The pivotal role of heart rate
in cardiovascular disease
The role of heart rate in cardiovascular disease
Elevated heart rate
+
+
Atherosclerosis
Endothelial dysfunction↑
Oxidative stress↑
Plaque stability↓
Arterial stiffness↑
+
Chronic heart failure
Oxygen demand↑
Ventricular efficiency ↓
Ventricular relaxation↑
+
Ischemia
Remodeling
Oxygen consumption↑
Cardiac hypertrophy↑
Duration of diastole↓
Coronary perfusion↓
The prognostic validity of resting heart rate
 Positive association with total and/or cardiovascular mortality
 Association independent of other cardiovascular risk factors
 Association valid in both genders, in the elderly, in different
ethnicities
 A strong predictor of mortality in patients with coronary artery
disease
 Relation to known pathophysiologic mechanisms of
coronary artery disease
 Clinical outcome benefit associated with heart rate reduction
The prognostic validity of resting heart rate
 Positive association with total and/or cardiovascular mortality
 Association independent of other cardiovascular risk factors
 Association valid in both genders, in the elderly, in different
ethnicities
 A strong predictor of mortality in patients with coronary artery
disease
 Relation to known pathophysiologic mechanisms of
coronary artery disease
 Clinical outcome benefit associated with heart rate reduction
The first evidence of the prognostic importance
of heart rate: 1945
70
Transient
Transient
tachycardia hypertension
–
–
–
+
+
–
+
+
Rate per 1000 person-years
60
50
40
30
20
10
0
25
Levy RL et al. JAMA. 129 (1945): 585-588.
30
35
40
45
Age (years)
50
55
60
Prognostic importance of resting heart rate:
epidemiological evidence (in general population and hypertensives)
Study
Population
Follow-up
Cardiovascular mortality RR
Chicago Gas Company ’80
Chicago Heart Ass.Project ’80
Framingham ’93
British Regional Heart ’93
Spandau ’97
Benetos ’99
Castel ’99
Cordis ’00
Reunanen ’00
Thomas ’01
Matiss ’01
Ohasama ’04
Okamura ’04
Jouven ’05
1 233 M
15 y
>94 vs. ≤60 bpm
2.3
33 781 M&W
22 y
≥90 vs. <70 bpm
M: 1.6 W: 1.1 (ns)
4 530 M&W HTN
36 y
>100 vs. <60 bpm
M: 1.5 W: 1.4 (ns)
735 M
8y
>90 vs. ≤ 90 bpm
IHD death 3.3
4 756 M&W
12 y
Sudden death
5.2 per 20 bpm
19 386 M&W
18.2 y
>100 vs. <60 bpm
M: 2.2 W: 1.1 (ns)
1 938 M&W
12 y
5th vs. 3rd quintile
M: 1.6 W: 1.1
3 257 M
8y
≥90 vs. <70 bpm
2.0
10 717 M&W
23 y
M: 1.4 (>84 vs. <60)
W: 1.5 (>94 vs.<66)
60 343 M HTN
14 y
>80 vs. ≤ 80 bpm
<55y:1.5 >55y:1.3
2 533 M
9y
per 20 bpm: 1.5
≥90 vs. <60 bpm: 2.7
1 780 M&W
10 y
M: 1.2 W: 1.1 (ns) per 5 bpm
8 800 M&W
16.5 y
per 11 bpm (1 SD) M: 1.3 W: 1.2
5 713 M
23 y
Sudden death from AMI
3.92 (>75 bpm)
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.
Sudden death risk increases progressively with
resting HR in the general population
The Paris Prospective Study I , general population, 5713 men; 23-year follow-up
4.0
P<0.001
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
<60
60-64
65-69
70-75
Resting heart rate (bpm)
Jouven X, et al., N Engl J Med. 2005;352:1951-1958.
>75
Prognostic dimension of resting heart rate
and its changes
The Paris Prospective Study I , general population, n=5139; > 20-year follow-up
Relative risk of total mortality according to baseline HR and HR change after 5 years (after adjustment)
Tertiles of baseline HR:
- low (64 bpm)
- medium (64 to 70 bpm)
- high (70 bpm)
Tertiles of HR change:
- tertile 1 - decrease 4 bpm
- tertile 2 - 4- 3 bpm
- tertile 3 - increase 3 bpm
Jouven X, et al. Am J Cardiol. 2009;103:279-283
All-cause mortality increases progressively
with resting heart rate in men with hypertension
Age-adjusted 2-year death rate per 1000
The Framingham Study, 2037 men with untreated hypertension, 36-year follow-up
60
CHD: 95% CI 1.20, 2.71
50
CVD: 95% CI 1.19, 2.37
All-cause: 95% CI 1.68, 2.83
40
30
20
10
0
<65
65-74
75-84
Resting heart rate (bpm)
Gillman MW, et al., Am Heart J. 1993;125:1148-1154.
