Heart rate and atherosclerotic plaque rupture: pathophysiological evidence and clinical perspectives






Jean-Claude TARDIF,1,2MD
Ekaterini A. KRITIKOU,1PhD
Catherine GEBHARD,1MD
1Montreal Heart Institute
Montreal, Quebec
CANADA
2Department of Medicine
Université de Montréal
Montreal, Quebec
CANADA

Heart rate and atherosclerotic plaque rupture: pathophysiological evidence and clinical perspectives


by C. Gebhard, E. A. Kritikou,
and J. C. Tardif,
Canada



Elevated heart rate seems to play a role in the development and progression of coronary atherosclerosis, and numerous studies have shown an association between increased heart rate and cardiovascular mortality. In line with this concept, recent clinical data show that selective heart rate reduction is beneficial for the secondary prevention of coronary events. The underlying explanations for these associations are still unclear. Furthermore, whether elevated heart rate is simply a compensatory response to existing cardiac pathology or has a direct causal role in the manifestation of cardiac events remains to be investigated. The mechanisms that may account for the pathophysiological effects of high heart rate on plaque morphology include endothelial dysfunction, vascular inflammation, as well as effects on vascular wall mechanics. Experimental data have highlighted the antiatherogenic potential of selective heart rate lowering and provide a strong rationale for its assessment in the clinical setting.

Medicographia. 2014;36:63-72 (see French abstract on page 72)



Many studies have shown that a high resting heart rate is a robust and independent risk marker for cardiovascular morbidity and mortality.1 However, although risk factors for atherosclerotic plaque growth are well understood, the risk factors for plaque vulnerability and rupture and subsequent clinical events remain unclear, and pathophysiological evidence is lacking. This is reflected by conflicting clinical data on the association between heart rate and acute coronary events.

Studies in different populations suggest that sustained elevation of heart rate is independently associated with an increased risk of acute coronary syndrome (ACS) or sudden cardiac death.2-11 A positive association between plaque disruption and an increased heart rate has also been demonstrated.12 Experimental data indicate that rupture of explanted human aortic plaques is increased with elevated heart rate,13 and that a high heart rate increases hemodynamic and mechanical vascular stress, which may play a critical role in the process of plaque destabilization.14 However, the mechanisms responsible for these effects are not well understood, and the balance between elevated heart rate as simply a compensatory response to existing cardiac pathology versus it playing a direct causal role in the manifestation of cardiac events remains in question. The aim of this review is to point out possible mechanisms that can account for the association between elevated heart rate and atherosclerotic plaque destabilization.


Figure 1
Figure 1. Adjusted hazard ratios of heart rate for sudden cardiac death in different studies and populations.

Only hazard ratios that have been adjusted for traditional cardiovascular risk factors are shown. Data are presented as hazard ratio and 95% confidence interval.
Abbreviations: bpm, beats per minute; CAD, coronary artery disease; NSTEMI, non-ST elevation myocardial infarction; RHR, resting heart rate.


Prognostic value of resting heart rate in acute cardiovascular events

Most epidemiological studies in this area have demonstrated an association between elevated heart rate and cardiovascular mortality, while the relationship between heart rate and acute coronary events or sudden cardiac death is less well understood. Several studies provide strong support for heart rate as an independent and strong risk predictor of sudden cardiac death in various populations (Figure 1),2-6 and it remains a risk predictor after adjustment for potential confounding variables.2-6,15 The prognostic value of heart rate in prediction of risk for nonfatal coronary events is less evident (Figure 2).3,4,7-11,16-21 High resting heart rate was shown to be an independent predictor of coronary events in postmenopausal women (n=129 135) after a mean follow-up period of 7.8 years.8 In addition, 2 recent studies demonstrated that ambulatory nighttime heart rate shows a strong association with acute coronary events in different populations, whereas day- time heart rate does not predict events (Figure 2).10,11 The differential effects of heart rate on cardiovascular outcomes may indicate that potential confounders, eg, increased sympathetic nervous system activity, play a greater role or have a higher prevalence in populations that experience plaque rupture compared with patients with stable atherosclerotic disease. However, differences may also have arisen in studies simply due to a lack of statistical power or because of the competitive risk phenomenon.





