Pathophysiological role of heart rate: from ischaemia to left ventricular dysfunction
1 Department of Cardiology, Università degli Studi di Ferrara, Ferrara, Italy
2 Cardiovascular Research Center IRCCS, Salvatore Maugeri Foundation, Gussago, Brescia, Italy
* Corresponding author. Tel: +39 0532 242011; fax: +39 0532 241885. E-mail address: fri{at}unife.it
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Abstract |
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 Top Abstract IntroductionPharmacological heart rate...Heart rate, atherosclerosis, and...Heart rate and myocardial...Heart rate, remodelling, and...ConclusionReferences |
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Myocardial ischaemia results from imbalance between myocardial oxygen demand and supply. An increase in heart rate (HR) will raise both demand and supply. HR is the most important determinant of myocardial oxygen consumption and of cardiac energy demand. HR reduction improves myocardial perfusion by increasing the fraction of the cardiac cycle occupied by diastole, which accounts for 80% of coronary flow. Besides these physiological characteristics, HR is also linked to the progression of atherosclerosis, at least in animals, and an increase in HR is associated with plaque rupture in humans. The symptom of chest pain in stable angina is almost always triggered by elevated HR owing to physical or emotional stress. Equally, an increased HR precedes an episode of asymptomatic or silent myocardial ischaemia. Therefore, it is not surprising that the efficacy of some anti-anginal drugs such as β-blockers and non-dihydropyridine calcium antagonists has been related to their effectiveness in reducing HR. In many studies, multivariate analysis has shown HR to be an independent predictor of mortality and of hospitalization for heart failure. A relationship has been found between HR reduction and mortality in patients with congestive heart failure treated with β-blockers. Thus HR is an important therapeutic target for ischaemia and left ventricular dysfunction or congestive heart failure, and it seems likely that relatively high HR is both causative and indicative of important pathophysiological processes: HR is a risk factor for cardiovascular morbidity and mortality throughout the cardiovascular continuum.
Key Words: Heart rate • Myocardial ischaemia • Remodelling • Ivabradine
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Introduction |
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TopAbstractIntroductionPharmacological heart rate...Heart rate, atherosclerosis, and...Heart rate and myocardial...Heart rate, remodelling, and...ConclusionReferences |
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The relationship between resting heart rate (HR) and cardiovascular risk and mortality has been demonstrated in a number of large-scale epidemiological studies over the last 25 years. These have been recently reviewed by Palatini et al.1,2 Moreover, in many studies, multivariate analysis has shown HR to be an independent predictor of mortality after correction for demographic and clinical variables, including blood pressure. A recent large study with a particularly lengthy follow-up has extended our understanding of the prognostic importance of HR. The study3 involved nearly 25 000 patients who underwent coronary arteriography for the presence of suspected or proven coronary artery disease (CAD). Patients with a resting HR between 77 and 82 bpm had a significantly higher risk of all-cause mortality (hazard ratio 1.16; 95% confidence interval 1.04–1.28) than patients with HR
62 bpm Moreover, the increased risk was observed independently of other cardiovascular risk factors (age, sex, presence of diabetes or hypertension, body mass index, ejection fraction, and treatment with β-blockers). This study indicates that HR is a prognostic factor in cardiovascular disease and highlights the need to measure and control HR in all coronary patients. Nonetheless, HR is not included in some widely known indices for cardiovascular risk (Copenhagen Risk Score,4 European SCORE project5), but has been included in the recent Cooper Clinic risk index for overall mortality.6 In the latter study, involving 21 766 men, a stepwise proportional hazards model showed relatively high HR to be an independent predictor of all-cause mortality, even though cardiorespiratory fitness was also included in the model. HR was assigned the same weighting as blood pressure and cardiorespiratory fitness in the overall score.6
Although the association between HR and outcome is suggestive, it does not, by itself, prove causality. One way to explore this hypothesis is to consider whether pharmacological HR reduction is beneficial.
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Pharmacological heart rate reduction |
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TopAbstractIntroductionPharmacological heart rate...Heart rate, atherosclerosis, and...Heart rate and myocardial...Heart rate, remodelling, and...ConclusionReferences |
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It has been reported that HR reduction by β-blockers improves survival after myocardial infarction7 and reduces mortality in patients with congestive heart failure.8 It is not possible to assume that all the beneficial effects of β-blockade are related to HR reduction alone. However, much of the anti-ischaemic effect of β-blockade can be eliminated by the suppression of its HR-reducing effect using atrial pacing,9 a result that emphasizes the independent role of HR and the value of any therapeutic strategy to reduce it.