>84
The prognostic validity of resting heart rate
 Positive association with total and/or cardiovascular mortality
 Association independent of other cardiovascular risk factors
 Association valid in both genders, in the elderly, in different
ethnicities
 A strong predictor of mortality in patients with coronary artery
disease
 Relation to known pathophysiologic mechanisms of
coronary artery disease
 Clinical outcome benefit associated with heart rate reduction
Resting heart rate independently predicts total
and CV mortality in men and women
French cohort study, n=19 386 (12 123 men, 7263 women), 18-year follow-up
Men: all-cause mortality
Survival probability
Women: all-cause mortality
Survival probability
1.00
1.00
0.95
0.95
0.90
0.90
0.85
0.85
0.80
0.80
0.75
0.75
P (Cox)=0.0001
0.70
1
3
5
7
9
P (Cox)=0.0001
0.70
11 13 15 17 19 21
1
3
Follow-up (years)
HR<60
Benetos A, et al., Hypertension.1999;33:44-52.
5
7
9
11 13 15 17 19 21
Follow-up (years)
60≤HR≤80
80<HR≤100
HR>100 bpm
Resting heart rate as an independent
predictor of coronary events in women
129 135 postmenopausal women, a mean of 7.8 years of follow-up
Resting heart rate as an independent predictor of coronary events (myocardial infarction or
coronary death) in multivariable analisys
Hazard ratio (95% CI)
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)
Hsia J et al. BMJ. 2009;338:b219
P value
Resting heart rate:
predicts survival in people aged >65 years
Cohort study in 1407 men aged from 65 to 70 years, follow-up 18 years
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
60-80
<60
Resting heart rate (bpm)
Benetos A et al., J Am Geriatr Soc. 2003;51:284-285.
>80
Resting heart rate independently predicts
mortality in Western and Asian populations
Survival probability curves for CV
mortality in French men (n=12 123)
Cumulative survival rates due to cardiac
events in Japanese men (n=3856)
Survival probability
Cumulative survival rate
1.00
1.00
Q1 <60 bpm
Q2 60-65 bpm
Q3 66-73 bpm
0.99
0.95
0.90
0.98
Q4 78 bpm
0.85
P (Cox)=0.0001
0.97
0.80
0
5
10
Person-years
HR<60
15
20
60≤HR≤80
Okamura T et al., Am Heart J. 2004;147:1024-1032.
1
3
80<HR≤100
5
7 13 10 13 15 17 19 21
Follow-up (years)
HR>100 bpm
Benetos A et al., Hypertension.1999;33:44-52.
The prognostic validity of resting heart rate
 Positive association with total and/or cardiovascular mortality
 Association independent of other cardiovascular risk factors
 Association valid in both genders, in the elderly, in different
ethnicities
 A strong predictor of mortality in patients with coronary artery
disease
 Relation to known pathophysiologic mechanisms of
coronary artery disease
 Clinical outcome benefit associated with heart rate reduction
Mortality versus admission heart rate
with acute myocardial infarction
1807 patients within 24 h of onset of symptoms of acute myocardial infarction
50
Mortality (%)
40
Total
In-hospital
Post-discharge
30
20
10
0
<50
50-59
60-69 70-79 80-89
90-99 100-109 110-119 120
Resting heart rate (bpm)
Hjalmarson A, et al., Am J Cardiol.1990;65:547-553.
Heart rate at admission and in-hospital mortality in MI
survivors
GISSI-3 study, 6-month follow-up; ECG
12
In-hospital mortality (%)
10.1
10
8
6.3
6
4
3.3
3.5
<60
60-80
81-100
>100
n=2364
n=5305
n=2785
n=713
2
0
Heart rate (bpm)
Zuanetti G, et al. Eur Heart J. 1999;1 (suppl. H):H52-H57.
Heart rate at discharge and 6-month mortality
in MI survivors
GISSI-3 study, 6-month follow-up; ECG
25
6-month mortality (%)
20.2
20
15
9.3
10
5
3.9
1.9
0
<60
60-80
81-100
>100
n=4038
n=5600
n=1278
n=114
Heart rate (bpm)
Zuanetti G, et al. Eur Heart J. 1999;1 (suppl. H):H52-H57.
