Short- and long-term effects of digitalis on resting and posthandgrip hemodynamics in patients with...

Short- and Long-Term Effects of Digitalis on Resting and

Posthandgrip Hemodynamics in Patients With

Coronary Artery Disease

ROBERT VOGEL, MD JOHN FRISCHKNECHT, MD PETER STEELE, MD

Denver, Colorado

From the Division of Cardiology, Department of Medicine, Denver Veterans Administration Hospital, University of Colorado Medical Center, Denver, Colorado. This study was supported by research funds of the Veterans Administration, Washington, D. C. Manuscript received October 18, 1976; revised manuscript received February 4, 1977, accepted February 9, 1977.

Address for reprints: Robert Vogel, MD, Denver Veterans Administration Hospital, 1055 Clermont Street, Denver, Colorado 60220.

The short-term effects at rest of 0.01 mg/kg of ouabain given intravenously and the long-term effects at rest of daily oral administration of 0.25 mg of digoxin on left ventricular ejection fraction, left ventricular end-diastolic volume, cardiac index, blood pressure and heart rate were measured in eight patients with coronary artery disease using a single crystal scintillation probe. Measurements were also made after handgrip exercise (1 minute of 33 percent of maximal) in two of these patients and in two others with coronary artery disease. In all patients the left ventricular ejection fraction was less than 0.50. Ouabain increased resting left ventricular ejection fraction (0.39 f 0.03 to 0.55 f 0.03 [mean f standard error of the mean], P <O.Ol) and decreased resting left ventricular end-diastolic volume index (86 f 12 to 64 f 5 ml/m*, P <O.Ol) and heart rate (75 f 6 to 69 f 6 beats/min, P <0.02). Ouabain did not change resting cardiac index or blood pressure significantly. Handgrip exercise increased heart rate and blood pressure significantly. Left ventricular ejection fraction after handgrip exercise was 0.33 f 0.02 (difference not significant), but it increased after ouabain administration to 0.55 f 0.03 from the control value of 0.36 f 0.01 (P <0.05). After 2 weeks of daily oral administration of digoxin, associated with a digoxin level of 1.0 f 0.2 ng/ml, all resting hemodynamic variables were statistically unchanged from control levels. in the four patients tested daily, the return to control levels took 1 to 5 days. Left ventricular ejection fraction after handgrip exercise remained eie- vated at 0.50 f 0.04 (P <0.05). Thus, with long-term digoxin administration, volumetric variables at rest are initially improved but later return to control values whereas values after exercise continue improved.

Digitalis preparations have been widely recommended for the treatment of congestive heart failureI- including that caused by coronary artery disease.srO Studies measuring the short-term hemodynamic effects of digitalis have shown both improvement in cardiac contractility’l-l4 and decrease of right and left ventricular filling pressures.15-l8 Cardiac output, however, has frequently been shown not to increase.13J-23 Re- cent work from our institutionz4 has demonstrated a short-term increase in the left ventricular ejection fraction after administration of ouabain in patients with coronary artery disease. This finding provides further evidence of the primary cardiac effects of digitalis previously docu- mented with the use of isovolumic phase contractility variables.13,14,2122

Few data exist to document the continued effect of digitalis on hemodynamics in patients with coronary artery disease. Directly measured changes in hemodynamic variables in normal persons have been shown to disappear in approximately 5 days. 25,26 Data on indirect measurements (systolic time intervals) in long-term studies have been conflict- ing27-2g although persistent directly measured inotropic changes have been demonstrated in experimental animals.aO We undertook this study to confirm the short-term hemodynamic changes of digitalization and

August 1977 The American Journal of CARDIOLOGY Volume 40 171

ACUTE AND CHRONIC EFFECTS OF DIGITALIS-VOGEL ET AL.

to determine whether these changes persist in patients with coronary artery disease and left ventricular dysfunction.

Methods

Patients

Ten men (Cases 1 to 10) aged 46 to 61 years, were informed of the nature of the study and consented to participate. Pa- tients 1 to 8 underwent measurements at rest, and Patients 2,4,9 and 10 underwent measurements both at rest and after exercise. Patients 1 and 6 had isolated left anterior descending coronary arterial obstruction (greater than 70 percent of lu- minal diameter), Patients 7 had two vessel coronary artery disease and the remaining seven patients had three vessel disease. Left ventricular ejection fraction ranged from 0.20 to 0.45 as assessed from single plane angiographic films in the right anterior oblique projection obtained at prior cardiac catheterizations. Patients 5 and 7 had no angina; the remaining eight patients had one to six episodes of angina daily. Patients 2,4,8 and 9 required diuretic drugs for clinical congestive heart failure. Patient 6 had an occluded single left anterior descending coronary bypass graft, Patient 8 had occluded left anterior descending and right coronary bypass grafts; the remaining eight had had no operative intervention. All patients had normal sinus rhythm and none had valvular heart disease.

