The pivotal role of heart rate in cardiovascular disease
description
Transcript of The pivotal role of heart rate in cardiovascular disease
The pivotal role of heart rate The pivotal role of heart rate in cardiovascular diseasein cardiovascular disease
AtherosclerosisAtherosclerosis
Endothelial dysfunction↑Endothelial dysfunction↑
Oxidative stress↑Oxidative stress↑
Plaque stability↓Plaque stability↓
Arterial stiffness↑Arterial stiffness↑
IschemiaIschemia
Oxygen consumption↑Oxygen consumption↑
Duration of diastole↓Duration of diastole↓
Coronary perfusion↓Coronary perfusion↓
RemodelingRemodeling
Cardiac hypertrophy↑Cardiac hypertrophy↑
Chronic heart failureChronic heart failure
Oxygen demand↑Oxygen demand↑
Ventricular efficiency ↓Ventricular efficiency ↓
Ventricular relaxation↑Ventricular relaxation↑
Elevated heart rateElevated heart rate
+
+ +
+
The role of heart rate in cardiovascular diseaseThe role of heart rate in cardiovascular disease
Positive association with total and/or cardiovascular mortality Positive association with total and/or cardiovascular mortality
Association independent of other cardiovascular risk factors Association independent of other cardiovascular risk factors
Association valid in both genders, in the elderly, in differentAssociation valid in both genders, in the elderly, in different
ethnicities ethnicities
A strong predictor of mortality in patients with coronary artery A strong predictor of mortality in patients with coronary artery
disease disease
Relation to known pathophysiologic mechanisms ofRelation to known pathophysiologic mechanisms of
coronary artery diseasecoronary artery disease
Clinical outcome benefit associated with heart rate reductionClinical outcome benefit associated with heart rate reduction
The prognostic validity of resting heart rateThe prognostic validity of resting heart rate
Positive association with total and/or cardiovascular mortality Positive association with total and/or cardiovascular mortality
Association independent of other cardiovascular risk factors Association independent of other cardiovascular risk factors
Association valid in both genders, in the elderly, in differentAssociation valid in both genders, in the elderly, in different
ethnicities ethnicities
A strong predictor of mortality in patients with coronary artery A strong predictor of mortality in patients with coronary artery
disease disease
Relation to known pathophysiologic mechanisms ofRelation to known pathophysiologic mechanisms of
coronary artery diseasecoronary artery disease
Clinical outcome benefit associated with heart rate reductionClinical outcome benefit associated with heart rate reduction
The prognostic validity of resting heart rateThe prognostic validity of resting heart rate
The first evidence of the prognostic importanceThe first evidence of the prognostic importanceof heart rate: 1945of heart rate: 1945
Levy RL et al. JAMA. 129 (1945): 585-588.
Age (years)
Rat
e p
er 1
000
pers
on-y
ears
Transienttachycardia
––++
Transienthypertension
–+–+
0
10
20
30
40
50
60
70
25 30 35 40 45 50 55 60
Prognostic importance of resting heart rate:Prognostic importance of resting heart rate:epidemiological evidence epidemiological evidence (in general population and hypertensives)(in general population and hypertensives)
During 25 years - more than 155 000 patients, follow-up 8-36 years
Adapted from V. Aboyans et al., J Clin Epidemiol. 2006;59:547-558.