A subanalysis of the placebo arm of the prospective BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary artery disease [CAD] and left ventricULar dysfunction) showed that heart rates of ≥70 beats per minute (bpm) were associated with more admissions to hospital for myocardial infarction (MI) than heart rates of <70 bpm (46% increase, P=0.0066).9 Numerous other studies have shown that increasing heart rate is associated with increased risk for MI7,22,23 or left ventricular remodeling following MI.24 Clinical studies have shown that episodes of myocardial ischemia in patients with stable CAD are triggered by an increase in heart rate,25,26 and ischemic activity and heart rate have been demonstrated to show similar circadian variations.27 Results of a study by Heidland and colleagues point toward a possible mechanism accounting for the association between heart rate and adverse outcomes. They showed a positive association between plaque disruption and a mean heart rate above 80 bpm in patients who underwent 2 coronary angiograms within 6 months, indicating that hemodynamic forces might have a critical role in the process of plaque destabilization.12

Elevated heart rate—pathophysiology

♦ Causative factor or epiphenomenon?
One question that remains to be answered is the following: does a high heart rate signal a more “damaged” heart than a low heart rate? An elevated heart rate is often found to correlate with traditional cardiovascular risk factors such as hypertension, dyslipidemia, diabetes, and obesity.28 Not surprisingly, the correlation between cardiovascular disease (CVD) and high resting heart rate seems to be more pronounced in patients with these risk factors.28 Increased resting heart rate is also associated with poor exercise capacity, which is itself a strong predictor of mortality.29

Nonetheless, in most epidemiological studies, when adjustments were made for traditional risk factors, heart rate still independently predicted risk for cardiovascular mortality. However, this is not always the case for risk prediction of acute coronary events. Indeed, clinical confounders appear to attenuate the association between increased heart rate and MI.18 Thus, it seems likely that an elevated heart rate is causative in progression of atherosclerosis, but the relationship between heart rate and ACS or sudden cardiac death seems to be more difficult to explain. So, does heart rate mediate the deleterious effects of sympathetic hyperactivity? It is known that patients with ACS have impaired autonomic function with sympathetic hyperactivity,30 and that increased sympathetic nerve activity is associated with an adverse outcome following MI.31 This observation is supported by experimental studies in monkeys in which psychosocial stress induced endothelial injury and subsequent atherosclerotic lesion formation in coronary arteries.32 Sympathetic hyperactivity is detected not only in patients with MI, hypertension, or cerebrovascular disease, but also in patients with obesity, metabolic syndrome, and diabetes mellitus.33,34 Experimental studies have shown that stimulation of the sympathetic nervous system can cause myocardial apoptosis as well as sudden cardiac death.35 In summary, it is currently difficult to strictly separate the effects of sympathetic neuroendocrine regulation and elevated heart rate on acute cardiac events. Experimental studies with pure heart rate–lowering drugs will certainly help to establish whether fast heart rate is a marker or a mediator of sympathetic overactivity in the induction of risk.

♦ Heart rate and plaque progression
Clinical data have shown that heart rate is directly associated with progression of CVD.1 Increasing evidence indicates that shear stress might be the link between heart rate and atherosclerosis. A fast heart rate increases the magnitude and frequency of repetitive tensile stress on the arterial wall by increasing mean blood pressure.36 By shortening the diastolic phase of the cardiac cycle, the exposure of the endothelium to the low and oscillatory systolic shear stress is prolonged, while protective diastolic shear stress is reduced.37,38 In addition, high heart rate intensifies the pulsatile motion of the heart and, consequently, the frequency of intense phasic changes in torsion that also induce significant shear stress to the coronary vessels.39


Figure 2
Figure 2. Adjusted hazard ratios of heart rate for acute coronary events in different studies and populations.
Only hazard ratios that have been adjusted for traditional cardiovascular risk factors are included. Data are presented as hazard ratio and 95% confidence interval.

Abbreviations: bpm, beats per minute; CAD, coronary artery disease; CVI, cerebrovascular incident; HR, heart rate; MI, myocardial infarction; NSTEMI, non-ST elevation myocardial infarction; RHR, resting heart rate.



