Heart Rate Modulation in Heart Failure

Time to Slow Down?

• chronotropic incompetence
• exercise capacity
• heart failure
• heart rate

Exercise intolerance is a cardinal manifestation of heart failure (HF) that potently predicts adverse outcomes. The gold standard indicator of exercise tolerance is oxygen consumption at peak exercise (pVo₂) (1). In HF, there is impairment in the reserve capacity of each component of the coordinated metabolic machinery that permits increased oxygen utilization during exercise (Figure 1) (2,3). Our understanding of how exercise capacity is influenced by selectively altering single components of this integrated metabolic machinery remains incomplete. Insights into the relative contribution and interaction of variables that affect exercise capacity in HF may ultimately guide individualized therapeutic interventions.

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Figure 1

The Integrated Metabolic Machinery of Exercise

Shown are the multiple, coordinated components of the exercise metabolic machinery and the role of cardiopulmonary exercise testing in their assessment. Highlighted are changes associated with exercise within each component including central augmentation of stroke volume and heart rate as well as peripheral augmentation of oxygen extraction. C(a-v)O₂ = arterio-venous oxygen content difference; CPET = cardiopulmonary exercise testing; Hb = hemoglobin; HR = heart rate; PVR = pulmonary vascular resistance; SV = stroke volume; SVR = systemic vascular resistance; Vasc = vasculature; V_CO2 = carbon dioxide output; V_O2 = oxygen consumption; V_T = tidal volume.

Of the myriad components of the metabolic machinery, abnormal heart rate (HR) augmentation during exercise (i.e., chronotropic incompetence [CI]) has been a focal point, given its prevalence (estimated to be 60% to 80% in HF with reduced ejection fraction [EF]), the potential for its modulation (e.g., via adjustment of nodal agents, cardiac pacing), and its association with adverse clinical outcomes (4). There remains, however, considerable debate regarding the benefits of HR augmentation in HF with reports of marked improvement in exercise capacity (5) counterbalanced by null associations (6).

In this issue of the Journal, Jamil et al. (7) examine the relationship between exercise heart rate rise (HRR) and exercise capacity in patients with HF and reduced EF (HFrEF). They report a retrospective analysis of 195 patients referred for cardiopulmonary exercise testing (CPX) as well as 2 randomized, crossover interventional studies in patients with HFrEF, clinical stability, and previous pacemaker implantation. Prospectively evaluated interventions included: 1) exercise HR augmentation in 79 patients via rate-adaptive pacing (vs. fixed-rate pacing); and 2) exercise HR decrement in 40 patients using either pharmacotherapy (ivabradine) or lowering of the programmed pacemaker rate. Exercise testing was performed using a modified Bruce protocol with an initial low-level phase. The efficacy of HR interventions were assessed based on their impact on pVo₂, exercise time, and other CPX measures known to influence prognosis in HF such as exercise ventilatory efficiency (i.e., V_E/V_CO2).

In their retrospective analysis, the correlation between HRR and pVo₂ was highest for participants without HF (r² = 0.42) and progressively weaker for those with HF and modest left ventricular (LV) dysfunction (LVEF 35% to 50%; r² = 0.37) or severe (LVEF <35%; r² = 0.18). In this referral population, the prevalence of CI (defined as a ratio of observed HR increment to age-adjusted expected HR increment <0.80) in those with HF was 73%. Those with CI had lower exercise time and pVo₂ compared to those without CI. In prospective analyses, the impact of HR modulation was examined separately for those in sinus rhythm (SR) and atrial fibrillation (AF). HR augmentation was associated with an increased pVo₂ in AF but not SR. In contrast, HR decrement during exercise was associated with a prolonged exercise time but no change in pVo₂ in AF; there was no impact on exercise indices with HR decrement for those in SR.

Jamil et al. (7) should be congratulated on this important contribution to our understanding of the relationship between HR and exercise capacity in HF. In particular, the use of prospective randomized crossover design interventions focused on HR modulation and the inclusion of gas exchange measures related to prognosis in HF are features that distinguish these data from the previous literature. The study is particularly important and timely in light of the growing body of evidence linking lowering resting HRs to improved outcomes in HF and recent approval of ivabradine for the treatment of HFrEF (8). The findings of Jamil et al. (7) cast significant doubt on the causative role of CI in exercise intolerance in HF and on a uniform strategy aiming for higher exercise HRs among unselected HF patients. However, patient selection, study design, and analytic measures utilized are important to consider for contextualizing these findings and help frame opportunities for future investigation.