Study Population Follow-up Cardiovascular mortality RR
Chicago Gas Company ’80 1 233 M 15 y >94 vs. ≤60 bpm 2.3
Chicago Heart Ass.Project ’80 33 781 M&W 22 y ≥90 vs. <70 bpm M: 1.6 W: 1.1 (ns)
Framingham ’93 4 530 M&W HTN 36 y >100 vs. <60 bpm M: 1.5 W: 1.4 (ns)
British Regional Heart ’93 735 M 8 y >90 vs. ≤ 90 bpm IHD death 3.3
Spandau ’97 4 756 M&W 12 y Sudden death 5.2 per 20 bpm
Benetos ’99 19 386 M&W 18.2 y >100 vs. <60 bpm M: 2.2 W: 1.1 (ns)
Castel ’99 1 938 M&W 12 y 5th vs. 3rd quintile M: 1.6 W: 1.1
Cordis ’00 3 257 M 8 y ≥90 vs. <70 bpm 2.0
Reunanen ’00 10 717 M&W 23 y M: 1.4 (>84 vs. <60) W: 1.5 (>94 vs.<66)
Thomas ’01 60 343 M HTN 14 y >80 vs. ≤ 80 bpm <55y:1.5 >55y:1.3
Matiss ’01 2 533 M 9 y per 20 bpm: 1.5 ≥90 vs. <60 bpm: 2.7
Ohasama ’04 1 780 M&W 10 y M: 1.2 W: 1.1 (ns) per 5 bpm
Okamura ’04 8 800 M&W 16.5 y per 11 bpm (1 SD) M: 1.3 W: 1.2
Jouven ’05 5 713 M 23 y Sudden death from AMI 3.92 (>75 bpm)
The Paris Prospective Study I , general population, 5713 men; 23-year follow-up
Sudden death risk increases progressively withSudden death risk increases progressively withresting HR in the general populationresting HR in the general population
Jouven X, et al., N Engl J Med. 2005;352:1951-1958.
0.00.0
0.50.5
1.01.0
1.51.5
2.02.0
2.52.5
3.03.0
3.53.5
4.04.0
Rel
ativ
e ri
sk
Resting heart rate (bpm)
<60 60-64 65-69 70-75 >75
P<0.001
Prognostic dimension of resting heart rate and its changes
The Paris Prospective Study I , general population, n=5139; > 20-year follow-up
Jouven X, et al. Am J Cardiol. 2009;103:279-283
Tertiles of baseline HR:Tertiles of baseline HR:- low (64 bpm) - low (64 bpm) - medium (64 to 70 bpm)- medium (64 to 70 bpm)- high (70 bpm) - high (70 bpm)
Tertiles of HR change:Tertiles of HR change:- tertile 1 - decrease 4 bpm- tertile 1 - decrease 4 bpm- tertile 2 - 4- 3 bpm- tertile 2 - 4- 3 bpm- tertile 3 - increase 3 bpm- tertile 3 - increase 3 bpm
Relative risk of total mortality according to baseline HR and HR change after 5 years (after adjustment)
The Framingham Study, 2037 men with untreated hypertension, 36-year follow-up
All-cause mortality increases progressivelyAll-cause mortality increases progressivelywith resting heart rate in men with hypertension with resting heart rate in men with hypertension
Gillman MW, et al., Am Heart J. 1993;125:1148-1154.
00
1010
2020
3030
4040
5050
6060
<65<65 65-7465-74 75-8475-84 >84
CHD: 95% CI 1.20, 2.71CHD: 95% CI 1.20, 2.71
CVD: 95% CI 1.19, 2.37CVD: 95% CI 1.19, 2.37
All-cause: 95% CI 1.68, 2.83All-cause: 95% CI 1.68, 2.83
Age
-adj
uste
d 2-
year
dea
th r
ate
per
1000
Age
-adj
uste
d 2-
year
dea
th r
ate
per
1000
Resting heart rate (bpm)Resting heart rate (bpm)
Positive association with total and/or cardiovascular mortality Positive association with total and/or cardiovascular mortality
Association independent of other cardiovascular risk factorsAssociation independent of other cardiovascular risk factors
Association valid in both genders, in the elderly, in differentAssociation valid in both genders, in the elderly, in different
ethnicities ethnicities
A strong predictor of mortality in patients with coronary artery A strong predictor of mortality in patients with coronary artery
disease disease
Relation to known pathophysiologic mechanisms ofRelation to known pathophysiologic mechanisms of
coronary artery diseasecoronary artery disease
Clinical outcome benefit associated with heart rate reductionClinical outcome benefit associated with heart rate reduction
The prognostic validity of resting heart rateThe prognostic validity of resting heart rate
French cohort study, n=19 386 (12 123 men, 7263 women), 18-year follow-up
Benetos A, et al., Hypertension.1999;33:44-52.