Shear stress has been shown to affect endothelial cell gene and protein expression profiles, to alter vascular smooth muscle cell proliferation, and to increase oxidative stress. Contributing mechanisms include induction of growth-promoting factors, matrix-degrading enzymes,40 cytokines,41 and adhesion and prothrombotic molecules and chemoattractants,42 as well as increased expression of proatherogenic genes (eg, endothelin-1).37,43 In turn, nitric oxide activity is reduced44 and uptake of oxidative enzymes (reduced nicotinamide adenine dinucleotide phosphate, xanthine oxidase) and low-density lipoprotein are increased (Figure 3).45,46 Indeed, it has been shown that an experimental increase in heart rate in rats significantly increases cardiac oxidative stress.47 The reverse was shown in apolipoprotein E knockout (apoE–/–) mice treated with the heart rate–lowering drug ivabradine.48

In humans, microinflammatory markers have been found to increase progressively with heart rate,49 and systemic inflammation and endothelial dysfunction have been shown to be associated with an increased heart rate in the elderly.50 Following shear stress, changes in endothelial submembranous cytoskeleton51 might result in higher endothelial permeability, facilitating migration of inflammatory cells and infiltration of inflammatory markers (Figure 3).52,53 Experimental studies have shown that heart rate reduction with ivabradine prevents or reverses endothelial dysfunction associated with dyslipidemia, and this was associated with >40% and >70% reductions in atherosclerotic plaque size.54,55 Accordingly, heart rate has been shown to be a strong predictor of microalbuminuria prevalence, a marker of generalized endothelial injury that correlates with end organ damage.56


Figure 3
Figure 3. Heart rate and vulnerable plaque development.

Schematic diagram of hypothetical effects of heart rate on plaque destabilization, involving mechanisms contributing to necrotic core enlargement (blue panels) and fibrous cap thinning (red panels). Elevated heart rate is thought to cause coronary endothelial dysfunction and inflammation of the vascular wall by lowering shear stress and increasing cyclical wall stresses. Dysfunctional endothelium is characterized by secretion of growth factors, cytokines, adhesion molecules, an increase in reactive oxygen species and depletion of nitric oxide due to decreased activity of endothelial nitric oxide synthase (eNOS). This promotes monocyte recruitment, platelet aggregation, migration of inflammatory cells and secretion of inflammatory molecules. eNOS is known to depress sympathetic activity, which in turn has been shown to induce apoptosis of vascular cells.
Abbreviations: EC, endothelial cell; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase; NO, nitric oxide; oxLDL, oxidized low-density lipoprotein; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; TF, tissue factor; TNF-α, tumor necrosis factor α; VCAM-1, vascular cell adhesion protein 1; VSMC, vascular smooth muscle cell.



In vascular smooth muscle cells, shear stress induces upregulation of extracellular matrix protein growth factors, matrix metalloproteinases, and osteogenic markers, resulting in the breakdown of elastin and an increased vascular rigidity (Figure 4).14 Two recent studies have shown that arterial stiffness is an independent predictor of cardiovascular events and mortality in healthy individuals and patients with CAD.57,58 Experimental studies in rats have shown that tachycardia promotes marked reductions in arterial compliance and distensibility in coronary and femoral arteries.59,60 Consistent with this finding, treatment with ivabradine improved aortic compliance in rats and apoE–/– mice.61 In vitro data indicate that stretching of human smooth muscle cells enhances the release of angiotensin II in a frequency-dependent manner, thereby stimulating production of collagen in the vascular wall.62 In hypertensive and normotensive humans, a heart rate of >80 bpm is associated with increased arterial rigidity of large peripheral arteries,63,64 and an elevated heart rate during sleep is significantly associated with increased arterial rigidity in patients with chronic kidney disease.65 Whether this effect also occurs in coronary arteries remains unclear; however, it seems reasonable that an increase in the number of stretch cycles experienced by large elastic arteries would accelerate deterioration of arterial wall components such as elastin fibers, leading to increased arterial stiffness (Figure 4).


Figure 4
Figure 4. Heart rate in cardiovascular pathophysiology.

Simplified diagramof the main mechanisms through which elevated heart rate promotes myocardial ischemia, plaque progression, plaque rupture, and sudden cardiac death.
Abbreviations: eNOS, endothelial nitric oxide synthase; LDL, low-density lipoprotein; MVO2, myocardial oxygen consumption; NO, nitric oxide; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cell.



