
in Pa
tien
ts
with
Ao
rtic
Va
lve
Dise
ase
(Pre
sent
and
Pr
evio
us
Stud
ies)
.
163
a Q Qw W wEh Eh Eh0 OdO O OEh P» P< Pn> ^ 00 w r- w W N1 cnCO dP 1—1 od -h* c*; rHZ — ■
Eh Eh EhO O OZ 2 Z
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O UU XIM-4 W —
0>1 tnG g go O -H•H 4-> 5-1 N 1 00
4-1 <0 0 CN CN CN CN CN CN N*fd ■— i 4-iM G -H3 4Q GQ g 00 g
cn• 4-10 gg a)•H<—1 4-1 ro CN in 00 00 00 cn0 rd cn O »—i ro CN CN cn4-> a, i—10Eh M-4
O
ro00cn X—»tH X-V CN- CN 00x-v 00 cn*— 1 m cn i—ifd i"- i—i — -
cn ■-- CO4-1 i—i •— I cnQ) '— ■ 1—1 0 i-H
0 --G i— i 4-1 >i0 X-N. 0 4-1 0 rH XIin 0 0 PP CO ■P U 4-1fd cn 0 Cn 0 4-> CO
,G 1—1 G 4-1 0in >1 •H •H -P
XI i-H 0 in Go G 0 rH U •H 0
•H g •H rC 4-» ing 0 a .g o U) 00 i— 1 0 o 0 0 P> Z z CO Z to
CVA
= co
mple
x ve
ntri
cula
r ar
rhyt
hmia
s NSVT
= no
nsus
tain
ed
vent
ricu
lar
tach
ycar
dia
164
studies by a number of workers. Buxton et al (1984),
performed electrophysiological studies on 83 consecutive
patients with spontaneous NSVT documented on ambulatory
electrocardiographic monitoring. Thirty-three of these 83
patients had coronary artery disease, 18 had
cardiomyopathy, 8 had mitral valve prolapse and 24 had no
heart disease. Patients were followed up for a mean
period of 33 months. There was a suggestion that the
presence of NSVT on its own did not necessarily indicate
an increased risk of sudden death. However, when this
occurred in combination with severe left ventricular
dysfunction, the risk of sudden death was high.
Gomes and his colleagues (Gomes et al, 1984) performed
electrophysiological studies on 73 patients most of them
with atherosclerotic heart disease and with previously
documented high grade ventricular arrhythmias (Lown grades
3, 4A and 4B) on 48 hour ambulatory electrocardiogaphic
monitoring. Ventricular tachycardia was inducible in 20
patients, all of whom had atherosclerotic heart disease.
After a follow-up period of 30 ± 15 months, sudden death
was significantly higher in the 2 0 patients who were
inducible at electrophysiological study. Radionuclide
ejection fraction of less than 40% was also associated
with a poor survival. An interesting finding in this
study is that the grade of ventricular extrasystoles (Lown
grades 3 to 4B) was not significantly different between
the patients with and those without inducible ventricular
tachycardia or between survivors and non-survivors.
165
Zheutlin et al (1986) studied 8 8 patients with organic
heart disease including 8 patients with valvular heart
disease, who had ventricular ectopy (_>_ Lown grade 3). All
patients underwent programmed electrical stimulation.
Ventricular tachycardia was inducible in 33 patients and
interestingly all the 8 patients with valvular heart
disease were non-inducible. Patients with valvular heart
disease tended to have higher left ventricular ejection
fractions. In agreement with Gomes et al's findings, the
grade of ventricular arrhythmias could not predict
inducibility at electrophysiological study. After a 44
month follow-up period, no major arrhythmic events had
occurred in the non-inducible group while there was a 1 2 %
incidence of major arrhythmic events in the inducible
group.
In the present study, 9 patients (9%) had NSVT on 48 hour
ambulatory electrocardiographic monitoring, and of these 9
patients, only one had late potentials on SAECG. Thus,
there is little evidence to suggest the presence of an
arrhythmogenic substrate in these patients. This is
supported by the reported strong correlation between
ventricular tachycardia inducible at electrophysiologic
study and the presence of an abnormal SAECG (Simson et al,
1983; Freedman et al, 1985; Lindsay et al, 1986; Dennis et
si, 1987; Winters et al, 1988; Turitto et al, 1988;
Borbola, Ezri and Denes, 1988; Nalos et al, 1988).
Furthermore, the prognostic significance of late
potentials has been prospectively studied by Breithardt
and his colleagues (Breithardt, Martinez-Rubio and
Borggrefe, 1990). They showed a higher risk of major
166
arrhythmic complications including sudden cardiac deaths
in patients with late potentials on SAECG.
The present findings are in agreement with those recently
reported by Pringle et al (1989). Nonsustained
ventricular tachycardia on ambulatory electrocardiographic
monitoring occurred in 11 out of a total of 90 hyper
tensive patients with electrocardiographic left
ventricular hypertrophy. Of these 11 patients, only one
had ventricular late potentials on SAECG. I am aware of
no other studies on SAECG in patients with left
ventricular hypertrophy and especially in those with
aortic valve disease.
5.5 Summary
This part of the study has documented the occurrence of
infrequent, but complex ventricular arrhythmias in
patients with aortic valve disease. Nonsustained
ventricular tachycardia occurred in 9 patients (9%).
However, there is little evidence from SAECG to suggest
that these patients have an underlying arrhythmogenic
substrate. Signal-averaged electrocardiography detected
ventricular late potentials in 6 (6 %) patients of whom
only one had NSVT on ambulatory electrocardiographic
monitoring. From these findings, the reported 15 to 20%
incidence of sudden deaths in these patients cannot be
entirely explained on the basis of ventricular
tachyarrhythmias. There are probably other yet
unexplained mechanisms responsible for sudden death in
Patients with aortic valve disease.
167
C H A P T E R S I X
C L I N I C A L O U T C O M E O F P A T I E N T S
168
Of the total 100 patients in the study, 75 were on the
waiting list for cardiac surgery. The remaining 25
patients were being followed up by their investigating
Cardiologists. The majority of these patients did not
have sufficient clinical or haemodynamic indications for
cardiac surgery while a few had other medical conditions
that influenced the treating Cardiologists' decision in
not referring them for operation. Two patients refused to
undergo cardiac surgery due to personal r e a s o n s .
The waiting list for elective cardiac surgery in our
institution is usually between 6 to 18 months. At the
time of writing up this thesis, 60 patients had undergone
cardiac surgery. Table 6.1 shows the distribution of
patients according to the type of surgical procedure
performed. Forty-two patients (70%) underwent aortic
valve replacement (AVR) alone. In addition to AVR, 10
patients (17%) had coronary artery bypass graft surgery
(CABG), 5 (8 %) had mitral valve replacement (MVR), one
(2%) had mitral valvotomy and two (3%) had MVR plus CABG.
There have been a total of 7 deaths in the study to date.
Sudden death, defined as death that occurred within
minutes of symptom onset or during sleep in a previously
stable patient, occurred in 3 patients (Cases 24, 71 and
77; Tables 6.2. and 6.3). Case 71 was witnessed to have
suddenly collapsed and died within minutes. She had
combined AS and AR as well as severe mitral regurgitation
with an enlarged left atrium (6 . 8 cm). Her basic rhythm
was atrial fibrillation. In Cases 24 and 77 the deaths
were unwitnessed, both occurring at home and thus assumed
169
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170
to have occurred suddenly. Both had severe calcific
aortic stenosis accompanied with substantial echocardio-
graphic left ventricular hypertrophy. All these 3
patients were on the surgical waiting list thus giving an
incidence of sudden death of 4% in this study group.
Case 2 6 who was not yet referred for surgery died a few
hours following an emergency hospital admission due to a
prolonged episode of severe chest pain culminating in
uncontrolled severe left ventricular failure. There was
no electrocardiographic or cardiac enzyme evidence of
myocardial infarction. Doppler transaortic gradient
during this admission was 100 mmHg.
Two deaths occurred during or immediately after surgery.
The first (Case 4) was a 77 year old lady who died during
aortic valve replacement. Postmortem revealed severe 3
vessel coronary artery disease which was not suspected
prior to surgery. The second patient (Case 43) failed to
recover his heart pump function following AVR and CABG and
died 8 days following surgery. Left ventricular function
assessed immediately before operation showed echocardio-
graphic ejection fraction of approximately 30%. Post
mortem coincidentally revealed a large right renal
carcinoma.
The remaining patient (Case 5) died of a gastric carcinoma
3 months following AVR.
Tables 6 . 2 and 6 . 3 outline clinical, echocardiographic,
ambulatory electrocardiographic and signal-averaged
171
electrocardiographic (SAECG) findings in the 7 patients
who have died. None of the 7 patients had freguent VES
(>30/h) or couplets (>10 couplets/24hrs) on ambulatory
electrocardiographic monitoring. Two patients had NSVT
(Case 26 and 77). Case 26 had a single episode of NSVT
comprising 4 VES while Case 77 had 3 such episodes, the
longest one comprising 10 VES. All patients had entirely
normal SA E C G S .
