Rethinking heart rate modulation in heart failure: physiological basis, clinical evidence, and individualized targets: a narrative review

Introduction

Background

Heart failure (HF) is a chronic, progressive clinical syndrome and remains a leading cause of morbidity and mortality worldwide. Despite substantial advances in pharmacological and device-based therapeutics, HF continues to impose a considerable burden on healthcare systems (1). In particular, the prognosis of patients with HF who have experienced prior hospitalization remains poor, with reported 5-year mortality rates of approximately 50–75%, contributing to a major global health and socioeconomic burden (2). These realities underscore the persistent need to identify and refine therapeutic targets that can further improve outcomes in HF.

Resting heart rate (HR) is a fundamental parameter with a profound impact on cardiovascular function and prognosis in HF. HR plays a central role in determining cardiac output, and elevated resting HR has consistently been associated with adverse clinical outcomes, including increased rates of hospitalizations and mortality (3-5). Importantly, HR can be assessed easily, noninvasively, and at low cost, making it an attractive therapeutic target in routine clinical practice.

β-Blockers constitute a cornerstone of evidence-based therapy for HF. Their benefits extend beyond HR reduction and include modulation of neurohumoral activation and protection against arrhythmias. However, titration of β-blockers to achieve adequate HR control can sometimes be limited by adverse effects such as hypotension, bradycardia, conduction defects, or worsening congestion. In this context, ivabradine—a selective inhibitor of the funny current (If) in the sinoatrial node—offers a more targeted HR-lowering strategy without negative inotropic effects. Its clinical use is currently restricted to patients with HF with reduced ejection fraction (HFrEF) and sinus rhythm (SR).

More recently, the concept of an individualized, or “personalized” target heart rate (THR) has been proposed (6). This approach is based on the premise that optimal hemodynamics vary among patients and that an individualized HR target may better ensure adequate ventricular filling and hemodynamically efficient circulation. A retrospective study from our research group has suggested that achieving an appropriate THR is associated with more favorable survival among patients with HFrEF and SR, supporting the concept of THR (7).

Rationale and knowledge gap

Resting HR is a key determinant of cardiovascular performance and prognosis in HF, particularly in patients with HFrEF and SR. While randomized trials have established HR reduction as an effective disease-modifying strategy in HFrEF, important knowledge gaps remain.

All pivotal β-blocker trials adopted a dose-based titration strategy, escalating the study drug toward a fixed target dose (8-11). HR had a significant role as safety [e.g. symptomatic bradycardia <~50–55 beats per minute (bpm)]. Post-hoc and meta-analyses consistently showed that achieved HR or magnitude of HR reduction predicted survival better than β-blocker dose. Yet this insight emerged after the trials, not from their design. Further, importantly, no trial protocol defined an “optimal” or “target” HR.

Most clinical studies have applied uniform HR thresholds without considering interindividual differences in myocardial systolic and diastolic properties. Moreover, although force-frequency and relaxation-frequency relationships provide a physiological rationale for HR modulation, these concepts have not been fully translated into individualized therapeutic targets.

In addition, the prognostic significance of HR and the benefits of HR reduction differ across HF phenotypes, being consistent in HFrEF with SR but inconsistent in atrial fibrillation (AF) and controversial in HFpEF. In HFrEF, emerging evidence suggests that individualized HR targets, such as the THR derived from transmitral flow dynamics, may better reflect optimal hemodynamics than fixed cutoffs. However, the clinical relevance of this approach has not been systematically reviewed. In HFpEF, HR may not uniformly represent a target for reduction, and both HR lowering and HR support may be appropriate depending on the underlying phenotype and hemodynamic profile.

Objective

This review aims to:

• Summarize the physiological role of HR in cardiac function, with emphasis on frequency-dependent myocardial properties.
• Review the evidence for HR modulation strategies across major HF phenotypes.
• Summarize the differences in the prognostic significance of HR across HF phenotypes, including HFrEF, HFpEF, and AF.
• Introduce the concept of an individualized target HR (THR) and discuss its potential clinical implications, with a focus on phenotype-specific approaches.

We present this article in accordance with the Narrative Review reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-676/rc).

Methods

A literature search was performed in PubMed covering publications up to December 2025. The following keyword combinations were used: HF and HR. These search terms had to be identified anywhere in the text of the articles. The authors also chose literature depicting the current guidelines or randomized controlled trials (RCTs).

We examined the HR in RCTs assessing medications aimed at improving prognosis in HF. The search was limited to original research involving humans, published in English at any time. All abstracts were screened to determine if they met the inclusion criteria. After this initial screening, a manual search of the reference lists of all eligible articles was conducted. Two authors (i.e., Y.Y. and Y.N.) independently assessed the methodological quality of studies before including them in the review (Table 1).

The role of HR in the pathophysiology of HF

HR is a key determinant of myocardial oxygen demand and coronary perfusion. In the healthy heart, autonomic regulatory mechanisms precisely regulate HR to maintain an optimal balance between myocardial oxygen supply and systemic metabolic demands (12). Increases in HR are accompanied by parallel changes in coronary blood flow and myocardial oxygen consumption, underscoring the close coupling between HR and cardiac energetic requirements (13).

Beyond its effects on myocardial energetics, HR is a fundamental determinant of cardiac performance. In normal human hearts, increases in HR are associated with enhanced myocardial contractility, a phenomenon known as the force-frequency relationship, as well as accelerated myocardial relaxation, referred to as the positive relaxation-frequency relationship (14-16). These frequency-dependent properties allow the healthy heart to augment cardiac output efficiently during physiological stress. In patients with HFrEF both the force-frequency and relaxation-frequency relationships are markedly impaired (Table 2) (14-16). The blunted or inverted force-frequency relationship in HFrEF has been attributed to abnormalities in sarcoplasmic reticulum Ca²⁺ handling, including reduced Ca²⁺ uptake and release, as well as delayed mechanical restitution due to insufficient recovery time of Ca²⁺ release channels. Consequently, tachycardia in HFrEF may fail to enhance contractile performance and instead exacerbates energetic inefficiency.