♦ Heart rate and plaque rupture
Clinical data suggest that elevation of heart rate is associated with an increased risk of ACS and sudden cardiac death.2-4,8,9,15 This is supported by findings from an angiographic study in humans, as well as ex vivo data demonstrating that disruption of vascular plaques is augmented with increasing heart rates.12,13 A retrospective analysis in patients with obstructive CAD revealed that patients with heart rates of <50 bpm develop collateral vessels more often than patients with heart rates of >60 bpm.66 This notion was supported by experimental data in rats showing that pharmacological induction of bradycardia with alinidine enhanced vascularity and coronary reserve and preserved the function of surviving myocardium in the postinfarcted heart by upregulation of vascular endothelial growth factor (Figures 3 and 4).67

In the presence of a well-developed collateral system, the occlusion of an epicardial vessel results in reduced tissue necrosis during an MI and may thus result in lower mortality. In addition, elevated heart rates are associated with disproportionate decreases in the duration of diastole. As a consequence, coronary perfusion and myocardial oxygen supply are reduced, leading to induction or exacerbation of myocardial ischemia, which may result in or contribute to ACS. Finally, increasing the heart rate of patients with CAD by atrial pacing causes paradoxical coronary vasoconstriction, thereby further compromising coronary perfusion and myocardial performance (Figure 4).68 As discussed, there is evidence that heart rate is a stronger predictor of sudden cardiac death than of nonfatal coronary events. This could be explained by the fact that in experimental models of myocardial ischemia, an increase in baseline heart rate not only triggered ischemic episodes, but also lowered the threshold for both supraventricular and ventricular arrhythmias (Figure 4).69 In humans, high resting heart rate was independently associated with ventricular arrhythmia, the major cause of sudden cardiac death.70 Accordingly, in mice, ivabradine reduced lethal arrhythmias associated with dilated cardiomyopathy.71

The probability of plaque rupture depends on the stability of the fibrous cap covering the plaque shoulder, the size of the lipid core, as well as the mechanical stress imposed upon it (Figure 3).72 An increased heart rate could induce mechanical stress on the vessel wall, as the latter depends on the duration and frequency of cardiac cycles. Mechanical stresses affecting plaque morphology include circumferential wall stress, repetitive tensile stress, and low systolic shear stress, but also flexion and mechanical stresses induced by cardiac motion, which have been consistently linked to the development of vulnerable plaques73,74 and an increased risk of plaque disruption (Figure 3).75,76 In rupture-prone areas, cyclic bending (which increases with heart rate) has been identified by computational magnetic resonance imaging–based models as a relevant stressor that provokes plaque disruption.77 Modified endothelial shear stress and pulsatile wall stress profiles lead, via mechanoreceptors, to secretion of growth factors, cytokines, and adhesion molecules, and an increase in reactive oxygen species and depletion of endothelial nitric oxide synthase (eNOS).78-80 This promotes monocyte recruitment,81 platelet aggregation, migration of inflammatory cells, and secretion of inflammatory molecules, which may promote weakening of the fibrous cap (Figure 4). In addition, eNOS is known to depress sympathetic activity, likely by increasing parasympathetic tone,82 and eNOS depletion may therefore account for the sympathetic drive and the increase in norepinephrine observed with increasing heart rate (Figures 3 and 4).83

Clinical implications

♦ Clinical outcome benefits associated with heart rate reduction
A meta-analysis of randomized clinical trials strongly suggests that the beneficial effects of β-blockers and nondihydropyridine calcium antagonists are proportionally related to the reduction in resting heart rate.84 Pharmacological intervention with the If current inhibitor ivabradine85 exerted antianginal and anti-ischemic effects in patients with CAD or microvascular angina in randomized clinical trials, and appeared to significantly reduce coronary event rates in the subgroup of patients with a heart rate of ≥70 bpm in BEAUTIFUL.86-91 Ivabradine has no direct effects on the vascular system other than to reduce heart rate, and therefore opens up promising opportunities for the study of the effects of exclusive heart rate lowering on the progression of atherosclerosis as well as plaque rupture.

The 2012 European Society of Cardiology guidelines for heart failure treatment recommend ivabradine for patients in sinus rhythm with an ejection fraction of ≤35%, a heart rate remaining at ≥70 bpm, and persisting symptoms despite β-blocker treatment (class IIa recommendation) or in those with β-blocker intolerance (class IIb recommendation).92