Mortality Rate in the Study Population
There were 7 deaths (7%) in this study population, two of
them occurring directly as a consequence of cardiac
surgery. Three of these 7 deaths are of interest for a
couple of reasons. Firstly, they all occurred suddenly
and in patients who were already on the cardiac surgical
waiting list, thus leading to the speculation that had the
waiting list not been long, these deaths could have been
preventable. This however is not entirely true as all
these 3 patients died within the first 7 months of being
on the waiting list (Figure 6.1). Case 24 died after 3.5
months, Case 77 after 4 months and case 71 after 7 months
of being on the waiting list. As illustrated in Figure
6 .1 , the median waiting time for surgery in the operated
patients was 7.5 months. Thus, in order to prevent all
these 3 deaths, surgery would have had to be performed
within the first 3 . 5 months of being on the waiting list.
Hence, the incidence of sudden death while on the waiting
list for cardiac surgery in this group of patients was 4%.
This mortality rate is slightly higher when compared to
the operative mortality following AVR quoted by different
Summ
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Pati
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Peri
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172
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Figure 6 . 1 Waiting time for surgery in 60 operatedand 3 sudden death patients. The median waiting time for surgery was 7.5 months. All the 3 sudden deaths occurred within the first 7 months.
174
workers (see Table 4.18, Chapter 4). Secondly, in all
these 3 patients sudden death could not be predicted from
either the ambulatory electrocardiographic monitoring or
from SAECG. Although case 77 had 3 episodes of NSVT, the
longest comprising 10 VES, the significance of this was
not substantiated by SAECG results. However, these 3
patients were nevertheless at a high risk of sudden
cardiac death due to the presence of severe
echocardiographic left ventricular hypertrophy (Levy et
al, 1990).
Summary
Of the total 100 patients in the study, 60 have had
cardiac surgery to date. A total of 7 deaths (7%)
occurred in this study population. Three of the deaths
occurred suddenly and in patients on the surgical waiting
list. Thus the incidence of sudden death while awaiting
operation was 4% which is slightly higher compared to
previously reported operative mortality following AVR.
Both ambulatory electrocardiographic monitoring and SAECG
could not predict these sudden deaths. However, all these
3 patients had severe echocardiographic left ventricular
hypertrophy.
175
C H A P T E R S E V E N
P R E V A L E N C E O F V E N T R I C U L A R A R R H Y T H M I A S I N T H E E A R L Y
P O S T - O P E R A T I V E P E R I O D
176
7.1 Introduction
Aortic valve replacement usually results in major clinical
improvement and substantial reduction of the haemodynamic
burdens imposed by aortic stenosis and regurgitation
(Bristow et al, 1964; Kennedy, Doces and Stewart, 1977).
However, successful aortic valve replacement does not
completely eliminate the risk of death particularly sudden
cardiac death in both the early and late post-operative
periods (Shean et al, 1971; Hirshfeld et al, 1974;
Barratt-Boyes, Roche and Whitlock, 1977; Rubin et al,
1977; Samuels et al, 1979). The underlying mechanism in
these sudden deaths is still unclear and remains
speculative, but it has been presumed by some workers to
be secondary to malignant ventricular tachyarrhythmias
(Rubin et al, 1977; Samuels et al, 1979).
Despite the widespread use of ambulatory electrocardio
graphic recording to detect arrhythmias in a variety of
cardiac conditions, few data have been reported concerning
the prevalence of ventricular arrhythmias in the early
post-operative period following aortic valve replacement.
In this study, therefore, ambulatory electrocardiographic
monitoring was performed in patients with aortic valve
disease in the immediate post-operative period following
valve replacement to analyse for the presence and severity
of ventricular arrhythmias.
7 • 2 Patients and Methods
Sixty of the 1 0 0 study patients have had cardiac surgery
177
to date. Of these 60 patients, 38 were studied by
ambulatory electrocardiographic monitoring using the same
equipment as that for the pre-operative study. The
recordings were made between the 5th and 7th pos t
operative days before the patient was discharged home.
Serum potassium levels were obtained during the monitoring
period. The recordings were analysed as previously
described in Chapter 3.
7.3 Results
Prevalence of Ventricular Arrhythmias (VAO
Five of the 38 patients studied had technical problems
with their ambulatory ECG recordings. Therefore the
results of the remaining 33 patients are presented here.
None of the patients had hypokalaemia during the m onitor
ing period and the mean serum potassium of the study group
was 4.45 ± 0.32 mmols/L.
Twenty-two patients were monitored for 48 hours while 1 1
patients had recordings for only 24 hours. Table 7.1 ou t
lines the results of ambulatory ECG monitoring of the 33
patients. Twenty-two patients (67%) had infrequent
ventricular extrasystoles (<10 VES/h) and of these 22
patients no VES were detected in 2 patients. Five
patients (15%) had 10-30 VES/h and frequent VA (>30 VES/h)
occurred in 6 patients (18%). Two patients (6 %) had
frequent couplets (>10 couplets/24hrs) while infrequent
couplets (<10 couplets/24hrs) were recorded in 9 patients
( 2 7 % ) . Runs of nonsustained ventricular tachycardia were
Prev
alen
ce
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cula
r Ar
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179
recorded in 6 patients (18%). None of the 33 patients
suffered a cardiac arrest during the post-operative
hospital stay.
Nonsustained Ventricular Tachycardia (NSVTM
Table 7.2 outlines episodes of NSVT and their relationship
to other forms of VA. There were a total of 14 episodes
of NSVT occurring in 6 p a t i e n t s . One patient in whom a
single episode of NSVT occurred, had 24 hours of
ambulatory ECG monitoring (patient number 40). In the 5
patients with 48 hours of monitoring, 5 of the episodes of
NSVT occurred in the first 24 hour period, while 8
occurred in the second 24 hour period. Patient number 55
had 9 episodes of NSVT, all episodes consisting of 3 VES,
while the remaining patients had a single episode each.
The longest episode comprised of a run of 10 VES (patient
number 40) (Figure 7.1). None of the patients reported
any symptoms coinciding with these episodes of NSVT. All
the patients except patient number 51 had couplets,
occurring most frequently in patients number 6 and 55. It
is noteworthy to point out that none of the 6 patients
with NSVT had coronary artery disease.
Lown Grading (Table 7 . 3 )
The majority of the patients (8 8 %) were in Grade 5, two
(6 %) in Grade 0 and 2 (6 %) in Grade 1. Thus, in terms of
complexity (Grades 3 to 5) 8 8 % of the patients had complex
V A ' s .
Epis
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of
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180
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NSVT
comp
risi
ng
10 VES
at a
rate
of 190
beat
s per
minu
te
reco
rded
in
a 66
year
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man
who
had
unde
rgon
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.
Dist
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Vent
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Arrh
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Acco
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182
7.4 Discuss jon
There is scant data in the literature concerning the
incidence of ventricular arrhythmias in patients with
aortic valve disease in the immediate post-operative
period following aortic valve replacement. Three studies
have reported a low incidence of ventricular arrhythmias
(Angelini et al, 1974; Smith et al, 1972; Michelson,
Morganroth and MacVaugh, 1979) while in another study
(Schilling et al, 1982) a high incidence of ventricular
arrhythmias occurred,
Angelini et al (1974) studied 178 unselected and
consecutive patients undergoing heart surgery to assess
the incidence of arrhythmias. Twenty-eight of these 178
patients were adults with aortic valve disease undergoing
aortic valve replacement. They reported a very low
incidence of ventricular arrhythmias in these 28 patients,
ventricular extrasystoles (VES) occurring in only 4
patients (14%). No episodes of ventricular tachycardia
were reported during the entire hospital stay (mean 12.3
days). There are two major setbacks in the design of this
study. Firstly, detection of ventricular arrhythmias
relied solely on clinical observations confirmed by
electrocardiographic rhythm strips. The other method used
for detecting arrhythmias was by routine electrocardio
grams, generally one being done daily in the first 3 pos t
operative days and one before discharge. Secondly,
ventricular arrhythmias of less than 2 VES per minute were
excluded from analysis. This would obviously lead to an
183
underestimation of the true incidence of ventricular
arrhythmias.
Smith et al (1972) studied 50 consecutive patients with a
variety of valvular lesions and undergoing cardiac valve
replacement. Arrhythmias were assessed by continuous
monitoring using a bedside electrocardiographic monitor
during the first 7 days following operation. Sixteen of
the 50 patients had undergone aortic valve replacement.
Ventricular arrhythmias were reported in 3 of these 16
patients (2 1 %) who had undergone aortic valve replacement
(AVR). Three patients out of the total of 50 patients
enrolled in the study had episodes of ventricular tachy
cardia (VT) . As the data was pooled together it was not
clear as to how many of these 3 patients with VT belonged
to the group of patients who had undergone AVR.
The only study in this series to use ambulatory electro
cardiographic monitoring for the detection of arrhythmias
was that by Michelson and his colleagues (Michelson,
Morganroth and MacVaugh, 1979). They studied 70
consecutive patients undergoing cardiac surgery, 15 of
whom underwent valve replacement. Of these 15 patients,
12 had aortic valve disease and were undergoing AVR.
Twenty-four hour ambulatory electrocardiographic m onitor
ing was performed on the 4th and 8 th post-operative days.