In contrast, in HF with preserved ejection fraction (HFpEF), where diastolic dysfunction represents the central pathophysiology, the force-frequency relationship is generally preserved, whereas the relaxation-frequency relationship is impaired, particularly at higher HR (Table 2) (17-19). Under these conditions, increases in HR disproportionately compromise ventricular relaxation and filling, leading to elevated filling pressures and reduced diastolic reserve. When interpreted through the framework of frequency-dependent myocardial properties, HR reduction exerts distinct physiological effects in HFrEF and HFpEF. In HFrEF, impaired force-frequency coupling renders tachycardia maladaptive, supporting HR reduction a mechanistically rational strategy to improve cardiac efficiency. In HFpEF, disrupted relaxation-frequency dynamics together with impaired ventricular-arterial coupling at higher HRs, primarily limit diastolic reserve, suggesting that HR modulation may have heterogeneous effects in HFpEF, with HR reduction potentially alleviating symptoms in some phenotypes, whereas preservation or augmentation of HR may be required in others (Table 2) (17-19).

Elevated resting HR is an independent risk factor for cardiovascular mortality and morbidity in both individuals without cardiovascular disease and in patients with established conditions such as hypertension, coronary artery disease, and HF (20). Notably, resting HR has been associated with an increased risk of cardiovascular death and HF hospitalization from values as low as approximately 70 bpm (21). As summarized in Figure 1, baseline HR at study enrollment was generally higher in early clinical trials conducted before β-blockers became standard therapy compared with more contemporary trials in which β-blockers were routinely prescribed. Baseline HR at study enrollment was positively correlated with observed annual mortality (Spearman’s ρ=0.58, P=0.022, Figure 2), although the strength of this association may vary across studies depending on patient populations and clinical settings. Although the median resting HR in treated populations has decreased by approximately 10 bpm, it frequently remains above 70 bpm, and long-term prognosis in HF continues to be suboptimal, underscoring the need for more refined and individualized approaches to HR management.

Figure 1 Baseline HR at study enrolment and annual mortality in major clinical trials. In the early clinical trials conducted before beta-blockers became the standard of care—those shown in the upper half of the figure—baseline HRs at the time of enrolment were generally higher than in more recent trials, in which beta-blockers were routinely prescribed. *, overall mortality adjusted by mean follow-up period. bpm, beats per minute; HR, heart rate; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

Figure 2 The correlation of baseline HR at study enrolment and annual mortality in major clinical trials in patients with HFrEF with and without β-blockers at baseline. Red dots indicate early clinical trials without β-blockers at baseline. Blue dots indicate more contemporary trials in which β-blockers were routinely prescribed. The reported ρ [rho] value represents a Spearman’s rank correlation coefficient. The ASTRONAUT study (acute heart failure population) shows a different pattern compared with chronic HF trials, possibly reflecting differences in clinical setting and patient characteristics. Please see Table 2. bpm, beats per minute; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HR, heart rate.

The significance of HR reduction in HF

HR reduction by β-blockers

β-Blockers have long been a central component of therapy for HFrEF, primarily because of their ability to counteract chronic sympathetic nervous system overactivation and to modulate HR. Through these effects, β-blockers decrease myocardial oxygen demand, improve left ventricular (LV) function, and are associated with substantial improvements in survival in HF patients (9). Extensive experimental and clinical evidence has demonstrated that HFrEF is characterized by maladaptive alterations in the myocardial β-adrenergic receptor system leading to impaired signal transduction and progressive deterioration of cardiac function over time (22). This heightened adrenergic drive in the failing heart provides the fundamental rationale for anti-adrenergic therapy.

The clinical utility of β-blockers in HFrEF was first demonstrated in the mid-1970s, when Waagstein and colleagues reported that β-blockade was safe and associated with improvements in clinical status and ventricular function (23). These pioneering observations were subsequently confirmed by several RCTs, which definitively established β-blockers as disease-modifying therapy in HFrEF. Major trials conducted in the late 1990s primarily enrolled HFrEF patients with New York Heart Association (NYHA) functional class II–III symptom (8-10). In these studies, carvedilol, bisoprolol, and metoprolol succinate significantly improved survival, with particularly strong effects on the prevention of arrhythmic sudden cardiac death, while also reducing overall mortality and HF-related hospitalizations.

The magnitude and prognostic relevance of HR reduction achieved with β-blocker therapy are summarized in Table 3.

In the US Carvedilol Heart Failure Study, treatment with carvedilol resulted in an approximate 12-bpm reduction in HR and was associated with a 65% relative reduction in mortality compared with placebo, reflecting substantial prevention of both progressive HF death and sudden cardiac death (13). In MERIT-HF, metoprolol controlled release/extended release (CR/XL) reduced all-cause mortality by 34% (9). CIBIS-II, which enrolled patients with NYHA class III–IV HF and a left ventricular ejection fraction (LVEF) <35%, demonstrated a 42% reduction in sudden cardiac death in the bisoprolol group, which constituted the largest contributor to the observed mortality benefit (10). Notably, patients with higher baseline HR (>86 bpm) experienced greater mortality risk, and mortality appeared to decline progressively with greater HR reduction.

Importantly, a meta-analysis of RCTs of β-blockers conducted up to the early 2000s demonstrated that the extent of HR reduction, rather than the prescribed β-blocker dose, was independently associated with survival. Specifically, each 5-bpm reduction in HR was associated with an approximately 18% reduction in the risk of death (Table 3) (24). These findings further reinforced β-blockers as a cornerstone of HF therapy and underscored the potential prognostic relevance of HR modulation.

