Focus: Heart rate reduction in heart failure: pathophysiological perspectives

Michael BÖHM, MD, PhD
Jan-Christian REIL, MD
Universitätsklinikum des Saarlandes
Klinik für Innere Medizin III

Heart rate reduction in heart failure: pathophysiological perspectives

by M. Böhm, J .C. Reil,
and F. Custodis,

Heart rate regulates cardiovascular output during stress and exercise. Chronic elevated heart rate is associated with increased morbidity and mortality in the general population at risk and in patients with cardiovascular disease. Physiological studies have shown that a high resting heart rate induces endothelial dysfunction, predisposes plaque to rupture, and is associated with cardiovascular end points like myocardial infarction and heart failure. High heart rates produce endothelial dysfunction through alteration of shear stress, and also accelerate atherosclerosis. Furthermore, elevated heart rate reduces the energy supply of the heart by reducing the length of diastole and increasing oxygen consumption. In heart failure, cardiac output is reduced through an inversion of the positive Treppe phenomenon (Bowditch effect). Heart rate is now regarded not only as a risk indicator, but a risk factor, because heart rate reduction has been shown to reduce cardiovascular events in patients with chronic heart failure. Meanwhile, clinical studies have provided pathophysiological proof for concepts that were generated through experimental investigation and observational and epidemiological studies.

Medicographia. 2011;33:444-450 (see French abstract on page 450)

Elevation of heart rate usually occurs as an adaptation of the cardiovascular system to increased demand from the peripheral circulation. Heart rate is regulated by the sympathetic and parasympathetic nervous systems and reflects important parameters in health and disease. Heart rate is a major determinant of myocardial oxygen demand, coronary blood flow, and myocardial performance, and has an effect at nearly all stages of cardiovascular disease.1,2

Many studies have focused on the predictive value of heart rate for cardiovascular outcomes in both the general population and individuals affected by cardiovascular diseases.3 Data show that elevated resting heart rate is an indicator of cardiovascular risk independent of currently accepted risk factors and other potentially confounding demographic and physiological characteristics,4-7 and that it is an important predictor of mortality in patients with coronary artery disease, myocardial infarction, and chronic heart failure.8-10 Experimental and clinical evidence suggests that sustained elevation in heart rate—irrespective of the underlying trigger—plays a direct and causal role in the pathogenesis of atherosclerosis and myocardial injuries, affects initiation and progression as well as severity of the disease, and contributes to precipitation of vascular and myocardial events.11

Atherosclerosis and myocardial infarction

Many studies have shown that an increase in heart rate is associated with an increase in stiffness of vessels, in particular the aorta.12 In vascular muscle cells, it was found that there is an increase in collagen production after stretching. This effect was dependent on the rate and amplitude of stretch.13 Accordingly, in primates with tachycardic pacing, there was decreased compliance of the carotid arteries.14 Correspondingly, in patients who died after an acute myocardial infarction, it was shown that the extent of coronary atherosclerosis was closely related to (higher) heart rate (Figure 1).8,15 In primates, ablation of the sinus node was associated with a reduction in cholesterol-induced atherosclerosis.16 Consistent with this finding, in Apo-E knockout mice, it was observed that cholesterol-induced atherosclerosis could be reversed by 70% when rate heart was decreased by 10% using the If channel inhibitor ivabradine (Figure 2).17 In addition, ivabradine was able to improve endothelial function in early forms of cholesterol-induced atherosclerosis.18 Improvement in endothelial function was associated with a reduction in free radicals.17 As shear stress during diastole is important for maintenance of endothelial function, it was speculated that reduction in shear stress during diastole could induce endothelial dysfunction and increase free radical formation in the vessel wall, and that this could be a target for treatment with a heart rate– reducing agent like the If channel blocker ivabradine.17,18

Figure 1
Figure 1. Effect of heart rate (bpm, beats per minute) on mortality
in patients with myocardial infarction.

After reference 8: Hjalmarson A et al. Am J Cardiol. 1990;65:547-553. © 1990,
Elsevier Inc.