The Norwegian Timolol Multicenter Study10 gave similar results. In this study, HR during follow-up was a significant predictor of overall mortality. Timolol treatment was associated with a 41.6% reduction in mortality, but mortality at a given HR was similar in the timolol and placebo groups. In logistic regression analysis, HR remained predictive but treatment did not, indicating that the major effect of timolol on mortality could be attributed to its effect on HR. In contrast, the Acebutolol et Prévention Secondaire de l’Infarctus study in high-risk patients with acute myocardial infarction suggested that low-dose treatment with acebutolol produced large reductions in all-cause and cardiovascular mortality (48 and 58%, respectively), in spite of only a modest effect on HR.11
Variations in HR can also affect the symptoms of CAD. For example, the symptom of chest pain in stable angina is often triggered by elevated HR owing to physical or emotional stress, which then aggravates myocardial ischaemia. An increase in HR also precedes episodes of asymptomatic or silent myocardial ischaemia. Indeed, the efficacy of some anti-anginal drugs has been related to their effectiveness in reducing HR.12
In a double-blind study comparing low and high doses of three different calcium channel blockers in 335 stable angina patients, the improvements in time to ischaemia during bicycle exercise tolerance tests were directly related to the reductions in exercise HR. Regression analysis showed that the beneficial anti-ischaemic effect of the drugs was largely dependent on their effect on HR.13
In addition, Kjekshus and Gullestad8 analysed the relation of treatment to HR and outcome in patients with heart failure. A relationship was found between reduction in HR and in mortality; in addition, agents that increased HR tended to increase mortality. Results of most recent studies in heart failure have been consistent with this finding. In the Cardiac Insufficiency BIsoprolol Study (CIBIS), treatment with bisoprolol reduced HR by 
15 bpm relative to placebo; HR reduction was the most powerful predictor of survival in multivariate analysis.14 In the larger CIBIS II trial,15 baseline HR and HR change were both significant predictors of mortality. In the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure study, however, the benefits with metoprolol were independent of the change in HR achieved,16 suggesting that HR reduction is not the only mechanism of the benefit of β-blockers in heart failure.
Thus, HR is an important therapeutic target, and it seems likely that relatively high HR is both causative and indicative of important pathophysiological processes. HR might have several deleterious effects on the cardiovascular continuum, affecting atherosclerosis, degree, and severity of ischaemia, post-ischaemic remodelling, and eventually heart failure.
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Heart rate, atherosclerosis, and arterial stiffness |
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TopAbstractIntroductionPharmacological heart rate...Heart rate, atherosclerosis, and...Heart rate and myocardial...Heart rate, remodelling, and...ConclusionReferences |
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In cynomolgus monkeys, naturally occurring differences in HR are related to the extent of coronary artery atherosclerosis.17 HR reduction by sinoatrial node ablation reduces both the severity of individual atherosclerotic stenoses and the area covered by lesions within the coronary arteries.18 In humans, HR is directly associated with the progression of coronary atherosclerosis19 and also has been significantly related to the likelihood of disruption of pre-existing atherosclerotic plaque.20
Increases in HR induced by electrical pacing in rats are accompanied by progressive and marked reductions in arterial compliance and distensibility.21 Similarly, HR is strongly and directly associated with arterial rigidity in hypertensive patients, after adjustment for age and blood pressure.22 These results suggest that HR impacts directly on the status of the arterial wall, probably because of mechanical pulsatile stress, and also possibly involving the pro-inflammatory actions of oscillatory fluid shear stresses acting on the vascular endothelium.23
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Heart rate and myocardial ischaemia |
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TopAbstractIntroductionPharmacological heart rate...Heart rate, atherosclerosis, and...Heart rate and myocardial...Heart rate, remodelling, and...ConclusionReferences |
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Ischaemia results from imbalance between myocardial oxygen demand and supply. An increase in HR will raise both demand and supply. HR is the main determinant of myocardial oxygen or energy demand or both and, by improving myocardial perfusion, controls oxygen supply or energy supply or both.
Heart rate and myocardial energy expenditure
Adenosine triphosphate (ATP) is the primary source of energy in the heart and is used for electrical excitation, contraction, relaxation, and recovery of the resting electrochemical gradients across membranes. The heart may suddenly increase its output up to six-fold, thus requiring a huge amount of energy. However, unlike other tissues, it stores only small quantities of ATP, just sufficient to power a few beats. These low ATP levels in the heart are counterbalanced by a higher level of creatine phosphate, whose breakdown furnishes phosphate for the synthesis of ATP from adenosine diphosphate, through a phosphorylation reaction catalysed by creatine kinase.24 In the heart, ATP is synthesized in the mitochondria from a variety of aerobic substrates including glucose, free fatty acids, lactate, and even amino acids and ketone bodies.25 In humans, the heart beats an average of 100 800 times per day, which corresponds to 36.8 x 106 times per year, or 29 x 108 heart beats in a lifetime (80 years on average). In so doing, the heart produces and immediately consumes 30 kg of ATP every day, i.e. nearly 11 000 kg/year and 880 000 kg in a lifetime. It follows that the cost of each heart beat is 300 mg of ATP. Slowing the HR by 10 bpm would result in a saving of 5 kg of ATP every day. To produce ATP, the myocardium needs oxygen, which is used by the mitochondria during oxidative phosphorylation. It has been calculated that, in all animals, the basal oxygen consumption/body atom is approximately 10 molecules of oxygen/lifetime, which, referred to HR, corresponds to 10–8 molecules of oxygen per heart beat.17 Surprisingly, the total number of heart beats per lifetime calculated with these data (10 x 108) is similar to the mean value observed among mammals (7.3 x 108). Even though these calculations are based on simplified figures, they point to the pivotal role of HR reduction at the cellular level.