Autonomic imbalance, characterized by sympathetic overactivation and parasympathetic withdrawal, is a hallmark of HF syndrome and likely represents a major mechanism underlying elevated resting HR in HF. The clinical benefits of β-blockers are mediated through multiple mechanisms beyond HR reduction, including reduction in blood pressure, myocardial ischemia, arrhythmia burden, metabolic shifts from free-fatty acid utilization toward more efficient glucose metabolism, attenuation of oxidative stress; and inhibition of catecholamine-induced cardiomyocyte apoptosis (25,26). In addition, carvedilol exhibits intrinsic antioxidant properties that are distinct from its adrenergic effects (27,28) (Figure 3A). Accordingly, HR reduction likely represents only one component of the overall cardioprotective effects of β-blocker therapy (Figure 3A).

Figure 3 The mechanisms of beneficial effects by administration of (A) β-blockers and (B) ivabradine. β-blockers have pleiotropic effects beside HR lowering effect. Its beneficial effects on LV remodeling and clinical outcome have been well established by multiple clinical trials, the contribution of each specific effect, including HR lowering effect, cannot be investigated, although the prior studies demonstrated a significant association of HR lowering with clinical outcome or LVEF improvement (see text). On the other hand, ivabradine solely shows HR lowering effect through the inhibition of HCN channel. SHIFT study showed the clinical benefit of ivabradine in terms of LV reverse remodeling and improved clinical outcome. These findings suggest the clinical benefit of HR lowering per se in patient with HFrEF. HCN, hyperpolarization-activated cyclic nucleotide-gated; HFrEF, heart failure with reduced ejection fraction; HR, heart rate; LV, left ventricle; LVEF, left ventricular ejection fraction; SHIFT, Systolic Heart Failure Treatment with the If Inhibitor Ivabradine.

Nevertheless, multiple analyses have demonstrated that achieved HR or the degree of HR reduction during β-blocker therapy has been more closely associated with LV reverse remodeling and subsequent clinical outcomes than either reductions in blood pressure or the administered β-blocker dose (24,29,30). Whether HR reduction itself directly mediates these benefits or instead reflects secondary improvements in hemodynamics and myocardial function remains an important and unresolved question (Figure 3A).

HR reduction by ivabradine

HR is governed by spontaneous diastolic depolarization in pacemaker cells of the sinoatrial node, a process critically mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (31,32). Upon membrane hyperpolarization, these channels open to generate the inward “funny” current (If), allowing sodium ion influx and initiating phase 4 depolarization. Among the four HCN isoforms (HCN1–4), HCN4 is the predominant isoform in the sinoatrial node, and is primarily responsible for physiological HR regulation.

Ivabradine is currently the only clinically available selective If channel inhibitor. By specifically inhibiting HCN4, ivabradine suppresses sinoatrial node pacemaker activity, leading to HR reduction in patients with SR, without exerting significant effects on blood pressure, myocardial contractility, or intracardiac conduction (33). This pharmacological profile distinguishes ivabradine from β-blockers, which exert broader hemodynamic and neurohormonal effects.

Preclinical studies have demonstrated that ivabradine selectively reduces HR without impairing LV contractility, as assessed by LV dP/dt, in contrast to propranolol, which reduces both HR and contractile performance (34). Even in acute HF, it has been reported that controlling HR with the addition of ivabradine is associated with improvements in stroke volume and a reduction in cardiac work index, both of which contribute to energy conservation without compromising cardiac output (35). Clinically, selective HR reduction with ivabradine has been shown to improve outcomes in patients with HFrEF and SR. In the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine (SHIFT) trial, ivabradine significantly reduced resting HR and lowered the risk of the primary composite endpoint of cardiovascular death or hospitalization for worsening HF compared with placebo (5). Notably, achieved HR at 28 days was strongly associated with subsequent clinical outcomes, with lower achieved HR being associated with greater risk reduction (21). These observations are consistent with earlier reports demonstrating an association between resting HR and prognosis in patients with HFrEF and SR (21,36). Beyond clinical outcomes, ivabradine has also been shown to improve cardiac structure and function. In echocardiographic substudies of SHIFT and in the Japan-specific J-SHIFT trial, ivabradine therapy was associated with significant improvements in LVEF, suggesting favorable reverse remodeling effects potentially attributable to HR reduction (37,38). Collectively, these data indicate that selective HR reduction per se may contribute to improvements in cardiac function and clinical outcomes in patients with HFrEF and SR, and that the benefits of ivabradine are closely linked to achieved HR rather than pleiotropic pharmacologic effects (39). This contrasts with β-blockers, whose therapeutic effects arise from multiple mechanisms beyond chronotropic control (Figure 3A). Ivabradine therefore provides a useful clinical model to isolate the effects of HR reduction and to better understand its potential prognostic and therapeutic significance in HF (Figure 3B).

HR reduction in patients with AF

AF is a common comorbidity in patients with HF, with a complex and bidirectional relationship. HF predisposes to the development of AF through structural and electrical remodeling, while AF, in turn, exacerbates HF and is associated with worse clinical outcomes (40,41). With progressive population aging, the prevalence of AF continues to rise and may exceed 50% in patients with advanced HFrEF (41). AF adversely affects cardiac hemodynamics by abolishing coordinated left atrial contraction, which normally contributes approximately 20–25% of cardiac output. In addition, rapid ventricular response during AF shortens diastolic filling time, further impairing LV filling and potentially contributing to acute HF decompensation, particularly at higher HR.

