Heart rate: from risk marker to risk factor in coronary artery disease




Jeffrey S. BORER, MD
Division of Cardiovascular Medicine, Cardiovascular Translational Research Institute
Howard Gilman Institute for Heart Valve Disease – State University of New York
New York, NY USA

Heart rate:
from risk marker to risk factor
in coronary artery disease

by J . S. Borer, USA

Several clinical/biological “markers” can aid in detection of patients likely to develop clinical evidence of coronary artery disease and its major sequelae. Thesemay also help guide efforts directed at prevention of cardiovascular events. Heart rate is a well-known risk marker in patients with coronary artery disease, and it is an important component in the generation of ischemia in such patients. Experimental data and clinical observations support a role for heart rate in the pathophysiology of atherosclerosis and plaque rupture. A growing body of evidence points to high resting heart rate as being more than simply a risk marker, but in fact, a risk factor, for adverse outcomes in various populations including those with coronary disease, as heart rate reduction now seems to beneficially alter certain outcomes. The relationship between resting heart rate and cardiovascular mortality is strong, graded, and independent of other factors such as blood pressure and physical activity. The results of the recent BEAUTIFUL (morBidity-mortality EvAl- UaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) study underline the importance of heart rate reduction in managing stable coronary disease. Prospective analysis of data from the placebo arm of this study demonstrated that a resting heart rate of ≥70 bpm is a strong independent predictor of clinical outcome. Consistent with these data, ivabradine significantly improved coronary outcomes in patients with a heart rate of ≥70 bpm. Thus, emerging data suggest that heart rate has joined the list of risk factors for coronary artery disease, importantly altering management strategies for affected patients. Heart rate has already appeared in European guidelines for the prevention of cardiovascular events, and should seriously be considered in future guidance documents for patients with coronary artery disease.

Medicographia. 2009;31:349-355 (see French abstract on page 355)

Coronary artery disease (CAD) is a highly prevalent condition and has potentially life-threatening consequences. It affects a large proportion of the general population over the age of 60 years, and according to the Framingham Heart Study,1 the lifetime risk of developing CAD in individuals aged 40 years is 48% in men and 31% in women. CAD thus represents an important public health problem that is both costly for society and responsible for relatively high mortality and morbidity levels in affected patients. Therefore, there is a clear medical need for guidance on efforts directed at preventing disease progression and associated clinical sequelae. Much of our current understanding of risk markers that identify those like- ly to develop clinically evident disease comes from observational studies and randomized trials; additionally, such investigations have further defined those risk markers that can be modified to achieve clinical benefit—so-called “risk factors.”2,3 The major risk factors for CAD and the first to be identified, aside from sex and age, were total cholesterol, systolic and diastolic blood pressures, smoking, and diabetes. Other less predictive risk factors include obesity, physical inactivity, and a family history of CAD (particularly in young individuals). Among the more recently recognized markers of CAD risk are resting heart rate and the metabolic syndrome. It is the aim of this article to present and assess the accumulating evidence in support of the evolution of heart rate—an easily measured clinical parameter—from risk marker, to risk factor in CAD mortality and morbidity.

Table
Table. Epidemiological studies on the relationship between heart rate and cardiovascular mortality in the general and hypertensive populations.

Abbreviations: AMI, acute myocardial infarction; bpm, beats per minute; HTN, hypertension; IHD, ischemic heart disease; M, men; NS, nonsignificant; SD, standard deviation; W, women. After reference 9: Aboyans V, Criqui MH. J Clin Epidemiol. 2006;59:547-558. Copyright © 2006, Elsevier Inc.

Difference between risk marker and risk factor

Risk markers and risk factors are both identified from correlations between the presence of the factor and subsequent development of the disease. A risk marker can be considered a risk factor if intervention to modulate this factor also results in a parallel modulation of risk—provided that the analysis demonstrating the risk modulation also accounts for possible confounding factors. For example, systemic arterial hypertension is well established as a risk factor for CAD and its sequelae, and also for stroke,4 not only because it identifies patients at risk for cardiovascular events, but because many studies with many different agents have demonstrated that in hypertensive individuals, risk is reduced when blood pressure is reduced.5-8 The demonstration of the benefits of blood pressure reduction with many different agents is important: some antihypertensives, including the angiotensinconverting enzyme inhibitors ramipril and perindopril, reduce events through pharmacological effects that appear to be in addition to the benefits of the antihypertensive action itself.5,6 Several criteria have been developed in order to allow one to validate a risk marker as a risk factor, and these are detailed later in this article.

