Review Article

Heart Failure in Hypertrophic Cardiomyopathy

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Abstract

End-stage hypertrophic cardiomyopathy (ES-HCM) presents on a spectrum between the classic left ventricular systolic dysfunction and a lessrecognised, restrictive phenotype with small-to-normal-sized left ventricular cavity and preserved ejection fraction. Relatively poor prognoses follow those on this morpho-functional spectrum, marked by low cardiac output and high arrhythmic risk. Contemporary guideline-directed therapies, such as ICDs, CRT and cardiac transplantation, have significantly improved outcomes, reshaping the natural history of ES-HCM. Meanwhile, the roles of neurohormonal modulation and left ventricular assist devices remain less well defined. Still, timely recognition and intervention remain essential in patients with ES-HCM, given its considerable morbidity and mortality. As cardiac myosin inhibitors and antifibrotic strategies advance, early targeted treatment may modify the natural history of hypertrophic cardiomyopathy, leading to a reduction in the incidence of ES-HCM. Moving forward, broader adoption of phenotype-specific approaches and equitable application of advanced therapies are critical to address the rare but clinically significant burden of ES-HCM.

Keywords

Hypertrophic cardiomyopathy, left ventricular systolic dysfunction, restrictive cardiomyopathy, cardiac failure, advanced, end stage, heart transplant,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/cfr.2025.25

Disclosure: AM reports research grants from Pfizer, Ionis, Attralus, Cytokinetics and Janssen and fees from Cytokinetics, BMS, BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, Akros, Edgewise, Rocket, Lexeo, Prothena, BioMarin, AstraZeneca, Avidity, Neurimmune and Tenaya. ON and DK are supported by National Institutes of Health T32 Grant # 5T32HL166128-02.

Correspondence: Ahmad Masri, Hypertrophic Cardiomyopathy Center, Knight Cardiovascular Institute, Oregon Health & Science University, Mail code: UHN-62, 3181 SW Sam Jackson Rd, Portland, OR 97239, US. E: masria@ohsu.edu

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Burnt-out or end-stage hypertrophic cardiomyopathy (ES-HCM) is an uncommon clinical entity associated with heightened risk of death related to progressive heart failure and malignant arrhythmia. ES-HCM has a prevalence of approximately 3–8.5% and is commonly defined as having a left ventricular (LV) ejection fraction (LVEF) <50%.1–5 The development of ES-HCM has been previously reported at 14 ± 10 years from the initial onset of hypertrophic cardiomyopathy (HCM) symptoms, with rapid progression to death or transplantation 2.7 ± 2 years following end-stage diagnosis.6 While patients with ES-HCM have increased adverse event rates, outcomes remain heterogeneous.1,2,6

Additionally, relying on systolic dysfunction to define clinically-advanced stages of HCM excludes patients with advanced restrictive cardiomyopathy who typically have LVEF >50%.6 The restrictive phenotype has been under-reported in large ES-HCM studies, despite its substantial prevalence and poor outcomes.4,7–9 In this review, we cover various aspects of ES-HCM, including phenotype, pathogenesis, outcomes and management.

Pathophysiology

HCM is a disorder of the myocardial sarcomere, affecting both thick and thin myocardial filaments. Patients who progress to ES-HCM often have pathogenic or likely pathogenic variants.1,10–12 At the molecular level, these mutations result in hypercontractility, altered calcium sensitivity, reduced myocardial compliance and diastolic dysfunction.13 Excessive ATP is consumed to restore and maintain an isokinetic state.14–18

This elevated ATP demand compromises the sarcoendoplasmic reticulum calcium ATPase function, resulting in cytosolic calcium accumulation that activates downstream hypertrophic and pro-apoptotic signalling pathways.19 The result is progressive myocardial hypertrophy, myofibre disarray and interstitial fibrosis.19–21

Approximately 0.5–0.75% of patients with HCM develop ES-HCM annually (Supplementary Table 1).1,11,22 This transition is thought to be driven by adverse remodelling and severe microvascular dysfunction.23–25 Impaired perfusion stems from structural changes in intramural coronary arterioles, worsened by elevated LV filling pressures, increased wall stress, and heightened adrenergic stimulation – particularly during tachyarrhythmias.10,26