Despite these pathophysiological considerations, observational data have yielded conflicting results. Some studies, largely involving patients without HF, have suggested an association between resting HR and prognosis in AF (42). One large observational study reported that lenient rate control (resting HR <110 bpm) was associated with a higher adjusted risk of death and all-cause readmission compared with strict rate control (resting HR <80 bpm) (43). In contrast, other studies have demonstrated that elevated HR has been shown to predict increased mortality in HFrEF patients with SR but not consistently in those with AF, although β-blocker therapy was associated with improved survival in both rhythm groups (44,45). Subanalyses and meta-analyses of β-blocker RCTs have also shown that neither baseline HR nor achieved HR during follow-up was associated with mortality in patients with HFrEF and AF (46,47). Furthermore, a Japanese randomized study evaluating the optimal dose of carvedilol demonstrated that HR reduction during therapy was associated with LV reverse remodeling and more favorable clinical outcomes in patients with SR, but not consistently in those with AF (48). No apparent benefit of strict HR control was demonstrated in RACE II trial, an RCT enrolling patients with chronic AF, including those without HF. In this trial, strict HR control did not confer superior cardiovascular outcomes compared with a more lenient strategy (49). Consequently, unlike in patients with SR, the relationship between resting HR and prognosis in HFrEF patients with AF has not been consistently established, and may differ substantially from that observed in patients with SR.

Several mechanisms may explain the attenuated prognostic significance of HR in AF. First, the irregular ventricular rhythm inherent to AF leads to beat-to-beat variability, which may reduce the accuracy and reproducibility of resting pulse measurements. Second, in SR, resting HR often correlates with average HR over 24 hours, whereas this relationship appears weaker in AF, potentially due to exaggerated and highly individualized HR responses during physical activity (50). Third, in AF, the loss of atrial contraction compromises LV filling, and a relatively higher ventricular rate may be necessary to preserve cardiac output and maintain peripheral perfusion in some patients.

Taken together, these findings suggest that the prognostic and therapeutic implications of HR reduction in HF may differ between patients with SR and those with AF. In contrast to SR, where HR serves as a relatively consistent therapeutic target, the role of HR in AF appears more complex, and optimal HR control strategies likely need to be individualized based on clinical context.

HR modulation in patients with HFpEF

HFpEF is a heterogeneous clinical syndrome encompassing multiple phenotypic subtypes and is particularly prevalent among older adults, women, and patients with a high burden of comorbidities (51). In contrast to HFrEF, myocardial remodeling in HFpEF is influenced by diverse mechanisms beyond HR elevation, including systemic inflammation, endothelial dysfunction, and myocardial fibrosis (52).

Data linking resting HR to adverse outcomes in HFpEF are relatively limited. However, several observational studies (36) and post-hoc analyses of large RCTs such as CHARM (53), I-PRESERVE (54) and TOPCAT (55) have consistently demonstrated an association between higher resting HR and worse clinical outcomes in HFpEF patients in SR. These findings suggest that HR may serve as a prognostic marker in HFpEF, although its role as a therapeutic target remains uncertain.

In contrast to HFrEF, in which HR reduction is a central disease-modifying strategy, HR modulation in HFpEF may involve either HR reduction or HR support depending on the underlying phenotype and hemodynamic constraints. Evidence regarding the benefit of β-blockers in HFpEF is conflicting. While meta-analyses of observational studies suggest an association between β-blocker use and reduced mortality, meta-analyses of RCTs have failed to confirm such benefit. Moreover, post hoc analysis of the TOPCAT trial have suggested worse outcomes among patients treated with β-blockers. In addition, withdrawal of β-blockers in HFpEF patients with chronotropic incompetence has been shown to improve exercise capacity, as assessed by peak oxygen consumption (peak VO₂) (56). Collectively, these findings raise concern that the adverse effects of β-blockers—particularly chronotropic incompetence—may exacerbate hemodynamic limitations during exercise and may contribute to unfavorable outcomes in selected HFpEF patients.

Given these limitations, ivabradine has been investigated as a potential alternative for selective HR reduction in HFpEF. Proposed mechanisms include prolongation of diastolic filling time, enhancement of myocardial relaxation through increased phosphorylation of phospholamban and stimulation of sarcoplasmic reticulum Ca²⁺-ATPase (SERCA), increased myocardial compliance via modulation of titin isoform expression and collagen content, and improvements in arterial stiffness and endothelial function (57-59). However, randomized trials evaluating ivabradine in HFpEF have yielded inconsistent results. Small randomized studies reported conflicting effects on exercise capacity (60,61), whereas the larger EDIFY trial did not demonstrate significant improvement in LV filling pressures (E/e'), exercise capacity (6-minute walk distance), or N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (62). Meta-analyses have suggested modest improvements in exercise capacity with ivabradine but no significant effects on diastolic function indices or clinical outcomes (63,64). Interestingly, improvements in global longitudinal strain following ivabradine therapy have been reported, indicating a potential benefit on subclinical LV systolic dysfunction in selected patients (65).

Thus, the current body of evidence does not support routine HR reduction therapy with either β-blockers or ivabradine for improving clinical outcomes in unselected patients with HFpEF. Accordingly, contemporary clinical practice guidelines do not provide specific recommendations for the use of these agents in HFpEF (66-68).

Instead of lowering HR, pacing-based HR modulation in HFpEF has been explored in acute hemodynamic studies, which suggest that moderate HR acceleration may reduce left-sided filling pressures (69). These data provide proof-of-concept that HR targeting in HFpEF may, in some patients, involve HR support rather than HR reduction in selected patients. The myPACE randomized trial demonstrated that moderately accelerated, personalized physiologic atrial pacing in HFpEF patients with pre-existing pacemakers demonstrated that personalized accelerated pacing (myPACE group: median HR 75 bpm) improved quality of life, NT-proBNP levels, physical activity, and lowered device-detected AF burden compared to the usual 60 bpm setting with acceptable safety (70). Longer-term follow-up further demonstrated accelerated, personalized physiologic atrial pacing was associated with lower rate of clinical adverse events, mainly driven by HF events, in per-protocol analysis (71).