These pathophysiological findings are in line with the clinical and epidemiological findings. The long-term prognosis of patients with stable coronary artery disease was found to be dependent on resting heart rate.19 In another study of 24 913 patients, it was found that total mortality rate, cardiovascular disease mortality rate, and the rate of cardiovascular rehospitalization increased with increasing heart rate.9 Patients with a resting heart rate of more than 83 beats per minute (bpm) had an increased overall relative risk of 1.24 and an elevated cardiovascular mortality risk of 1.31 compared with controls. Myocardial infarction develops when coronary plaques rupture and thrombosis occludes the vessel. Accordingly, the significance of heart rate regarding prognosis after myocardial infarction has also been shown; patients with myocardial infarction had significantly elevated heart rates compared with controls. Furthermore, higher heart rates at hospital discharge correlated with an increased mortality rate after 1 year. Metaanalyses of the Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico (GISSI)-2 and GISSI-3 trials, which included about 20 000 patients, demonstrated that the in-hospital mortality rate in patients post–myocardial infarction rose from 3.3% for those with admission heart rates of <60 bpm to 10.1% for those with heart rates >100 bpm on admission.20 The relevance of heart rate after myocardial infarction is supported by results from β-blocker trials. Heart rate reduction with β-blockers is associated with a decrease in total mortality and sudden cardiac death.15,21-23 In addition, heart rate–reducing verapamil-like calcium antagonists have been shown to exhibit beneficial effects on the prognosis of patients after myocardial infarction in the absence of heart failure.24

Figure 2
Figure 2. Aortic atherosclerosis in Apo-E knockout mice treated with vehicle or ivabradine.

Staining of aortic plaque in the aortic sinus (upper panels) and ascending aorta (lower panels), and quantification of plaque load (far right). A 10% reduction in heart rate is associated with a 50% to 75% reduction in plaque load.
After reference 17: Custodis et al. Circulation. 2008;117: 2377-2387. © 2008, American Heart Association, Inc.

Figure 3
Figure 3. Force of contraction (left) and change in diastolic tension (right) in isolated human papillary muscle strips.

The human papillary muscle strips from patients with severe heart failure (NYHA class IV) were compared with preparations from nonfailing donor hearts. Note that increasing stimulation rates
produced a decline in force of contraction and a relaxation deficit in failing human myocardium.Abbreviations: NF, nonfailing (donor heart); NYHA, New York Heart Association.
After reference 28: Böhm et al. Clin Investig. 1992;70:421-425. © 1992, Springer International.

Results of the important first morbidity and mortality trial investigating pure heart rate reduction in coronary heart disease were recently published by the BEAUTIFUL investigators (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary artery disease and left ventricULar dysfunction).10,25 This international multicenter trial was a randomized, double-blind, placebo-controlled investigation, and enrolled 10 917 patients with coronary artery disease and left ventricular dysfunction (left ventricular ejection fraction [LVEF] <40%). The aim of the study was to investigate whether heart rate reduction with ivabradine reduces cardiovascular death and morbidity in these patients. The active treatment group was treated with 5 mg twice daily of ivabradine, with a target dose of 7.5 mg twice daily. All patients continued their high-level therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (90%), as well as β-blockers (87%). The mean heart rate at entry was rather low (71.6 bpm) and the corresponding mean LVEF (32.4%) was significantly depressed. The primary end point comprised a composite of cardiovascular death, admission to hospital for acute myocardial infarction, admission to hospital for new onset or worsening of heart failure, and revascularization. The aforementioned clinical and epidemiological data provide proof of concept that the pathophysiological finding of a high heart rate is of clinical relevance to the structure and function of the vascular cell.

Heart failure

Elevated heart rate at rest is one of the key findings in acute and chronic heart failure. Chronic heart failure is associated with maladaptive neuroendocrine activation processes, which involve an elevation of resting and exercise heart rates. Pathophysiologically, in failing human myocardium, there is an inverse of the so-called Treppe phenomenon (Bowditch effect26), which results in reduced contractility when heart rate is increased.27,28 In addition to the reduction of developed force, diastolic function is also reduced at elevated heart rates (Figure 3).28

Large-scale randomized controlled morbidity and mortality studies have been performed in patients with heart failure with reduced ejection fraction with β-blockers, ACE inhibitors, angiotensin receptor blockers, and aldosterone antagonists. All studies have demonstrated a significant reduction in both mortality and morbidity (up to 30%) with the investigated agent.29,30 β-Blockers on top of standard therapy was generally regarded to be necessary.