Recurrent ischaemia accelerates myocyte loss through necrosis and apoptosis, leading to replacement fibrosis.27 As fibrosis progresses, LV walls thin, contractile function declines and dilative remodelling ensues.25,28 Replacement fibrosis can be measured using late gadolinium enhancement (LGE) imaging, and extensive LGE (>20% of LV mass) is associated with a more than threefold increased risk of ES-HCM within 5 years.29

Finally, these structural changes create patchy arrhythmogenic substrates, enabling re-entrant circuits and sustained ventricular arrhythmias.30 Concurrent ionic remodelling, including late sodium current augmentation and impaired calcium reuptake, prolongs action potentials and further heightens arrhythmic risk and the risk of sudden cardiac death (SCD).31

Presentation

Low cardiac output is a hallmark feature of ES-HCM (Figure 1), driving symptoms such as fatigue, light-headedness, syncope, angina and classic heart failure manifestations including dyspnoea, orthopnoea and paroxysmal nocturnal dyspnoea. While the classic form of ES-HCM with LV systolic dysfunction (HCM-LVSD) can be readily identified by 2D echocardiography, recognising the restrictive form of ES-HCM can be particularly challenging.

Figure 1: Hypertrophic Cardiomyopathy Pressure–Volume Loops

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Not only is LVEF frequently over-interpreted as a stand-alone marker of cardiac function, but these patients also often lack overt signs of volume overload such as peripheral oedema. As a result, the condition may go unrecognised, delaying appropriate therapy despite a prognosis comparable with HCM-LVSD.

Accurate phenotyping requires a comprehensive approach that integrates careful clinical evaluation with multimodality imaging (Table 1 and Figure 2).32 2D echocardiography serves as the cornerstone first-line imaging modality, providing a broad differential that can be refined using cardiac MRI techniques, including LGE and T1- and T2-weighted imaging. Clinical clues that should prompt further haemodynamic assessment with Doppler echocardiography and right heart catheterisation for possible ES-HCM with restrictive filling include recurrent heart failure hospitalisations, persistent New York Heart Association (NYHA) class >II symptoms despite optimised therapy, pulmonary hypertension, right heart failure and comorbid AF.33 Secondary complications, particularly AF, may precipitate abrupt heart failure decompensations or recurrent admissions, revealing limited cardiopulmonary reserve.

Table 1: A Multimodal Imaging Approach to the Diagnosis of End-stage Hypertrophic Cardiomyopathy

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Although ES-HCM can present across a spectrum, two principal morpho-functional phenotypes are recognised (Figure 2):

  • HCM-LVSD is characterised by excessive LV remodelling and wall thinning, presenting with LVEF <50%.6 While increased LV end-diastolic diameter (LVEDD) can be observed, LV cavity dilation is not required for this diagnosis and those with this morpho-functional phenotype may have concomitant restrictive filling.
  • Restrictive ES-HCM is a phenotype that features significant diastolic dysfunction, with supporting features of peak E/A ratio ≥2 and rapid deceleration time.7 LV size is small-to-normal and systolic function is mildly reduced or preserved (LVEF >50–55%).4 Patients typically exhibit symptoms of NYHA functional class II or higher.

Regarding LV outflow tract obstruction (LVOTO), this morphological feature is rarely seen in HCM-LVSD.1,5,23 This is an expected finding given the extensive fibrosis and progressive hypocontractility associated with advanced remodelling.

Figure 2: Clinical Characteristics of End-stage Hypertrophic Cardiomyopathy

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Atrial and Ventricular Arrhythmias

Arrhythmias are a hallmark of HCM disease progression, with both atrial and ventricular forms becoming increasingly prevalent in patients experiencing adverse myocardial remodelling.1,2,5,6,23,34 Key contributors to this arrhythmogenic milieu include LV myocardial fibrosis, elevated LV filling pressures and progressive remodelling of the left atrium, ultimately leading to left atrial (LA) enlargement. These changes create an ideal substrate for atrial arrhythmias, particularly AF.

