Heart rate as a CV risk factor

Transcription

1 Heart rate as a CV risk factor What is the association between resting heart rate and the development of CVD? Drs Marie Therese Cooney, Alexandra Dudina and Prof Ian Graham examine the issue Cardiovascular disease (CVD) remains the most common cause of death in Ireland and throughout the developed world. Atherosclerosis, which is implicated in the pathogenesis of most CVDs, is usually caused by multiple risk factors which interact with each other. These risk factors include hypertension, dyslipidaemia, smoking, diabetes, physical inactivity, obesity, family history, along with many other emerging risk factors. Resting heart rate, a very easily obtained clinical measure, has been shown to be associated with the development of CVD. However, its importance as a CV risk factor may have been overlooked in recent years. The development of an If channel blocking agent which selectively reduces heart rate without effects on blood pressure has prompted renewed interest in the value of heart rate as a CV risk factor. In this review, we examine the available evidence for the association between heart rate and CVD and in particular assess whether the relationship fulfils the criteria for causality. We will also review the recommendations concerning heart rate in the recently published 4 th Joint task force of European societies guidelines on CVD prevention. 1 Animal studies Smaller mammals with faster heart rates tend to have shorter life expectancies than larger mammals with slower heart rates. Levine has demonstrated an inverse semi-logarithmic relationship between heart rate and life expectancy in mammalian species, with humans being the only exception. 2 This is illustrated in Figure 1. Furthermore, he has shown that the average number of heart beats in a mammalian lifetime is reasonably constant, within one order of magnitude; 7.4 +/- 5.6 x If inter-species differences in heart rate determine longevity, the next question is whether heart rate also determines disease and life expectancy within a species. The role of heart rate in the development of atherosclerosis has been shown in animal models by Kaplan et al 3 and Beere et al. 4 They demonstrated that, in cholesterol-fed monkeys the extent of coronary atherogenesis is 8

2 Figure 1 Relationship between heart rate and life expectancy in mammals 1, Mouse Hamster Heart rate beats/min Marmot Dog Rat Tiger Ass Monkey Cat Giraffe Lion Horse Elephant Man 20 Whale Whale Life expectancy/years significantly reduced in those monkeys randomised to heart rate reduction, either through sinoatrial ablation or pharmacological modification. Epidemiological studies Several prospective studies have examined the relationship between resting heart rate and development of CVD in healthy persons initially free of CVD. These have been conducted men and women and in many different populations In general, a significant association between the development of CVD and elevated heart rates has been demonstrated. The relationship has been strongest and most strongly graded in men. For example, in the British Regional heart study, a resting heart rate of > 90bpm was associated with a 3.3-fold increased risk of ischaemic heart disease mortality compared to those with heart rates < 60 bpm. 14 The relationship is illustrated in Figure 2. The effect of elevated heart rate on risk of sudden death was shown to be even stronger. The relationship also held when hypertensive and non-hypertensive patients were analysed 5, 14 separately. However, the association has not been entirely consistent. For example, in women, many studies have shown that the relationship did not remain significant after adjustment for other CV risk factors or that the risk gradient in women was less steep than that demonstrated in men. 9 In some studies, only certain sub-groups showed a significant relationship in women 7, 8 and in others the relationship was only for the total mortality endpoint not specifically for CVD 8

3 Figure 2 Relationship between increasing heart rate and CV mortality and sudden death 6 5 > 90 Adjusted relative risk < > 90 < IHD mortality Sudden death mortality or events. 5, 9 Some of this difference may be due reduced power of the studies in women because fewer events occurred during the observation time. Some smaller studies have looked at the effect of heart rate on mortality endpoints in older individuals. 11, 16 There was considerable heterogeneity between these studies and the results have been inconsistent. The question of independence is particularly important in considering the effect of heart rate on CVD because of its association with other CV risk factors, most notably blood pressure and physical activity. In general, the relationship has remained independent after adjustment for blood pressure, although in some the relationship was considerably attenuated after adjustment for blood pressure. 6, 8, 12 Several of the studies have shown the relationship to be independent of 5, 7, 10, 13, 14 measures of activity and physical fitness. The relationship between resting heart rate and prognosis in the population with established coronary artery disease has also been investigated. One large study showed a relative risk of 1.31 ( ) for total mortality comparing heart rates > 83bpm to < 62bpm. 17 This relationship held after adjustment for a variety of possible confounding variables including ejection fraction and use of beta-blocking agents. Randomised controlled trials (RCTs) To date, no RCT of the effect of pharmacological heart rate reduction in healthy people has been conducted. The only available evidence for a beneficial effect of heart rate reduction is from trials of beta blocker and calcium channel blocker therapy in patients either post-myocardial infarction (MI) or with congestive cardiac failure (CCF). In these settings, heart rate lowering therapies have been associated with reduced total mortality and improved prognosis. For example, in systematic reviews, beta-blocker therapy is associated with an odds ratio for total mortality of 0.76 in post MI patients and 0.65 in CCF patients. The number of lives saved per 100 treated 18, 19 for one year were: 1.3 and 3.8 respectively. 10