By contrast, in RAPID-HF trial (72), implanting and programming a pacemaker for rate-adaptive atrial pacing in HFpEF patients with chronotropic incompetence increased exercise HR but did not improve exercise capacity or quality of life, highlighting that HR augmentation alone may be insufficient when stroke volume reserve and peripheral limitations dominate. Although the mechanisms underlying this discrepancy are not fully understood, these findings support the concept that an individualized “optimal” HR may exist in HFpEF rather than a uniform direction of HR change (Table 4).

Therefore, HFpEF should not be considered a uniformly ‘HR-lowering’ condition. Rather, patient-specific HR optimization may involve either HR reduction or HR support, depending on the underlying phenotype and hemodynamic profile. Further mechanistic and phenotype-driven clinical studies are warranted to better define individualized HR modulation strategies in HFpEF.

What is the optimal HR for HFrEF? The concept of “THR”

Pharmacological HR reduction—primarily through β-blocker therapy—is a cornerstone of disease-modifying treatment for patients with HFrEF and SR. As discussed in section “The role of HR in the pathophysiology of HF”, impairment of both the force-frequency relationship and the relaxation-frequency relationship in HFrEF renders tachycardia maladaptive, thereby positioning HR reduction as a central therapeutic strategy (Table 2). However, defining an optimal HR remains challenging, and additional physiological perspectives beyond uniform resting HR thresholds are likely required.

To date, no RCTs have been specifically designed to determine the optimal HR target in HF. In major β-blocker trials, the achieved resting HR generally remained above approximately 65 bpm (29). In contrast, in the SHIFT trial, ivabradine was uptitrated to achieve a resting HR of 50–60 bpm according to the study protocol. In that trial, patients who achieved a resting HR <60 bpm at 28 days experienced the lowest incidence of the primary composite endpoint of cardiovascular death or hospitalization for acute decompensated HF (21). Collectively, these data suggest that lower achieved HR is associated with improved outcomes in HFrEF; however, these associations do not establish an optimal THR. Importantly, these observations are derived from trial protocols and post hoc analyses, and should not be interpreted as defining an optimal HR target for clinical practice. Nevertheless, from a pathophysiological standpoint, the optimal HR is likely to vary according to individual systolic and diastolic properties.

LV diastolic filling consists of early rapid filling (E wave), diastasis, and late atrial contraction (A wave). As HR increases, total diastolic filling time shortens. Because the durations of the E and A waves are relatively preserved, diastasis becomes disproportionately abbreviated, leading to overlap between the E and A waves (E-A overlap) on transmitral Doppler flow (Figure 4) (73,74). Greater E-A overlap has been associated with increased A-wave amplitude and elevated left atrial pressure in both experimental models (75) and human studies (76). These observations suggest that tachycardia-induced E-A overlap reflects impaired diastolic filling and may contribute to elevated filling pressures and pulmonary congestion.

Figure 4 Pulsed wave Doppler of mitral inflow in cases with (A) E-A gap and (B) E-A overlap.

Although modest increases in HR may augment cardiac output, excessive HR elevation can paradoxically worsen hemodynamics by inducing E-A overlap, a phenomenon reflecting incomplete ventricular relaxation. Conversely, excessively low HR may also be hemodynamically unfavorable and can precipitate symptomatic HF, a condition that often necessitates pacemaker implantation. Thus, both tachycardia and excessive bradycardia may represent suboptimal extremes (Figure 5). From this perspective, an individualized HR that minimizes or eliminates E-A overlap may represent a physiologically favorable range rather than a universally applicable target. Because LV systolic and diastolic properties vary among patients, the HR at which E-A overlap disappears is also likely to differ between individuals. Kusunose et al. reported that the presence of E-A overlap was associated with a higher risk of HF readmission and cardiovascular death, and that incorporation of E-A overlap into risk models significantly improved prognostic performance (76).

Figure 5 The concept of ideal HR in patients with HF. HF, heart failure; HR, heart rate; LAP, left atrial pressure.

Building on this concept, Izumida et al. (6) proposed a formula to estimate an individualized THR that theoretically minimizes E-A overlap in patients with HFrEF. They quantified the E-A gap/overlap duration in 368 patients with HFrEF. Using multivariable linear regression analyses, they derived the following equation to estimate the HR at which E-A overlap is minimized:

THR(bpm)=93−0.13×decelerationtime(ms)[1]

In this model, deceleration time serves as a surrogate of diastolic function, and the coefficients were empirically derived from the observed relationship between deceleration time and E-A overlap. This formula is based on the hypothesis that an HR eliminating E-A overlap represents an ideal hemodynamic state, although this assumption has not yet been prospectively validated.

The prognostic relevance of the THR concept has been evaluated in real-world populations. Our research group explored this issue using data from the multicenter prospective West Tokyo Heart Failure (WET-HF) registry enrolling all patients with acute decompensated HF (7). This study demonstrated that discharge HR lower than the individualized THR, estimated from echocardiographic data, was associated with significantly lower rates of all-cause death and HF readmission. Notably, a uniform HR cutoff of 70 bpm failed to discriminate subsequent outcomes in this cohort (7). These findings suggest that THR may reflect patient-specific hemodynamic conditions, although causality cannot be inferred. However, as these observations are derived from post hoc analyses of registry data and are subject to residual confounding, they should be considered hypothesis-generating and require prospective validation before clinical implementation. Thus, prospective studies specifically designed to test individualized HR strategies are warranted. At present, these concepts remain investigational, and guideline-directed medical therapy should remain the primary approach.

