Cardiac Resynchronization Therapy in Heart Failure with Preserved Ejection Fraction in the Setting of Left Bundle Branch Block and Dyssynchrony: A Comprehensive Review

Cardiac Resynchronization Therapy in Heart Failure with Preserved Ejection Fraction in the Setting of Left Bundle Branch Block and Dyssynchrony: A Comprehensive Review | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 16 July 2025 V1 Latest version Share on Cardiac Resynchronization Therapy in Heart Failure with Preserved Ejection Fraction in the Setting of Left Bundle Branch Block and Dyssynchrony: A Comprehensive Review Authors : Hussam Al Hennawi [email protected] and Behzad Pavri 0000-0003-1240-7812 Authors Info & Affiliations https://doi.org/10.22541/au.175262404.41669015/v1 318 views 159 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Heart failure with preserved ejection fraction (HFpEF) remains a complex and therapeutically challenging syndrome. A subset of HFpEF patients with left bundle branch block (LBBB), wide QRS complexes (≥130 ms), and mechanical dyssynchrony may benefit from cardiac resynchronization therapy (CRT). While CRT is an established therapy in heart failure with reduced ejection fraction (HFrEF), its role in HFpEF is under active investigation. Emerging data from mechanistic studies, case reports, and observational trials suggest CRT may offer promising hemodynamic signals, functional improvement, and quality of life enhancement in carefully selected HFpEF patients. This review critically examines the pathophysiological rationale, evolving evidence base, patient selection criteria, and future directions for CRT in HFpEF with LBBB. Cardiac Resynchronization Therapy in Heart Failure with Preserved Ejection Fraction in the Setting of Left Bundle Branch Block and Dyssynchrony: A Comprehensive Review Hussam Al Hennawi, MD 1 , Behzad B. Pavri, MD, FHRS 3 Department of Internal Medicine, Jefferson Abington Hospital, Abington, Philadelphia, USA Department of Medicine, Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, USA Correspondence: Hussam Al Hennawi, MD Jefferson Abington Hospital 1200 Old York Road, Abington, PA 19001 Phone: 267-266-8100 Email: [email protected] Abstract Heart failure with preserved ejection fraction (HFpEF) remains a complex and therapeutically challenging syndrome. A subset of HFpEF patients with left bundle branch block (LBBB), wide QRS complexes (≥130 ms), and mechanical dyssynchrony may benefit from cardiac resynchronization therapy (CRT). While CRT is an established therapy in heart failure with reduced ejection fraction (HFrEF), its role in HFpEF is under active investigation. Emerging data from mechanistic studies, case reports, and observational trials suggest CRT may offer promising hemodynamic signals, functional improvement, and quality of life enhancement in carefully selected HFpEF patients. This review critically examines the pathophysiological rationale, evolving evidence base, patient selection criteria, and future directions for CRT in HFpEF with LBBB. Keywords Heart failure with preserved ejection fraction (HFpEF); left bundle branch block (LBBB); cardiac resynchronization therapy (CRT); mechanical dyssynchrony; wide QRS complex; conduction system pacing Key Points • HFpEF patients with LBBB and mechanical dyssynchrony may represent a distinct CRT-responsive subgroup. • Current CRT guidelines exclude HFpEF, though observational and mechanistic studies suggest potential benefit. • Large randomized trials are warranted to validate CRT in this population. Introduction Heart failure with preserved ejection fraction (HFpEF) defined by a left ventricular ejection fraction (LVEF) of ≥50%, accounts for nearly 50% of all heart failure cases. It is characterized by elevated LV filling pressures and diastolic dysfunction [1, 2]. While significant therapeutic progress has been made in HFrEF, treatment for HFpEF remains limited [3, 4]. A subgroup of HFpEF patients exhibits electrical conduction abnormalities—particularly LBBB with QRS prolongation (≥130 MS)—which may contribute to mechanical dyssynchrony and impaired ventricular function [5, 6]. These abnormalities mirror electromechanical dysfunction patterns observed in HFrEF, where CRT has proven beneficial [7]. Emerging data support this potential. The KaRen study demonstrated a high prevalence of mechanical dyssynchrony in HFpEF patients with LBBB [8]. Similarly, Swedish registry data associated QRS prolongation with increased mortality across EF ranges [9]. Case studies and small trials have reported functional improvements following CRT in HFpEF [10], with the PROSPECT substudy suggesting benefit even in patients with EF >35% [11]. However, clinical adoption is constrained by limited high-quality evidence. The 2022 AHA/ACC/HFSA guidelines do not recommend CRT for HFpEF, citing a lack of data from large randomized trials [12]. While critics argue that HFpEF’s heterogeneity complicates CRT response prediction, advocates suggest that targeting specific phenotypes(e.g., those with LBBB and mechanical dyssynchrony) may provide real benefit [13]. This review aims to critically assess CRT’s role in HFpEF with LBBB (Table 1), synthesizing pathophysiological, clinical, and mechanistic evidence to evaluate whether CRT could serve as an effective therapy in this complex population. Review of the literature Prevalence of LBBB and Mechanical Dyssynchrony in HFpEF A significant proportion of HFpEF patients exhibit LBBB and mechanical dyssynchrony, conditions potentially amenable to CRT. The KaRen study found that 70% of HFpEF patients with LBBB had mechanical dyssynchrony [14]. Santos et al. observed dyssynchrony in 45% of patients using strain imaging, with LBBB strongly associated [5]. Lund et al.reported QRS prolongation (≥120 ms) in 20–30% of HFpEF patients, linked to worse prognosis, although not isolating LBBB [9]. Mechanistic Insights LBBB introduces asynchronous ventricular activation, prolongs isovolumic contraction, and delays lateral wall contraction, worsening already compromised lusitropic properties in HFpEF. Pressure-volume loop analysis in a case by Penicka et al. showed reduced LV end-diastolic pressure and improved relaxation with CRT [10]. Wang et al. Conducted a study using temporary biventricular pacing in 24 patients with LVEF >50% and mechanical dyssynchrony, observing improved dP/dt and reduced mechanical delay, highlighting that HFpEF patients may retain sufficient contractile reserve for CRT responsiveness [11]. Guo et al. reported improved synchrony and perfusion with CRT [15], while Liu et al. demonstrated normalization of septal motion and enhanced twist mechanics [16]. Zhang et al. reported lowered LV end-diastolic pressure and increased stroke volume [17], while Ye et al. found improved radial synchrony and longitudinal strain in a preclinical model [18]. Clinical Outcomes Observational studies report moderate benefits post-CRT. Friedman et al. (2021) found 65% of HFpEF patients improved in NYHA class and reported better quality of life [3]. Their 2018 study showed increased walking distance and reduced NT-proBNP in two patients [19]. Ye et al. (2023) reported 30% NT-proBNP reduction and improved oxygen consumption in 38 patients [20]. Abraham et al. noted reduced hospitalizations in one patient with exercise-induced dyssynchrony [21]. (Table 2) Comparative Effectiveness A PROSPECT trial substudy showed that 24% of patients with LVEF patients [11]. However, Zhang et al. (2024) found CRT effects in HFpEF were less pronounced compared to HFrEF, particularly in reverse remodeling and NYHA class improvement [22]. Patient Selection Careful phenotyping is critical. Proposed criteria (summarized in Table 1) include: EF ≥50%, QRS ≥140 ms (men) or ≥130 ms (women), LBBB morphology, mechanical dyssynchrony on imaging, NYHA class II–IV, and elevated NT-proBNP [3, 5, 18]. These remain exploratory and require validation in larger studies. Safety and Adverse Events CRT appears comparably safe in HFpEF as in HFrEF. Friedman et al. (2021) reported a 5% complication rate (e.g., lead dislodgement) [3]. Penicka et al. observed no complications [10]. Potential issues with inappropriate defibrillator therapy in HFpEF are theoretical and underexplored. The lack of a guideline indication in HFpEF alters the procedural risk–benefit balance, underscoring the need for randomized trial validation. Electromechanical Substrate in HFpEF with LBBB In HFpEF, diastolic abnormalities such as impaired lusitropy, elevated LVEDP, and reduced compliance are central to functional limitation. Superimposed LBBB aggravates these abnormalities by inducing intra- and interventricular dyssynchrony. This electromechanical mismatch delays activation of the lateral LV wall, prolongs isovolumic phases, and contributes to inefficient myocardial work and elevated filling pressures [3, 23]. Advanced imaging has shown regional delay in >80% of HFpEF patients with LBBB, supporting the role of electrical dyssynchrony