A high resting heart rate as an independent
predictor of mortality in CAD patients
The Coronary Artery Surgery Study (CASS) registry; 24 913 CAD patients; 14.1-year follow-up
Cumulative survival
Adjusted survival curves for
overall mortality
Adjusted survival curves
for cardiovascular mortality
1.0
1.0
0.9
0.9
0.8
0.8
P<0.0001
P<0.0001
0.7
0.7
0.6
0.6
0.5
0.5
0
5
10
15
20
0
5
10
15
20
Years after enrolment
Diaz A, et al. Eur Heart J. 2005;26:867-874.
≤62
63-70
71-76
77-82
≥83 bpm
Impact of heart rate in patients with
hypertension and coronary artery disease
INVEST study, 22 192 CAD patients; 2.7-year follow-up
Outcome (all-cause death, nonfatal MI, or nonfatal stroke)
50
Hazard ratio
4.5
4.0
3.5
40
3.0
2.5
30
2.0
20
1.5
10
1.0
0.5
0
0
Mean follow-up heart rate (bpm)
Kolloch et al., Eur Heart J. 2008;29:1327-34.
Estimated hazard ratio
Adverse outcome incidence (%)
60
Resting heart rate as a predictor of prognosis
in patients with stable CAD
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
JE. Ho et al. Presented at ACC 2009
Heart rate as a predictor of
cardiovascular death
Prospective data from the BEAUTIFUL placebo arm; 5438 patients with stable CAD and LVSD
% with cardiovascular death
15
Hazard ratio = 1.34 (1.10 – 1.63)
P = 0.0041
Heart rate ≥ 70 bpm
10
5
Heart rate < 70 bpm
0
0
Fox K, et al. Lancet. 2008;372:817-821
0.5
1
Years
1.5
2
Heart rate as a predictor of
hospitalization for heart failure
Prospective data from the BEAUTIFUL placebo arm; 5438 patients with stable CAD and LVSD
% with hospitalization for heart failure
15
Hazard ratio = 1.53 (1.25 – 1.88)
P < 0.0001
Heart rate ≥ 70 bpm
10
5
Heart rate < 70 bpm
0
0
Fox K, et al. Lancet. 2008;372:817-821
0.5
1
Years
1.5
2
Heart rate as a predictor of
hospitalization for myocardial infarction
Prospective data from the BEAUTIFUL placebo arm; 5438 patients with stable CAD and LVSD
% with hospitalization for fatal and nonfatal MI
8
Hazard ratio = 1.46 (1.11 – 1.91)
P = 0.0066
Heart rate ≥ 70 bpm
6
4
Heart rate < 70 bpm
2
0
0
0.5
1
Years
Fox K, et al. Lancet. 2008;372:817-821
1.5
2
The prognostic validity of resting heart rate
 Positive association with total and/or cardiovascular mortality
 Association independent of other cardiovascular risk factors
 Association valid in both genders, in the elderly, in different
ethnicities
 A strong predictor of mortality in patients with coronary artery
disease
 Relation to known pathophysiologic mechanisms of
coronary artery disease
 Clinical outcome benefit associated with heart rate reduction
Role of elevated HR in the pathophysiology of CAD
Elevated Heart Rate
Vascular damage
Atherosclerosis
Increased O2 demand
Decreased supply
Progression of
atherosclerosis
Ischemia
Major CV events
Short term
Long term
Plaque
rupture
HR as a trigger of ischemia in stable angina patients
n=19 men with stable CAD; 48-AECG
100
**
Heart rate, bpm
95
* P <0.05
** P <0.01
**
90
*
**
80
75
*
**
85
*
Angina
STdepression
70
65
60
20
10
4
2 Event
2
Time (min)
Kop W et al. J Am Coll Cardiol. 2001;38:742.
10
20
60
Heart rate as a major determinant of ischemia
n=50 stable CAD patients; 48-AECG
Likelihood of ischemia, %
20
x2
16
12
8
4
0
<60
60-69
70-79
80-89
Heart rate at rest, bpm
Andrews TC et al. Circulation.1993;88:90-100.
>89
Heart rate as predictor of ischemic episodes:
multivariate analysis
n=50 stable CAD patients;
n=5048-AECG
stable
CAD patients; 48-AECG
Multivariate analysis of variables predictive of an ischemic episode
after a period of HR increase
Standardized estimate
P
Magnitude of heart rate increase
-0.56
0.0001
Baseline heart rate
-0.45
0.0001
Duration of heart rate increase
-0.04
0.05
Andrews TC et al. Circulation.1993;88:90-100.
