Jeffrey S. BORER, MD
Waqas KHAN, MD
Division of Cardiovascular Medicine, Department of Medicine, State University of New York Downstate
Medical Center and College of Medicine
Brooklyn and New York
Heart rate in heart failure: a novel cardiovascular risk factor
Heart rate (HR) is an easily measured parameter employed universally in clinical evaluation. Multiple studies during the past 65 years have established the utility of HR as a riskmarker for cardiovascular events and for total mortality in unselected (“nondiseased”) populations, as well as in cohorts with coronary artery disease, hypertension, and heart failure. However, to establish a risk marker as a risk factor, it is necessary to demonstrate not only that outcome is quantitatively related to the factor, but also thatmodification of the putative risk factor similarly modifies disease outcome. In order to demonstrate that HR is a risk factor for heart failure, it is necessary, first, to have a therapeutic modality that modifies HR, but no other cardiovascular parameter, and then to apply the therapy in patients with heart failure. Ivabradine meets the first criterion, and SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) showed that ivabradine is markedly superior to placebo in improving cardiovascular outcomes when administered on a background of guideline-based standard pharmacological therapy for heart failure. Thus, based on SHIFT, HR should be considered a risk factor for heart failure. Modulation of HR, specifically with ivabradine, should be considered in the management of patients with moderate-to-severe systolic heart failure.
Heart rate (HR), a simple and easily measured clinical parameter, is now known to hold a substantial amount of independent prognostic information in the free-living population as a whole,1,2 and in a number of subpopulations with various forms of heart disease. The latter include those with coronary artery disease (CAD), hypertension, and chronic heart failure (HF) (Figure 1).3-5 Much of the supporting information is derived from epidemiological studies and, thus, suggests that HR is a risk factor for these conditions, but in the absence of prospective demonstration from randomized clinical trials, cannot definitively establish HR as a risk factor. Nonetheless, this association is biologically plausible: experimentally, HR has been shown to be directly related to the progression of coronary atherosclerosis6,7; clinically, HR is directly related to the likelihood of disrupting preexisting atherosclerotic plaque.8 Most recently, in a large placebo-controlled clinical trial, HR was found to be directly associated with outcome among patients with HF.9,10 The latter association also has biological plausibility: failing myocardium has a negative force-frequency association and is energetically starved.11,12 HR reduction can improve contractility, perhaps by reducing energy expenditure, decreasing myocardial oxygen consumption, and enhancing the relationship between energy requirements and energy availability.13,14 Therefore, it is possible that HR-slowing therapies may hold a particular advantage for patients with various forms of cardiovascular disease (CVD). Indeed, guidelines from the European Society of Cardiology and European Society of Hypertension for the prevention of CVD already recommend recognition of HR as a cardiovascular risk factor.15,16 This review article aims to assess the accumulating evidence in support of HR as a risk factor for cardiovascular mortality and morbidity, specifically in HF.
Figure 1. Heart rate as a predictor of outcome in patients with coronary artery disease receiving placebo.
After reference 3: Fox et al. Lancet. 2008;372:817-821. © 2008, Elsevier Ltd.
Heart rate and mortality in different populations
_ Unselected populations
Beginning as early as 1945, many epidemiological studies have reported that HR is strongly and directly associated with all-cause and cardiovascular mortality in unselected (“nondiseased”) populations.1,2,17-20 For example, in a Framingham cohort of 5070 subjects free from clinically apparent CVD at study entry, cardiovascular and noncardiovascular mortality increased progressively with resting HR, irrespective of age.1 Similarly, in three studies organized in Chicago, all in males, HR at rest was directly associated with sudden cardiac death.2 More recently, two large prospective studies have confirmed the strong and graded relationship between resting HR and cardiovascular and total mortality.18,19 In the Paris Prospective Study of >5000 men aged 42 to 53 years, HR was measured at rest every year for 5 consecutive years.18 Those participants whose HR decreased during the 5 years had a 14% (P=0.05) decrease in mortality risk compared with those whose HR was unchanged; men with increased HR during the 5 years had a 19% (P<0.012) increase in mortality. Among 21 853 men and women in the prospective national FINRISK study (Finland Cardiovascular Risk Study), a strong, graded, independent relationship between resting HR and incident CVD was also demonstrated.19
A resting HR of more than 90 beats per minute (bpm) was associated with an almost twofold increase in cardiovascular mortality rate in men and a threefold increase in women, compared with a resting HR of less than 60 bpm. These results confirmed findings from other studies indicating the independence of HR effect from sex.19 Finally, in a prospective study of Chinese adults followed on average for 8.3 years, HRs of 75-89 bpm and ≥90 bpm in men resulted in a 1.12- fold and 1.32-fold increase in the risk of CVD, respectively, compared with lower HR.20 Similarly, in women, there was a 1.23-fold increase in risk if HR exceeded 90 bpm. A unique finding in this study was increased stroke risk in subjects with HR ≥90 bpm, not found in Western populations.21,22
Figure 2. Data from the Framingham cohort demonstrating the relationship between heart rate and death from all causes, cardiovascular disease, and coronary heart disease among individuals with hypertension.
