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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

The pivotal role of heart rate in clinical practice: from atherosclerosis to acute coronary syndrome

Jean-Claude Tardif*

Department of Medicine, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Canada H1T 1C8

* Corresponding author. Tel: +1 514 376 3330, ext. 3612; fax: +1 514 593 2500. E-mail address: jean-claude.tardif{at}icm-mhi.org


   Abstract
Top
 Abstract
Heart rate and cardiovascular...
 Heart rate and pathophysiology...
 Conclusion
 References
 
Heart rate is a predictor of major cardiovascular events in both the general population and patients with various cardiovascular diseases. The association between resting heart rate and mortality has been observed in patients with hypertension and with metabolic syndrome and in the elderly. The prognostic value of heart rate has also been shown in patients with stable coronary heart disease. We assessed the relationship between resting heart rate at baseline and cardiovascular mortality and morbidity, while adjusting for risk factors. A total of 24 913 patients with suspected or proven coronary artery disease from the Coronary Artery Surgery Study registry were studied for a median follow-up of close to 15 years. All-cause and cardiovascular mortality and cardiovascular re-hospitalizations were increased with increasing heart rate (P < 0.0001). When compared with the reference group, patients with resting heart rate ≥83 bpm at baseline had a significantly higher risk for total mortality [hazard ratio 1.32; confidence interval (CI) 1.19–1.47; P < 0.0001] and cardiovascular mortality (hazard ratio 1.31; CI 1.15–1.48; P < 0.0001) after adjustment for multiple clinical variables. When comparing patients with heart rates between 77–82 and ≥83 bpm with patients with a heart rate ≤62 bpm, the hazard ratios for time to first cardiovascular re-hospitalization were 1.11 and 1.14 (P < 0.001 for both). Resting heart rate has also been shown to be associated with the severity and rate of progression of coronary atherosclerosis and to be an independent predictor of plaque rupture in coronary arteries. Resting heart rate is a simple measurement with prognostic implications.

Key Words: Heart rate • Atherosclerosis • Risk factors • Acute coronary syndrome

The total number of heart beats in a lifetime remains fairly constant across species and there exists an inverse relationship between resting heart rate and life expectancy.1 Epidemiological studies have addressed the issue of the importance of heart rate in healthy humans.2–12 The association between resting heart rate and mortality has been observed in patients with hypertension and metabolic syndrome and in the elderly.13–18 More recently, the prognostic value of resting heart rate has also been demonstrated in patients with coronary artery disease.

Heart rate reduction is the cornerstone of anti-anginal therapy. In addition to the beneficial effects of heart rate reduction for prevention of angina, in epidemiological studies a lower heart rate is also associated with a more favourable prognosis in patients with coronary artery disease. This is clinically important because it supports the relevance of testing the effect of lowering heart rate to reduce cardiovascular mortality and morbidity. Experimental and clinical studies have already suggested that heart rate reduction may improve coronary endothelial function and atherosclerosis.19–29 We have also reported the results of a study that evaluated the relationship between resting heart rate and future cardiovascular events in a large population of patients with suspected or proven coronary artery disease with an extended follow-up.30


   Heart rate and cardiovascular mortality and morbidity in patients with coronary artery disease
Top
 Abstract
 Heart rate and cardiovascular...
Heart rate and pathophysiology...
 Conclusion
 References
 
Our study focused on the 24 913 patients included in the Coronary Artery Surgery Study (CASS) registry undergoing coronary arteriography for the presence of suspected or proven coronary artery disease.31 Baseline resting heart rate was obtained manually at enrolment with radial pulse measurement during 60 s with the patient in the sitting position. The variables evaluated in CASS have been previously described in detail.30 Median duration of follow-up (and inter-quartile range) was 14.7 years (9.0–16.1 years). The date of enrolment was that of the initial angiographic evaluation. Annual clinical follow-up was mandatory for all patients in the registry. Additional information was obtained for all patients in the registry who suffered a ‘coronary event’.

The baseline demographic and clinical characteristics of the 24 913 patients included in this study are presented in Table 1. The mean age was higher in the lower heart rate quintiles. There was a higher proportion of males than females in all groups, with women having a trend towards a higher resting heart rate. There were higher proportions of dyslipidaemics, smokers, hypertensives, and diabetic patients in the higher quintiles. Left ventricular ejection fraction was lower in patients with a high heart rate at baseline. Patients in the higher heart rate quintiles received less treatment with beta-blockers and were treated more often with diuretics. There were no significant differences between the different quintiles with regard to body mass index and use of antiplatelets or lipid-lowering drugs.