TABLE I

Hemodynamic Data at Rest After Ouabain and After 2 Weeks of Maintenance Digoxin in Eight Patients With Coronary Artery Disease (Group 1)

Case no. BP HR Cl EF SVI EDVI

1 Control Ouabain

Digoxin

2

Control

Ouabain

Digoxin

3

Control

Ouabain

Digoxin 4

Control

Ouabain

Digoxin

5

Control

Ouabain

Digoxin

6

Control

Ouabarn

Digoxin

7

Control

Ouabain

Digoxin

8

Control

Ouabain

Digoxrn

134186 60 2.8 0.40 46 116 15218% 4% 1.9 0.50 41 81

12618% 64 2.6 0.73 40 55

1201100 6% 3.0 0.35 44 126 122192 64 2.3 0.42 36 86 108176 68 2.2 0.32 32 99

116174 84 2.6 0.47 31 66 118172 72 2.4 0.63 33 53 11 O/80 76 2.7 0.42 35 84

110186 75 2.1 0.36 29 79 106174 71 2.2 0.61 32 52 95165 72 2.9 0.41 40 97

90160 64 3.2 0.40 50 125 105160 64 2.9 0.64 45 71 116168 60 3.0 0.34 50 147

12418% 60 122184 52

128188 80

0.4% 23 47 0.66 36 54 0.35 28 79

122178

118178

11 O/68

88

80

80

104

100

100

1.4

1 .9

2.2

2.0

1 .9

1 .9

1.9

2.1

2.1

0.46 23 49 0.50 24 49 0.36 24 66

122182

142192

128192

0.24 18 76 0.45 20 47 0.34 21 62

BP = blood pressure (mm Hg); Cl = cardiac index (liters/min per

m’); EDVI = left ventricular end-drastolic volume index (ml/m’); EF

= left ventricular ejection fraction; HR = heart rate (beats/min); SVI

= stroke volume index (ml/m’).

Protocol

Hemodynamic testing: Patients stopped taking digitalis and propranolol 2 weeks and 2 days, respectively, before testing. Isosorbide dinitrate and nitroglycerin were not ad- ministered within 6 hours of hemodynamic testing. Left ventricular ejection fraction, cardiac index, stroke volume index and left ventricular end-diastolic volume index were determined with use of the single 2 inch (5.1 cm) crystal scintillation probe technique with background correction as described by Van Dyke and Steele and their co-workers.siJs The center of the left ventricular silhouette was fluoroscopi- tally determined and an initial 1 mCi dose of indium-113m was used for the left ventricular curve and 0.5 mCi for the background curve. The indium was injected into the superior vena cava through a catheter introduced percutaneously into either the external jugular vein or a brachial vein. The left ventricular ejection fraction was calculated as the ratio of the difference between the systolic and diastolic count rates divided by the diastolic count rate, with background counts subtracted from the systolic and diastolic values. Cardiac index was determined with use of the area under, and equili- bration value of, the left ventricular curve.:33 Stroke volume index was defined as cardiac index divided by heart rate, and left ventricular end-diastolic volume index as stroke volume index divided by left ventricular ejection fraction. Blood pressure was determined with a sphygmomanometer.

Ouabain: The control hemodynamic variables obtained at rest were measured during and after 15 minutes of supine rest in the eight patients in group 1 studied only at rest (Cases 1 to 8). In subsequent studies, four patients (Cases 2,4,9 and 10) additionally had repeat testing while performing 33 per-

TABLE II

Hemodynamic Data at Rest and After Handgrip Exercise in the Control State, After Ouabain and After 2 Weeks of Maintenance Digoxin in Four Patients With Coronary Artery Disease (Group 2)