Ventricular arrhythmias were considered to be significant
find hence reported, on the occurrence of VES more than or
equal to 30 per hour, ventricular couplets, ventricular
tachycardia (_>_3 consecutive VES) and multiform VES. Thus
VES of less than 30 per hour were not included in the
184
analysis. Accordingly, significant ventricular
arrhythmias occurred in 3 of 15 patients (20%) who under
went valvular replacement. No patient in this group had
ventricular tachycardia.
Schilling et al (1982 ) using a different method of grad
ing ventricular arrhythmias, reported a high incidence of
ventricular arrhythmias in their patients. They studied
38 patients with aortic valve disease by 24 hour
ambulatory electrocardiographic monitoring 2 weeks follow
ing AVR. Complex ventricular arrhythmias (Lown Grades 3,
4A and 4B) occurred in 33 of the 38 patients (87%).
In the present study, frequent ventricular arrhythmias
(>30 VES/h) were present in 18% of the patients, couplets
were also quite common, occurring in 33% and episodes of
nonsustained ventricular tachycardia (NSVT) were recorded
in 18%. The incidence of complex ventricular arrhythmias
and in particular episodes of NSVT in the present study
was higher than previously reported. This can be directly
attributed to an increase in arrhythmia detection due to
the use of a longer electrocardiographic monitoring
period. Most of the patients in this study (22 out of 33)
had 48 hours of ambulatory electrocardiographic
monitoring. The usefulness of longer periods of
ambulatory monitoring is clearly evident from this study.
Of the 13 episodes of NSVT recorded in 5 of the 6 patients
with NSVT who had 48 hours of ambulatory monitoring, 8
(62%) of them were detected in the second 24 hour period.
Thus, the incidence of NSVT would have been greatly
underestimated had 24 instead of 48 hours of monitoring
185
been performed. One must therefore be aware of this point
when comparing the results of studies using different
periods of ambulatory monitoring. This may explain the
variation in the prevalence and severity of ventricular
arrhythmias in different studies.
The clinical significance of these early post-operative
ventricular arrhythmias following AVR is not known.
Further follow-up of these patients may determine whether
these arrhythmias contribute to sudden death or to other
complications after discharge from hospital.
7.5 Summary
The incidence of complex VA including episodes of NSVT in
the present study was higher than that reported by the
majority of previous studies. Complex VA (Lown grades 3
to 5) occurred in 8 8 % of patients. The importance and
usefulness of longer periods of ambulatory electrocardio
graphic monitoring was demonstrated. Further follow-up of
these patients will be needed in order to verify the
prognostic significance of these early post-operative VA
following AVR.
186
C H A P T E R E I G H T
E F F E C T O F A O R T I C V A L V E R E P L A C E M E N T O N E C H O C A R D I O- G R A P H I C L E F T V E N T R I C U L A R H Y P E R T R O P H Y A N D C A R D I A C
A R R H Y T H M I A S
187
8 .1 Introduction
Left ventricular hypertrophy, irrespective of the criteria
used to define it, whether by electrocardiography, chest
x-ray or echocardiography, is associated with an increased
risk of sudden death (Kannel, W.B, 1983). This increased
risk has been speculated by various workers to be due to
the increased incidence of frequent and complex
ventricular arrhythmias (Levy et al, 1987; Siegel et al,
1990). Sudden death is also not an uncommon occurrence in
patients with aortic valve disease (Ross and Braunwald,
1968). This may not be surprising given the fact that
electrocardiographic left ventricular hypertrophy is found
in 85% of patients with severe aortic valve disease
(Braunwald, 1988). Furthermore, several studies on
patients with significant aortic valve disease have shown
a high incidence of complex ventricular arrhythmias
(Kennedy et al, 1975; Schilling et al, 1982; Von
Olshaussen, 1983; Kostis et al, 1984; Klein, 1984)
Regression of left ventricular hypertrophy either follow
ing a period of adequate control of blood pressure in
cases of hypertension, or following valve replacement in
patients with significant aortic valve disease, would be
expected to lead to a decrease in ventricular ectopic
activity and hence result in a reduction of the risk of
sudden death in these patients.
Therefore, in this part of the study, 30 of the original
1 0 0 patients were investigated by echocardiography and
doppier ultrasound, ambulatory electrocardiographic
monitoring and signal-averaged electrocardiography, an
average of 121 ± 24 days following aortic valve replace
ment. The results of these investigations were compared
with the pre-operative data. Twenty-one of the original
1 0 0 patients had ambulatory electrocardiographic record
ings performed during the pre-operative, early post
operative (5-7 days post AVR) and late post-operative (121
± 24 days post AVR) periods and the prevalence of
arrhythmias during these 3 periods was compared.
8 .2 Methods
8.2.1. Study Patients (Table 8 .1 )
The study group consisted of 30 of the 100 patients
studied before surgery. These comprised of 18 men and 12
women with a mean age of 60 ± 10 years (range 36 to 77
years). The studies were performed 121 ± 24 days (range
85 to 199 days) following cardiac surgery. Twenty-two
patients had undergone aortic valve replacement (AVR)
alone. In addition to AVR, 3 patients had coronary artery
bypass graft surgery (CABG), one had a mitral valvotomy, 3
had mitral valve replacements (MVR) and one had a MVR plus
CABG. Eleven patients had received Bjork-Shiley
mechanical prosthesis, 13 had received Carpentier-Edwards
porcine xenografts and 6 had received bioflo pericardial
bioprostheses in the aortic position. The native aortic
valve was bicuspid in 14 and tricuspid in 16 patients.
Oper
ativ
e Data
of Pa
tien
ts189
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CONT
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D/.
. /CONTINUED
190
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191
8.2.2. Study Protocol
Explanatory letters together with appointments were sent
to the patients who were asked to attend a special out
patient clinic. After explaining the study protocol in
detail to the patient, an informed consent was obtained.
A thorough history with particular stress on the
prevalence of exertional chest pain, breathlessness,
palpitations and syncope was obtained. Current drug
therapy and the smoking status of the patient was
documented. A thorough physical examination was then
carried out including the height and weight of the
patient. Appropriate blood investigations were done and
finally signal-averaging of the electrocardiogram was
performed. The patient was then fitted with an Oxford
Medilog II frequency modulated recorder to wear around the
waist for a period of 48 hours. During this period, all
patients were fully ambulatory and none was receiving
anti-arrhythmic medications. Hypokalaemia (serum K + <3.5
mmols/L) was not present in any patient. On the return
appointment which was 48 hours later, detailed
echocardiographic and doppler ultrasound examinations were
performed. All data were analysed using the methodology
previously described in Chapter 3.
Pre and post-operative clinical, echocardiographic,
signal-averaged electrocardiographic and ambulatory
electrocardiographic data were compared. In 21 patients
who had ambulatory electrocardiographic monitoring
performed during the pre-operative, early post-operative
(5-7 days post AVR) and late post-operative (121 ± 24 days
192
post AVR) periods, a comparison in the prevalence of
arrhythmias during these 3 periods was made.
8 .3 Results
8.3.1. Clinical Characteristics of Patients
Table 8.2 presents the clinical characteristics of
patients before and after surgery. Chest pain typical of
angina pectoris was reported in only one patient post-
operatively compared to 12 patients before surgery. This
patient with post-operative angina had a normal coronary
angiogram performed prior to operation. Palpitations were
reported by 2 patients while none of the patients reported
syncope post-operatively. There was a marked improvement
in the functional status of the patients following
surgery. Seventy percent of the patients were in NYHA
functional Class I compared to only 20% prior to surgery.
On the other hand, 13% of patients were in NYHA functional
Class 3 before and none after surgery. Digoxin was
prescribed more frequently after surgery and likewise
atrial fibrillation was the basic rhythm in more patients
post-operatively (9 Vs 7 patients). On the other hand, a
slightly smaller number of patients continued to smoke
cigarettes after operation and this may reflect an
improvement in the awareness of the patients on the ill-
effects of smoking.
Clin
ical
Ch
arac
teri
stic
s of
Pati
ents
Be
fore
and
Aft.
er193
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NYHA
= New
York
Hear
t As
soci
atio
n fu
ncti
onal
Cl
ass
194
8.3.2. Echocardiography
Echocardiographic left ventricular hypertrophy (LVMI >1342 • 7g/m m males and >110 g/m in females) was present in 24
of the 30 patients (80%) post-operatively compared to 28
of the 30 patients (93%) pre-operatively. Table 8.3
depicts pre and post-operative echocardiographic data in
the 30 patients distributed according to the predominant
aortic valve lesion prior to operation. In patients with
predominant AS, AVR was accompanied by a significant
decrease in PWTd (1.29 ± 0.08 Vs 1.08 ± 0.05; p <0.004),
LVMI (190 + 12 Vs 154 ± 11; p <0.02) and as expected a
marked reduction in the aortic gradient ( 8 1 + 6 Vs 12 ± 2;
p <0.0001) and LVSP (219 ± 7 Vs 156 ± 6 ; p <0.0001). Left
ventricular systolic function was significantly reduced
although still remaining within normal limits following
AVR as assessed by both EF ( 6 6 + 4 Vs 57 + 3; p <0.04) and
FS (37 ± 3 Vs 30 ± 2; p <0.03). Left ventricular
diastolic function as assessed by E/A ratio showed some
improvement following surgery, although this did not reach
statistical significance. Marginal improvement in IVSTd
(1.44 ± 0.10 Vs 1.20 ± 0.14; p <0.06), significant
reduction in LVMI (235 ± 22 Vs 172 ± 20; p <0.02) and not
surprisingly aortic gradient (61 ± 6 Vs 14 ± 3; p <0.0002)
and LVSP (218 ± 14 Vs 160 ± 11; p <0.003) was noted in
patients with combined AS and AR following AVR. Left
atrial size on the other hand was significantly increased
in these patients following surgery (3.75 ± 0.30 Vs 4.23 ±
0*15; p <0.03). Aortic vavle replacement did not result
in any significant changes in echocardiographic variables
in patients with predominant AR.