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  		Table 1 Baseline characteristics divided by resting heart rate quintiles (n=24 913 patients)

 
In order to summarize the independent variables and to better understand their relationship with heart rate, descriptive statistics are presented by heart rate quintiles: <62, 63–70, 71–76, 77–82, and >83 bpm After adjusting the multivariable Cox proportional hazard model for age, sex, diabetes, hypertension, cigarette smoking, left ventricular ejection fraction, number of clinically significant diseased coronary vessels, type of recreational activity, and concomitant treatments (including beta-blockers), patients with resting heart rate between 77 and 82 bpm had a significantly higher risk for total mortality (hazard ratio 1.16; 99% CI 1.04–1.28). This effect was even larger for patients with a resting heart rate ≥83 bpm, with a hazard ratio of 1.32 (CI 1.19–1.47; Figure 1).


Figure 1
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  		Figure 1 Left: Adjusted for age, gender, hypertension, diabetes, smoking, clinically significant coronary vessel disease, ejection fraction, recreational activity, treatment with antiplatelets, diuretics, beta-blockers, and lipid-lowering drugs. Right: Adjusted for age, gender, hypertension, diabetes, smoking, clinically significant coronary vessel disease, ejection fraction, recreational activity, treatment with antiplatelets, diuretics, beta-blockers, lipid-lowering drugs, and body mass index. CV, cardiovascular; RHR, resting heart rate.

 
The multivariable Cox proportional hazard model for cardiovascular mortality was adjusted for the same covariates as for overall mortality plus body mass index. A high resting heart rate (≥83 bpm) was a strong predictor of cardiovascular mortality (hazard ratio 1.31; CI 1.15–1.48). Age, hypertension, diabetes, body mass index, current smoking, and number of clinically significant diseased coronary vessels remained strongly associated with cardiovascular death. Ejection fraction and treatment with diuretics showed a protective effect. Figure 1 shows the adjusted cumulative survival curves for cardiovascular mortality by highest and lowest quintiles of resting heart rate.

There was also a marked difference in time to first cardiovascular re-hospitalization between the two highest heart rate quintiles and the other groups. When comparing patients with heart rates between 77–82 and ≥83 bpm with patients with a heart rate of ≤62 bpm, the hazard ratios for time to first re-hospitalization due to any cardiovascular event were, respectively, 1.11 (CI 1.00–1.24) and 1.14 (CI 1.0–1.27) (P < 0.0001 for both) (Figure 2). A high resting heart rate was also an independent predictor of time to first re-hospitalization due to angina and heart failure.


Figure 2
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  		Figure 2 Left: Asterisk indicates adjustments as in Figure 1. The green and black lines are superimposed. CV, cardiovascular; RHR, resting heart rate. Right: Asterisk indicates adjusted for age, gender, hypertension, diabetes, clinically significant coronary vessel disease, ejection fraction, recreational activity, treatment with antiplatelets, diuretics, beta-blockers, and lipid-lowering drugs. CHF, congestive heart failure.

 
The association between heart rate and total mortality held true in all analysed subgroups: men vs. women, old (>65 years) vs. young, diabetics vs. non-diabetics, hypertensives vs. normotensives, BMI > 27 or BMI < 27, those with EF > 50% or EF < 50%, and patients treated with beta-blockers compared with those without such a treatment (Figure 3).


Figure 3
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  		Figure 3 Subgroup analyses on total mortality per standard deviation (12.4 bpm) of heart rate increment.

 
It might be argued that in subjects with ischaemic heart disease a higher heart rate might reflect some degree of left ventricular dysfunction. According to this view, the higher mortality rate among subjects with tachycardia would be caused by the underlying systolic dysfunction. However, heart rate was an important predictor of all-cause and cardiovascular mortality both in subjects with and without left ventricular dysfunction. The better prognosis of the subjects with lower heart rates was not simply due to a protective effect of beta-blockers, because the predictive value of heart rate for mortality persisted in the subjects not treated with this class of agents. Another important finding of this study is that the predictive power of heart rate for mortality was observed both in men and women. A gender-related difference in the association between heart rate and mortality has been found in some studies conducted either in elderly subjects32 or in patients with myocardial infarction.33 A high heart rate appeared to be a weaker predictor of death from coronary artery disease in women in several studies. Data from our study in patients with stable coronary artery disease indicate that a higher heart rate can also be deleterious in women.