Case no BP HR Cl EF SVI EDVI

2

Control, R

Control, H

Ouabain, R

Ouabain, H

Digoxin, R

Digoxin, H 4

Control, R

Control, H

Ouabain, R

Ouabain, H

Digoxin, R

Digoxin, H

9

Control, R

Control, H

Ouabain, R

Ouabain, H

Disoxin, R

Digoxin, H

IO

Control, R 130178 65 2.0 0.33 31 93 Control, H 144194 70 1.7 0.27 24 90 Ouabain, R 128176 JO 1 .8 0.34 26 76 Ouabain, H 144194 JO 1.7 0.47 24 52 Digoxin, R 118177 70 2.8 0.32 40 125 Digoxin, H 130184 75 7.6 0.53 35 65

10%/74 60 2.1 0.39 35 90 1301100 65 2.3 0.33 51 154 114178 55 1 .J 0.42 31 74

135/100 60 1.6 0.50 27 53

116184 60 1 .J 0.51 2% 56 122192 60 2.0 0.56 33 60

11 O/82 60 1 .8 0.37 30 81

1321106 80 2.0 0.35 25 71 118192 55 1.2 0.50 22 44 1461112 70 1.6 0.6% 23 34 110176 60 1.8 0.34 30 88 118190 80 1.6 0.3% 20 53

93160 112/80

90160 l2Ol80 106168 120180

ii 60 75 65 75

2.9 0.35 41 11% 2.4 0.36 30 83 2.2 0.46 37 80 2.3 0.54 31 57 2.5 0.35 38 110 3.2 0.54 43 79

H = after handgrip exercise; R = at rest. Other abbrewations as in

Table I.

172 August 1977 The American Journal of CARDIOLOGY Volume 40


TABLE III

Hemodynamic Measurements at Rest (average t standard error of the mean) in the Control State, After Ouabain and After 2 Weeks of Maintenance Digoxin in Eight Men With Coronary Artery Disease (Group I)

EF Cl WI EDVI HR BP

Control

Ouabain

Digoxin

0.39 t 0.027

0.55 + 0.034

P <O.Ol l

0.41 ? 0.047

NS

2.4 + 0.22

2.2 + 0.12

NS+ 2.5

i- 0.14 NS

33 86 75 ? 4.3 i 12 i 5.5

33 64 69 + 2.8 f 5.4 * 5.8

NS P <O.Ol P co.02 35 90 75

+ 3.3 f 11 + 4.4 NS NS NS

117182 + 4.614.1

123/80 ? 5.813.9

NSINS 115178

+ 4.113.7 NSINS

‘Compared with control values. tNot statistically significant. NS = not significant; P = probability; other abbreviations as in Table I

cent of maximal handgrip maneuver initiated 1 minute before testing. Handgrip exercise was performed by squeezing a sphygmomanometer bulb and was measured with the sphygmomanometer. Then 0.01 mg/kg of ouabain was ad- ministered intravenously over a period of 15 minutes under electrocardiographic monitoring. After an additional period of 15 minutes, all variables were redetermined at rest and after handgrip exercise for those so previously tested.

Digoxin: The patients were then given daily oral doses of 0.25 mg of digoxin. At the end of 2 weeks, a serum digoxin level was drawn approximately 5 hours after the daily digoxin dose and all hemodynamic variables were again measured during and after 15 minutes of supine rest, with repeat handgrip testing additionally for the four patients who had previously been so tested. Four of the eight patients in the first group (Cases 1, 2,4 and 8) were tested a second time at rest, after ouabain administration, and daily thereafter for 5 days while continuing to receive the daily dose of digoxin. Serum digoxin levels were assayed by the Kallestad Laboratories, Inc 1251- Digoxin Quantitopea technique.

Statistical change of the means of the hemodynamic variables was determined using Student’s paired t test.

TABLE IV

Hemodynamic Data (average * standard error of the mean) in Four Patients (Cases 2,4,9 and IO) Before and After Ouabain and After 2 Weeks of Maintenance Digoxin

Ejection Fraction

Cardiac Index (liters/

min per mZ)

Heart Rate

(beats/

Control Rest Handgrip

After Ouabain Rest

Handgrip

After digoxin Rest

Handgrip

0.36 k 0.01 2.2 ? 0.2 0.33 * 0.02 2.1 f 0.2

NS” NS

0.41 k 0.04

0.55YO.05 P <o.o5t

1.7 k 0.2 P co.02 1 .8 i 0.2 P co.05

0.38 ?- 0.04 NS

0.50 t 0.04 P co.05

2.2 ? 0.3 NS

2.4 + 0.4 NS

64 i 2 74 i 4

60 * 4

69 ? 3

64+2

73 i- 4

Blood Pressure (mm Hg)

