Since 1953, sinus tachycardia has been defined as a heart rate (HR) in sinus rhythm of >100 beats per minute (bpm). However, this number has never been formally evaluated, and no established threshold values for special groups, such as those with heart failure (HF) accompanied by a reduced ejection fraction (HFrEF). Herein, we provided evidence that lowering the HR of patients with HFrEF to <70 bpm with medications such as ivabradine improves outcomes. Numerous large-scale trials and smaller clinical studies have shown that reducing the HR in patients with HFrEF improves cardiovascular and overall outcomes. Evidence suggests that a HR of <70 bpm is appropriate for patients with HFrEF. Examination of HF registries indicates that in a large proportion of these patients the HR exceeds 80 bpm, and no consideration is given to lowering the HR, due in large part to lack of physician awareness of the benefits of a lower HR. Evidence indicates that the first-line medication for lowering HR in patients with HFrEF is ivabradine. In conclusion, the improved prognosis following appropriate HR management in patients with HFrEF suggest that the cut-off value for sinus tachycardia in these patients should be redefined as 75 bpm. Maintaining a HR of <70 bpm in patients with HFrEF is associated with improved cardiovascular and overall outcomes.
Introduction
Although many efforts have been made in the past 2 decades to increase medical treatments for patients with heart failure (HF) (e.g., angiotensin-converting enzyme inhibitors, little has been published with respect to the role of heart rate (HR) and outcomes of patients with HF, nor is there extensive knowledge in the medical community that lowering the HR of patients with HF with medical treatments can improve outcomes. Thus, the purpose of this report is to review the role that HR plays in the outcomes of patients with HF, and to increase awareness that proper management of HR with medical therapy to lower HR can rapidly improve the outcomes of patients with HF accompanied by a reduced ejection fraction (HFrEF).
Heart Rate as a Risk Factor for Poor Cardiovascular Outcomes
In the general population and patients with HF, an elevated resting HR (in sinus rhythm) increases the risk of adverse cardiovascular events. Relations between cardiovascular outcomes in patients with HF and HR in the emergency department, at hospital admission, and at hospital discharge have been observed. There is consensus in the medical community that a patient’s vital signs in the emergency department can be used for risk stratification and management of HF. Claret et al. analyzed the data of 1,638 patients over the age of 50 years with acute HF, and found that patients with a HR of <50% of their maximal HR had fewer severe adverse events, whereas patients with a HR of >75% of their maximal HR had the highest rate of severe adverse events.
In patients with acute decompensated HF, the baseline HR at hospital admission is a useful predictor of outcomes. However, HR at hospital admission only represents a transient hemodynamic status, and is thus only predictive of early cardiovascular events and not predictive of adverse events in the long-term. ,
With respect to HFrEF, a lower pulse rate at the time of HFrEF diagnosis and across follow-up visits has been shown to be strongly associated with a lower risk of mortality and hospitalization, independent of the use of beta-blockers. An analysis of data obtained in 2 large studies of HFrEF (the PARADIGM-HF and ATMOSPHERE trials) concluded that an elevated baseline HR (in sinus rhythm) was an independent predictor of adverse cardiovascular outcomes, even after adjustment for N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) level.
Mechanisms by Which Lowering Heart Rate Improves Heart Function and Symptoms
Pharmacological HR reduction has been demonstrated to improve symptoms and prognosis in patients with HFrEF . However, the mechanisms by which HR affects cardiac performance in patients with HF are rarely discussed. An elevated HR can cause endothelial cell dysfunction, and thus increase the risk of plaque rupture, reduce coronary blood flow because of a shortened diastolic period, increase myocardial oxygen consumption further inducing myocardial ischemia, and depress the positive force–frequency relation (Bowditch effect); effects that are especially prominent in patients with HFrEF. , This review focuses on the hemodynamic effects of HR reduction in patients with HF, which are the cornerstone of HR-lowering therapies in patients with HFrEF.