Abbreviations: bpm, beats per minute; CHD, coronary heart disease; CVD, cardiovascular disease.
1993;125:1148-1154. © 1993, Elsevier Inc.
HR varies directly with sympathetic activity and therefore could be directly related to the proclivity for hypertension. This may be one explanation for the observation that, in subjects with hypertension, cardiovascular mortality risk increases directly with HR (Figure 2).21,23,24 One of the strongest relationships in hypertensive patients was found by Benetos et al, who studied more than 12 000 French men aged 40 to 69 years. During 20 years of follow-up, the investigators found that HR was directly related to cardiovascular death, with hazard ratios of 1.35 (95% confidence interval [CI], 1.01-1.80) for HR of 60 to 80 bpm, 1.44 (95% CI, 1.04-2.00) for HR of 81 to 100 bpm, and 2.18 (95% CI, 1.37-3.47) for HR >100 bpm, compared with HR <60 bpm.21 In the Systolic Hypertension in Europe (Syst-Eur) trial, clinic and ambulatory HR was directly associated with all-cause, cardiovascular, and noncardiovascular mortality among both elderly hypertensive men and women.23 In addition to the association between initial study HR and outcome, HR while on treatment in hypertensive patients also predicts likelihood of subsequent cardiovascular or all-cause mortality, independent of treatment modality.24 In a study of 9190 hypertensive patients with echocardiogramindicated left ventricular hypertrophy followed for almost 5 years while being treated with losartan-based or atenololbased regimens, HR increments of 10 bpm while on treatment were associated with a 25% increment in cardiovascular death and a 27% increment in all-cause mortality. In an alternative analysis, persistence or development of HR ≥84 bpm (upper quintile of baseline HR) was associated with an 89% greater risk of cardiovascular death and a 97% increased risk of all-cause mortality compared with lower HR. These findings support the value of serial assessment of HR for risk stratification in hypertensive patients.
The relationship between resting HR and adverse outcomes in patients with hypertension and CAD was examined in INVEST (INternational VErepamil-SR/trandolapril STudy).4 In this study of 22 576 hypertensive patients with CAD randomized to either verapamil SR-based or atenolol-based treatment strategies, baseline HR was directly associated with adverse outcomes, which were twofold greater among patients with HR >100 bpm than among those with HR <100 bpm. A linear relationship was observed between baseline HR and risk of adverse outcomes: 5-bpm increments were associated with 6% risk increments.
Impaired autonomic function is associated with abnormal concentrations of serum insulin and abnormal insulin resistance, independent of blood glucose concentrations.25 This suggests that autonomic dysfunction may be a consequence and also a precursor to hyperglycemia. The relationship between autonomic dysfunction and development of diabetes was further explored in the ARIC study (Atherosclerosis Risk In Communities).26 The authors demonstrated that individuals with autonomic dysfunction, determined by low HR variability and high resting HR, were at a relatively high risk of developing diabetes over the succeeding 9 years, even when body mass index and physical activity were taken into account. Furthermore, in a post hoc analysis of the Diabetes Prevention Program (DPP) randomized trial of more than 3000 nondiabetics with abnormal fasting and postload plasma glucose concentrations, who were assigned to placebo, metformin, or a lifestyle-modification program, lower HR was associated with lower risk of developing diabetes, independent of weight change.27
HR is also a powerful predictor of cardiovascular outcomes in established diabetics. This was clearly demonstrated in a study of 475 patients (aged 55 to 75 years) with type 2 diabetes who were followed over the course of 5 years, during which 57 (13.5%) died due to cardiovascular causes.28 In this population, HR >75 bpm was associated with an odds ratio for cardiovascular death of 3.3 (95% CI, 1.33-8.19) compared with the risk at lower HR. In another study of 14 992 Medicare participants aged 35 to 64 years who were free from diabetes at baseline (1992), over the next 10 years, HR was associated with diabetes mortality in those aged 35 to 49 years at baseline when adjustment was made for postload glucose and body mass index.29
_ Coronary artery disease