   Heart rate and pathophysiology of coronary heart disease
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 Abstract
 Heart rate and cardiovascular...
 Heart rate and pathophysiology...
Conclusion
 References
 
A high heart rate is a major determinant of myocardial ischaemia, as it leads to both greater myocardial oxygen consumption (MVO2) and decreased myocardial perfusion, the latter because of the shortening in the duration of diastole. The likelihood of the occurrence of an ischaemic episode increases at higher baseline heart rates. With a baseline heart rate less than 60 bpm, the likelihood of occurrence of ischaemic episodes with heart rate acceleration was 8.7%, while at rates in excess of 90 bpm, the likelihood increased to 18.5%.34 An increased heart rate has also been found to be an independent risk factor for cardiovascular morbidity and mortality in the general population,2,7,8 in elderly subjects,18 in hypertensive cohorts,13 and in patients with myocardial infarction.35 The relationship between reduction in heart rate and decrease in mortality has been well established with beta-blockers, especially after myocardial infarction and in patients with heart failure.36–39 As far as these beta-blocker trials are concerned, the magnitude of the effect on mortality was correlated with the degree of reduction in heart rate in most studies.36,37

There is experimental and clinical evidence that suggests that sustained elevations in heart rate may play a direct role in the pathogenesis of coronary atherosclerosis. Heart rate was significantly correlated with the severity and progression of atherosclerosis on coronary angiography among men who had developed myocardial infarction at a young age.27,28 Accelerated atherogenesis resulting from increased heart rate may be due to both mechanical and metabolic factors. Increased stress on the vascular wall may contribute to endothelial injury, potentially promoting the complex cascade of events leading to increased atherosclerosis. Experimental data have also demonstrated that a reduction in heart rate can delay the progression of coronary atherosclerosis in monkeys.20,25 Beere et al.20 showed that male cynomolgus monkeys subjected to sinus node ablation or those with innately low heart rates had significantly less coronary atherosclerosis than animals with higher heart rates. These observations are supported by results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS) randomized trial, which has shown that a beta-blocker reduced the rate of progression of carotid intima-media thickness in asymptomatic patients.29 A high heart rate has also been associated with an increased risk of coronary plaque disruption.40,41 In this retrospective angiographic study evaluating patients who underwent two coronary angiograms within 6 months, logistic regression analysis identified positive associations between plaque disruption and a mean heart rate above 80 bpm. This association again indicates that haemodynamic forces may play a critical role in the process of plaque disruption (Table 2). A further study42 has shown that a high heart rate is strongly associated with increased arterial rigidity, reduced vascular distensibility, and elevated pulse-wave velocity, characteristics that are all associated with myocardial infarction and cardiac death.


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  		Table 2 Heart rate as a predictor of coronary plaque rupture

 
In addition, a retrospective study has examined the relationship between bradycardia and the development of coronary collateral vessels visible on angiography in patients with obstructive coronary artery disease. Patel et al. observed that a larger number of patients with heart rates ≤50 bpm had developed collateral vessels (potentially decreasing the ischaemic burden) compared with control patients with heart rates ≥60 bpm (P < 0.001). The presence of collaterals was independent of the history of angina or the use of beta-blockers.43 Finally, a high heart rate may reflect an imbalance of the autonomic nervous system and may therefore be a marker of sympathetic overactivity.44–46 Some investigators have hypothesized that many of the risk factors (hypertension, diabetes, dyslipidaemia, smoking, and sedentarity) are also related to sympathetic overactivity.46–48


   Conclusion
Top
 Abstract
 Heart rate and cardiovascular...
 Heart rate and pathophysiology...
 Conclusion
References
 
In summary, studies have shown that a high resting heart rate is a strong predictor of total and cardiovascular mortality in healthy populations as well as in patients with suspected or proven coronary artery disease. Patients with resting heart rate above 77 bpm are also prone to more re-hospitalizations for cardiovascular reasons, independently of major risk factors when compared with patients with lower resting heart rates. Resting heart rate has also been shown to be associated with the severity and rate of progression of coronary atherosclerosis and to be an independent predictor of plaque rupture in coronary arteries. Resting heart rate is a simple measurement with important prognostic implications.

Conflict of interest: none declared.


   References
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 Abstract
 Heart rate and cardiovascular...
 Heart rate and pathophysiology...
 Conclusion
 References
 

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