Resting heart rate and prognosis in the general population

Several epidemiological studies support the predictive value of resting heart rate regarding total and cardiovascular mortality (Table).9 The Chicago Peoples Gas Company Study (including 1233 men followed for 15 years), the Chicago Western Electric Company Study (including 1899 men followed for 17 years), and the Chicago Heart Association Detection Project (including 5784 men followed for 5 years), reported together in 1980, were among the earliest studies to demonstrate the prognostic importance of resting heart rate for allcause mortality in large populations.8 Indeed, multivariate analysis using age, blood pressure, total blood cholesterol, smoking, and body weight as covariates, found heart rate to be an independent predictor both of sudden cardiac death and of noncardiovascular mortality in 2 out of the 3 cohorts studied. A 30-year follow-up of the Framingham study, reported in 1987, demonstrated a significant relationship between heart rate, cardiovascular mortality, coronary heart dis- ease, and sudden coronary death in both men and women.10 Paralleling these findings, a study of 19 386 “white collar” employees in France followed over a period of 20 years found that resting heart rate was a significant predictor of noncardiovascular mortality in both men and women.11 In men, the risk of cardiovascular death was lowest among those with a heart rate of <60 beats per minute (bpm); in comparison with this group, the relative risks among men with a resting heart rate of 60-80 bpm, 81-100 bpm, and >100 bpm were 1.35, 1.44, and 2.18, respectively (all statistically significant). Cardiovascular deaths were primarily and predominantly due to coronary events, and not to cerebrovascular accidents. In men, the predictive value of heart rate was independent of age, hypertension, total cholesterol, body mass index, smoking status, and exercise activity. In women, heart rate did not influence cardiovascular mortality.

Parallel results were reported from the MATISS Project (Malattie cArdiovascolari aTerosclerotiche, Istituto Superiore di Sanità), which included 2533 men aged 40 to 69 years. With 24 457 subject-years of follow-up, heart rate was found to independently predict total mortality, cardiovascular mortality, and noncardiovascular mortality.12 In another French cohort study that included 5713 asymptomatic apparently healthy working men aged between 42 and 53 years at study entry, a 23-year follow-up demonstrated a significant association between resting heart rate and both sudden and myocardial infarction–related death.13 The study found that compared with a resting heart rate of <60 bpm, a resting heart rate of >75 bpm defined a relative risk of 3.92 for sudden death. A recently published study undertaken in a French population of 5139 healthy men found that resting heart rate and the change in resting heart rate over 5 years were both predictors of death, independent of the conventional risk factors.14 After adjustments were made for confounding factors including baseline heart rate at rest, and results were compared with subjects with an unchanged heart rate, those whose heart rate decreased during the 5 years had a 14% lower mortality risk (P=0.05), whereas men whose heart rate increased over the 5 years had a 19% higher mortality risk (P<0.012).

Resting heart rate and prognosis in patients with coronary artery disease

Hjalmarson et al15 demonstrated that in patients with acute myocardial infarction (AMI), inhospital mortality and post-discharge mortality increased with increasing heart rate on admission. Total mortality was 15% for patients whose heart rate on admission ranged between 50 and 60 bpm, 41% for those with a heart rate of >90 bpm, and 48% for a heart rate of >110 bpm. Mortality after hospital discharge up to 1 year was also related to the maximal heart rate observed in the coronary care unit and heart rate at discharge. The prognostic significance of heart rate was also assessed in 8915 patients with AMI in GISSI-2 (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico–2), who were treated with fibrinolytic therapy.16 Increased heart rate on admission was associated with a progressive increase in hospital mortality (from 7.1% for a heart rate of <60 bpm to 23.4% for a heart rate >100 bpm). In addition, a progressive increase in 6- month mortality was noted with increasing heart rate at discharge (from 0.8% for a heart rate <60 bpm to 14.3% for a heart rate >100 bpm).Tardif and colleagues17 investigated 24 913 men and women with suspected or proven CAD who were followed for an average of 14.1 years, and found that resting heart rate was an independent risk marker for total and cardiovascular mortality. The prognostic value of heart rate persisted when analysis was adjusted for hypertension, diabetes, and smoking status, as well as for left ventricular ejection fraction and the number of diseased coronary vessels. Patients with a heart rate ≥83 bpm also had a significantly higher risk of hospital admission for cardiovascular causes than those with a heart rate ≤62 bpm (Figure 1).

Figure 1
Figure 1. The risk of death progressively increases with increasing heart rate.
Data are from the Coronary Artery Surgery Study, including 24 913 men and women with suspected or proven coronary artery disease, with 14.7 years of follow-up. Based on data from reference 17. Bpm, beats per minute.

In the INternational VErapamil SR/trandolapril STudy (INVEST), the relationship between resting heart rate at baseline and follow-up and adverse outcomes (all-cause death, nonfatal myocardial infarction, and nonfatal stroke) was evaluated in 22192 patients with hypertension and CAD treated either with verapamil or with atenolol. Resting heart rate was found to be directly associated with adverse events, and heart rate on receiving treatment was even more predictive than baseline heart rate,18 consistent with the concept that heart rate is a risk factor.