Men: all-cause mortality Women: all-cause mortality
Resting heart rate independently predicts totalResting heart rate independently predicts totaland CV mortality in men and womenand CV mortality in men and women
1.00
0.95
0.90
0.85
0.80
0.75
0.70
Survival probability
Follow-up (years)
1 3 5 7 9 11 13 15 17 19 21
P (Cox)=0.0001
1.00
0.95
0.90
0.85
0.80
0.75
0.70
Survival probability
Follow-up (years)
1 3 5 7 9 11 13 15 17 19 21
P (Cox)=0.0001
HR<60 60≤HR≤80 80<HR≤100 HR>100 bpm
Resting heart rate as an independent Resting heart rate as an independent predictor of coronary events in womenpredictor of coronary events in women
129 135 postmenopausal women, a mean of 7.8 years of follow-up
Hsia J et al. BMJ. 2009;338:b219Hsia J et al. BMJ. 2009;338:b219
Resting heart rate as an independent predictor of coronary events (myocardial infarction or coronary death) in multivariable analisys
Hazard ratio (95% CI) P value
Resting heart rate, bpm 0.001
< 62 (reference) 1.00
63 – 66 1.02 (0.89 to 1.17))
67-70 1.08 (0.95 to 1.23)
71-76 1.02 (0.89 to 1.16)
> 76 1.26 (1.11 to 1.42)
Cohort study in 1407 men aged from 65 to 70 years, follow-up 18 years
Resting heart rate:Resting heart rate:predicts survival in people aged >65 yearspredicts survival in people aged >65 years
Benetos A et al., J Am Geriatr Soc. 2003;51:284-285.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2<60 60-80 >80
Resting heart rate (bpm)Resting heart rate (bpm)
Resting heart rate independently predictsResting heart rate independently predictsmortality in Western and Asian populationsmortality in Western and Asian populations
Okamura T et al., Am Heart J. 2004;147:1024-1032. Benetos A et al., Hypertension.1999;33:44-52.
HR<60 60≤HR≤80 80<HR≤100 HR>100 bpm
Survival probability curves for CVmortality in French men (n=12 123)
7 10 15 21Follow-up (years)
1.00
0.95
0.85
0.80
1 17 1913131353
0.90
P (Cox)=0.0001
Survival probability
Cumulative survival rates due to cardiacevents in Japanese men (n=3856)
Q1
Q2Q3
Q4
<60 bpm
60-65 bpm66-73 bpm
78 bpm
1.00
0.99
0.98
0.97
Cum
ula
tive
sur
viva
l rat
e
0 5 10 15 20Person-years
1.00
0.99
0.98
0.97
0
Positive association with total and/or cardiovascular mortality Positive association with total and/or cardiovascular mortality
Association independent of other cardiovascular risk factors Association independent of other cardiovascular risk factors
Association valid in both genders, in the elderly, in differentAssociation valid in both genders, in the elderly, in different
ethnicities ethnicities
A strong predictor of mortality in patients with coronary artery A strong predictor of mortality in patients with coronary artery
disease disease
Relation to known pathophysiologic mechanisms ofRelation to known pathophysiologic mechanisms of
coronary artery diseasecoronary artery disease
Clinical outcome benefit associated with heart rate reductionClinical outcome benefit associated with heart rate reduction
The prognostic validity of resting heart rateThe prognostic validity of resting heart rate
1807 patients within 24 h of onset of symptoms of acute myocardial infarction
Mortality versus admission heart rate Mortality versus admission heart rate with acute myocardial infarction with acute myocardial infarction
Hjalmarson A, et al., Am J Cardiol.1990;65:547-553.
