Heart rate and arrhythmic risk: old markers never die

The medical literature of the last 30 years has increasingly emphasized the role of elevated resting heart rate as an independent predictor of all-cause and cardiovascular mortality among men and women in the general population and in several pathological conditions, including coronary artery disease, myocardial infarction, and heart failure. 1 The independent contribution of heart rate to cardiovascular outcomes after adjustment for the effects of known risk factors has been clearly established in large series of apparently healthy subjects 2 and supports the recent re-appreciation of heart rate as a ‘new’ cardiovascular risk factor rather than a simple risk predictor reflecting other pathogenetic connections. 3 Epidemiological evidence has also indicated that elevated heart rate reflects an increased propensity to sudden cardiac death in apparently healthy subjects. 4–6 In the Framingham Heart Study, 5 patients with the highest quintile of heart rate (>88 bpm) had a 5- and 2-fold higher risk of sudden death in men and in women, respectively, compared with subjects with heart rates <65 bpm. In the British Regional Heart Study, 6 a wide range of established risk factors for ischaemic heart disease have been examined in relation to sudden and non-sudden cardiac death in a cohort of 7735 middle-aged men with and without pre-existing ischaemic heart disease. Increased heart rate (>90 bpm) emerged as a potential specific factor for sudden cardiac death in that the significant association with cardiovascular mortality was largely due to increased risk of sudden cardiac death. Of interest, the magnitude of relative risk of sudden cardiac death was greater in individuals without pre-existing ischaemic heart disease. Similarly, in the Paris Prospective Study which included 7746 male subjects aged 42–53 years, 7 over a 23-year follow-up, the relative risk for sudden cardiac death significantly exceeded the relative risk for total mortality, cardiovascular death, and fatal myocardial infarction. Specifically, the risk in men with the highest quintile of heart rate (>75 bpm) was 3.8-fold than in those in the lowest quintile (<60 bpm), whereas risk for fatal myocardial infarction, cardiovascular, and total mortality was approximately twice greater. Moreover, when traditional risk factors, parental history of sudden death, and sports activity were entered into the survival model, resting heart rate remained independently related to sudden death but not to fatal myocardial infarction. Although factors affecting heart rate are multiple, there is no doubt that neural influences, either central or reflex in nature, play a major role in determining heart rate. Under normal physiological conditions, resting heart rate is mainly under parasympathetic control as shown by a higher level of the ‘intrinsic heart rate’ observed after pharmacological blockade of autonomic influences (with atropine and propranolol). 8 Chronic imbalance of the autonomic nervous system characterized by activation of the sympathetic nervous system and/or diminished parasympathetic activity is a marker of an unhealthy cardiovascular system and is associated with increased risk of cardiovascular events and mortality. 9 Increased sympathetic activity elicited by acute myocardial ischaemia may be a trigger for life-threatening arrhythmias. 10 Moreover, in dogs with high spontaneous heart rate, acute myocardial ischaemia was likely to induce ventricular fibrillation, while ventricular fibrillation did not occur following administration of propranolol as well as in dogs with low spontaneous heart rate. 11 There are several mechanisms by which increased heart rate may be detrimental to cardiac electrophysiology thus favouring the occurrence of ventricular tachyarrhythmias. Besides the already mentioned arrhythmogenic effects of the autonomic nervous system, 9 many of the electrophysiological properties of myocardial cells depend upon the cycle length. Increased heart rate may decrease action potential duration and effective refractory periods, slow conduction velocity and facilitate the occurrence of delayed afterdepolarizations and triggered activity in the presence of a diseased myocardium. 12 Soliman et al.13 explored the relation of resting heart rate and other electrocardiographic and clinical parameters that are related to ventricular arrhythmogenesis, namely heart rate variability, ventricular late potentials, and arrhythmia counts. All the subjects who had been referred for a 24 h Holter recording over 2 years were considered for inclusion into analysis provided they had good quality resting ECG and Holter recordings for at least 12 h. Resting heart rate was obtained from a 10 s ECG before recording. The analysis included 867 patients of whom 57% were females. Less than 15% of patients had a history of coronary heart disease or heart failure and mean left ventricular ejection fraction was rather well preserved. After resting heart rate had been divided into quartiles, a significant association was found between increased heart rate and the prevalence of reduced heart rate variability, the presence of late potentials and ventricular arrhythmias. ST segment depression was also included in the analysis and showed a significant association with outcome. Although the strength of the association is not reported, these variables remained significant after adjustment for demographic risk factors and left ventricular ejection fraction. Because of the lack of follow-up data, the predicted value of the observed association with outcome could not be confirmed. Moreover, newer measures reflecting electrophysiological properties, such as instability of ventricular repolarization—which may contribute to the development of ventricular tachycardia or ventricular fibrillation—have not been taken into account in the present study. Microvolt T-wave alternans, a marker of susceptibility to life-threatening arrhythmias, significantly depends on heart rate. In ambulatory ECG recordings, differences in MTWA values at times of higher heart rate were observed between patients who experienced cardiac arrest or arrhythmic death and matched controls. 14 Despite these limitations, the study by Soliman et al.13 represents an additional contribution to the definitive entrenching of the concept of heart rate as a risk factor for life-threatening arrhythmias. Furthermore, less immediately dangerous arrhythmias seem to be favoured by high heart rates. Indeed, elevated heart rate has been shown to affect not only ventricular but also atrial electrophysiology. In a recent post hoc analysis of the Losartan Intervention For End point reduction in hypertension (LIFE) study, Okin et al.15 examined the relationship of heart rate changes over time in patients with hypertension and left ventricular hypertrophy on the risk of subsequent development of atrial fibrillation. In-treatment persistence or development of heart rate ≥84 bpm was associated with a 61% increased rate of atrial fibrillation after adjusting for baseline risk factors and changes in therapy. Heart rate changes over years have been shown to have prognostic implications in apparently healthy individuals. Among 5138 asymptomatic working men, those with decreased heart rate during a 5-year observation period had a 14% lower risk of death after adjustments for confounding factors, including baseline heart rate at rest, whereas subjects with increased heart rate during the 5 years had a 19% increased mortality risk. 16 Although heart rate is a simple clinical variable, a single measurement might be biased because of different conditions at sampling, physical, psychological, and environmental factors. Recommendations for the measurement of resting heart rate have been developed 17 for future trials. In specific populations, the limitation of a single measurement can be overcome by continuous measurements which can provide mean heart rate values over a longer time period. 18 One fundamental issue is the distinction between the demonstration of a biological association linking a risk factor with prognosis and the practical demonstration that the marker can be used to select patients who may warrant treatment. The linear relationship between a reduction in heart rate and improved survival, observed in the studies of beta-blockers, provides strong evidence of the adverse effects of increased heart rate among patients with known heart disease. 19 , 20 Pure heart rate reduction with the If inhibitor ivabradine has been suggested to confer a benefit on cardiovascular outcomes in patients with elevated heart rate (≥70 bpm) and left ventricular dysfunction, 21 although there was no measurable benefit of treatment on the primary endpoint in the entire study population. Sudden death was not included as a separate endpoint. The question is whether the pharmacological heart rate reduction might be beneficial in patients without cardiac disorders as well as to what extent the association between increased heart rate and sudden death in the general population might be primarily related to the underlying autonomic imbalance. Better understanding of the relationship between heart rate and arrhythmogenesis will help find new targets for interventions. Conflict of interest: none declared.