AF in HCM is associated with significant morbidity and can mark a more advanced disease stage as it is associated with increased risk of death (Supplementary Table 2). AF is twice as common in patients with HCM-LVSD than in those with non-HCM-LVSD and is highly prevalent in patients with ES-HCM (Supplementary Table 3).1,5,6,35 On average, AF precedes the diagnosis of HCM-LVSD by approximately 5.9 ± 6.3 years.2,36

While AF may initially present in a paroxysmal form, it can progress to a persistent state as atrial remodelling advances. This transition is clinically significant, as it is associated with a fourfold increase in the development of ES-HCM, with substantially higher combined probability of HCM-related death, functional impairment and stroke.37,38

Ventricular tachyarrhythmias represent another complication with associated morbidity and mortality (Supplementary Table 2). Up to 75% of patients with HCM-LVSD exhibit sustained or non-sustained ventricular tachycardia (VT) on Holter monitoring.35 The most feared consequence of ventricular arrhythmias is SCD, which has been reported to occur in as many as half of patients with HCM-LVSD over 5–10 years of follow-up.22,35

Risk Factors

Multiple studies have evaluated predictors of HCM-LVSD (Supplementary Table 1). Unsurprisingly, patients with earlier disease onset and with more severe phenotype appear more likely to undergo adverse remodelling. Additional risk factors are summarised in Table 2, with selected elements discussed in more detail below.1,2,4–7,39–41 By contrast, risk factors for restrictive ES-HCM remain poorly characterised, underscoring the need for further investigation across the spectrum of ES-HCM to better inform prevention strategies for this highly morbid disease state.

Table 2: End-stage Hypertrophic Cardiomyopathy Risk Factors

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Genetics

Rowin et al. found that those with ES-HCM were sixfold more likely to have a family history of ES-HCM (12% versus 2%; p=0.002).2 Data from the Sarcomere Human Cardiomyopathy Registry (SHaRe) further linked HCM-LVSD to the presence of one or more pathogenic or likely pathogenic sarcomere variants, including thin filament genes.1 A smaller study of patients with HCM-LVSD and restrictive filling reported similar associations but highlighted a predominance of thick filament variants (e.g. MYBPC3, MYH7) over thin filament variants (e.g. TNNT2, TNNI3, TPM1, ACTC1).7 Importantly, implementation of genetic cascade screening enables earlier identification of at-risk individuals, potentially allowing intervention before adverse remodelling ensues and improving long-term outcomes.

Septal Reduction Therapies

For patients with obstructive HCM and severe symptoms, septal reduction therapies (SRT) are effective and safe, offering lasting symptom relief and improved quality of life. Targeting the underlying LVOTO has been an important therapeutic target to prevent the progression of HCM phenotype HCM-LVSD.42 While the sub-cohort of 1,832 patients undergoing myectomy or alcohol septal ablation (ASA) in the SHaRe had a 2.6-fold increased risk of developing HCM-LVSD, with a 2–5% annual incidence following SRT (11% of those who had SRT developed ES-HCM), several other studies report more reassuring findings.1

A binational sub-cohort showed that among 708 post-myectomy patients, 34 (4.8%) developed ES-HCM, a rate identical to that observed in 1,504 non-operated patients (4.8%; p=0.84), with an RR of 1.02 (95% CI [0.70–1.50]).2 Similarly, among 409 patients who underwent myectomy between 2007 and 2012, none developed HCM-LVSD at 5- or 10-year follow-up.40 Additionally, a large Russian ASA cohort (n=597), including patients who underwent repeat procedures, reported no incident HCM-LVSD over a mean 5.9 ± 3.9 years. Long-term survival remained favourable at 97.4%, 93.2% and 84.9% at 1, 5 and 10 years of follow-up, respectively, and was similar between patients undergoing single versus repeat procedures.41 Studies are needed to clarify who might be at risk of HCM-LVSD development, post-SRT.

Left Ventricular Ejection Fraction 50–60%

Although reductions in LVEF can herald impending HCM-LVSD, reliance on this measure alone is limited by its geometric assumptions, which may not apply to remodelled HCM ventricles.1,5,37 This limitation is particularly pronounced in restrictive HCM, where diastolic and systolic volumes are relatively fixed.33 A multimodal imaging approach is therefore essential. Using speckle-tracking echocardiography, Choi et al. demonstrated that LV global longitudinal strain (LV-GLS) ≤10.5% in patients with preserved LVEF (50–60%) was predictive of progression to SCD (or equivalent arrhythmic event), cardiovascular death or all-cause mortality within a median of 4.1 years.43 Detailed phenotypic evaluation beyond LVEF is typically required for an adequate evaluation of patients with HCM.