The BEAUTIFUL (morBidity mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) investigators have added substan- tially to current knowledge concerning the prognostic value of heart rate. They carried out a prospective analysis of data from the placebo arm of BEAUTIFUL (comprising a relatively large, well-treated population [n=5438] with stable CAD and left ventricular dysfunction) to assess the association between heart rate and clinical outcome.19 The results showed that compared with a heart rate of 60 to 69 bpm, resting heart rate _70 bpm is a significant predictor of adverse outcome (including mortality and major CAD morbidity) in patients with stable CAD and left ventricular dysfunction. This held true even after results were adjusted for all variables that differed between the two groups at baseline, including â-blocker intake and other background therapy. Compared with those whose heart rate was <70 bpm, those with a heart rate of _70 bpm were 34% more likely to die from cardiovascular causes (hazard ratio [HR], 1.34; 95% confidence interval [CI] 1.10-1.36; P=0.0041), 53% more likely to be hospitalized for new or worsening heart failure (HR, 1.53; 95% CI, 1.25-1.88; P<0.0001), 46% more likely to suffer fatal and nonfatal myocardial infarction (HR, 1.46; 95% CI, 1.11-1.91; P=0.0066) and 38% more likely to undergo coronary revascularization (HR, 1.38; 95% CI, 1.02-1.86; P=0.037) (Figure 2). The BEAUTIFUL placebo data were also analyzed regarding the effect of incremental increases in resting heart rate on cardiovascular outcomes. In fact, for all outcomes, the risk increased with heart rate values >65 bpm. For ischemia-related outcomes (fatal and nonfatal myocardial infarction, revascularization, etc.), risk tended to plateau as heart rate exceeded 70 bpm. By contrast, for heart failure, events continued to increase as heart rate rose. In another analysis in which baseline heart rate was treated as a continuous variable, there were substantial increases in risk with every 5-bpm heart rate incremental increase, and these were highly significant for both hospitalization for heart failure (16%; HR, 1.16; 95% CI, 1.11-1.21; P<0.0001) and cardiovascular death (8%; HR, 1.08; 95% CI, 1.03-1.12; P=0.0005). Though less striking, each 5- bpm increase in heart rate was also associated with an 8% increase in the likelihood of coronary revascularization (HR, 1.08; 95% CI, 1.01-1.16; P=0.034) and a 7% increase in fatal and nonfatal myocardial infarction (HR, 1.07; 95% CI, 1.00- 1.14; P=0.052).

BEAUTIFUL provides the first prospective assessment of the association between resting heart rate and cardiovascular outcomes in patients with stable CAD. The results lend credence to the results of previous studies in the general population and in normotensive and hypertensive CAD patients.9,17,18 This study is also the first clear demonstration that a relatively high resting heart rate places patients at risk for coronary events, even if they are apparently well treated (including with â-blockade) according to current guidelines. Indeed, the majority of subjects in BEAUTIFUL received concomitant â-blocker therapy—87% of patients in the placebo arm received â- blockers, which is a considerably higher percentage than that observed in population surveys in patients with stable CAD. Thus, the results from the placebo arm of BEAUTIFUL underline the potential value of addressing—and reducing— a resting heart rate of _70 bpm in patients with stable CAD.

Figure 2
Figure 2. Elevated heart rate (≥70 beats per minute; bpm) was a predictor of cardiovascular outcomes in the placebo population of
BEAUTIFUL (morBidity mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction).
Adapted from reference 19: Fox K, Ford I, Steg PG, et al. Lancet. 2008;372:817-821. Copyright © 2008, Elsevier Ltd.

Role of heart rate in the development of
atherosclerosis and coronary events

The most common coronary manifestations of atherosclerosis are stable angina pectoris and acute coronary syndromes. The role of heart rate in the development of myocardial ischemia in patients with stable angina or those suffering from AMI is well known (Figure 3). Increasing heart rate contributes to an imbalance between myocardial oxygen demand and supply, causing both an increase in myocardial oxygen demand and a decrease in coronary blood supply (the latter primarily via a reduction in the duration of diastole, the period during which most myocardial perfusion occurs). Thus, the risk of finding objective evidence of development of myocardial ischemia is related to baseline resting heart rate, with the risk doubled in patients with a baseline heart rate of _90 bpm compared with a heart rate of 60 bpm.20 Experimental evidence supports the role of heart rate in endothelial dysfunction and atherosclerosis progression. Pressure wave–induced vascular stress, sensed by vascular mechanoreceptors that, in turn, trigger a cascade of signaling molecules, alters endothelial responses. Abnormal mechanical stress is thought to directly induce endothelial injury and to increase endothelial permeability to low density lipoprotein particles and circulating inflammatory mediators.21 An increased heart rate may also be directly involved in plaque rupture, resulting in coronary thrombosis,22 presumably by increasing the time during which plaques undergo mechanical perturbation. Based on these considerations, it is reasonable to infer that heart rate reduction may be a key therapeutic strategy in patients with CAD, both to prevent ischemia and to prevent cardiovascular events.