0
10
20
30
40
50
Mor
talit
y (%
)
<50 50-59 60-69 70-79 80-89 90-99 100-109 110-119 120
Total
In-hospital
Post-discharge
Resting heart rate (bpm)Resting heart rate (bpm)
Heart rate at admission and in-hospital mortality in MI survivors
Zuanetti G, et al. Eur Heart J. 1999;1 (suppl. H):H52-H57.
GISSI-3 study, 6-month follow-up; ECG
Heart rate (bpm)
n=2364 n=5305 n=2785 n=713
10.1
6.3
3.53.3
In-h
ospi
tal m
orta
lity
(%)
0
2
4
6
8
10
12
<60 60-80 81-100 >100
Heart rate at discharge and 6-month mortalityin MI survivors
Zuanetti G, et al. Eur Heart J. 1999;1 (suppl. H):H52-H57.
20.2
9.3
3.91.9
Heart rate (bpm)
n=4038 n=5600 n=1278 n=114<60 60-80 81-100 >100
6-m
onth
mor
talit
y (%
)
0
5
10
15
20
25
GISSI-3 study, 6-month follow-up; ECG
A high resting heart rate as an independentA high resting heart rate as an independentpredictor of mortality in CAD patientspredictor of mortality in CAD patients
The Coronary Artery Surgery Study (CASS) registry; 24 913 CAD patients; 14.1-year follow-up
Diaz A, et al. Eur Heart J. 2005;26:867-874.
Years after enrolmentYears after enrolment
Adjusted survival curves foroverall mortality
Adjusted survival curvesfor cardiovascular mortality
Cum
ula
tive
sur
viva
l
P<0.0001
0 5 10 15 20
0.5
0.6
0.7
0.8
0.9
1.0
P<0.0001
0 5 10 15 20
0.5
0.6
0.7
0.8
0.9
1.0
≤62 63-70 71-76 77-82 ≥83 bpm
Kolloch et al., Eur Heart J. 2008;29:1327-34.
INVEST study, 22 192 CAD patients; 2.7-year follow-up
Impact of heart rate in patients with Impact of heart rate in patients with hypertension and coronary artery diseasehypertension and coronary artery disease
50
20
10
40
30
0
60
0
3.5
4.0
4.5
3.0
2.5
2.0
1.5
1.0
0.5
Outcome (all-cause death, nonfatal MI, or nonfatal stroke)
Hazard ratio
Mean follow-up heart rate (bpm)
≤ 50
> 50
to ≤
55
> 55
to <
60
> 60
to ≤
65
> 65
to ≤
70
> 80
to ≤
85
> 85
to ≤
90
> 70
to ≤
75
> 75
to ≤
80
> 90
to ≤
95
> 95
to ≤
100
> 10
0
Adv
erse
ou
tcom
e
inci
denc
e (%
)E
stima
ted hazard
ratio
Resting heart rate as a predictor of prognosisResting heart rate as a predictor of prognosis in patients with stable CAD in patients with stable CAD
JE. Ho et al. Presented at ACC 2009JE. Ho et al. Presented at ACC 2009
Post hoc analysis in 9580 patients from the TNT study, median follow-up was 4.9 years
JE. Ho et al. Presented at ACC 2009
Heart rate as a predictor ofHeart rate as a predictor ofcardiovascular deathcardiovascular death
% with cardiovascular death
Heart rate < 70 bpm
Heart rate ≥ 70 bpmP = 0.0041
Hazard ratio = 1.34 (1.10 – 1.63)
Years0 0.5 1 1.5 2
0
5
10
15
Fox K, et al. Lancet. 2008;372:817-821
Prospective data from the BEAUTIFUL placebo arm; 5438 patients with stable CAD and LVSD
Heart rate as a predictor ofHeart rate as a predictor ofhospitalization for heart failurehospitalization for heart failure
% with hospitalization for heart failure
0
5
10
15
Years0 0.5 1 1.5 2
P < 0.0001
Hazard ratio = 1.53 (1.25 – 1.88)
Heart rate < 70 bpm
Heart rate ≥ 70 bpm
Fox K, et al. Lancet. 2008;372:817-821
Prospective data from the BEAUTIFUL placebo arm; 5438 patients with stable CAD and LVSD
Heart rate as a predictor of Heart rate as a predictor of hospitalization for myocardial infarctionhospitalization for myocardial infarction
P = 0.0066
Hazard ratio = 1.46 (1.11 – 1.91)
Years
0 0.5 1 1.5 2
0
Heart rate < 70 bpm
Heart rate ≥ 70 bpm
8
% with hospitalization for fatal and nonfatal MI
0
4
6
2
Fox K, et al. Lancet. 2008;372:817-821
Prospective data from the BEAUTIFUL placebo arm; 5438 patients with stable CAD and LVSD