Experimental data suggest that tachycardia results in development and progression of atherosclerosis. Reasons may include the direct relation of HR to hemodynamic shear stress (possibly due to shortening of diastole and changes in flow direction), which may damage intercellular junctions, increasing the permeability of endothelial cells and facilitating the ingress of atherogenic particles into the tunica media.30 Tachycardia also tends to increase mean arterial pressure by shortening diastole, thus increasing pulse pressure. The result is an increase in cardiac workload and thickening of arteriolar smooth muscle.31 HR is also inversely related to arterial compliance.32 Studies in experimental animals support the relationship between HR and CAD. Beer et al ablated the sinus node in adult monkeys and also studied an equal number of nonablated monkeys, all fed on an atherogenic diet for 6 months.6 The controls, with persistently higher HR, had a significantly higher number of and more serious coronary artery atherosclerotic lesions than the test animals (P<0.02). Similar relationships have been reported in other studies.33
A direct relationship between HR and progression of coronary atherosclerosis has also been shown in humans. Perski et al observed that HR on 24-hour ambulatory electrocardiogram predicted progression of CAD, independently of (and, indeed, more predictively than) conventional risk factors.7 Huikuri et al described the association between HR and progression of focal coronary atherosclerosis in patients with coronary artery bypass grafts.34
The prognostic importance of HR in patients with known chronic CAD and in those surviving after myocardial infarction has been repeatedly demonstrated. In a large cohort of Israeli patients hospitalized for acute myocardial infarction in 1985-1986, Disegni et al recorded all deaths during initial hospitalization and at 1 year post discharge.35 On multivariate analysis, admission HR was an independent predictor of in-hospital and 1-year postdischarge mortality. The CASS (Coronary Artery Surgery Study) registry investigated the longterm prognostic value of resting HR in nearly 25 000 patients with suspected or proven CAD.36 Cardiovascular mortality increased progressively with increasing HR: resting HR ≥83 bpm was a strong predictor of overall mortality (hazard ratio, 1.32; 95% CI, 1.19-1.47; P<0.0001) and cardiovascular mortality (hazard ratio, 1.31; 95% CI, 1.15-1.48; P<0.0001), independent of known risk markers such as hypertension, diabetes, smoking, left ventricular ejection fraction, and the number of hemodynamically significantly diseased coronary vessels. In INVEST, in patients with hypertension and CAD, baseline and follow-up resting HR were directly associated with risk of adverse outcomes.4 Hjalmarson et al demonstrated that admission HR in patients with myocardial infarction is directly related to clinical outcome: they reported all-cause mortality at 1 year of 14% when admission HR was <60 bpm, 41% when admission HR was >90 bpm, and 48% when admission HR was >110 bpm.37 Meta-analyses of the GISSI-2 and GISSI-3 trials (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico), which included about 20 000 patients, found that in-hospital mortality rates after myocardial infarction rose from 3.3% for patients with admission HR <60 bpmto 10.1%for patients with admission HR >100 bpm.38 As a corollary, both mean HR and failure of HR to fall between hospital days 1 and 7 carry a poor prognosis.39 HR is also an independent prognosticator in patients with acute ST-segment– elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. An analysis of 6- month follow-up data from 2477 consecutive patients with STEMI treated by primary percutaneous coronary intervention revealed that HR >80 bpm was associated with more than a twofold increased risk of death compared with lower HR.40
The value of HR as a prognostic factor was also evaluated in the 5438 patients in the placebo arm of BEAUTIFUL (mor- Bidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary artery disease and left ventricULar dysfunction).3 This large cohort with stable CAD and left ventricular dysfunction was divided into those with HR ≥70 bpm and those with HR <70 bpm at study entry. The group with higher entry HR had significantly higher adverse cardiovascular outcome rates compared with those who entered with lower HR (34%greater cardiovascular death, and higher hospital admissions for HF, myocardial infarction, and revascularization [53%, 46%, and 38%, respectively]). These findings have recently been corroborated by results from the TNT trial (Treating to New Targets).41 An analysis of 9580 subjects followed for a median of 4.9 years revealed a major cardiovascular event rate of 11.9% in those with a baseline HR of ≥70 bpm compared with a rate of 8.8%in those with a baseline HR <70 bpm.