Conclusions

HR modulation is a fundamental component of disease-modifying therapy in patients with HFrEF. Accumulating evidence supports the prognostic importance of HR reduction in appropriately selected patients, particularly those with HFrEF and SR. However, emerging data suggest that uniform HR targets may be suboptimal and that individualized approaches to HR management warrant consideration.

The concept of a patient-specific THR, defined by underlying systolic and diastolic properties and aimed at optimizing hemodynamics rather than achieving arbitrary HR thresholds, represents a potential conceptual framework. Preliminary observational evidence suggests that achieving an HR below the estimated THR may be associated with more favorable clinical outcomes, whereas fixed cutoffs may fail to adequately discriminate risk. However, these findings are hypothesis-generating and require prospective validation.

Prospective, phenotype-driven studies are needed to validate the THR concept, clarify its clinical applicability, and determine whether individualized HR-guided therapy can improve outcomes, particularly in HFrEF. In contrast, in HFpEF, optimal HR modulation may differ substantially across phenotypes and may involve either HR reduction or HR support depending on the underlying hemodynamic context. These considerations underscore the need to explore phenotype-specific HR strategies across the broader HF spectrum. At present, guideline-directed medical therapy remains the standard of care, and individualized HR targets should be considered investigational.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-676/rc

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-676/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-676/coif). Y.N. serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from September 2025 to December 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Shiraishi Y, Kohsaka S, Sato N, et al. 9-Year Trend in the Management of Acute Heart Failure in Japan: A Report From the National Consortium of Acute Heart Failure Registries. J Am Heart Assoc 2018;7:e008687. [Crossref] [PubMed]
2. Savarese G, Becher PM, Lund LH, et al. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res 2023;118:3272-87. [Crossref] [PubMed]
3. Lechat P, Hulot JS, Escolano S, et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial. Circulation 2001;103:1428-33. [Crossref] [PubMed]
4. Fox K, Borer JS, Camm AJ, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007;50:823-30. [Crossref] [PubMed]
5. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875-85. [Crossref] [PubMed]
6. Izumida T, Imamura T, Nakamura M, et al. How to consider target heart rate in patients with systolic heart failure. ESC Heart Fail 2020;7:3231-4. [Crossref] [PubMed]
7. Yumita Y, Nagatomo Y, Takei M, et al. Personalized Target Heart Rate for Patients with Heart Failure and Reduced Ejection Fraction. J Pers Med 2022;12:50. [Crossref] [PubMed]
8. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349-55. [Crossref] [PubMed]
9. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-7. [Crossref] [PubMed]
10. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II). a randomised trial. Lancet 1999;353:9-13. [Crossref] [PubMed]
11. Krum H, Roecker EB, Mohacsi P, et al. Effects of initiating carvedilol in patients with severe chronic heart failure: results from the COPERNICUS Study. JAMA 2003;289:712-8. [Crossref] [PubMed]
12. Reil JC, Böhm M. The role of heart rate in the development of cardiovascular disease. Clin Res Cardiol 2007;96:585-92. [Crossref] [PubMed]
13. Tanaka N, Nozawa T, Yasumura Y, et al. Heart-rate-proportional oxygen consumption for constant cardiac work in dog heart. Jpn J Physiol 1990;40:503-21. [Crossref] [PubMed]
14. Glick G, Sonnenblick EH, Braunwald E. Myocardial force-velocity relations studied in intact unanesthetized man. J Clin Invest 1965;44:978-88. [Crossref] [PubMed]
15. Feldman MD, Alderman JD, Aroesty JM, et al. Depression of systolic and diastolic myocardial reserve during atrial pacing tachycardia in patients with dilated cardiomyopathy. J Clin Invest 1988;82:1661-9. [Crossref] [PubMed]
16. Izawa H, Yokota M, Takeichi Y, et al. Adrenergic control of the force-frequency and relaxation-frequency relations in patients with hypertrophic cardiomyopathy. Circulation 1997;96:2959-68. [Crossref] [PubMed]
17. Kass DA. Force-frequency relation in patients with left ventricular hypertrophy and failure. Basic Res Cardiol 1998;93:108-16. [Crossref] [PubMed]
18. Yamanaka T, Onishi K, Tanabe M, et al. Force- and relaxation-frequency relations in patients with diastolic heart failure. Am Heart J 2006;152:966.e1-7. [Crossref] [PubMed]
19. Wachter R, Schmidt-Schweda S, Westermann D, et al. Blunted frequency-dependent upregulation of cardiac output is related to impaired relaxation in diastolic heart failure. Eur Heart J 2009;30:3027-36. [Crossref] [PubMed]
20. Böhm M, Reil JC, Deedwania P, et al. Resting heart rate: risk indicator and emerging risk factor in cardiovascular disease. Am J Med 2015;128:219-28. [Crossref] [PubMed]
21. Böhm M, Swedberg K, Komajda M, et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet 2010;376:886-94. [Crossref] [PubMed]