Figure 3
Figure 3. Role of heart rate in the pathophysiology of coronary
artery disease. CV, cardiovascular.

Criteria for validating heart rate as a risk factor

Several criteria are used to assess the validity of epidemiologic associations in CAD.23,24 Plausibility, based on our current understanding of pathophysiology, provides a basis for concluding that a relation is consistent with the associated disease— CAD in this case. Strength is determined by the relative risk of developing an outcome with the factor versus the risk without. Gradation of effect, analogous to a dose-response curve in pharmacology, is defined by the quantitative impact of a change in the magnitude of the factor or the duration of exposure to the factor versus the outcome of interest. The clearer the gradation of effect, the more likely the factor is indeed a beneficially modifiable risk factor. Consistency is the demonstration of an association between the factor and outcome in a variety of populations, for example, cohorts involving various age groups, both sexes, and different ethnic groups. Perhaps most importantly, if the factor is modifiable with currently available strategies, a diminution of the factor should beneficially modify the outcome. In theory, heart rate reduction should reduce mortality, particularly cardiovascular mortality, in patients with CAD, and most especially, those suffering from AMI. Consistent with this hypothesis, in a review of â-blocker trials on AMI, Kjekshus et al25 observed a relationship between reduction in resting heart rate and a reduction in mortality. Furthermore, a recent meta-regression of randomized clinical trials of â-blockers and calcium channel blockers post-AMI strongly suggested that the beneficial effects of these agents are proportionally related to the reduction in resting heart rate.26 A statistically significant relationship was found between reduction in resting heart rate and decreases in cardiac death, all-cause death, sudden death, and recurrence of nonfatal myocardial infarction. This meta-regression suggests that reduction of resting heart rate could be a major determinant of the clinical benefits seen in these trials. This hypothesis was also tested more recently in randomized controlled trials of â-blockers in heart failure caused by left ventricular systolic dysfunction. There was a close relationship between the all-cause annualized mortality rate and heart rate in these studies, and a strong correlation between change in heart rate and change in left ventricular ejection fraction.27 However, â-blockers not only reduce heart rate, but also have several other cardiovascular effects. The novel specific heart rate–lowering agent, ivabradine, therefore provides an opportunity to assess the effects of lowering heart rate without directly altering other aspects of cardiovascular function. In this context, the BEAUTIFUL results have added substantially to our understanding of the role of heart rate reduction in the prevention of coronary events,19,28 as reviewed above. In patients with stable CAD and left ventricular systolic dysfunction who had an elevated heart rate, _70 bpm, ivabradine reduced the relative risk of hospitalization for fatal and nonfatal AMI by 36% (P=0.001) and reduced coronary revascularization by 30% (P=0.016) (Figure 4, page 353).28

Figure 4
Figure 4. Treatment with ivabradine reduces the risk of coronary outcomes in patients with stable coronary artery disease and left ventricular
systolic dysfunction with a resting heart rate 70 beats per minute. RRR, relative risk reduction.
Adapted from reference 27: Fox K, Ford I, Steg PG, et al. Lancet. 2008;372:807-816. Copyright © 2008, Elsevier Ltd.

Treatment with ivabradine was also associated with a 22% reduction in the relative risk of a composite end point of hospitalization for fatal and nonfatal AMI and unstable angina pectoris (P=0.023) compared with placebo. These data suggest that heart rate is a risk factor for CAD, and that its reduction may decrease coronary events in this population. Heart rate has already appeared in European guidelines regarding the prevention of cardiovascular events, and should be seriously considered in future guidance documents relating to patients with CAD.

Conclusion

Resting heart rate has been directly related to all-cause mortality, cardiovascular mortality, and development of clinically evident cardiovascular disease in the general population, hypertensive patients, and patients with CAD. These data emphasize the importance of heart rate as a cardiovascular risk factor, particularly among patients with CAD. As a result, heart rate should be measured routinely in daily clinical practice. The results of BEAUTIFUL suggest that treatment with ivabradine in patients with ischemic heart disease and a heart rate _70 bpm may reduce coronary outcomes. Thus, emerging data support the addition of heart rate to the list of risk factors for CAD, potentially importantly altering management strategies for patients with CAD. _

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