Echo
card
iogr
aphi
c Data
in Pa
tien
ts
Stud
ied
Befo
re
and
Afte
r Su
rger
y:
Data
Pres
ente
d Ac
cord
ing
to the
Pred
omin
ant
Aort
ic
Valv
e Le
sion
195
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CONT
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196
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197
8.3.3. Ambulatory Monitoring
Technical problems with the recordings were encountered in
7 p a t i e n t s . Two of these 7 patients had repeat recordings
and hence the data of 25 patients are presented in this
part of the study.
8.3.4. Prevalence of Ventricular Arrhythmias (VA)(Table 8.4^
Twenty patients (80%) had infreguent ventricular extra
systoles (VES) (<10 V E S / h ) . Of these 20 patients, 3 (12%)
had no VES detected during the entire 48 hour period. Two
(8 %) patients had 10-30 VES/h while frequent VA (>30
VES/h) occurred in only 3 (12%) patients. Frequent
couplets (>10 couplets/24hrs) were recorded in only one
patient (4%) while infrequent couplets (<10
couplets/24hrs) occurred in 4 patients (16%). Four
patients (16%) had nonsustained ventricular tachycardia
(NSVT) . The total number of VES per 24 hours was
correlated with echocardiographic variables in the 25
patients (Table 8.5). No correlation was observed between
frequency of VES and any echocardiographic variable.
Nonsustained Ventricular Tachycardia (Table 8 .6 )
There were a total of five episodes of NSVT occurring in 4
patients, one patient (patient 23) having 2 episodes of 3
VES and 4 VES recorded during the ambulatory period. The
longest episode comprising 9 VES occurred in patient
number 14 (Figure 8.1). Two episodes of NSVT were
Prev
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re
8.1:
An ep
isod
e of
NSVT
comp
risi
ng
9 VES
at a
rate
ofap
prox
imat
ely
120
beat
s per
minu
te
reco
rded
in
a 59
year
old
woma
n du
ring
the
late
post
-ope
rati
ve
peri
od.
201
recorded in the first 24 hours while 3 episodes were
recorded in the second 24 hour period. All these 5
episodes were asymptomatic. There was only one patient
(patient 40) with NSVT who also had frequent couplets as
well as frequent VES.
Table 8 .7 summarises the operative data and echocardio
graphic findings in the 4 patients with NSVT. Two of
these 4 patients were in atrial fibrillation and had
mitral valve replacement in addition to aortic valve
replacement. Left ventricular mass index was normal in
only one patient (patient 49).
Table 8 . 8 presents the distribution of VA according to
their maximum Lown Grade. Three (12%) patients were in
Grade 0, 4 (16%) in Grade 1, one (4%) in Grade 4A and 17
(6 8 %) in Grade 5. Thus, 72% of the patients had complex
ventricular arrhythmias (Grades 3 to 5).
8.3.5. Frequency of Arrhythmias in the 3 Study Periods
Twenty-one of the total 1 0 0 patients in the study had
ambulatory electrocardiographic recordings before,
immediately after and late following aortic valve replace
ment. Table 8.9 and 8.10 show the prevalence of
arrhythmias in these 21 patients during the 3 study
periods. Ventricular extrasystoles per 24 hours tended to
have occurred more frequently in the early post-AVR study
(328 + 460, range 0 to 1519) compared to the other 2 study
periods (74 ± 174, range 0 to 726 before AVR and 134 ±
251, range 0 to 837 late post-AVR). These differences did
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not reach statistical significance. On the other hand,
early VES per 24 hours (R on T phenomenon) were
significantly more frequent in the early post-AVR period
(67 ± 170) compared to the pre-operative period (2 ± 6 , p
= 0.025). There was no significant difference between the
groups in the frequency of atrial ectopics. Nonsustained
ventricular tachycardia was more common in the early post-
AVR period, occurring in 5 patients (24%) compared to p r e
operative (1 patient, 5%) and late post-operative (3
patients, 14%) periods.
Complex VES (Grades 3 to 5) were present in 16 patients
before, in 17 patients early after, and in 15 patients
late after aortic valve replacement (Figure 8.2). Twelve
patients had Complex VES while only 2 had simple VES
(Grades 1 and 2) in all the 3 recordings.
8.3.6. Signal-Averaged Electrocardiography (S A E C G )
Signal-averaged electrocardiograms were technically satis
factory in 29 of the 30 patients, one patient being
excluded due to an unacceptably high noise level (1.4 u V ) .
Table 8.11 depicts the prevalence of abnormal S A E C G S . QRS
duration was prolonged in 5 patients (17%), low amplitude
signals under 40 microvolts (LAS4 0) were prolonged in 2
(7%) patients and root mean square voltage of the signals
in the terminal 40 milliseconds (R M S V 4 0 ) was abnormally
decreased in 2 (7%) patients. Late potentials were
present (i.e. ± 2 abnormal criteria) in only 2 (7%)
Patients, one of whom had all the 3 criteria positive on
the SAECG.
CO
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Figure 8.2 Presence of Complex Ve nt r ic u l a r Ext rasystoles Before, Early A f t e r And Late A f t e r Aor t ic Valve Replacement
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209
Table 8.12 presents operative, echocardiographic and
ambulatory electrocardiographic data in the 2 patients
with abnormal S A E C G S . Patient 47 also had an abnormal
SAECG before surgery. Left ventricular systolic function
assessed by echocardiographic ejection fraction was satis
factory while diastolic function (E/A ratio) was markedly
abnormal in both the patients. Substantial left
ventricular hypertrophy was present in patient 47 while
LVMI was at the upper limit of normal in patient 58.
Ambulatory electrocardiographic monitoring showed
infrequent VES and absence of couplets in both. Neither
of the two patients had episodes of nonsustained
ventricular tachycardia (NSVT) throughout the 48 hours of
ambulatory monitoring. Thus, in the 4 patients with
episodes of NSVT (Table 8 .6 ), none had late potentials on
the SAECG.
8.3.7. SAECGS Before and Late After AVR
Table 8.13 depicts SAECG results in 29 patients studied
before and late after AVR. Although there was a prolong
ation in the LAS40 post-operatively, the difference did
not reach statistical significance. Root mean square
voltage of the signals in the terminal 40 milliseconds on
the other hand was significantly reduced post-operatively
(119.7 ± 69.4 uV Vs 87.7 ± 65.4 uV; p = 0.04).
8 • 4 Discuss i on
a result of improvement in intra-operative and post-
°perative management, aortic valve replacement (AVR) can
Summ
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210
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212
now be accomplished with an operative risk of 5 % or less
(Mullany et al, 1987; Jones et al, 1989; Lytle et al,
1989). However, late sudden death following AVR remains
an important and unfortunately unresolved problem (Isom et
al, 1977). These sudden deaths have been reported to
account for 17 to 45 percent of all late deaths after AVR
(Hirshfeld et al, 1974; Rubin et al, 1977; Barratt-Boyes,
Roche and Whitlock, 1977; Samuels et al, 1979). Malignant
ventricular tachyarrhythmias are thought by most workers
to be the most likely underlying mechanism in these sudden
deaths (Rubin et al, 1977; Samuels et al, 1979; Santinga
et al, 1980). Santinga and co-workers (1980) compared
pre-operative and post-operative data of 16 patients who
died unexpectedly at least 2 years following AVR, with the
data of 52 age-matched late survivors who had received the
same type of aortic valve prosthesis. Post-operative
ventricular arrhythmias were significantly more prevalent
in the patients who had died suddenly compared with the
survivors. In addition to this, fewer patients in the
sudden death group were in NYHA functional Class 1 and
significantly more were in congestive heart failure post-
operatively compared with the control group.
In the present study 30 patients were investigated by
echocardiography and doppler ultrasound and in 25
patients, 48 hour ambulatory electrocardiographic m onitor
ing was performed at an average of 121 ± 24 days after
AVR. Substantial symptomatic improvement was noted
following AVR, angina being present in only one patient,
Palpitations in 2 while syncope was not reported in any.