First, the mode of CPX has important implications in the analysis of exercise intolerance and HR interventions in HF. Although treadmill exercise is preferable to cycle ergometry to trigger rate-responsive pacing, this study utilized a Bruce protocol that employs significant stepwise increments that pose a challenge to HF patients. Indeed, the exercise times in the HR intervention arms of this study appear to cluster just beyond the steep transition from stage 1 to 2 of the Bruce protocol. Moreover, the lower respiratory exchange ratio values in HF patients compared to controls suggests that HF patients may have stopped exercising prematurely due to challenges with the ramp protocol, potentially confounding the reported HRR-Vo₂ relationships. To the extent that exercise was limited by mechanisms related to the protocol itself, there may have been decreased power to detect differences in the effects of HR interventions in this study. In contrast, more gradual treadmill ramp protocols such as the modified Naughton protocol used in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) (9) or the National Heart, Lung, and Blood Institute Heart Failure Network Protocol (10) may better reflect “real-world” exertion in HF patients and better capture the impact of HR interventions during different phases of exercise (e.g., submaximal vs. maximal).

Second, Jamil et al. (7) present convincing data that exercise HR modulation is not associated with changes in exercise capacity in the population of HF patients studied. Using a binary categorization of HR response (CI present vs. absent), Jamil et al. (7) found no significant difference in response to HR interventions. This analysis is based on limited power conferred by the rare prevalence of “absent CI” (e.g., 13 of 79 patients in the HR augmentation protocol). Whether patients with the greatest degree of CI derive benefit from HR augmentation remains an open question. The magnitude of changes in exercise HR achieved is also important to consider. For example, was the difference in ΔHR for the HR augmentation intervention (∼+90% vs. +70% with rate-response “on” vs. “off” for the SR group) sufficient to detect a difference in pVo₂? By comparison, in a previous study of rate-responsive pacing in advanced HF that required the presence of CI for inclusion, HRR in the rate-response “off” arm was only +30% and there was a significant correlation between ΔHR and ΔVo₂ with rate-responsive pacing (5). Further highlighting the importance of patient selection in chronotropic interventions are the recent and conflicting data regarding HR lowering in HF with preserved EF, with 1 study reporting a significant improvement in pVo₂ with ivabradine (ΔVo₂: +3 ml/min/kg) (8) and the other reporting significant worsening (ΔVo₂: -3 ml/min/kg) (11).

Third, although this study did assess change in pVo₂ and exercise duration in response to HR interventions, there was no direct measurement of the impact of HR modulation on the other components of the metabolic machinery (Figure 1). The relationship between HR modulation and SV, for example, is influenced by ventricular compliance (e.g., LV hypertrophy) (12) and previous work has highlighted the potential inverse relationship between rapid atrial pacing and SV in HFrEF (13). Jamil et al. (7) appropriately highlight the possibility of ineffective calcium handling and impaired myocardial energetics at higher HRs, and the impact of HR modulation on SV may have been further influenced by pacing mode (e.g., biventricular vs. asynchronous right ventricular apical pacing). Direct assessment of stroke volume would have provided critical insight into why Vo₂ was unchanged in response to HR modulation.

It is also important to consider the critical role of peripheral oxygen (O₂) transport in limiting exercise capacity in HF, which may in turn blunt the efficacy of cardiac-specific interventions. There is antagonism between convective delivery and diffusive transport of O₂ such that increasing cardiac output alone during exercise does not normalize Vo₂ augmentation (14). Ultimately, future studies that delineate the relative contribution of each Vo₂ pathway component (central and peripheral) to exercise intolerance may help identify which patients, if any, would benefit from exercise HR modulation. Whether these exercise subphenotypes cluster by clinical phenotypes (e.g., AF vs. SR) would be of additional clinical interest.

In summary, through carefully performed prospective crossover studies, Jamil et al. (7) have highlighted that “faster is not better” for exercise HR in patients with HFrEF. Looking ahead, we believe there are ample opportunities to better define sub-phenotypes of exercise intolerance in HF. Such a mechanistic, precision medicine approach to exercise intolerance will help to refine selection of those who may benefit most from our expanding armamentarium of pharmacologic and device-based interventions. The null findings of this study regarding HR modulation and exercise capacity in HF should only speed up our collective efforts to understand and target mechanisms of exercise intolerance in this ever-expanding population.

• American College of Cardiology Foundation