HR as a predictor of coronary events
n=1311 older CHD patients; 48-month follow-up; 24-h AECG
5 bpm of HR = 1.14 incidence of coronary events
New coronary events, %
70
60
P<0.0001
50
40
30
20
10
0
<60
61-70
Aronov W. S et al. Am J Cardiol. 1996;78:1175-1176.
71-80
81-90
Mean heart rate
91-100
>100
Heart rate and coronary atherosclerosis
16 MI survivors, 6-month follow-up; 2 coronary angiographies; 24-hour ECG
4
3
2
1
r= 0.70
P<0.002
0
40
50
60
70
Minimum heart rate (bpm)
Perski A, et al. Am Heart J. 1988;116:1369-1373.
80
90
Heart rate and coronary plaque rupture
106 patients with 2 coronary angiographies; 6-month follow-up; 24-h EGG
Multivariate analysis of association with coronary
plaque disruption
OR (95% CI)
P
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
ACE inhibitors
0.51 (0.19-1.34)
0.06
Statins
0.42 (0.16-1.22)
0.06
Heidland UE, Strauer BE. Circulation. 2001;104:1477-1482.
Variation of coronary flow and shear stress
during the cardiac cycle
SYSTOLE
120 mm Hg
10 mm Hg
DIASTOLE
No flow
Coronary arterial flow
(even retrograde subendocardial flow)
(myocardial perfusion)
Low and oscillatory shear stress
Increased shear stress
Coronary arteries are prone to atherosclerosis
Adapted from Giannoglou G et al. Int J Cardiol. 2008;126:302-312
Heart rate and atherosclerosis: potential mechanisms
Elevated heart rate
Mechanical arterial
wall stress
Shortening of
diastolic period
Endothelial damage
Shortening of coronary perfusion
time
Wall damage
Shift of endothelial cells to an
atherosclerotic phenotype
Atherosclerosis
Plaque rupture
Adapted from Giannoglou G et al. Int J Cardiol. 2008;126:302-312
Long-term consequences of a low shear stress for the
coronary arterial wall
Low shear stress
Impaired NOdependent
atheroprotection
ROS
Apoptosis and
proliferation
NO
eNOS
NAPDH
oxidase
ROS
oxLDL
LDL uptake and
synthesis
Matrix degradation
VCAM-1, ICAM-1
E-selectin
TNF– 
IL-1, IFN-
Inflammation
Growth
promoters
Thrombogenicity
Growth inhibitors,
eg, TGF-, NO
Angiogenesis
Matrix synthesis
Atherosclerotic plaque formation/progression and vascular remodeling
Adapted from Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379–2393
Natural history of coronary atherosclerosis
Inner curvature:
low ESS region (artherosclerosis-prone)
Low ESS
•
Local factors, eg, low ESS
•
Systemic factors, eg, hyperlipidemia
•
Genetic factors
Early fibroatheroma
Fibroproliferation
Microruptures
Physiologic ESS
Lower ESS
Vulnerability
Limited inflammation
High ESS
Compensatory expansive remodeling
Constricitve remodeling
Quiescent plaque
Stenotic plaque
Intense inflammmation
Excessive expansive remodeling
Thin cap fibroatheroma
Rupture
Asymptomatic
Acute coronary
Stable angina
Adapted from Chatzizisis YS et al. J Am Coll Cardiol. 2007;49:2379-93)
syndrome
Putative mechanisms underlying
pro-atherosclerotic effect of increasing heart rate
 Increases the mechanical load on the arterial wall
 Induces structural and functional changes of the endothelial
cells making intima more permeable to circulating LDL and
inflammatory cells
 Promotes the weakening of the fibrous cap, leading to plaque
disruption and the onset of acute coronary syndrome
The prognostic validity of resting heart rate
 Positive association with total and/or cardiovascular mortality
 Association independent of other cardiovascular risk factors
 Association valid in both genders, in the elderly, in different
ethnicities
 A strong predictor of mortality in patients with coronary artery