110174 k 815 131195 + 716

113177 ? 817

136197 ? 617

113177 ? 313

122187 f 313

*Not statistically significant. +Compared with control value at rest

Results

Resting hemodynamics: Individual patient hemodynamic data in group 1 (Cases 1 to 8), who underwent resting measurements, and in group 2 (Cases 2,4,9 and lo), who underwent resting and posthandgrip measurements, are shown in Tables I and II, respectively. The mean values for the resting hemodynamic variables measured in the eight patients in group 1 are shown in Table III. The mean resting cardiac index of 2.4 liters/ min per m2 is consistent with mild congestive heart failure for the group as a whole. Left ventricular ejection fraction increased and heart rate and left ventricular end-diastolic volume index were significantly decreased from mean control values after administration of ouabain. The other measured variables did not change significantly. After 2 weeks of digoxin administration, all values were statistically unchanged from control levels. The mean serum digoxin level at this time was 1.0 f 0.2 ng/ml (average f standard error of the mean). Individual patient values for left ventricular ejection fraction, cardiac index and left ventricular end-diastolic volume index are shown in Figures 1 to 3.

In all four patients who underwent additional daily hemodynamic measuring (Cases 1, 2, 4 and 8), left ventricular ejection fraction returned to, or dropped below, control level on the first, second, fifth and third day, respectively, after digitalization (Fig. 4).

Posthandgrip hemodynamics: The mean resting and posthandgrip hemodynamic measurements in group 2 are shown in Table IV. In Patients 2 and 4 resting left ventricular ejection fraction was similar to that previously determined but blood pressure and cardiac index showed some variation. Resting left ventricular ejection fraction for all four patients increased, but not significantly, after ouabain administration. After 2 weeks, ejection fraction was again not significantly different from control levels. Resting cardiac index decreased significantly with short-term digitalization, but was unchanged from control levels after 2 weeks.

Handgrip exercise resulted in an overall mean increase in blood pressure from 112/76 f 4/3 to 130/93 f 3/3 mm Hg (P <O.Ol) and in heart rate from 63 f 2 to



.E

.7

.2 _ Control Following

Ouaboin F30Holo~kf

Digoxin

FIGURE 1. Left ventricular ejection fraction at rest before and after 0.01 mg/kg of ouabain intravenously, and after 2 weeks of daily oral administration of 0.25 mg of digoxin in eight patients with coronary artery disease (Cases 1 to 8, group 1).

FIGURE 2. Cardiac index (liters/min per m* at rest before and after 0.01 mg/kg of ouabain intravenously and after 2 weeks of daily oral administration of 0.25 mg digoxin in eight patients with coronary artery disease (Cases 1 to 8, group 1).

72 f 2 beats/min (P <0.05) for the control, postouabain and 2 week digoxin studies combined. Posthandgrip left ventricular ejection fraction decreased nonsignificantly before digitalis but was significantly higher than control level both after digitalization and after 2 weeks of maintenance digoxin therapy. Cardiac index dropped from control levels with handgrip exercise after digitalization and was nonsignificantly higher than control level after 2 weeks of maintenance therapy.

n : ” Control

FIGURE 3. Left ventricular end-diastolic volume index at rest before and after 0.01 mg/kg of ouabain intravenously and after 2 weeks of daily oral administration of 0.25 mg of digoxin in eight patients with coronary artery disease (Cases 1 to 8, group 1).

E .- t E .7 !_I_

0’ .6 .- t .% !A .5

4 z .4 .- L

$ .3

3 .2 0 1 2 3 4 5

Days

FIGURE 4. Left ventricular ejection fraction at rest before and after 0.01 mg/kg of ouabain intravenously and daily in four patients with coronary artery disease (Cases 1, 2, 4 and 8, group 1).

Discussion

Validity of single crystal scintillation probe method: Although not widely used, the single crystal scintillation probe method using background correction has been shown to have good correlation with standard techniques. Berndt et al.34 and Steele et a1.32 both found a correlation coefficient of 0.90 between left ventricular ejection fraction measured with angiography and the scintillation probe method in groups of 17 and 36 patients, respectively, with left ventricular ejection frac- tions ranging from 0.10 to 0.85 and 0.18 to 0.90, respectively. Berndt et al. 34 also found a 0.88 correlation coefficient between cardiac output measured with the dye-dilution or Fick method and scintillation probe method as well as the same good correlation between left ventricular end-diastolic volume index measured with angiography and scintillation probe method in patients without valve insufficiency.