Congestive heart failure
The prognostic value of resting HR extends to patients with chronic HF. HF is common, disabling, and serious, affecting roughly 2% to 3% of the population in developed countries.42 Standard pharmacological treatment for HF includes β-blockers and renin-angiotensin-aldosterone system antagonists. β-Blockers, amainstay of therapy, are associated with reduced morbidity and mortality beyond that achieved with renin-angiotensin- aldosterone system antagonists.43 These benefits seem to be linked, at least in part, to their HR-lowering properties.44,45 HR reduction may be particularly important in chronic HF, as it decreases energy expenditure,14 increases coronary blood supply by prolonging diastole, and improves in vivo46 and in vitro12 force-frequency associations. Furthermore, HR is directly related to vascular elastance, and thus, ventricular loading.47 Thus, HR reduction unloads the ventricle, with the greatest effect in diseased hearts.48 The effect of β-blocker–induced HR reduction has been analyzed in different studies.44,49,50 HR reduction in these studies was fairly similar, and the results suggested that mortality benefits were directly related to magnitude of HR reduction. However, these studies could not separate the effects of HR reduction from those of other potentially important actions of β-blockers, such as antiarrhythmic effects, inhibition of maladaptive β-adrenergic signaling pathways producing apoptosis,51 or reduction of β-adrenergic signaling dysregulating contractility.
Figure 3. Ivabradine improves outcomes in heart failure.
After reference 9: Swedberg K et al. Lancet. 2010;376:875-885. © 2010, Elsevier Ltd.
Figure 4. Ivabradine significantly reduces death from heart failure.
Abbreviations: HF, heart failure; HR, hazard ratio.
After reference 9: Swedberg K et al. Lancet. 2010;376:875-885. © 2010,
Figure 5. Data from the placebo group in SHIFT.
Data show that heart rate is a predictor of cardiovascular death and/or heart failure hospitalizations in
chronic heart failure. Increase in risk of 2.9% per 1 bpm, 15.6% per 5 bpm.
Abbreviations: bpm, beats per minute; SHIFT, Systolic Heart failure treatment with the If inhibitor ivabradine Trial.
After reference 10: Boehm et al. Lancet. 2010;376:886-894. © 2010, Elsevier Ltd.
The impact of SHIFT
In recent decades, the association between HR and cardiovascular morbidity and mortality in HF has been increasingly appreciated, but the impact of HR modulation has remained less than totally clear because of the relationship between HR and conventional CVD risk factors.52 Thus, it has been unclear as to whether HR is a marker of underlying hemodynamic and metabolic abnormalities and therefore, of risk, or whether HR is truly an independent risk factor, downward modification of which is associated with reduction in risk. Assessment of this issue required a therapeutic modality that could reduce HR without affecting other aspects of cardiovascular function and pathophysiology. Ivabradine, as a selective HR-reducing agent (via blockade of the sinoatrial nodeIf current [“funny” current, mediated by voltage-dependent cyclic AMP interactions] with no other apparent cardiovascular effects), provided a unique opportunity to define the impact of pure HR reduction in HF. To address this, SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) investigated the effects of HR reduction with ivabradine on clinical outcomes in HF.9,10 SHIFT was an event-driven, randomized, double-blind, placebo-controlled trial in which either ivabradine or placebo was administered for a median of 22.9 months to 6505 patients who were also receiving a background of guideline-defined standard multidrug therapy on evidence-based recommended doses ormaximally achievable dosages if lower than recommended. The primary outcome event in SHIFT was the composite of death or HF hospitalization in patients with moderate-to-severe chronic HF and left ventricular systolic dysfunction.
To establish the clinical validity of epidemiological association between a risk factor and any CVD, several criteria should be satisfied.53 The risk factor must have a direct relation with the likelihood of a disease, should contribute to the development of the disease regardless of sex, age, or race, should manifest a relationship with outcome that is statistically independent of other known or previously accepted risk factors and, most importantly, when it is modified to reduce its magnitude, this modification must similarly modify the outcome (beneficially) of the disease. In addition, to be clinically useful, the risk factor must be readily measurable and there must be considerable evidence linking the risk factor to the disease.
As noted previously, many studies have shown that HR, an easily measured clinical variable, is a significant predictor of total mortality and cardiovascular mortality. This relationship is strong, graded, and independent of other prognostic factors. Confirmation from SHIFT that HR reduction reduces cardiovascular events in patients with HF9,10 clearly establishes HR as a true risk factor for this disease, as it also appears to be for CAD.53 Therefore, it is reasonable and appropriate to consider HR in risk stratification and as a guide for medical therapy, specifically that involving the administration of ivabradine in addition to other already established HF therapies, in patients with HF. _
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Keywords: cardiovascular disease; coronary artery disease; heart failure; heart rate; ivabradine; risk factor; risk marker