Of more clinical significance was the dramatic improvement
213
in the NYHA functional Class post-operatively. All
patients were in NYHA Classes 1 and 2 post-operatively
compared to 87% before surgery (Table 8.2). This is in
agreement with previously reported improvement in NYHA
functional Class of patients with aortic valve disease
following AVR (Von Olshausen et al, 1984; Galloway et al,
1990). In a recent follow-up study reported by Galloway
et al ( 1990), AVR was also shown to result in marked
symptomatic improvement. Pre-operatively 9% of patients
were in NYHA Class 2, 32% were in NYHA Class 3 and 59%
were in NYHA Class 4, compared to 7 6 % in NYHA Class 1 and
2, 22% in NYHA Class 3 and only 2% in NYHA Class 4 post-
operatively. It must however be noted that the extent to
which clinical improvement is associated with regression
of left ventricular hypertrophy and abnormalities of
ventricular function is not known (Gaasch, Andrias and
Levine, 1978). Hence the finding of an impairment in left
ventricular systolic function in the present study in
patients with predominant AS was not entirely unexpected
(Table 8.3).
8*4.1. Regression of Left Ventricular Hypertrophy
Left ventricular hypertrophy in significant aortic valve
disease, whether stenotic or insufficient, occurs as a
result of substantial haemodynamic stress on the left
ventricle in the form of pressure or volume overload, thus
enabling the heart to maintain systolic wall stress at or
near normal levels (Grossman, Jones and McLaurin, 1975).
This response to volume and pressure overload develops
over many years as the disease progresses. Thus
214
regression of left ventricular hypertrophy following
successful correction of volume or pressure overload by
AVR would be expected to be a slow and continuous process,
probably taking many years to reach a steady state.
In the present study AVR was accompanied with a
significant reduction in LVMI in patients with AS and
combined AS and AR (Table 8.3). Although patients with
predominant AR also showed a noticeable decrease in LVMI,
this did not reach statistical significance probably due
to the very small number of patients belonging to this
group. Previous clinical studies have reported similar
results (Kennedy, Doces and Stewart, 1977; Gaasch, Andrias
and Levine, 1978; Pantely, Morton and Rahimtoola, 1978).
Kennedy and his colleagues (1977) studied 24 patients
with aortic valve disease, 9 with pure AS, 10 with
combined AS and AR and 5 with AR. They demonstrated a
marked reduction in LVMI 19 ± 12 months after AVR. How
ever, despite the impressive reduction in hypertrophy,
LVMI did not return to within 2 standard deviations of
normal. Contrary to these findings, Gaasch and his co
workers (1978) reported significant changes in left
ventricular muscle mass in 19 patients with AR who had
serial echocardiographic studies following AVR. Between 9
and 24 months after AVR, left ventricular muscle mass was
within 2 standard deviations of the average for their
normal controls. Furthermore, in a recent study reported
by Monrad et al (1988), regression of left ventricular
hypertrophy continued to take place to as late as 8 . 1 ±
2.9 years after AVR.
215
The present study has demonstrated a substantial reduction
in LVMI following AVR, but regression of left ventricular
hypertrophy was nevertheless incomplete. This was not
unexpected given the fact that regression of left
ventricular hypertrophy after AVR is a slow and continuous
process which may take years before LVMI returns to
normal. It is therefore possible that further reduction
in hypertrophy will occur in these patients if they
continue to have good prosthetic valve function over a
longer period of time.
8*4.2. Prevalence of Ventricular Arrhythmias (VA^
In the present study ventricular ectopic activity was
present in 22 of the 25 patients (8 8 %) studied by
ambulatory electrocardiographic monitoring. The majority
(80%) of patients had infrequent VA (<10 VES/h) while
frequent VA (>30 VES/h) occurred in only 3 (12%) patients.
Frequent couplets were recorded in only one (4%) patient
while episodes of NSVT occurred in 4 (16%) patients (Table 8.4) .
Gradman et al (1981) monitored 45 patients for 48 hours at
a mean interval of 3.3 years after aortic valve replace
ment. Eighty-nine percent of their patients had complex
VA. in close agreement with their findings, complex VA
occurred in 72% of patients in the present study (Table
8 .8 ) However, their incidence of NSVT was higher,
occurring in 36% of their patients compared to 16% in the
present study. The main reason for the high incidence of
NSVT in the study of Gradman et al was the considerable
216
impairment in left ventricular function seen in some of
their patients. In fact, 70% of episodes of NSVT occurred
in the patients with impaired left ventricular function.
Von Olshausen et al (1984) studied 45 patients with aortic
valve disease 1 4 + 7 months after AVR. They reported a
low incidence of complex VA in their p a t i e n t s . In
contrast to their findings, Kostis et al (1984) reported a
higher prevalence of complex VA in 13 patients with aortic
valve disease studied 3 months following AVR.
These differing incidences in the frequency and complexity
of VA reported by different studies may be explained by
several factors. Firstly, these studies were performed at
different periods following AVR. Secondly, patients were
not comparable in terms of their age, type of aortic valve
disease, prevalence of concomitant coronary artery
disease, the degree of impairment of left ventricular
function and most importantly the surgical procedure and
the type of aortic valve prostheses. Thirdly, the methods
used for arrhythmia detection and quantification were not
uniform. Finally, there was a marked variability in the
size of the study populations in the different studies.
Furthermore, a spontaneous and marked variability in the
frequency and complexity of VA of individual patients has
been well documented (Morganroth et al, 1978; Michelson
and Morganroth, 1980).
The present study has also shown the importance of longer
periods of ambulatory electrocardiographic monitoring.
Five episodes of NSVT occurred in 4 patients and of these
5 episodes, only 2 were recorded in the first 24 hour
217
period (Table 8 .6 ) Thus, if only 24 hours of ambulatory
monitoring had been performed, 60% of episodes of NSVT
would have been missed. Obviously, longer recording
periods (>48 hours) would have picked up more complex
arrhythmias but the patients' tolerance and convenience
have to be taken into consideration.
8.4.3. Significance of NSVT
Five episodes of NSVT occurred in 4 patients (16%) in the
present study. However, none of these 4 patients had late
potentials on their SAECG (Table 8.12). Signal-averaged
electrocardiography has been shown by several workers to
be the most accurate predictor for the induction of
sustained ventricular tachycardia by programmed
ventricular stimulation in patients with NSVT recorded on
ambulatory electrocardiographic monitoring (Buxton et al,
1987; Turitto et al, 1988). Furthermore, the prognostic
significance of late potentials has been studied
prospectively by Breithardt, Martinez-Rubio and Borggrefe
(1990). in patients with ischaemic heart disease and
previous myocardial infarction, they showed a higher risk
of major arrhythmic complications including sudden cardiac
deaths in patients with late potentials on SAECG. Thus,
the absence of late potentials in the 4 patients with NSVT
in the present study would suggest a low risk for serious
future arrhythmic events in these patients. Further
follow-up of these patients would be needed in order to
verify this prospectively.
218
8.4.4. Effect of AVR on VA and SAECG
Twenty-one of the total 100 study patients had ambulatory
electrocardiographic monitoring performed before AVR,
immediately after and late after AVR (Table 8.9 and 8.10).
There were no significant differences in VES frequency in
the 3 study periods. This is in agreement with Kostis et
al's findings in 13 patients studied before and 3 months
after AVR (Kostis et al, 1984). They showed no difference
in pre and post-operative VES frequency (1073 ± 6 6 Vs 621
± 355 VES/24 h r s ). In another study Von Olshausen and co
workers reported a significant reduction in VES frequency
only in a subgroup of their patients in whom AVR was
accompanied with improvement in left ventricular function
(Von Olshausen et al, 1984).
Signal-averaged electrocardiographic results in 29
patients studied before and late after AVR were compared
(Table 8.13). Aortic valve replacement was accompanied by
a significant reduction in RMSV40 (119.7 ± 69.4 uV before
and 87.7 ± 65.4 uV after AVR; p <0.05). This finding has
not been previously reported in patients with aortic valve
disease.
8 .5 Summary
This part of the study has shown that infrequent, but
complex VA occur in patients with aortic valve disease
late after AVR. Nonsustained ventricular tachycardia
occurred in 16% of the patients. However, there is little
evidence to suggest the presence of an arrhythmogenic
219
substrate in these patients in view of the absence of late
potentials on the SAECG. Aortic valve replacement was
accompanied by a significant regression in LVH in patients
with predominant AS and those with combined AS and AR, but
this was however not associated with a decrease in VES
frequency. Thus, the reported high incidence of late
sudden deaths following AVR cannot entirely be explained
on the basis of ventricular tachyarrhythmias.
220
C H A P T E R N I N E
I M P A I R E D C A R D I O V A S C U L A RA U T O N O M I C F U N C T I O N I NA O R T I C V A L V E D I S E A S E
221
9.1 Introduction
Cardiovascular autonomic failure was first detected by
Bradbury and Eggleston (1925) but it was in 1955 that one
of the first large studies on cardiovascular autonomic
disturbances was reported by Sharpey-Schafer. He
demonstrated a conspicuous difference in continuous
arterial pressure records between patients with heart
failure and normal subjects during Valsalva manoeuvre. In
the early sixties reports on abnormal circulatory reflexes
in diabetic patients began to appear in the literature.