The significance of heart rate on mortality was retrospectively addressed in subanalyses of the Cardiac Insufficiency Bisoprolol Study–II (CIBIS-II),31 MEtoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure (MERIT-HF),32 and Carvedilol Or Metoprolol European Trial (COMET).33 These large studies together enrolled a total of almost 10 000 patients with advanced systolic heart failure (New York Heart Association class II-IV). The general trend from these three trials clearly demonstrates that high heart rate at rest contributes to poor survival. These results are in line with those from previous studies of β-blockers and other drugs approved for heart failure therapy demonstrating greater benefits with higher baseline heart rates (>80 bpm), as well as with markedly reduced heart rates after drug treatment (>10 bpm reduction).29 It is currently unknown, however, as to whether— or to what extent—the benefit of β-blockers for patients with heart failure is due to heart rate reduction per se, or other beneficial effects derived from interrupting maladaptive β-signaling pathways (apoptosis, fetal gene expression, Ca²+ handling, etc).34 As β-blockers considerably reduce heart rate (negative chronotropy), they are most appropriate for comparison with ivabradine,35 a recently designed drug that delivers pure heart rate reduction through If channel inhibition.36

The first evidence providing proof of concept regarding the role of heart rate in heart failure came from Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT). SHIFT investigated the effect of selective heart rate reduction with ivabradine on top of proven recommended therapies in heart failure patients with a heart rate of >70 bpm in sinus rhythm and an LVEF of <35%. This controlled trial randomized 6500 patients with stable symptomatic heart failure (New York Heart Association II–IV) to ivabradine (target dose 7.5 mg twice daily) or placebo. Patients were intensively treated with recommended therapies (ACE inhibitors or angiotensin receptor blockers [92%], β-blockers [90%]). Ivabradine reduced heart rate by 11 bpm from an average baseline heart rate of 80 bpm. Heart rate reduction with ivabradine reduced the primary composite end point of cardiovascular death and hospitalization for worsening heart failure by 18%.37 Patient risk was closely dependent on baseline heart rate.38 Patients with a heart rate of <60 bpm on treatment with ivabradine had the lowest risk, while the risk doubled in patients remaining at a heart rate >80 bpm. A 5-bpm higher resting heart rate at increased the risk by 15% each year for cardiovascular death and heart failure hospitalization (Figure 4). SHIFT produced the first evidence that selective heart rate reduction with no other myocardial effects, as provided by ivabradine, has beneficial effects in patients with reduced ejection fraction.

Figure 4
Figure 4. Cardiovascular outcome in patients with stable heart failure (NYHA class IIIV)
treated with ivabradine according to heart rate achieved at day 28 after uptitration.

Abbreviations: NYHA, New York Heart Association; bpm, beats per minute.
After reference 38: Boehm et al. Lancet. 2010;376:886-894. © 2010, Elsevier Ltd.

Heart failure with preserved ejection fraction (HFPEF) is characterized by concentric left ventricular hypertrophy with impaired relaxation and reduced compliance, accompanied by only mildly impaired ejection fraction of ≥50%.39 Survival rates in patients with HFPEF have remained largely unchanged over the last two decades.40 Currently, only symptomatic treatment is given. Apart from the prescription of diuretics for HFPEF patients with pulmonary congestion and edema, the therapeutic goals are treatment of hypertension and myocardial ischemia, maintenance of sinus rhythm, optimal treatment of diabetes mellitus, and heart rate control. In addition to reducing afterload, heart rate reduction prolongs diastole and left ventricular filling time, providing additional time for diastolic relaxation due to improved Ca²+ ion reuptake into the sarcoplasmic reticulum. Consequently, lower heart rate reduces pulmonary pressure and extends diastolic coronary perfusion time, thereby preventing ischemia-induced diastolic dysfunction.1,2

Figure 5
Figure 5. Hemodynamic effects induced by heart rate reduction in a patient with heart failure with preserved ejection fraction.

