Contextualizing Heart Rate: Visit-to-Visit Fluctuations and Their Impact on Prognosis in Heart Failure

This article refers to “Visit-to-visit changes in heart rate in heart failure: A pooled participant-level analysis of the PARADIGM-HF and PARAGON-HF trials” by H. Lu et al., published in this issue on pages xxx. Heart rate is primarily regulated by the autonomic nervous system. Elevated resting heart rate is a risk factor for cardiovascular morbidity and mortality in the general population1 and across several cardiovascular conditions, including hypertension, coronary artery disease, and chronic heart failure.2, 3 In heart failure with reduced ejection fraction (HFrEF), high heart rate, particularly when combined with low systolic blood pressure, is a modifiable risk factor.2 Therapies that lower heart rate, such as beta-blockers and the If inhibitor ivabradine, have demonstrated to reduce cardiovascular death or heart failure hospitalizations.2, 4, 5 These clinical findings are supported by data showing that lowering heart rate can improve energy expenditure,6 coronary blood flow,7 and force–frequency associations (Bowditch effect).8 As a result, guidelines recommend targeting a heart rate <70 bpm in symptomatic patients with HFrEF and sinus rhythm, primarily through beta-blocker therapy.9, 10 If the resting heart rate remains >70 bpm despite beta-blocker therapy or if patients do not tolerate beta-blockers, ivabradine should be considered.9, 10 However, the relationship between heart rate and prognosis is less well established in heart failure with preserved ejection fraction (HFpEF) and in patients with heart failure and atrial fibrillation (Figure 1).9 Evidence from post-hoc analyses of trials like the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved,11 the Irbesartan in Heart Failure and Preserved Ejection Fractions (I-Preserve),12 and Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT)13 trials suggest that higher resting heart rate in HFpEF are linked to poor outcomes.11, 12 However, it remains unclear whether lowering heart rate improves outcomes in HFpEF,14-16 partially because up to half of these patients have chronotropic incompetence, making heart rate management more complex.17 An analysis of the overall CHARM population, including patients with HFpEF and HFrEF, of which 1148 had atrial fibrillation, found that higher heart rate was not associated with worse outcomes.11 Additionally, in patients with chronic heart failure and atrial fibrillation, strict rate control, defined as <80 bpm at rest and <110 bpm during moderate exercise, did not improve outcomes compared with more lenient rate control targeting heart rate of <110 bpm.18 In this issue of the Journal, Lu and colleagues report the results of a post-hoc analysis of patient-level data from the Prospective Comparison of ARNi with ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) and Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trials comprising 13 194 patients with chronic heart failure to explore the prognostic implications of visit-to-visit heart rate changes.19 The PARADIGM-HF and PARAGON-HF trials were international, randomized, controlled trials that compared sacubitril/valsartan with active controls (enalapril or valsartan) in patients with either reduced (HFrEF, left ventricular ejection fraction ≤40%) or preserved (HFpEF, left ventricular ejection fraction ≥45%) ejection fraction.20, 21 In PARADIGM-HF, sacubitril/valsartan reduced the rate of hospitalizations for heart failure and death from cardiovascular causes compared to enalapril in HFrEF,20 while PARAGON-HF did not show a benefit over valsartan in HFpEF.21 Unlike most analyses that focus only on baseline resting heart rate, this study employed a time-updated approach, which incorporated the most recent available heart rate data for each patient at each visit. By calculating the difference between heart rates recorded at two consecutive visits, the study provides a more dynamic assessment of heart rate changes over time allowing for a more accurate evaluation of how fluctuations in heart rate may impact clinical outcomes in heart failure. The key findings of this post hoc analysis are that (i) a higher resting heart rate at baseline and (ii) time-updated rise in heart rate, particularly if this rise exceeds 10 bpm between two visits, were associated with a higher risk of the primary composite outcome. The prognostic significance of visit-to-visit heart rate changes was consistent regardless of beta-blocker use, left ventricular ejection fraction, or pacemaker status. Although an increase in heart rate between visits was associated with poorer prognosis in patients with atrial fibrillation, the association was even stronger in those without atrial fibrillation. Moreover, the authors found that, in hindsight, heart rate increased 6–12 months before a heart failure hospitalization. As addressed by the authors, this study has some limitations that need to be considered when interpreting the results. Firstly, the stringent inclusion and exclusion criteria may limit generalizability of the findings to all patients with heart failure. Women, who are more prone to HFpEF and have more severe heart failure symptoms and poorer quality of life, were underrepresented (33%). Compared with men, women with HFpEF tend to have smaller ventricular chambers and vasculature, increased ventricular wall thickness, more concentric myocardial remodelling, reduced diastolic compliance, and greater arterial stiffness.17 As a result, some women may rely more heavily on higher heart rates and a stronger heart rate response to maintain adequate cardiac output. Notably, in a post-hoc analysis of the PARAGON-HF trial, which did not show an overall benefit, women experienced a greater reduction in the primary outcome with sacubitril/valsartan compared to men, highlighting potential sex-specific differences in treatment response.21 Additionally, patients with known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy (e.g. amyloidosis or glycogen storage disease), as well as those with atrial fibrillation or atrial flutter with a ventricular rate >110 bpm, were excluded from PARAGON-HF. This exclusion is important because patients with restrictive physiology often have limited tolerance for heart rate-lowering therapies, as lower heart rates can exacerbate symptoms by failing to meet the demands necessary to maintain an adequate cardiac output.10 Secondly, while a high heart rate itself is associated with adverse events, those patients typically also present with more severe heart failure, indicated by higher natriuretic peptide levels, lower left ventricular ejection fraction, and worse patient-reported health status. Thus, an elevated heart rate may reflect more advanced heart failure, potentially with autonomic dysfunction or poor tolerance to beta-blockers due to factors like low blood pressure—a phenomenon called ‘reverse causality’. Lastly, heart rates were measured in an office setting by medical personnel and thus might be influenced by external circumstances inherent with the same limitations that apply for office blood pressure measurements. Future studies should explore the prognostic value of longitudinal self-measurement of heart rate by patients in their home environment. Such data may pertain complementary information to the measurements at clinical visits. The authors should be commended for presenting valuable data on the prognostic importance of heart rate, a simple and inexpensive parameter to assess, across the spectrum of left ventricular ejection fraction. This analysis emphasizes that heart rate should not be evaluated as a single snapshot value but rather as a dynamic variable, with changes over multiple visits and time providing critical information. Visit-to-visit increases in heart rate, especially if exceeding 10 bpm, should raise concerns about potential deterioration in both HFrEF and HFpEF, even when heart rate itself is not exceedingly high. Conflict of interest: L.L. has received speaker honoraria and/or consultant fees from AstraZeneca, Medtronic, Pfizer, and Recor Medical. O.P. has received speaker honoraria and/or consultant fees from AstraZeneca, Bayer, Boehringer Ingelheim, CSL Vifor, MSD, Novartis, Novo Nordisk, Pfizer, and Sanofi. F.M. is supported by Deutsche Gesellschaft für Kardiologie (DGK), Deutsche Forschungsgemeinschaft (SFB TRR219, Project-ID 322900939), and Deutsche Herzstiftung. Saarland University has received scientific support from Ablative Solutions, Medtronic and ReCor Medical. Until May 2024, F.M. has received speaker honoraria/consulting fees from Ablative Solutions, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, ReCor Medical, Servier, and Terumo.