Sharpey-Schafer and Taylor (1960) demonstrated an abnormal
response to Valsalva manoeuvre in 20% of a total of 337
patients attending a diabetic clinic. In another study,
Ewing et al (1973) reported a higher incidence (62%) of an
abnormal heart-rate and blood pressure response to
Valsalva manoeuvre in 37 diabetics with symptoms or signs
of autonomic neuropathy. Two years later Murray and his
colleagues showed for the first time the presence of
abnormal autonomic cardiovascular reflexes in diabetics
without any clinical features of autonomic neuropathy
(Murray et al, 1975). Their findings were supported by
subsequent reports (Bennett et al, 197 6 ; Rubier, Chu and
Bruzzone, 1985). In a recent and elegant study, Hornung
and his co-workers by performing 24 hour ambulatory
heartrate monitoring, demonstrated a decrease in diurnal
heart-rate variation in patients with diabetes mellitus
(Hornung, Mahler and Raftery, 1989). The mere presence of
abnormal autonomic reflexes in patients with diabetes
mellitus has been shown by several workers to be
accompanied by a significant increase in both morbidity
222
and mortality (Ewing, Campbell and Clarke, 1976; Clarke,
Ewing and Campbell, 197 9; Ewing, Campbell and Clarke,
1980; Niakan et al, 1986; Burgos et al, 1989).
Several studies have demonstrated signs of autonomic
disturbances in patients following acute myocardial
infarction (Webb, Adgey and Pantridge, 1972; Kirby 1977;
Bigger et al, 1988 and McAreavey et al, 1989). Correction
of these disturbances by pharmacologic means was followed
by a noticeable reduction in the in-hospital mortality
(Webb, Adgey and Pantridge, 1972) and improvement in
autonomic function occurred when the tests were repeated
in the late convalescent period (Imaizumi et al, 1984).
Furthermore, the prognostic importance of cardiac
autonomic dysfunction in these patients has been assessed
by several follow-up studies (Kleiger et al, 1987; Martin
et al, 1987 and La Rovere et al., 1988 ). These workers
have reported an increased mortality including sudden
death in those patients with impaired autonomic function.
In a recent study, patients with aortic stenosis have been
shown to have significantly impaired vagal heart-rate
control when compared to age-matched healthy volunteers
(Airaksinen et al, 1988). This impairment in vagal heart-
rate control did not improve following aortic valve
replacement (AVR).
The aim of this part of the study was therefore to assess
the prevalence of impaired cardiovascular autonomic
function in patients with aortic valve disease using non-
invasive bedside tests and to relate the findings to
223
clinical and haemodynamic features. The effect of AVR on
autonomic function was also evaluated in 10 patients 3
months following operation.
9.2 Study Population
Forty-seven of the original 100 patients were included in
this part of the study. The predominant lesion was AS in
23, AR in 8 and combined AS and AR in 16 patients.
Twenty-eight of the patients were males, 19 were females,
their ages averaging 56 ± 12 years (range 32 - 78 years).
Ewing et al (1985) reported no sex differences in normal
values for autonomic function. None of the patients had
hypertension, diabetes mellitus or uraemia. All patients
were in sinus rhythm and none was receiving anti-
arrhythmic medication, beta blockers or medication known
to have anticholinergic activity. Three patients were
taking digoxin and 14 were on diuretics. In 10 patients
the tests were repeated after AVR.
The control group consisted of 20 male healthy volunteers
of a mean age of 46 + 6 years (range 40 - 61 years). They
were considered to be healthy as confirmed by patient
history, physical examination, echocardiographic and
doppler examinations and exercise electrocardiography.
9 .3 Methods
Bedside cardiovascular autonomic function tests were
performed. These included heart-rate response to Valsalva
manoeuvre (Valsalva ratio), heart-rate (R-R interval)
224
variation during deep breathing, immediate heart-rate
response to standing (30:15 ratio) and blood pressure
response to standing (fall in systolic blood pressure).
These methods were described in detail in Chapter 3.
9.4 Results
Table 9.1 presents the results of autonomic function tests
according to the predominant aortic valve lesion of the
patients. Although heart-rate response to Valsalva
manoeuvre, heart-rate variation during deep breathing,
immediate heart-rate response to standing and blood
pressure response to standing were marginally less
abnormal in patients with predominant AS than in the other
2 groups, these differences were far from achieving any
statistical significance. In view of this, it was felt
unnecessary to divide the patients into the 3 subgroups in
subsequent analysis of the results.
Generally accepted values were used (Ewing and Clarke,
1982) and accordingly heart-rate response to Valsalva
manoeuvre, heart-rate variation during deep breathing,
immediate heart-rate response to standing and blood
pressure response to standing were abnormal in 4.3%, 38%,
4% and 4% respectively, while borderline impairment
occurred in 28.3%, 36%, 13% and 32% respectively (Table
9.2) .
Table 9.3 depicts autonomic function test results in 2 0
healthy controls. Immediate heart-rate response to stand-
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228
ing was the only variable that was abnormal, occurring in
only one subject (5 %).
Heart-rate response to Valsalva manoeuvre was markedly
reduced in patients compared to controls (1.37 ± 0.31 Vs
1.90 ± 0.40; p=0.00005). The same was the case with
heart-rate variation during deep breathing (12.6 ± 5.9
beats/minute Vs 22.3 + 8.2 beats/minute; p=0.0003)
(Figures 9.1 and 9.2). The 2 groups did not differ in
respect to immediate heart-rate response to standing as
well as blood pressure response to standing (Table 9.4).
In view of the differences in age between patients and
controls, comparisons between the 2 groups were made after
correcting for age. This was done by regression of the
response variables on age separately for the 2 groups and
subsequently by comparison of these regression equations
(Pocock, 1989 ) .
Figures 9.3 and 9.4 illustrate examples of normal and
abnormal heart-rate response to Valsalva manoeuvre
respectively. Figure 9.5 shows normal (upper sample) and
abnormal (lower sample) heart-rate variation during deep
breathing. Examples of normal and abnormal immediate
heart-rate response to standing (30:15 ratio) are
illustrated in Figures 9.6 and 9.7 respectively.
Table 9.5 shows results of patients according to the
presence (12 patients) or absence (35 patients) of
syncope. Surprisingly, all the 4 variables were
marginally less abnormal in patients with syncope, but the
differences were statistically insignificant.
Vals
alva
R
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Va lsa lva Ratio3.0 i
2.5 -
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Figure 9.1: Heart-rate response to Valsalva manoeuvrein 46 patients with aortic valve disease and 2 0 healthy controls.
HR
Var
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(bea
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20 -
Patients Controls
Figure 9 . 2 : Heart-rate variation during deep breathingin 4 7 patients with aortic valve disease and 2 0 healthy controls.
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Palpitations were present in 25 and absent in 22 patients.
There were no significant differences in autonomic
function test results between the 2 groups (Table 9.6).
Angina was present in 28 and absent in 19 patients. The
groups did not differ in respect to all the 4 autonomic
function tests (Table 9.7). The same was true when
comparing patients with ( 8 patients) to those without (34
patients) significant coronary artery disease (Table 9.8).
The effect of age on autonomic function tests was
assessed. Heart-rate variation during deep breathing was
the only variable that showed a weak, but significant
inverse relation to age occurring only in patients with
predominant AS (r = -0.579; p <0.01) (Figure 9.8). In
patients with predominant AS, heart-rate variation during
deep breathing also showed a weak, but significant inverse
relation to PWTd (r = -0.483; p <0.02) (Figure 9.9), IVSTd
(r = -0.491; p <0.02) (Figure 9.10), LVMI (r = - 0.463; p
<0.05), systolic blood pressure (r = -0.475; p <0.05)
(Figure 9.11) as well as LVSP (r = -0.510; p <0.02)
(Figure 9.12).
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Valsalva manoeuvre was directly related to PSLVWS
(Reichek's method) (r = 0.746; p <0.05) (Figure 9.13)
while heart-rate variation during deep breathing showed an
inverse relation to E/A ratio (r = -0.735; p <0.05)
(Figure 9.14). However, there was no relationship between
heart-rate variation during deep breathing and ejection
fraction (r = 0.289). Immediate heart-rate response to
232
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Plot of relation between Age and HR Variation DuringDeep Breathing in Patients with AS
30 n
20 -
1 0 -
♦ ♦ r = -0.579 p < 0 .0 1
0 H 1------- 1-------1------- 1------- 130 40 50 60 70 80
AGE (years)
Figure 9 . 8 : Correlation of age and heart-rate variationduring deep breathing (beats/min) in patients with predominant AS. A weak but significant inverse relation was obtained (r = "0.579; p <0.01) .
HR
V (b
eats
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)
Plot of relation between PWTd and HR Variation DuringDeep Breathing in Patients with AS
30 i
20 -
10 -
* ♦ ♦r = -0.483p < 0.02
0 — i—
1.20.6 0.8 1.0 1.4 1.6 1.8 2.0
PWTd (cm)
Figure 9 . 9 : Correlation of PWTd (cm) and heart-ratevariation during deep breathing (beats/min) in patients with predominant AS. A weak but significant inverse relation was obtained (r = “0.483; p <0.02).
Plot of relation between IVSTd and HR Variation DuringDeep Breathing in Patients with AS
30 n
♦
c'E*—•Q).Q>DCX
20 -
♦ ♦
♦ ♦ r = -0.491p < 0.02
1 0 -
00
IVSTd (cm)
Figure 9 . 1 0 : Correlation of IVSTd (cm) and heart-ratevariation during deep breathing (beats/min) in patients with predominant A S . A weak but significant inverse relation was obtained (r = “0.491; p <0.02).