as a modifiable contributor to clinical deterioration [3]. Nevertheless, causality is complex. Aging, AF, and comorbidities may also contribute to observed dysfunction, and as noted by Lau et al., the gradual nature of LBBB makes it difficult to isolate its pathogenic role [26]. Mechanistic Support for CRT in Preserved EF with Conduction Delay CRT aims to restore synchrony by counteracting abnormal activation-contraction patterns introduced by LBBB. In patients with preserved EF, CRT has demonstrated acute improvements in dP/dt_max and myocardial performance indices, as shown by Friedman et al. [18]. Similarly, Penicka et al. documented improved pressure-volume relationships and elastance modulation following CRT [10]. Temporary BiV pacing in patients with mechanical dyssynchrony and EF mechanical delay, indicating contractile reserve in this subgroup [11]. These findings suggest that CRT may benefit HFpEF patients by addressing inefficient electromechanical coupling. Other studies have confirmed improvements in regional synchrony, wall stress, perfusion, and LV twist mechanics post-CRT, particularly in those with LBBB and preserved EF [15, 24]. These hemodynamic effects offer a strong physiological rationale for expanding CRT considerations to selected HFpEF patients. Clinical Correlates and Observational Insights Data from the KaRen study and national registries reinforce the clinical importance of dyssynchrony in HFpEF. Prolonged QRS duration in this population correlates with elevated NT-proBNP and poor exercise capacity [8]. Furthermore, outcomes data from the Swedish HF registry show increased mortality risk across EF spectrums in patients with QRS prolongation, indicating that conduction delay is not benign in preserved EF [16]. Although evidence is largely observational, these associations suggest that CRT might be clinically impactful for selected HFpEF patients with LBBB and dyssynchrony. Barriers to Implementation and Patient Selection Despite promising signals, CRT use in HFpEF remains limited due to population heterogeneity. Electrical dyssynchrony may be a secondary phenomenon in some, complicating response prediction. Moreover, comorbidities such as AF, chronotropic incompetence, and extensive fibrosis further influence CRT outcomes. Optimal candidates are likely those with classic LBBB, QRS ≥130–150 ms, septal flash or apical rocking on imaging, and minimal scar burden (e.g., on CMR) [25–27]. NT-proBNP and echocardiographic surrogates of filling pressures (E/e′, LAVi) may further refine selection. Targeted phenotyping, combining electrocardiographic and imaging criteria, remains essential to optimize benefit while minimizing non-responder risk. Emerging Modalities and Forward Directions Novel pacing approaches such as CSP—including His bundle pacing and LBBAP—have emerged as promising alternatives to BiV CRT. CSP restores more physiological activation patterns and avoids coronary venous anatomy, which may be especially useful in HFpEF patients with borderline QRS or atypical conduction [28, 29]. Chen et al. (2024) reported that CSP reduced atrial high-rate episodes in HFpEF, suggesting anti-arrhythmic potential [28]. Direct comparison of CSP versus BiV in HFpEF populations is warranted to define relative efficacy. Additional innovations include leadless endocardial CRT (e.g., WiSE-CRT), which allows targeted LV activation. These modalities may broaden access and improve outcomes in anatomically challenging cases. Integration of imaging (strain, CMR), biomarkers (NT-proBNP), and ML algorithms for response prediction may enable individualized CRT delivery. A shift toward mechanistic, data-driven criteria beyond EF is likely necessary to define CRT’s full value in HFpEF [25]. Role of Heart Rate Programming Chronotropic incompetence is frequent in HFpEF and contributes to exercise intolerance. Studies from the Maastricht group suggest that increasing resting HR to ~70–75 bpm may improve lusitropy and augment stroke volume [30]. CRT programming that incorporates HR targets, especially in those with sinus node dysfunction, could optimize hemodynamics and enhance benefit in this subgroup. Synthesis of Clinical Outcomes Across observational studies and mechanistic reports, CRT in HFpEF patients with LBBB has yielded consistent signals of clinical benefit. Friedman et al. (2021) reported that 65% of patients improved by at least one NYHA class, alongside subjective quality of life gains [3]. In a separate pilot study, the same