disease
 Relation to known pathophysiologic mechanisms of
coronary artery disease
 Clinical outcome benefit associated with heart rate reduction
Heart rate reduction with Ivabradine prevents endothelial
Metoprolol does not prevent cerebral endothelial
dysfunction
associated
with dyslipidemia in mice
Procoralan prevents endothelial dysfunction
dysfunction associated with dyslipidemia
associated with dyslipidemia in mice
DL
Dyslipidemia
#
DL + IVA
DL+Procoralan
0.001
0.001 0.01
0.01
‡
*
0.1
0.1
11
10
10
ACh
ACh (M)
(M)
100
60
60
90
RENAL
CEREBRAL
CEREBRAL
50
50
WTtype
WT
Wild
Wild
type
*#
50
50
80
DL
Dyslipidemia
DL
80
Dyslipidemia
70
DL
DL+Procoralan
40
40
DL++IVA
MP
DL+
Metoprolol
60
30
30
50
20
40
20
30
10
10
20
00
10
0.0001
0.001
0.0001
0.0010.01
0.01 0.1
0.1
0
0.001
0.001 0.01
0.01
E
: ‡ P < 0.05 vs. to WT; # P < 0.05 vs. to DL
Emax
max: ‡ P < 0.05 vs. to WT; # P < 0.05 vs. to DL
CEREBRAL
†
‡
11
ACh
ACh (M)
(M)
0.1
1
WTtype
Wild
Dilation
Dilation
(% of
of maximal
maximal dilation)
dilation)
(%
80
80
70
70
60
60
50
50
40
40
30
30
20
20
10
10
00
WT type
Wild
Dilation
100
100
90
90
Dilation
Dilation
Dilation
(%
of
maximal
dilation)
(%
of
maximal
dilation)
(% of
of maximal
maximal dilation)
dilation)
(%
Dilation
Dilation
(% of
of maximal
maximal dilation)
dilation)
(%
RENAL
RENAL
10
10
10
10
pD
0.05
vs.
pD22:: ** P
P <<ACh
0.05(M)
vs. WT
WT and
and DL
DL
ACh
(M)
40
40
30
30
DL
Dyslipidemia
DLMetoprolol
+ MP
DL+
†
20
20
10
10
00
0.0001 0.001
0.0010.01
0.01 0.1
0.1
11
ACh
ACh (M)
(M)
EEmax
: † P < 0.05 vs. to WT; * P < 0.05 vs. to DL
max: † P < 0.05 vs. to WT; * P < 0.05 vs. to DL
Drouin et al. Br J Pharmacol. 2008;154:749-757.
Metoprolol does not prevent cerebral endothelial dysfunction associated with dyslipidemia
Drouin et al. BrJ Pharmacol. 2008;154:749-757.
Drouin et al. Br J Pharmacol. 2008;154:749-757
10
10
Reduction in atherogenesis with ivabradine
Apolipoprotein E–deficient mouse model
Aortic sinus
40
B
*
Plaque area
[% total]
A
 40%
30

20
10
0
*P<0.05
Ascending aorta
30
D
Plaque area
[%total]
C
 70%
20

10
0
Vehicle
Ivabradine
Böhm M et al. Circulation. 2008;117:2377-2387
Vehicle
Ivabradine
Ivabradine reduces fatal and nonfatal
myocardial infarction (HR ≥70 bpm)
Hospitalization for
fatal or nonfatal MI %
8
Hazard ratio = 0.64 (0.49 – 0.84)
Placebo
P = 0.001
(HR >70 bpm)
RRR 36%
4
Ivabradine
0
0
0.5
1
1.5
2
years
RRR: relative risk reduction
Fox K, et al. Lancet. 2008;372:807-816
Ivabradine reduces the need for
revascularization (HR ≥70 bpm)
8
Hazard ratio = 0.70 (0.52 – 0.93)
P = 0.016
Placebo
RRR 30%
4
Ivabradine
0
0
0.5
1
1.5
2
years
RRR: relative risk reduction
Fox K, et al. Lancet. 2008;372:807-816
Ivabradine reduces coronary risk in
stable coronary patients with HR ≥ 70 bpm
Predefined end point
Hazard
Risk
P value
ratio
reduction
Fatal MI
0.69
31%
0.114
Fatal and nonfatal MI
0.64
36%
0.001
Fatal and nonfatal MI or unstable angina
0.78
22%
0.023
Fatal and nonfatal MI, unstable angina
or revascularization
0.77
23%
0.009
Coronary revascularization
0.70
30%
0.016
Fox K, et al. Lancet. 2008;372:807-816
Ivabradine shifts the patients
from high risk to low risk
Hospitalization for
fatal or nonfatal MI %
8
Hazard ratio = 0.64 (0.49 – 0.84)
Placebo
P = 0.001
(HR >70 bpm)
RRR 36%
Placebo
(HR <70 bpm)
4
Ivabradine
(HR baseline > 70 bpm)
0
0
0.5
1
1.5
2
years
RRR: relative risk reduction
Fox K, et al. Lancet. 2008;372:807-816
Conclusions
 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