HR
V(b
eats
/min
)
Plot of Relation Between SBP And HR Variation DuringDeep Breathing in Patients With AS
30 n
20 -
120 140 160 180 200 2201
r=-0.475 p<0.05
SBP(mm Hg)
Figure 9 . 1 1 : Correlation of systolic blood pressure (mmHg) and heart-rate variation during deep breathing (beats/min) in patients with predominant AS. A weak but significant inverse relation was obtained (r = “0.475; p <0.05).
HR
V (b
eats
/min
)
Plot of relation between LVSP and HR Variation DuringDeep Breathing in Patients with AS
30 i
20 -♦♦ ♦
♦r = -0.510p < 0.02
10 -
0 H------------ 1------------ 1------------1100 200 300 400
LVSP (mm Hg)
Figure 9 . 1 2 : Correlation of left ventricular systolicpressure (nun Hg) and heart-rate variation during deep breathing (beats/min) in patients with predominant AS. A weak but significant inverse relation was obtained (r = "0.510; p <0 .0 2 ).
Vals
alva
R
atio
Plot of relation between PSLVWS (Reichek) andValsalva Ratio in Patients with AR
1.7 -]
1.6 -
1.5-
1 .4-
1 .3-
1.2 -
1.1 + 0
Figure 9 .1
♦
r = 0.746 p < 0.05
♦
1 0 0 200 300
PSLVWS (Reichek, dyn/cm2)
3: Correlation of peak systolic left— ventricular wall stress by Reichek's method
(dyne/cm ) and heart-rate response to Valsalva manoeuvre (Valsalva ratio) in patients with predominant AR. A moderate but significant direct relation was obtained (r = 0.746; p <0.05).
HR
V (b
eats
/min
)
Plot of relation between E/A Ratio and HR VariationDuring Deep Breathing in Patients with AR
20 -|
♦
1 0 -r = -0.735 p < 0.05
♦
0
E/A Ratio
Figure 9 , 1 4 : Correlation of the ratio between early (E)and late (A) left ventricular diastolic filling velocity (E/A ratio) and heart-rate variation during deep breathing (beats/min) in patients with predominant AR. A moderate but significant inverse relation was obtained (r = “0.7 35; p <0.05).
Plot of relation between IVSTd and 30:15 Ratioin Patients with AR
1.1 '
o03
LO
O00
1.0
r = -0.723 p < 0.05
0.9 i --------- 1----------1----------1--------- 1----------1----------10.6 0.8 1.0 1.2 1.4 1.6 1.8
IVSTd (cm)
Figure 9 . 1 5 : Correlation of IVSTd (cm) and immediateheart-rate response to standing (30:15 ratio) in patients with predominant AR. A moderate but significant inverse relation was obtained (r = “0.723; p <0.05).
235
standing on the other hand, was inversely related to IVSTd
(r = -0.723; p <0.05) (Figure 9.15), systolic blood
pressure (r = -0.809; p <0.02) (Figure 9.16) and LVSP
(r = -0.72; p <0.05) Figure 9.17).
In patients with combined AS and AR, heart-rate variation
during deep breathing showed a direct relation to PSLVWS
by both Reichek's (r = 0.591; p <0.02) (Figure 9.18) and
Quinones' (r = 0.652; p <0.01) (Figure 9.19) methods.
To assess the effect of valve replacement on cardio
vascular autonomic function, the tests were repeated in 1 0
patients 3 months after AVR. There were no significant
differences in the autonomic function test results before
and after AVR (Table 9.9)
9.5 Discussion
In the present study 19 (40%) patients had abnormality in
at least one autonomic function test. Of these 19
patients, 18 (38%) had abnormal heart-rate variation d u r
ing deep breathing (Table 9.2). This is not surprising
given the fact that heart-rate variation during deep
breathing is a sensitive, reproducible and specific test
for one of the earliest defects of autonomic dysfunction
i.e. cardiac vagal denervation (Watkins, 1990). Our
results are in close agreement with the findings reported
in the only study I am aware of that looked at cardiac
autonomic function in aortic valve patients (Airaksinen et
al, 1988). They reported a 46% incidence of abnormal
heart-rate variation during deep breathing in 24 patients
with AS. Furthermore, as is the case in the present
30:1
5 ra
tio
Plot of relation between SBP and 30:15 Ratioin Patients with AR
1.2 1
♦
1.1 ‘
♦
# r = -0.809# # p < 0.02
♦
1.0 - ♦
0.9 H----------- 1------------1------------1----------- 1------------1100 120 140 160 180 200
SBP (mm Hg)
Figure 9 . 1 6 : Correlation of systolic blood pressure (mmHg) and immediate heart-rate response to standing (30:15 ratio) in patients with predominant AR. A fairly strong and significant inverse relation was obtained (r = “0.809; p <0.02).
30:1
5 ra
tio
Plot of relation between LVSP and 30:15 Ratioin Patients with AR
1 .2 "I
♦
1.1 i ♦♦
♦
1.01
r = -0.72 p < 0.05 • ♦ r
0.91--------------- 1-------------- 1-------------- 1---------------1120 140 160 180 200
LVSP (mm Hg)
Figure 9 . 1 7 : Correlation of left ventricular systolicpressure (mm Hg) and immediate heart-rate response to standing (30:15 ratio) in patients with predominant AR. A moderate but significant inverse relation was obtained (r = ”0.72; p <0.05).
Plot of relation between PSLVWS (Reichek) and HR VariationDuring Deep Breathing in Patients with Combined AS and AR
30 1
20 -
c'E
»03CD_Q^>ccX
10 -
♦• ♦
♦
♦ ♦
r = 0.591p < 0.02
♦
♦
0100 200 300
PSLVWS (Reichek, dyne/cm2)
Figure 9 . 1 8 : Correlation of peak systolic leftventricular wall stress by R e i c h e k 's method (dyne/cm ) and heart-rate variation during deep breathing (beats/min) in patients with combined AS and AR. A weak but significant direct relation was obtained (r = 0.591;p < 0.02 ) .
Plot of relation between PSLVWS (Quinones) and HR VariatioDuring Deep Breathing in Patients with Combined AS and AR
30 n
♦
20 -
EwCO0)_Q>DCX
r = 0.652p < 0 .0 1
10 -
♦• •
0100 200 300 400 500
PSLVWS (Quinones, dyne/cm2)
Figure 9 , 1 9 : Correlation of peak systolic leftventricular wall stress by Quinones' method (dyne/cm ) and heart-rate variation during deep breathing (beats/min) in patients with combined AS and AR. A weak but significant direct relation was obtained (r = 0.652;p <0.01).
Card
iova
scul
ar
Auto
nomi
c Fu
ncti
on
Test
Resu
lts
in 10
Pati
ents
Be
fore
and
Afte
r Ao
rtic
Va
lve
Repl
acem
ent
(AVR
)
236
p -
value
0.79
0.91
0.76
0.46
in ro ro O CT\ cr>CN 00 • rH CN .
Oh . • • ro • » CN 00> O rH in cn O rH h ro
j_l + 1 1 +1 I + 1 1 +1 10 cti in ro o CN C\ vo oP ro o . . H CT> • —"4H • • in . . ov< iH rH i—i rH O
cn a\ ^ r- CN rH& iH • rH rj* r- ^> • • • in • • • CN
O CN r- cn O fH r- cn0 +| 1 +1 i + | 1 +1 1P0 in ro ro o CN OP rH . . rH O •--0 . • H • * in0Q i—1 rH rH r rH iH' '
0 Cnp G> •HG n0 GO 0G G p Cn0 0 cn G r-"E •H •H 0P 0 th p0 0 P G G> •H 0 CO
rH p Cn 0 P cn0 0 G cn cn 0W > *H G P
rH 0 rG 0 — 0 CU0 *H ^ p 0. 0 P> P rH 0 cn -h n0 0 0 0 P 0 00 p > p P 0 in 0P P X P G *H0 0 0 o n0 > P P in cuW »H G 0 0 fH cn 0G 0 •H 0 P •• 0 -H0 cn TJ 1 o P rHOi H cd p ro 0CO 0 i cn P 0 P
0 > cd G 0 P cnP w —" H 0 G > ip P in cn0 0 G cn-P P TJ 0 0 G0 0 P P *rH
P P 0 Ch1 1 •H rH
P P TJ T ) -HP P 0 O 00 0 O 4H0 0 § rHw M M CQ
<DcngfdpPc/i+1GfdoS
237
study, they also reported a significant difference in the
heart-rate variation during deep breathing between their
patients and healthy controls while on the other hand, the
2 groups did not differ in respect to the immediate heart-
rate response to standing (30:15 ratio).
There are several possible explanations for the impairment
in cardiac autonomic function in patients with aortic
valve disease. The reduced level of physical activity in
these patients may contribute to the diminished para
sympathetic tone and reflex heart-rate control. This
observation was made by Billman and his colleagues who
showed a significant alteration of autonomic control of
the heart by exercise in dogs possibly by decreasing
sympathetic and/or increasing parasympathetic tone
(Billman, Schwartz and Stone, 1984). Concomitant coronary
artery disease could also contribute to the impairment in
cardiac autonomic function (Airaksinen et al, 1987).