♦ Risk assessment and optimal target heart rate
There seems to be a continuous increase in risk with heart rate values of >60 bpm. In most clinical trials, a heart rate of >70 bpm has been chosen to identify patients at risk.7,9,18 Nevertheless, cutoff values to have shown a prognostic value for cardiovascular outcomes have varied widely between trials and have ranged between 70 bpm9 and 83 bpm17 in CAD patients, with lowest mortality rates seen at between 50 bpm and 59 bpm.21 The frequency of ambulatory ischemic episodes in patients with CAD has been reported to be twice as high for patients with a mean heart rate of >80 bpm as those with a heart rate of <70 bpm.93 In summary, defining precisely when a heart rate should be considered “elevated” is challenging; however, prospective studies including BEAUTIFUL9 show convincing evidence that a heart rate of >70 bpm is deleterious in patients with stable CAD. This would imply that heart rates that are presently considered to be normal may well be detrimental to prognosis. Although American guidelines recommend aiming for a heart rate of between 55 bpm and 60 bpm for the prevention of angina, current guidelines give no recommendation as to a target heart rate for improvement of cardiovascular prognosis.94 Resting heart rate is included in prognostic models for ACS such as the Global Registry of Acute Coronary Events (GRACE) risk prediction score,95 the Cooper Clinic risk index for overall mortality,96 and the recent dynamic Thrombolysis in Myocardial Infarction (TIMI) risk score for ST-segment elevation myocardial infarction.97 By contrast, heart rate is not included in the European SCORE project (Systematic COronary Risk Evaluation)98 or the Copenhagen Risk Score.99

The predictive value of ambulatory heart rate is still being debated, since both an increased heart rate and reduced heart rate variability seem to be independently associated with increased mortality.100 Thus, it may be useful to assess heart rate using 24-hour Holter recordings. This is emphasized by the results of 2 recent studies that demonstrated that ambulatory nighttime heart rate as assessed by 24-hour recording added to the risk stratification for cardiovascular events.10,11 Measuring nighttime heart rate seems to be an attractive alternative to outpatient heart rate monitoring for assessing the risk of these devastating events. However, to assess the risk of all-cause and cardiovascular mortality, heart rate measured with a conventional electrocardiogram seems to carry similar predictive power to 24-hour mean heart rate obtained from Holter recordings.101 The 2012 European guidelines on CVD prevention in clinical practice recommend measuring resting heart rate after a 5-minute rest, which should form part of the routine outpatient physical examination when assessing cardiovascular risk.

Heart rate recovery 3 minutes after exercise was recently identified as an additional measure to predict cardiovascular mortality. Indeed, in a recent study, a heart rate recovery of <46 bpm identified patients at risk for all-cause mortality and differentiated nonsurvivors from survivors.102 Moreover, the heart rate profile during exercise and recovery seems to be a predictor of sudden death.2 Observational studies have demonstrated that heart rate measured during follow-up after MI provides more prognostic information than heart rate measured at baseline.103,104 Prospective evidence determining whether modulation of measurement settings can reduce or increase the prognostic value of heart rate in different patient populations is needed.

Conclusions and future directions

Taken together, the evidence shows that an elevated heart rate is positively associated with cardiovascular mortality, cardiovascular events, and sudden cardiac death. This association is strong and is independent of other risk factors for cardiovascular mortality and sudden cardiac death, while the association between heart rate and acute cardiovascular events could be dependent on other risk factors and measurement time points.

There is a complex interaction between various biomechanical and hemodynamic stresses mediating the effect of heart rate on plaque vulnerability and the risk of rupture. Coronary imaging techniques such as intravascular ultrasonography, virtual histology, computer-assisted quantitative coronary angiography analysis, and optical coherence tomography may help in understanding the complex interactions that are involved in heart rate–induced changes in the morphological appearance of atherosclerotic vulnerable plaques and luminal stenoses.105 These imaging modalities are being used in MODIfY (reducing elevated heart rate in patients with Multiple Organ Dysfunction Syndrome [MODS) by Ivabradine), which is evaluating the effects of ivabradine on coronary atherosclerosis.

It has been demonstrated that despite frequent use of βblockers, stable CAD patients often have a resting heart rate of >70 bpm, which has been shown to be associated with worse overall health status and more frequent angina and ischemia. 106 Thus, further heart rate lowering is possible in many patients with CAD. Whether selective heart rate lowering improves cardiovascular outcomes will be tested in the large scale SIGNIFY trial (Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease) in patients with CAD, no heart failure, and a resting heart rate of ≥70 bpm in sinus rhythm. Finally, the worldwide CLARIFY registry (ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) will help obtain data on long-term prognosis in outpatients with elevated heart rate and stable CAD.106

Acknowledgments. Dr Tardif holds the Canada Research Chair in translational and personalized medicine and the Universite de Montreal endowed research chair in atherosclerosis. In the interest of brevity, we have referenced other reviews whenever possible and apologize to the authors of the numerous original papers that were not explicitly cited.



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Keywords: acute coronary syndrome; heart rate; ivabradine; plaque rupture