Upper panel: Left ventricular pressure (red pressure curve) and pulmonary artery pressure (white pressure curve) at high heart rate (120 bpm). Lower panel: after intravenous administration of 5 mg metoprolol, heart rate is reduced (96 bpm). As a result, the mean pressure of the pulmonary artery considerably declines (from 46 mm Hg to 27 mm Hg), while systemic pressure (aorta) remains virtually unchanged.
Abbreviations: DP, diastolic pressure; EDP, end diastolic pressure; LV, left ventricular; HR, heart rate; MP, mean pressure; SP, systolic pressure.
After reference 35: Reil et al. Trends Cardiovasc Med. 2009;19:152-157. © 2009, Elsevier BV.

Unloading of the left ventricle with heart rate reduction was elegantly demonstrated in a case study of a patient with HFPEF (Figure 5, page 448).35 In the upper panel, left ventricular and pulmonary artery pressure curves are depicted at high heart rate (119 bpm). After an injection of 5 mg metoprolol, the heart rate decreases (to 96 bpm) at nearly constant systemic pressure (aorta), while the pressure of the pulmonary artery considerably declines (lower panel). These findings demonstrate that in this patient with HFPEF, improvement of left ventricular diastolic filling is associated with a decrease in pulmonary pressure. At present, one can only speculate as to whether pure heart rate reduction with ivabradine could produce results even superior to those of β-blockers in this special hemodynamic setting. Currently, however, there are no data available in HFPEF patients on the use of specific heart rate–reducing agents. Studies of this condition evaluating the pathophysiology and practical clinical benefits of such therapies are highly warranted. Case reports dealing with special hemodynamic alterations in cardiovascular disease, in particular heart failure, can demonstrate individual experiences with ivabradine.41 One patient with heart failure with reduced ejection fraction and acute left ventricular decompensation on adequate heart failure medication developed sinus tachycardia (120 bpm) with dyspnea while under dobutamine infusion on a cardiac care unit. Ivabradine was subsequently carefully titrated orally up to a dose of 15 mg/day to reduce heart rate while the patient was still undergoing dobutamine therapy. Within 5 days, heart rate had decreased (–34%) and there was a striking increase in stroke volume (+40%) accompanied by a simultaneous decrease in systemic and pulmonary vascular resistance (Figure 6). After ivabradine withdrawal, hemodynamic values worsened again, but readministration of ivabradine led to a weaning from dobutamine therapy over the next 3 days, and the patient recovered. This report and previous studies demonstrate the beneficial hemodynamic effects of ivabradine, even in acute hemodynamic deterioration.42

Figure 6
Figure 6. Hemodynamic improvement on ivabradine during acute left ventricular decompensation in advanced heart failure.

Ivabradine was titrated, withdrawn (0 mg/day), and readministered in order to wean the patient from dobutamine infusion (9 μg/kg/min).
Abbreviations: BPM, beats per minute; HR, heart rate; PVR, pulmonary vascular resistance; SV, stroke volume; SVR, systemic vascular resistance.
After reference 41: Link et al. Clin Res Cardiol. 2009; 98:513-515. © 2009, Springer, Part of Springer Science+Business Media.


Clinical and experimental studies support a significant association between elevated heart rate and a broad range of maladaptive vascular and myocardial effects. Increased heart rate impairs endothelial function in animal models, and may contribute to reduced vascular function. Heart rate reduction inhibits formation of atherosclerotic plaque in animal models of lipid-induced atherosclerosis, and may prevent or retard the final development in chronic heart failure. While experimental, epidemiological, and observational data have attracted interest, studies like BEAUTIFUL and SHIFT have provided considerable proof of the pathophysiological concept. The major task is to broaden this concept to conditions like heart failure with preserved ejection fraction, for which there are currently no treatments available proven to have an effect on clinical end points. _

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Keywords: cardiovascular disease; heart failure; heart rate; pathophysiology; risk factor; ivabradine