However, only 8 of the 47 patients in the present study
had significant coronary artery disease. Of these 8
patients, only 2 had an abnormality in one or more
autonomic function tests. Moreover, there were no
differences in the autonomic function test results between
patients with compared to those without significant
coronary artery disease (Table 9.8).
Heart-rate variation during deep breathing in patients
with predominant AS and immediate heart-rate response to
standing in patients with predominant AR showed an inverse
relation to both systolic blood pressure and LVSP. This
finding may suggest that the chronically increased left
238
ventricular pressures in these patients may blunt the
baroreceptors within the left ventricle in the same way as
increased aortic pressure causes aortic baroreceptor
dysfunction in hypertension and so interfere with the
vagal heart-rate regulation (Johnston, 1980. Johnson,
1971). If this is true, AVR which should normalise left
ventricular pressures to a certain extent would be
expected to result in an improvement in cardiovascular
autonomic function. However, this was not the case in
both the present study and the findings of Airaksinen et
al (1988) who repeated the tests 6 weeks after AVR. It is
however possible that functional recovery of left
ventricular baroreceptors reguires a longer period and
therefore in order to explore this possibility further
follow-up with repeat evaluation of cardiac autonomic
function in these patients may be needed.
The significance of impaired cardiovascular autonomic
function in aortic valve disease is still speculative.
Previous studies on diabetic patients and in patients
following acute myocardial infarction have reported an
increased morbidity and mortality including sudden cardiac
death in those patients with impaired cardiovascular
autonomic function (Niakan et al, 1986, Burgos et al,
1989; Ewing, Campbell and Clarke, 1976; Ewing, Campbell
and Clarke, 1980; Kleiger et al, 1987; Bigger et al, 1988;
La Rovere et al, 1988). Kleiger et al (1987) investigated
808 patients who survived acute myocardial infarction and
followed them up for a mean period of 31 months. They
showed risk of mortality to be 5.3 times higher in
patients with decreased heart-rate variability. Decreased
239
heart-rate variability increased the risk of death
irrespective of average heart-rate, variables reflecting
left ventricular function, those measuring left
ventricular ectopic activity, clinical or demographic
variables or drug treatment particularly digitalis and
beta-adrenergic blocking d r u g s .
An increased risk of sudden cardiac death has been shown
to be associated with impaired autonomic function
(Billman, Schwartz and Stone, 1982; Schwartz, Billman and
Stone, 1984; Kleiger et al, 1987; Martin et al, 1987; La
Rovere et al, 1988). Given this fact, in addition to the
known association of aortic valve disease and the
occurrence of sudden death (Ross and Braunwald, 1968;
Chizner, Pearle and de Leon, 1980; Lombard and Selzer,
1987), it would be tempting to speculate about the
mechanism of sudden death in aortic valve disease on the
basis of impairment in cardiovascular autonomic function.
In most instances of sudden death, ventricular
fibrillation is regarded as the underlying mechanism (Lown
and Wolf, 1971). Decreased vagal tone decreases heart-
rate variability and predisposes to ventricular
fibrillation in animals with experimental myocardial
infarction (Lown and Verrier, 1976; Magid, Eckberg and
Sprenkle, 1983). Increased sympathetic activity during
experimental ischaemia or infarction promotes ventricular
fibrillation (Lown and Verrier, 1976; Corr, Witkowski and
Sobel, 1978) while increased vagal or decreased
sympathetic activity decreases vulnerability to
ventricular fibrillation (Magid, Eckberg, and Sprenkle,
1983; Lown and Verrier, 1976). Furthermore, beta-
240
adrenergic blocking drugs have been shown to reduce
ventricular fibrillation threshold in experimental m y o
cardial ischaemia or infarction (Sharma and Corr, 1983;
Anderson, Rodier and Green, 1983; Gang, Bigger and Uhl,
1984). Very low doses of atropine have been shown to
increase cardiac vagal efferent activity in dogs. Thus
increased vagal tone and heart-rate variability by small
doses of atropine resulted in reduced ventricular
fibrillation threshold both in normal dogs and dogs with
experimental myocardial ischaemia (Magid, Eckberg and
Sprenkle, 1983). Thus, the results of previous studies
suggest that patients with decreased heart-rate
variability have decreased vagal tone, increased
sympathetic activity or both and hence are at a higher
risk of developing ventricular fibrillation and sudden
death. This speculation may have therapeutic implications
as it may be assumed that the risk of sudden cardiac death
could be lowered by instituting agents that blunt
sympathetic activity e.g. beta-adrenergic blocking drugs
or agents that promote vagal tone e.g. transdermal
scopolamine (Dibner-Dunlap et al, 1985) particularly in
patients with decreased heart-rate variability. Beta-
adrenergic blockade in patients following an acute
myocardial infarction has been shown to cause a
significant reduction in sudden cardiac death (Wilhelmsson
et al, 1974; The Norwegian Multicenter Study Group, 1981).
9.6 Summary
This part of the study has shown that impairment in
cardiac autonomic function in patients with aortic valve
241
disease is quite common. Aortic valve replacement was not
accompanied by any improvement in autonomic function at
least in the short-term. The mechanism of sudden death in
aortic valve disease could be speculated on the basis of
impaired cardiac autonomic function and the issue of
therapeutic manipulation of cardiac autonomic control
particularly in those patients with marked impairment in
heart-rate variability is a possibility worth pursuing in
future studies. Beta-blocking drugs by blunting
sympathetic influences on the heart reduce the risk of
mortality after myocardial infarction and hence could be
one of the potential therapeutic options. However, the
myocardial depressant effect of these drugs would preclude
their use in patients with significant aortic valve
disease at least pre-operatively.
242
C H A P T E R T E N
S U M M A R Y O F T H E M A I N F I N D I N G S A N D C O N C L U S I O N S
243
Electrocardiographic and echocardiographic left
ventricular hypertrophy were present in 90% and 91% of
patients respectively. The mean echocardiographic left
ventricular mass index was 210 ± 72 g/m2 . Left
ventricular systolic and diastolic function were normal in
94% and 61% of patients respectively.
Significant coronary artery disease was present in 21 out
of a total of 89 patients who had coronary angiography.
Angina pectoris could predict the presence of significant
coronary artery disease with 95% sensitivity and 54%
specificity.
In agreement with most previous workers, complex
ventricular arrhythmias were present in the majority of
patients (74%). Nonsustained ventricular tachycardia was
uncommon, occurring in only 9 (9%) patients. There was no
relationship between ventricular arrhythmia frequency and
the degree of echocardiographic left ventricular
hypertrophy or the severity of aortic valve disease. Left
ventricular function did not have any effect on
ventricular arrhythmias. This may have resulted from the
fact that the majority of patients had normal left
ventricular function. Of the 9 patients with nonsustained
ventricular tachycardia, only 2 had significant coronary
artery disease.
The effect of AVR on left ventricular hypertrophy and
ventricular arrhythmias was assessed. Aortic valve
replacement was accompanied by a significant regression
in echocardiographic left ventricular hypertrophy in
244
patients with predominant AS and those with combined AS
and AR. However AVR did not result in a reduction in
ventricular ectopy. There were no differences in VES
frequency between pre-operative, early post-operative (5
to 7 days post AVR) and late post-operative (121 ± 24 days
post AVR) periods.
Nonsustained ventricular tachycardia occurred in 9 (9%)
patients pre-operatively and 4 (16%) patients 121 ± 24
days post AVR. Ventricular late potentials on SAECG were
present in only one patient pre-operatively and in none of
the 4 patients post-operatively. There was therefore
little to suggest an underlying arrhythmogenic substrate
in these patients.
Twenty-nine patients had a SAECG performed before and late
after AVR. Aortic valve replacement was accompanied by a
significant reduction in RMSV40. The significance of this
finding which has not been reported previously is unclear.
Of a total of 7 deaths in the study, 3 occurred suddenly
in patients awaiting surgery. Sudden death could not be
predicted by either ambulatory electrocardiographic
monitoring or SAECG.
Several studies have shown an association between an
increased risk of sudden cardiac death and impairment in
cardiovascular autonomic function. Given this fact, in
addition to the known association of aortic valve disease
and the occurrence of sudden cardiac death, it was
tempting to speculate about the mechanism of sudden death
245
in aortic valve disease on the basis of impairment in
cardiovascular autonomic function. Of the 47 patients
assessed, 19 (40%) had abnormality in at least one
autonomic function test. Of these 19 patients, 18 (38%)
had abnormal heart-rate variation during deep breathing.
Follow-up studies on diabetic patients and patients
following acute myocardial infarction have reported a
marked increase in the risk of mortality in patients with
decreased heart-rate variability. Thus long-term follow-
up of patients in this study will be needed to verify the
prognostic significance of impaired cardiovascular
autonomic function. In 10 patients re-studied 3 months
after operation, AVR was not accompanied by an improvement
in cardiovascular autonomic function at least in the
short-term.
Although the significance of impaired parasympathetic
heart-rate control in aortic valve disease patients is
still speculative, its presence could be regarded as one
of the potential predictors of sudden death as reduced
parasympathetic nervous activity has been shown in
previous experimental work to reduce ventricular
fibrillation threshold. Long-term follow-up in larger
numbers of patients will be needed in future to verify
t h i s .
246
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