22. Bristow MR, Ginsburg R, Minobe W, et al. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med 1982;307:205-11. [Crossref] [PubMed]
23. Waagstein F, Hjalmarson A, Varnauskas E, et al. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J 1975;37:1022-36. [Crossref] [PubMed]
24. McAlister FA, Wiebe N, Ezekowitz JA, et al. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med 2009;150:784-94. [Crossref] [PubMed]
25. Rizzi E, Guimaraes DA, Ceron CS, et al. β1-Adrenergic blockers exert antioxidant effects, reduce matrix metalloproteinase activity, and improve renovascular hypertension-induced cardiac hypertrophy. Free Radic Biol Med 2014;73:308-17. [Crossref] [PubMed]
26. Nakamura K, Murakami M, Miura D, et al. Beta-Blockers and Oxidative Stress in Patients with Heart Failure. Pharmaceuticals (Basel) 2011;4:1088-100. [Crossref] [PubMed]
27. Yue TL, Cheng HY, Lysko PG, et al. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther 1992;263:92-8. [Crossref] [PubMed]
28. Suzuki Y, Tanaka M, Sohmiya M, et al. Antioxidant properties of carvedilol: inhibition of lipid peroxidation, protein oxidation and superoxide generation. Neurol Res 2003;25:749-53. [Crossref] [PubMed]
29. Flannery G, Gehrig-Mills R, Billah B, et al. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol 2008;101:865-9. [Crossref] [PubMed]
30. Okamoto H, Hori M, Matsuzaki M, et al. Minimal dose for effective clinical outcome and predictive factors for responsiveness to carvedilol: Japanese chronic heart failure (J-CHF) study. Int J Cardiol 2013;164:238-44. [Crossref] [PubMed]
31. Ludwig A, Zong X, Jeglitsch M, et al. A family of hyperpolarization-activated mammalian cation channels. Nature 1998;393:587-91. [Crossref] [PubMed]
32. Ishii TM, Takano M, Xie LH, et al. Molecular characterization of the hyperpolarization-activated cation channel in rabbit heart sinoatrial node. J Biol Chem 1999;274:12835-9. [Crossref] [PubMed]
33. Savelieva I, Camm AJ. I f inhibition with ivabradine: electrophysiological effects and safety. Drug Saf 2008;31:95-107. [Crossref] [PubMed]
34. Simon L, Ghaleh B, Puybasset L, et al. Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther 1995;275:659-66. [Crossref] [PubMed]
35. Mortara A, Rossi J, Mazzetti S, et al. Hemodynamic effects of heart rate lowering in patients admitted for acute heart failure: the RedRate-HF Study (Reduction of heart Rate in Heart Failure). J Cardiovasc Med (Hagerstown) 2023;24:113-22. [Crossref] [PubMed]
36. Takada T, Sakata Y, Miyata S, et al. Impact of elevated heart rate on clinical outcomes in patients with heart failure with reduced and preserved ejection fraction: a report from the CHART-2 Study. Eur J Heart Fail 2014;16:309-16. [Crossref] [PubMed]
37. Tardif JC, O'Meara E, Komajda M, et al. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy. Eur Heart J 2011;32:2507-15. [Crossref] [PubMed]
38. Tsutsui H, Momomura SI, Yamashina A, et al. Efficacy and Safety of Ivabradine in Japanese Patients With Chronic Heart Failure - J-SHIFT Study. Circ J 2019;83:2049-60. [Crossref] [PubMed]
39. Fox K, Ford I, Steg PG, et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 2008;372:817-21. [Crossref] [PubMed]
40. Kotecha D, Piccini JP. Atrial fibrillation in heart failure: what should we do? Eur Heart J 2015;36:3250-7. [Crossref] [PubMed]
41. Sartipy U, Dahlström U, Fu M, et al. Atrial Fibrillation in Heart Failure With Preserved, Mid-Range, and Reduced Ejection Fraction. JACC Heart Fail 2017;5:565-74. [Crossref] [PubMed]
42. Steinberg BA, Kim S, Thomas L, et al. Increased Heart Rate Is Associated With Higher Mortality in Patients With Atrial Fibrillation (AF): Results From the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF). J Am Heart Assoc 2015;4:e002031. [Crossref] [PubMed]
43. Hess PL, Sheng S, Matsouaka R, et al. Strict Versus Lenient Versus Poor Rate Control Among Patients With Atrial Fibrillation and Heart Failure (from the Get With The Guidelines - Heart Failure Program). Am J Cardiol 2020;125:894-900. [Crossref] [PubMed]
44. Li SJ, Sartipy U, Lund LH, et al. Prognostic Significance of Resting Heart Rate and Use of β-Blockers in Atrial Fibrillation and Sinus Rhythm in Patients With Heart Failure and Reduced Ejection Fraction: Findings From the Swedish Heart Failure Registry. Circ Heart Fail 2015;8:871-9. [Crossref] [PubMed]
45. Cullington D, Goode KM, Zhang J, et al. Is heart rate important for patients with heart failure in atrial fibrillation? JACC Heart Fail 2014;2:213-20. [Crossref] [PubMed]
46. Mulder BA, Damman K, Van Veldhuisen DJ, et al. Heart rate and outcome in heart failure with reduced ejection fraction: Differences between atrial fibrillation and sinus rhythm-A CIBIS II analysis. Clin Cardiol 2017;40:740-5. [Crossref] [PubMed]
47. Kotecha D, Flather MD, Altman DG, et al. Heart Rate and Rhythm and the Benefit of Beta-Blockers in Patients With Heart Failure. J Am Coll Cardiol 2017;69:2885-96. [Crossref] [PubMed]
48. Nagatomo Y, Yoshikawa T, Okamoto H, et al. Differential Response to Heart Rate Reduction by Carvedilol in Heart Failure and Reduced Ejection Fraction Between Sinus Rhythm and Atrial Fibrillation - Insight From J-CHF Study. Circ Rep 2020;2:143-51. [Crossref] [PubMed]
49. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363-73. [Crossref] [PubMed]