AF

AF can be a major sign of HCM progression or a driver of clinical deterioration. While LA enlargement is a well-established predictor of AF, newer pre-clinical markers such as LA reservoir strain (LA-Sr) may offer earlier risk stratification.44 Patients with LA volume <37 ml/m2 versus ≥37 ml/m2 and LA strain >23.4 versus ≤23.4% have superior 5-year AF-free survival of 93% versus 80% (p=0.003) and 98% versus 74% (p=0.002), respectively.45 Combined, LA volume <37 ml/m2 and LA strain >23.4% yielded a high negative predictive value (93% and 98%, respectively) for new-onset AF.45 Furthermore, a LA-Sr <13.3% predicted clinically relevant AF events such as AF episodes requiring electrical cardioversion or catheter ablation, hospitalisation due to AF lasting >24 hours, or a clinical decision to accept permanent AF.46 Implementing a thorough evaluation for patients who develop AF can aid in uncovering of patients with or at risk of ES-HCM.

Evaluation

Diagnostic accuracy for ES-HCM is essential, as delays in recognising disease progression can postpone advanced therapies with significant clinical consequences. A comprehensive evaluation strategy should integrate surveillance for established risk factors (Table 2) and multimodality imaging. While LVSD is commonly used as the primary diagnostic criterion for ES-HCM, it lacks specificity. LVSD may arise from reversible causes such as ischaemic reperfusion injury (e.g. post-percutaneous intervention), tachyarrhythmias, catecholamine surge (e.g. stress-induced cardiomyopathy) or electrical dyssynchrony – processes of true ES-HCM.

In this setting, it is important to avoid attributing a decline in systolic function to disease progression when it may instead reflect underlying dyssynchrony. Careful evaluation of patients with conduction disease and pacing requirements is essential, and timely consideration of CRT can significantly improve LV systolic function and symptoms in appropriately selected patients.47

To enhance diagnostic confidence and reduce misclassification, we recommend incorporating a threshold of LGE >20% on cardiac MRI as supportive evidence of irreversible myocardial fibrosis (Table 1).23,25,28,29 Even prior to overt LVSD, speckle-tracking echocardiography can provide valuable prognostic information, enabling more precise mapping of disease trajectory in this clinically heterogeneous population. In particular, reduced LV-GLS serves as an early marker of systolic dysfunction and potentially restrictive filling.33,43

Outcomes

Mortality Trends and Sudden Cardiac Death

Early studies reported >10% mortality rates in patients with ES-HCM.6 However, outcomes have considerably improved with contemporary management, using ICDs and referring ES-HCM patients early for cardiac transplant evaluation.30 Contemporary outcomes now show markedly improved survival, with all-cause mortality falling to 2.2% annually and a 10-year survival rate of 83%.2 Data from SHaRe indicate that the time from recognition of LVSD to a composite of all-cause mortality, transplant, or LV assist device (LVAD) requirement – now spans up to 8.4 years.1 Nevertheless, these events still occur in approximately 35% of patients with HCM-LVSD.1

While HCM-LVSD patients carry a 4- to 5-fold higher risk of SCD compared with those with non-HCM-LVSD,1,2 the widespread adoption of ICDs since the early 2000s have prolonged the longevity of HCM patients and has markedly shifted the primary cause of death in ES-HCM toward circulatory failure – accounting for 50–60% of HCM-related mortality.11,30

AF and Prognosis

AF is associated with adverse outcomes in HCM. A meta-analysis of six studies involving 6,858 HCM patients – including 1,314 with AF – demonstrated that AF is independently associated with increased cardiac mortality, even after excluding stroke-related deaths (OR 2.6; 95% CI [1.6–4.2], p=0.0002).48 Among ES-HCM patients, AF similarly confers increased risk of mortality (HR 2.6; 95% CI [1.7–3.8]).1,4 Furthermore, progression from paroxysmal to persistent AF is associated with developing ES-HCM, requiring cardiac transplantation and facing HCM-related death.4,34,37