Heart rate and the pressure-volume loop
Reducing the HR can reduce afterload and relieve left ventricular wall stress, thus subsequently increasing stroke volume (SV). The relation between HR and afterload can be illustrated by the left ventricle (LV) pressure-volume (PV) loop. Effective arterial elastance (Ea) is the ability of vessels to accommodate pulsatile flow generated by contraction of the LV ( Figure 1 ). Ea serves as a surrogate marker of afterload, and is calculated by dividing the end-systolic pressure (ESP) by the SV. ESP is assumed to be similar to the mean systolic pressure, and is thus calculated as the product of cardiac output (CO) and total peripheral resistance. Therefore, Ea can be expressed as: Ea = HR × total peripheral resistance. As HR increases, the slope of Ea increases ( Figure 2 A and B, Ea’), which indicates an increased afterload.
Arterial pulsatile load and heart rate
Lowering the HR can also improve hemodynamic parameters as a result of reducing the pulsatile load. The arterial pulse begins with contraction of the LV, which rapidly increase pressure in the proximal aorta. The aorta and large arteries subsequently expand during systole to accommodate this pressure fluctuation. When the pressure falls during diastole, the walls of the aorta and large arteries recoil to maintain blood pressure and distal blood flow. This cushioning effect provided by the aorta and large arteries converts a discrete pulse into a nearly constant flow that feeds distal capillaries. The pulsatile arterial load is primarily determined by the stiffness of large conduit arteries, which is associated with HR. A study investigating patients with a permanent pacemaker demonstrated that a higher pacing frequency was associated with a higher pulse wave velocity, which is a standard measurement of arterial stiffness. The major arteries become less compliant as HR increases, and the vessel wall properties shift according to the Ea equation described in the prior section. Decreased arterial compliance results in reduced buffer function, and an increased pulsatile load from the aorta and major arteries. HFrEF patients showed significantly impaired left atrial (LA) reservoir function compared to normal subjects.
Impaired LV function and heart rate
As discussed, lowering HR can improve cardiac efficiency by decreasing arterial stiffness, and lowering an abnormally high HR is especially important for patients with a reduced EF. LV contractility increases with increasing HR through a mechanism known as the force–frequency effect, which may partially compensate for the elevated afterload caused by an increased HR ( Figure 2 A). As a result, an increase in afterload due to an increased HR without a concurrent increase in LV contractility results in a significantly reduced SV in patients with impairment of LV function ( Figure 2 B).
Left arterial pressure and heart rate
An increase of left atrial pressure can result in stiffness and alterations of the relaxation period of the left atrium (LA). During diastole, the LA drains into the LV due to a pressure gradient as the mitral valve opens. Therefore, if LV end-diastolic pressure increases there is an increase of left atrial pressure to maintain adequate filling of the LV. The LV diastolic filling period is correlated with HR, and an increase in HR reduces the time for diastole LV filling and induces an abrupt elevation of left atrial pressure. As such, HR is an indirect determinant of left atrial pressure. In a study of 331 patients who underwent radiofrequency catheter ablation for atrial fibrillation, left atrial pressure was directly measured via a catheter in the LA at different pacing frequencies. The results showed that the peak left atrial pressure increased as the HR increased from 90 bpm to 120 bpm, suggesting that a lower HR could favorably affect the hemodynamics of the LA and the LV.
Taken together, the aforementioned mechanisms suggest that a lower HR, and hence rate-lowering therapies, is important in the acute and chronic phases of HFrEF. The relation between HR-lowering treatments and prognosis was investigated in a study of 421 patients with acute decompensated HF. The results showed that a HR reduction at discharge of ≥ 27 bpm (as compared to the baseline value) reduced subsequent adverse events. These results suggest that adequate control of HR provides rapid benefits in patients with acute decompensated HF.