Heart rate and myocardial perfusion
Oxygen delivery to the heart mainly occurs during diastole, and the fraction of the cardiac cycle occupied by diastole increases as HR decreases. Therefore, HR reduction improves diastolic perfusion time and myocardial perfusion. Furthermore, often under ischaemic conditions, stenotic coronary arteries are connected via collaterals to intact or less severely stenotic arteries. This causes a typical re-distribution of coronary flow with a possible steal phenomenon. Any increase in HR would be deleterious, as it will further reduce diastolic perfusion, increase stealing from the ischaemic zone, and impair the flow at the ischaemic obstruction, which, in turn, further compromises coronary flow. Reduction in HR under these circumstances is therefore highly beneficial.
Increasing HR by atrial pacing in patients with CAD produces coronary constriction, further impairing oxygen supply.26,27 In patients with stable CAD, most episodes of ambulatory or exercise-induced myocardial ischaemia are preceded by an increase in HR.28 The likelihood of developing ischaemia is related to the baseline HR.27 The frequency of ischaemic episodes in patients with CAD is related to their mean HR: patients with HR >80 bpm experience ischaemia almost twice as often as those with HR <70 bpm.29
Increased HR and haemodynamic forces may play a role in plaque disruption. Plaque rupture is the main pathophysiological mechanism underlying acute coronary syndromes and the progression of coronary atherosclerosis.10 The role of haemodynamic forces, i.e. HR, has been investigated in 106 patients who underwent two coronary angiographic procedures within 6 months.30 This study identified positive associations between plaque rupture, left ventricular muscle mass >270 g, and a mean HR >80 bpm, and a negative association with HR-reducing medication.
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Heart rate, remodelling, and heart failure |
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TopAbstractIntroductionPharmacological heart rate...Heart rate, atherosclerosis, and...Heart rate and myocardial...Heart rate, remodelling, and...ConclusionReferences |
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In dogs, left ventricular dysfunction caused by surgically induced mitral regurgitation is substantially ameliorated by β-blocker treatment, but the amelioration is largely prevented by electrical pacing to the pre-β-blockade rate.31 In a rat model of heart failure, prolonged HR reduction with an HR-lowering agent that has no direct action on myocardial contractility or the autonomic nervous system improves left ventricular function and normalizes structure, including increasing capillary density.21 In patients with heart failure, HR reduction by β-blockade reduces oxygen requirement for non-mechanical work and increases mechanical efficiency, benefits that are abolished if HR is kept constant by atrial pacing.32 In a recent study30 in patients with heart failure fitted with permanent pacemakers and treated with β-blockers, pacing at 80 bpm as opposed to 60 bpm attenuated or reversed the beneficial effects of β-blockade on left ventricular volume and systolic function.
Interestingly, pure HR reduction by ivabradine has been shown to improve left ventricular function in congestive heart failure and to reduce remodelling subsequent to myocardial infarction.32 In post-myocardial infarction rats, HR reduction with ivabradine decreased left ventricular collagen density and increased left ventricular capillary density, without modifying left ventricular weight, indicating that HR reduction improves left ventricular function, increases stroke volume, and preserves cardiac output. This improvement in cardiac function was related not only to the HR reduction per se but also to the modification of the extracellular matrix and the function of the myocytes as a result of the long-term reduction in HR.21 These observations have been tested clinically with ivabradine in CAD patients with left ventricular dysfunction (ejection fraction <40%) with promising results.22 These results may be linked to modifications of left ventricular structure.
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Conclusion |
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TopAbstractIntroductionPharmacological heart rate...Heart rate, atherosclerosis, and...Heart rate and myocardial...Heart rate, remodelling, and...ConclusionReferences |
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There is little doubt that HR is a risk factor for cardiovascular mortality, throughout the cardiovascular continuum. Until today it has been difficult to determine whether HR reduction with β-blockers and non-dihydropyridine calcium antagonists or physical conditioning is responsible for the risk reduction because these interventions have multiple additional actions.
A definitive answer will be provided by the results of ongoing clinical trials with ivabradine. We can expect a number of clinical benefits from pure HR reduction in coronary patients. Pure HR reduction with ivabradine, which acts by specific and selective If inhibition, decreases oxygen demand and improves myocardial energetics; it increases diastolic perfusion time and preserves myocardial contractility and coronary vasodilatation during exercise. Ivabradine also protects the myocardium in acute ischaemic conditions and has favourable sustained remodelling properties in the long term. There is clinical proof of the anti-anginal and anti-ischaemic effects of ivabradine in stable angina.
Conflict of interest: Received consulting fees from Servier.
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