Short-term digitalization with ouabain: This procedure resulted in a small decrease in heart rate and a statistically insignificant increase in blood pressure similar to that reported by Murphy et a1.3 The statistically insignificant short-term change in cardiac index


agrees with the findings of several investigators13JsJgp23 whose patient populations had various degrees of left ventricular dysfunction. 0thers21,22135 also found no improvement in cardiac output, although their studies were in the setting of acute myocardial infarction. In contrast, Ferrer et a1.g showed an increase in cardiac output in patients with class IV congestive failure, and Bloomfield et al.s demonstrated a similar effect although 4 of 10 patients in their study had atria1 fibrillation.

As previously reported from our institution24 and in contrast to the data of De Mots et al.ls mean left ventricular ejection fraction increased acutely by 41 percent. This increase was associated with a decreased left ventricular end-diastolic volume index and an unchanged stroke volume index. We believe that this represents, in part, a primary increase in cardiac contractility because afterload did not statistically change and left ventricular ejection fraction is largely insensi- tive to changes in preload. 36 Recent work37 has shown closer correlation of clinical congestive heart failure with contractility indexes of the ejection rather than of the isovolumic phase. Our findings support the previously reported evidence for an increase in contractility after acute digitalis administration as assessed with isovolumic phase indexes.il-l4

Although left ventricular end-diastolic pressure was not measured, there was a 26 percent decrease in left ventricular end-diastolic volume index, and a reduction in this variable is thought to correlate with a decrease in end-diastolic pressure. Such a decrease in end-diastolic volume index has been shown by others.3J8p22p23 A part of this decrease may represent peripheral pooling effects of digitalis.15J6

Long-term effects of digoxin: Resting hemodynamic variables returned to predigitalization levels by the end of 2 weeks despite initially significant changes in heart rate, left ventricular end-diastolic volume index and left ventricular ejection fraction. Only one of the eight patients (Case 1) had a persistent increase in left ventricular ejection fraction (0.73) after 2 weeks. On subsequent restudy 5 months after the initial digitalization he had a left ventricular ejection fraction of 0.44 compared with an initial value of 0.40 despite continued maintenance digitalis therapy. The small possibly significant transient decrease in cardiac index with


short-term digitalization is in accord with the findings of Rytand25 and Rodman et al 26 who demonstrated disappearance of the decrease ‘i’n cardiac output and venous pressure in 3 to 7 days in normal persons re- ceiving maintenance doses of digitalis. The mean serum digoxin level of 1.0 ng/ml for the group (range 0.4 to 1.8 ng/ml) suggests patient compliance with a regimen of 0.25 mg of digoxin daily.38

In contrast to the lack of sustained resting hemodynamic improvement, the increase in posthandgrip left ventricular ejection fraction was almost as great after 2 weeks of maintenance therapy as immediately after digitalization. The short-term improvement confirms the findings of Murphy et a1.,3 who found improved hemodynamics with exercise after digitalization. It is also in agreement with the long-term effects of digitalis in normal dogs reported by Mahler et a1.,30 who found a more significant change in left ventricular wall motion over time with an increased afterload. Also in agreement with the latter study is our finding of unchanged left ventricular volume after 2 weeks of digitalis.

Hoeschen and Cuddy28 and Carliner et a1.2s did find persistent systolic time interval changes at rest with long-term digitalis administration, although Davidson and Gibson27 did not. A possible explanation for such a persistent effect at rest is that systolic time interval measurements reflect changes in rate of rise of left ventricular pressure more than changes in volumetric indexes such as left ventricular ejection fraction. A persistent increase in the rate of change of left ventricular pressure was demonstrated by Carliner et a1.2g

In summary, our study suggests that short-term digitalis administration improves both resting and exercise volumetric indexes of contractility (left ventricular end-diastolic volume index, left ventricular ejection fraction) in patients with coronary artery disease, whereas only exercise volumetric indexes are improved with long-term administration. Resting volumetric hemodynamics return to predigitalization levels in a few days in patients with clinically mild congestive heart failure.

Acknowledgment

We express our appreciation to Mrs. Carol Vandello for expert secretarial assistance.

References

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