Defining Sinus Tachycardia in HFrEF
A number of studies have indicated that higher HRs in patients with HF are associated with worse outcomes. One study reported that in patients with HF, a HR of ≥75 bpm at the time of discharge was significantly associated with increased all-cause mortality. In addition, a similar association was observed between HR and all-cause hospital readmission. In the EVEREST trial, a pre-discharge HR of ≥70 bpm was found to be an independent predictor of mortality within 4 weeks of discharge. Notably, a 5 bpm increase in HR during the first-week post-discharge was associated with a 13% increase in all-cause mortality. A sub-analysis of the ASCEND-HF trial data revealed a similar finding; i.e., a discharge HR ≥70 bpm was associated with an increased mortality rate.
The BEAUTIFUL trial demonstrated that sinus HR was critically involved in the pathophysiology of HF, and a reduction in HR interfered with the progression of the disease. An analysis of the data indicated that HR-lowering treatments in patients with coronary artery disease and systolic HF only resulted in improved outcomes in the subgroup of patients with a baseline HR of ≥70 bpm.
Taken together, the results of the aforementioned studies indicate that in patients with systolic HF, the sinus tachycardia should be defined as a HR of ≥75 bpm. Furthermore, treatment to lower the HR in these patients to <70 bpm may improve outcomes.
Sinus Tachycardia is Undertreated in Heart Failure, Especially HFrEF
While an elevated HR is associated with poorer outcomes in patients with systolic HF, a large proportion of patients are either untreated or undertreated. Studies of HF registries established in the last decade have indicated that the HR of patients with HF admitted to the hospital is generally >90 bpm. , Analysis of the TSOC-HFrEF registry found that the average HR at discharge was approximately 80 bpm. It should be noted that HR at discharge is a relatively new clinical endpoint, and is not reported in many studies.
HR management is often overlooked in patients with chronic stable HF undergoing “optimal” treatment. A multicenter study of 549 patients with chronic HF in sinus rhythm undergoing optimal treatment reported that 32% of patients had a HR of >70 bpm, and 21% had a HR of >75 bpm. The Sweden Heart Failure registry includes data of 18,858 patients with HFrEF treated with the goal of stabilization; 47% of patients with sinus rhythm had a HR of > 70 bpm. Interestingly, failure to achieve a target HR of <70 bpm in patients with HFrEF was related to physician decisions. Approximately 50% of physicians considered a HR of >70 bpm optimal. A similar number considered a HR of >70 bpm too high; however, many physicians did not recommend treatments even though they considered the HR too high. These findings suggest a lack of awareness and/or failure to adhere to optimal HR control in patients with HFrEF.
Heart Rate Lowering Treatments for Patients With HFrEF
Beta-blockers, I f -channel blocker, and digoxin are the recommended medications for lowering HR in patients with HFrEF.
Beta-blockers
Several randomized, controlled clinical trials have demonstrated that treatments of HF with beta-blockers significantly improve LVEF, reverse LV maladaptive remodeling, and reduce all-cause mortality after treatment from months to years. , Beta-blockers also reduce ventricular arrhythmias by blocking beta-1 receptors throughout the myocardium, and thus are beneficial for reducing medium-term risks.
Beta-blockers are widely used in clinically stable patients with HF, with a low dose initially administered which is then gradually tapered up to the maximum tolerable dose. However, beta-blockers can cause negative inotropic effects on cardiovascular hemodynamics, and this causes hesitation among many clinicians regarding prescribing beta-blockers for patients with HF, or increasing the doses. On the other hand, a meta-analysis reported that beta-blockers were beneficial for the treatment for acute decompensated HF, although long-term outcomes remain unknown.
I f -channel blocker
Ivabradine is a specific inhibitor of the I f current in the sinoatrial node that reduces the HR of patients in a sinus rhythm. Ivabradine is recommended for patients with HFrEF who are stable in sinus rhythm with a resting HR of ≥70 bpm. It could lower the HR by an average of 8 bpm in SHIFT study. Ivabradine significantly reduces the severity of HF over 1 week based on New York Heart Association class, and improves LVEF over 4 months. Lowering the HR have been demonstrated to reduce the hospitalization rate for HF after 30 days, and reduce the HF mortality rate at a follow-up period of 2.5 years.
A comparison of outcomes in HF patients treated with beta-blockers and ivabradine is shown in Table 1 .