group documented increased 6MWD and decreased NT-proBNP in HFpEF patients post-CRT, with two individuals experiencing >30% biomarker reduction [19]. Similarly, Ye et al. (2023) observed a mean NT-proBNP reduction of 30% and improved peak VO₂ following CRT in a cohort of 38 patients with preserved EF [20]. Wang et al. demonstrated shortened mechanical delay and enhanced dP/dt following temporary BiV pacing in patients with EF >50% [11]. QRS narrowing was also reported in several series, reflecting improved electrical synchrony. While these results are largely non-randomized, the consistency in directional improvement across multiple domains—functional class, exercise capacity, hemodynamics, and biomarkers—suggests a reproducible physiological effect that warrants validation in larger controlled trials. Future Directions A randomized trial enrolling HFpEF patients with LBBB, QRS ≥130 ms, and mechanical dyssynchrony is urgently needed. Such a trial should: • Compare CRT vs. Medical therapy (or CSP vs. Biv) • Use imaging (strain, CMR) and biomarker (NT-proBNP) guidance • Track clinical (NYHA, 6MWD) and structural (LVEDP, remodeling) outcomes Advanced imaging and machine learning–based phenotyping may refine selection and response prediction. Conclusion Though not currently guideline-approved, CRT may confer benefit in a well-defined HFpEF subgroup with LBBB and dyssynchrony. Observational and mechanistic evidence suggest promising hemodynamic effects, and early outcomes are encouraging. As pacing technologies evolve, randomized trials will be key to establishing CRT’s role in this challenging population. References 1. Reddy YN, Borlaug BA. Heart failure with preserved ejection fraction. Current problems in cardiology. 2016 Apr 1;41(4):145-88. 2. Hamo CE, DeJong C, Hartshorne-Evans N, Lund LH, Shah SJ, Solomon S, Lam CS. Heart failure with preserved ejection fraction. Nature reviews Disease primers. 2024 Aug 14;10(1):55. 3. Friedman DJ, Emerek K, Søgaard P, Kisslo J, Møgelvang R, Daubert JC. Left bundle-branch block is associated with a similar dyssynchronous phenotype in heart failure patients with normal and reduced ejection fractions. Am Heart J. 2021;236:106–115. doi:10.1016/j.ahj.2021.03.011. 4. 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Maastricht: Ridderprint, 2021. 175 p. Graphs: Figure 1: Pressure-volume loop demonstrating improved LV filling and reduced end-diastolic pressure after CRT. Table 1: Summary of proposed selection criteria. Ejection Fraction ≥50% QRS Duration ≥140 ms (men) or ≥130 ms (women) QRS Morphology Left Bundle Branch Block (LBBB) Mechanical Dyssynchrony Confirmed by echocardiography (speckle-tracking) Symptom Class NYHA II-IV Biomarkers Elevated NT-proBNP indicating high filling pressures Table 2: Baseline Characteristics of Patients in CRT-HFpEF Studies Friedman et al. (2021) 82 74 ± 9 52% ≥50% ≥130 ms 100% Elevated 84% positive Friedman et al. (2018) 2 68, 72 50% 55%, 58% ≥150 ms Yes Elevated Confirmed Penicka et al. (2010) 1 70 Female Preserved 160 ms Yes Not reported Confirmed Abraham et al. (2014) 1 63 Female 60% Prolonged Yes Not reported Exercise-induced Zhang et al. (2024) 1 66 Male 55% 140 ms Yes Elevated Yes Ye et al. (2023) 38 69 ± 10 54% ≥50% ≥130 ms All Elevated Yes (strain imaging) Donal et al. (2010) Registry Varied ~60% Mixed EF Varied Not specified Not reported ~70% had dyssynchrony Santos et al. (2014) 130 70 ± 8 45% ≥50% Mixed Subset Elevated Common (based on strain imaging) Information & Authors Information Version history V1 Version 1 16 July 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords clinical: electrophysiology – conduction disturbances clinical: implantable devices – biventricular pacing/defibrillation clinical: implantable devices – physiologic pacing clinical: non-invasive techniques – heart rate variability clinical: pediatrics – implantable devices Authors Affiliations Hussam Al Hennawi [email protected] Jefferson Abington Hospital View all articles by this author Behzad Pavri 0000-0003-1240-7812 Thomas Jefferson University Department of Medicine View all articles by this author Metrics & Citations Metrics Article Usage 318 views 159 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Hussam Al Hennawi, Behzad Pavri. Cardiac Resynchronization Therapy in Heart Failure with Preserved Ejection Fraction in the Setting of Left Bundle Branch Block and Dyssynchrony: A Comprehensive Review. Authorea . 16 July 2025. 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