Positive association with total and/or cardiovascular mortality Positive association with total and/or cardiovascular mortality
Association independent of other cardiovascular risk factors Association independent of other cardiovascular risk factors
Association valid in both genders, in the elderly, in differentAssociation valid in both genders, in the elderly, in different
ethnicities ethnicities
A strong predictor of mortality in patients with coronary artery A strong predictor of mortality in patients with coronary artery
disease disease
Relation to known pathophysiologic mechanisms ofRelation to known pathophysiologic mechanisms of
coronary artery diseasecoronary artery disease
Clinical outcome benefit associated with heart rate reductionClinical outcome benefit associated with heart rate reduction
The prognostic validity of resting heart rateThe prognostic validity of resting heart rate
Elevated Heart RateElevated Heart RateElevated Heart RateElevated Heart Rate
IschemiaIschemia Major CV eventsMajor CV events
Increased OIncreased O22 demand demand
Decreased supplyDecreased supplyIncreased OIncreased O22 demand demand
Decreased supplyDecreased supplyProgression of Progression of atherosclerosisatherosclerosisProgression of Progression of atherosclerosisatherosclerosis
PlaquePlaquerupturerupturePlaquePlaquerupturerupture
Short termShort term Long termLong term
AtherosclerosisAtherosclerosis
Vascular damageVascular damageVascular damageVascular damage
Role of elevated HR in the pathophysiology of CADRole of elevated HR in the pathophysiology of CAD
HR as a trigger of ischemia in stable angina patientsHR as a trigger of ischemia in stable angina patients
Kop W et al. J Am Coll Cardiol. 2001;38:742.
STdepressionSTdepression
100100
9595
9090
8585
8080
7575
7070
60 20 10 4 260 20 10 4 2 2 10 20 602 10 20 60EventEvent
Time (min)Time (min)
**
********
****
**** ****
100100
9595
9090
8585
8080
7575
7070
60 20 10 4 260 20 10 4 2 2 10 20 602 10 20 60EventEvent
**
********
****
**** ****
Angina Angina
100100
9595
9090
8585
8080
7575
7070
656560 20 10 4 260 20 10 4 2 2 10 20 602 10 20 60EventEvent
**
********
****
**** ****
Hea
rt r
ate
, b
pm
n=19 men with stable CAD; 48-AECGn=19 men with stable CAD; 48-AECG
* P <0.05** P <0.01
Heart rate as a major determinant of ischemiaHeart rate as a major determinant of ischemia
Andrews TC et al. Circulation.1993;88:90-100.
00
44
88
1212
1616
2020
Likelihood of ischemia, %Likelihood of ischemia, %
<60<60 60-6960-69 70-79 80-89 70-79 80-89 >89>89
Heart rate at rest, bpmHeart rate at rest, bpm
x2x2
n=50 stable CAD patients; 48-AECG
Heart rate as predictor of ischemic episodes: Heart rate as predictor of ischemic episodes: multivariate analysismultivariate analysis
Multivariate analysis of variables predictive of an ischemic episode Multivariate analysis of variables predictive of an ischemic episode after a period of HR increaseafter a period of HR increase
n=50 stable CAD patients; 48-AECG
Magnitude of heart rate increaseMagnitude of heart rate increase -0.56-0.56 0.00010.0001
Baseline heart rateBaseline heart rate -0.45-0.45 0.00010.0001
Duration of heart rate increaseDuration of heart rate increase -0.04-0.04 0.050.05
Standardized estimateStandardized estimate PP
Andrews TC et al. Circulation.1993;88:90-100.
n=50 stable CAD patients; 48-AECG
HR as a predictor of coronary eventsHR as a predictor of coronary events
Aronov W. S et al. Am J Cardiol. 1996;78:1175-1176.