50. Luo X, Xiong Q, Xu J, et al. Differences in Heart Rate Response and Recovery After 6-Minute Walk Test Between Patients With Atrial Fibrillation and in Sinus Rhythm. Am J Cardiol 2018;122:592-6. [Crossref] [PubMed]
51. Shah SJ, Kitzman DW, Borlaug BA, et al. Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction: A Multiorgan Roadmap. Circulation 2016;134:73-90. [Crossref] [PubMed]
52. Glezeva N, Baugh JA. Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target. Heart Fail Rev 2014;19:681-94. [Crossref] [PubMed]
53. Castagno D, Skali H, Takeuchi M, et al. Association of heart rate and outcomes in a broad spectrum of patients with chronic heart failure: results from the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity) program. J Am Coll Cardiol 2012;59:1785-95. [Crossref] [PubMed]
54. Böhm M, Perez AC, Jhund PS, et al. Relationship between heart rate and mortality and morbidity in the irbesartan patients with heart failure and preserved systolic function trial (I-Preserve). Eur J Heart Fail 2014;16:778-87. [Crossref] [PubMed]
55. O'Neal WT, Sandesara PB, Samman-Tahhan A, et al. Heart rate and the risk of adverse outcomes in patients with heart failure with preserved ejection fraction. Eur J Prev Cardiol 2017;24:1212-9. [Crossref] [PubMed]
56. Palau P, Seller J, Domínguez E, et al. Effect of β-Blocker Withdrawal on Functional Capacity in Heart Failure and Preserved Ejection Fraction. J Am Coll Cardiol 2021;78:2042-56. [Crossref] [PubMed]
57. Reil JC, Hohl M, Reil GH, et al. Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction. Eur Heart J 2013;34:2839-49. [Crossref] [PubMed]
58. Busseuil D, Shi Y, Mecteau M, et al. Heart rate reduction by ivabradine reduces diastolic dysfunction and cardiac fibrosis. Cardiology 2010;117:234-42. [Crossref] [PubMed]
59. Maczewski M, Mackiewicz U. Effect of metoprolol and ivabradine on left ventricular remodelling and Ca2+ handling in the post-infarction rat heart. Cardiovasc Res 2008;79:42-51. [Crossref] [PubMed]
60. Pal N, Sivaswamy N, Mahmod M, et al. Effect of Selective Heart Rate Slowing in Heart Failure With Preserved Ejection Fraction. Circulation 2015;132:1719-25. [Crossref] [PubMed]
61. Kosmala W, Holland DJ, Rojek A, et al. Effect of If-channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: a randomized trial. J Am Coll Cardiol 2013;62:1330-8. [Crossref] [PubMed]
62. Komajda M, Isnard R, Cohen-Solal A, et al. Effect of ivabradine in patients with heart failure with preserved ejection fraction: the EDIFY randomized placebo-controlled trial. Eur J Heart Fail 2017;19:1495-503. [Crossref] [PubMed]
63. Koroma TR, Samura SK, Cheng Y, et al. Effect of Ivabradine on Left Ventricular Diastolic Function, Exercise Tolerance and Quality of Life in Patients With Heart Failure: A Systemic Review and Meta-Analysis of Randomized Controlled Trials. Cardiol Res 2020;11:40-9. [Crossref] [PubMed]
64. Nadeem M, Hassib M, Aslam HM, et al. Role of Ivabradine in Patients with Heart Failure with Preserved Ejection Fraction. Cureus 2020;12:e7123. [Crossref] [PubMed]
65. Tanaka H, Yamauchi Y, Imanishi J, et al. Effect of Ivabradine on Left Ventricular Diastolic Function of Patients With Preserved Ejection Fraction - Results of the IVA-PEF Study. Circ Rep 2022;4:499-504. [Crossref] [PubMed]
66. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022;145:e895-e1032. [Crossref] [PubMed]
67. McDonagh TA, Metra M, Adamo M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2023;44:3627-39. [Crossref] [PubMed]
68. Kitai T, Kohsaka S, Kato T, et al. JCS/JHFS 2025 Guideline on Diagnosis and Treatment of Heart Failure. J Card Fail 2025;31:1164-322. [Crossref] [PubMed]
69. van Loon T, Rijks J, van Koll J, et al. Accelerated atrial pacing reduces left-heart filling pressure: a combined clinical-computational study. Eur Heart J 2024;45:4953-64. [Crossref] [PubMed]
70. Infeld M, Wahlberg K, Cicero J, et al. Effect of Personalized Accelerated Pacing on Quality of Life, Physical Activity, and Atrial Fibrillation in Patients With Preclinical and Overt Heart Failure With Preserved Ejection Fraction: The myPACE Randomized Clinical Trial. JAMA Cardiol 2023;8:213-21. [Crossref] [PubMed]
71. Infeld M, Cyr J, Novelli AE, et al. Clinical Outcomes With Personalized Accelerated Physiologic Pacing in Heart Failure With Preserved Ejection Fraction: Follow-up of the myPACE Trial. JAMA Cardiol 2025;10:1010-5. [Crossref] [PubMed]
72. Reddy YNV, Koepp KE, Carter R, et al. Rate-Adaptive Atrial Pacing for Heart Failure With Preserved Ejection Fraction: The RAPID-HF Randomized Clinical Trial. JAMA 2023;329:801-9. [Crossref] [PubMed]
73. Chung CS, Kovács SJ. Consequences of increasing heart rate on deceleration time, the velocity-time integral, and E/A. Am J Cardiol 2006;97:130-6. [Crossref] [PubMed]
74. Chung CS, Karamanoglu M, Kovács SJ. Duration of diastole and its phases as a function of heart rate during supine bicycle exercise. Am J Physiol Heart Circ Physiol 2004;287:H2003-8. [Crossref] [PubMed]
75. Appleton CP. Influence of incremental changes in heart rate on mitral flow velocity: assessment in lightly sedated, conscious dogs. J Am Coll Cardiol 1991;17:227-36. [Crossref] [PubMed]
76. Kusunose K, Arase M, Zheng R, et al. Clinical Utility of Overlap Time for Incomplete Relaxation to Predict Cardiac Events in Heart Failure. J Card Fail 2021;27:1222-30. [Crossref] [PubMed]