4 Figure 3 Relationship between mean heart rate reduction achieved and effect on outcome in beta-blocker and calcium channel blocker trials beta-blockers calcium channel blocker Relative risk (log) P < HR (bpm) However, there is a difficulty in ascertaining whether the beneficial effect is due to beta-blockade or specifically to the heart rate reduction achieved by beta-blockade. In a metaregression of beta-blocker and calcium channels blocker trials in post MI patients, Cucharet has shown an almost linear relationship between the level of heart rate reduction achieved in a trial and the improvement in outcome demonstrated. 20 This is illustrated in Figure 3. While this verifies the importance of heart rate reduction in the beneficial effect of beta-blockade, it does not conclusively demonstrate that it is the only favourable effect. Mechanisms Several mechanisms for the association between heart rate and CVD have been proposed, although none of these has been proven. They include the protective effect of a low heart rate by reducing risk of ischaemia and arrhythmia. The haemodynamic effect of high a heart rate on the vessel wall has also been postulated possible factor in atherogenesis and plaque rupture. Causal criteria Based on the evidence detailed above, we have assigned a value (0-3) for each of the causal criteria listed in Table 1 below. The value indicates the weight of evidence which supports fulfilment of that particular criterion; 0 = no evidence, 3 = strong evidence. For comparison, we have also included the values for another CV risk factor; total cholesterol. At present, heart rate does not fulfil all of the criteria for the relationship to be considered causal. 11

5 Table 1 Criteria for causality Heart rate Total cholesterol Biologically plausible 2 3 Strong 2 3 Temporal sequence 2 3 Graded 3 3 Consistent Independence 2 3 Agreement between disciplines 2 3 Treatable 3 3 Benefit results 1 3 Practical recommendations The recently published fourth version of the European guidelines on CVD prevention includes a section on heart rate. 1 Here it is recommended that assessment of heart rate forms an integral part of the assessment for total CVD risk, as elevated heart rates are known to be associated with increased risk. Resting heart rate is generally taken as the average of two readings, measured with the patient in the sitting position for five minutes. Heart rate reduction with beta-blockers (or calcium channel blockers if contraindicated) is recommended in the treatment of all those, including people with diabetes, who have established CVD. Both beta-blocking and If channel blocking agents have proven efficacy in the symptomatic treatment of stable angina. 21 With regard to the approach to the asymptomatic patient with an elevated heart rate, the first recommendation is to rule out other causes of tachycardia, for example, thyroid disorders, hypoxia, anaemia and lack of physical fitness. Conservative measures to reduce and prevent elevated heart rates, such as avoidance of psychological stress and excessive use of stimulants such as caffeine, as well as regular physical activity, may be advocated, particularly as many of these have been demonstrated to be beneficial for the primary prevention of CVD in their own right. Future steps Substantial evidence is available to suggest the role of heart rate as an independent risk factor for the development of CVD. However, the criteria for causality have not been met. The main deficiency is the lack of RCT evidence demonstrating the effect of heart rate-lowering in the general population for CVD prevention. Clearly, heart rate measurement should form part of the complete assessment for total CVD risk. At present, heart rate is not included in any risk estimation system; however, the value of inclusion of heart rate as an extra variable is currently under investigation by the SCORE group. 22 n Marie Therese Cooney and Alexandra Dudina are research fellows and Ian Graham is a consultant cardiologist at Tallaght Hospital and professor of cardiovascular disease, Trinity College Dublin and professor of preventive cardiology, RCSI References on request 12