New
co
ron
ary
eve
nts
, %
N
ew c
oro
nar
y ev
en
ts,
%
<60<60 61-7061-70 71-8071-80 81-9081-90 91-10091-100 >100>10000
1010
2020
3030
4040
5050
6060
7070
Mean heart rateMean heart rate
n=1311 older CHD patients; 48-month follow-up; 24-h AECGn=1311 older CHD patients; 48-month follow-up; 24-h AECG
P<0.0001
5 bpm of HR = 1.14 incidence of coronary events5 bpm of HR = 1.14 incidence of coronary events
Perski A, et al. Am Heart J. 1988;116:1369-1373.
Heart rate and coronary atherosclerosisHeart rate and coronary atherosclerosis
Minimum heart rate (bpm)
Cor
onar
y a
t her
oscl
eros
is s
core
(%
)
50
0
4
1
2
3
40 60 70 80 90
r= 0.70P<0.002
16 MI survivors, 6-month follow-up; 2 coronary angiographies; 24-hour ECG
Heart rate and coronary plaque ruptureHeart rate and coronary plaque rupture
Multivariate analysis of association with coronary plaque disruption
Left ventricular mass >270 g 4.92 (1.83-13.25) 0.02
Mean heart rate >80 bpm 3.19 (1.15-8.85) 0.02
-Blocker use 0.32 (0.13-0.88) 0.02
Wall thickness IVS 1.68 (0.57-9.91) 0.06
Fractional pulse pressure 1.81 (0.67-4.90) 0.07
Statins 0.42 (0.16-1.22) 0.06
OR (95% CI) P
ACE inhibitors 0.51 (0.19-1.34) 0.06
106 patients with 2 coronary angiographies; 6-month follow-up; 24-h EGG
Heidland UE, Strauer BE. Circulation. 2001;104:1477-1482.
Variation of coronary flow and shear stressVariation of coronary flow and shear stressduring the cardiac cycleduring the cardiac cycle
10 mm Hg DIASTOLEDIASTOLE120 mm Hg
Adapted from Giannoglou G et al. Int J Cardiol. 2008;126:302-312
SYSTOLESYSTOLE
No flow No flow (even (even retrograde subendocardialretrograde subendocardial flow)flow)
No flow No flow (even (even retrograde subendocardialretrograde subendocardial flow)flow)
Coronary arterial flow Coronary arterial flow (myocardial perfusion)(myocardial perfusion)
Coronary arterial flow Coronary arterial flow (myocardial perfusion)(myocardial perfusion)
Increased shear stressIncreased shear stressIncreased shear stressIncreased shear stressLow and oscillatory shear stressLow and oscillatory shear stressLow and oscillatory shear stressLow and oscillatory shear stress
Coronary arteries are prone to atherosclerosisCoronary arteries are prone to atherosclerosis
Heart rate and atherosclerosis: potential mechanisms
Adapted from Giannoglou G et al. Int J Cardiol. 2008;126:302-312
AtherosclerosisAtherosclerosis
Endothelial damageEndothelial damageEndothelial damageEndothelial damage
Elevated heart rateElevated heart rate
Shift of endothelial cells to Shift of endothelial cells to an atherosclerotic an atherosclerotic
phenotypephenotype
Shift of endothelial cells to Shift of endothelial cells to an atherosclerotic an atherosclerotic
phenotypephenotype
Plaque rupturePlaque rupture
Mechanical arterial Mechanical arterial wall stresswall stress
Shortening of Shortening of diastolic perioddiastolic period
Wall damageWall damageWall damageWall damage
Shortening of coronary Shortening of coronary perfusion timeperfusion time
Shortening of coronary Shortening of coronary perfusion timeperfusion time
Long-term consequences of a low shear stress for the Long-term consequences of a low shear stress for the coronary arterial wallcoronary arterial wall
Atherosclerotic plaque formation/progression and vascular remodelingAtherosclerotic plaque formation/progression and vascular remodelingAtherosclerotic plaque formation/progression and vascular remodelingAtherosclerotic plaque formation/progression and vascular remodeling
Adapted from Chatzizisis YS et al. Adapted from Chatzizisis YS et al. J Am Coll Cardiol.J Am Coll Cardiol. 2007;49:2379–2393 2007;49:2379–2393
ROSROS LDL uptake andLDL uptake andsynthesissynthesis
VCAM-1, ICAM-1VCAM-1, ICAM-1E-selectinE-selectin
TNF– TNF– IL-1, IFN-IL-1, IFN-
Growth Growth promoterspromoters
Growth Growth inhibitors,inhibitors,
eg, TGF-eg, TGF-, NO, NO
Apoptosis and Apoptosis and proliferationproliferation
ROSROS
NONO
eNOSeNOS
Impaired NO-Impaired NO-dependent dependent
atheroprotectionatheroprotection
ThrombogenicityThrombogenicity
oxLDLoxLDL Matrix degradationMatrix degradation InflammationInflammation AngiogenesisAngiogenesis Matrix Matrix synthesissynthesis
NAPDHNAPDHoxidaseoxidase
Low shear stressLow shear stress
Inner curvature:
low ESS region (artherosclerosis-prone)
Early fibroatheroma
Constricitve remodeling
Stenotic plaque
Stable angina
Compensatory expansive remodeling
Quiescent plaque
AsymptomaticAcute coronary
syndrome
Erosion
Microruptures
Rup
ture
Excessive expansive remodeling
Thin cap fibroatheroma
• Local factors, eg, low ESSLocal factors, eg, low ESS
• Systemic factors, eg, hyperlipidemiaSystemic factors, eg, hyperlipidemia
• Genetic factorsGenetic factorsLow ESS
Physiologic ESS
Limited inflammation High ESS
Lower ESS
Vulnerability
Intense inflammmation
Fibroproliferation
Natural history of coronary atherosclerosisNatural history of coronary atherosclerosis
Adapted from Chatzizisis YS et al. Adapted from Chatzizisis YS et al. J Am Coll Cardiol.J Am Coll Cardiol. 2007;49:2379-93) 2007;49:2379-93)
Increases the mechanical load on the arterial wallIncreases the mechanical load on the arterial wall
Induces structural and functional changes of the endothelialInduces structural and functional changes of the endothelial
cells making intima more permeable to circulating LDL andcells making intima more permeable to circulating LDL and
inflammatory cellsinflammatory cells
Promotes the weakening of the fibrous cap, leading to plaquePromotes the weakening of the fibrous cap, leading to plaque
disruption and the onset of acute coronary syndrome disruption and the onset of acute coronary syndrome
Putative mechanisms underlyingPutative mechanisms underlyingpro-atherosclerotic effect of increasing heart ratepro-atherosclerotic effect of increasing heart rate
Positive association with total and/or cardiovascular mortality Positive association with total and/or cardiovascular mortality
Association independent of other cardiovascular risk factors Association independent of other cardiovascular risk factors
Association valid in both genders, in the elderly, in differentAssociation valid in both genders, in the elderly, in different
ethnicities ethnicities
A strong predictor of mortality in patients with coronary artery A strong predictor of mortality in patients with coronary artery
disease disease
Relation to known pathophysiologic mechanisms ofRelation to known pathophysiologic mechanisms of
coronary artery diseasecoronary artery disease
Clinical outcome benefit associated with heart rate reductionClinical outcome benefit associated with heart rate reduction
The prognostic validity of resting heart rateThe prognostic validity of resting heart rate
Heart rate reduction with Ivabradine prevents endothelial Heart rate reduction with Ivabradine prevents endothelial dysfunction associated with dyslipidemia in micedysfunction associated with dyslipidemia in mice
Drouin et al. Br J Pharmacol. 2008;154:749-757
Metoprolol does not prevent cerebral endothelial dysfunction associated with dyslipidemiaMetoprolol does not prevent cerebral endothelial dysfunction associated with dyslipidemia
CC DD
AA BB
Reduction in atherogenesis with ivabradineReduction in atherogenesis with ivabradine
Böhm M et al. Circulation. 2008;117:2377-2387
Ascending aorta *P<0.05
Apolipoprotein E–deficient mouse model
Aortic sinus
IvabradineVehicle
40
30
20
10
0
Pla
que
are
a[%
to
tal]
*
30
20
10
0
Pla
que
are
a[%
tota
l]
Vehicle Ivabradine
40%
70%
Ivabradine reduces fatal and nonfatal Ivabradine reduces fatal and nonfatal myocardial infarction (HR ≥70 bpm)myocardial infarction (HR ≥70 bpm)
Ho
spit
aliz
atio
n f
or
fata
l o
r n
on
fata
l M
I %
Placebo(HR >70 bpm)
Ivabradine Ivabradine
P = 0.001
Hazard ratio = 0.64 (0.49 – 0.84)
years
0 0.5 1 1.5 2
0
4
8
RRR 36%
RRR: relative risk reduction
Fox K, et al. Lancet. 2008;372:807-816
years
0 0.5 1 1.5 2
0
4
Ivabradine Ivabradine
8
Co
ron
ary
reva
scu
l ari
zati
on
% P = 0.016
Hazard ratio = 0.70 (0.52 – 0.93)
RRR 30%
Fox K, et al. Lancet. 2008;372:807-816
Placebo
Ivabradine reduces the need for Ivabradine reduces the need for revascularization (HR ≥70 bpm)revascularization (HR ≥70 bpm)
RRR: relative risk reduction
0.1140.11431%31%0.690.69Fatal MIFatal MI
0.0230.02322%22%0.780.78Fatal and nonfatal MI or unstable anginaFatal and nonfatal MI or unstable angina
0.0160.01630%30%0.700.70Coronary revascularizationCoronary revascularization
0.0090.00923%23%0.770.77Fatal and nonfatal MI, unstable anginaFatal and nonfatal MI, unstable anginaor revascularizationor revascularization
0.0010.00136%36%0.640.64Fatal and nonfatal MIFatal and nonfatal MI
P valueP valueRiskRiskreductionreduction
HazardHazardratioratio
Predefined end pointPredefined end point
Ivabradine reduces coronary risk inIvabradine reduces coronary risk instable coronary patients with HR ≥ 70 bpmstable coronary patients with HR ≥ 70 bpm
Fox K, et al. Lancet. 2008;372:807-816
years
Ho
spit
aliz
atio
n f
or
fata
l o
r n
on
fata
l M
I %
Fox K, et al. Lancet. 2008;372:807-816
Placebo(HR >70 bpm)
Ivabradine(HR baseline > 70 bpm)
Ivabradine(HR baseline > 70 bpm)
P = 0.001
Hazard ratio = 0.64 (0.49 – 0.84)
0 0.5 1 1.5 2
0
4
8
RRR 36%Placebo
(HR <70 bpm)
Ivabradine shifts the patients Ivabradine shifts the patients from high risk to low riskfrom high risk to low risk
RRR: relative risk reduction
ConclusionsConclusions
Heart rate is a risk factor for cardiovascular mortality, independent of major conventional risk factors
Heart rate should be used to assess cardiovascular risk and to guide medical therapy of patients with coronary disease
BEAUTIFUL data suggest benefit from heart rate reduction with Ivabradine in patients with coronary artery disease and heart rate above 70 bpm