Systemic Embolism and Stroke

Even in the absence of AF, HCM has an increased risk of thromboembolism. Independent predictors of thromboembolic events include age ≥65 years, heart failure-related dyspnoea, and LV hypertrophy (LVH).11,49–51 Among patients with HCM-LVSD, this risk is particularly pronounced by the stagnation of blood associated with myocardial dyskinesis.27 In one cohort, mural thrombus was present in 19% and cerebral thromboembolism occurred in 20% of HCM-LVSD patients, yet only 36% were anticoagulated – despite 53% having AF – underscoring an opportunity for stroke prevention.11 In the SHaRe registry, HCM-LVSD was associated with 8.4% stroke-related mortality and a 3.7-fold higher risk compared with those without LVSD.1 Additionally, systemic embolism has been observed in 2% of the HCM-LVSD population, adding to the morbidity of this disease.11

The Restrictive Phenotype

While most published data focus on HCM-LVSD, a smaller, but clinically significant, group presents with advanced heart failure symptoms despite preserved ejection fraction, often with restrictive physiology. Although this phenotype affects 6% of the HCM population, it remains under-recognised and under-treated.9 One-third of these patients reach mortality-equivalent outcomes such as transplant, ICD discharge or death, with a 3.5-fold increased risk of sudden cardiac events.8,9

Despite this, patients with restrictive disease often receive less aggressive management. A recent Italian retrospective study of 331 ES-HCM patients found no notable differences in HCM-related mortality or need for advanced therapies between restrictive HCM and HCM-LVSD subgroups.4 However, patients with restrictive HCM were more severe in presentation (i.e. NYHA class III/IV, AF) and were disproportionately older and female.2,4 High NYHA functional class is itself independently linked to worse outcomes, yet restrictive HCM patients were less frequently considered for transplant or LVAD.2,4,7,11,39

These disparities mirror findings from the SHaRe registry, where older women with preserved ejection fraction were overrepresented among patients who developed advanced symptoms following ASA.52 As such, guidelines recommendations are to consider patients with advanced symptoms and haemodynamic compromise for cardiac transplantation irrespective of systolic function.7,36,47

Treatment

Neurohormonal Modulation

ES-HCM treatment must be individualised based on haemodynamic phenotype and tolerability. Broadly, HCM therapy aims to reduce myocardial demand and improve diastolic function, which is thought to be indirectly achieved by beta-blockers, non-dihydropyridine calcium channel blockers and disopyramide.47 More recently, cardiac myosin inhibitors (CMIs) have been developed to directly target the underlying sarcomere-driven hypercontractility, which is discussed further below.53,54

Once LVEF falls below 50%, neurohormonal modulation, which represents the standard therapeutic approach in heart failure with reduced ejection fraction, is empirically recommended.47 This includes β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor–neprilysin inhibitors, mineralocorticoid receptor antagonists or sodium–glucose cotransporter 2 inhibitors. However, no clinical trials have specifically validated these therapies in ES-HCM, leaving their role uncertain and highlighting the need for further research in this distinct population.

AF Management

There are no randomised controlled trials specifically addressing AF management in ES-HCM. While similar strategies to those for patients with non-HCM heart failure are recommended, rhythm control is generally preferred over rate control for control of symptoms and for avoidance of worsening the low-output state of ES-HCM. However, rhythm control in HCM is challenging, and catheter ablation, surgical ablation and anti-arrhythmic drugs are used with mixed success.55 Because the recurrence rate is higher in patients with HCM compared with other conditions, thorough counselling of patients is essential.

Thrombosis and Stroke Management

HCM significantly increases thromboembolic risk, particularly in the setting of AF, which elevates this risk by 8.4-fold.38,51,56,57 In those with HCM-LVSD, AF is even more prevalent, occurring in up to 42–58%.1,2,6,35 Given this heightened risk, current guidelines recommend anticoagulation with a direct-acting oral anticoagulant for patients with clinical or subclinical AF, regardless of CHA₂DS₂-VASc score.47,58 These recommendations reflect the limited utility of the CHA₂DS₂-VASc score in HCM, as it was not originally validated in this population and performs poorly in predicting thromboembolic events.37,38,51

ICDs

As discussed in the Outcomes section, the use of ICDs in HCM, coupled with contemporary SCD risk stratification, has notably reduced HCM-related mortality.59 In the general heart failure population, ICDs are recommended for primary SCD prevention in patients with LVEF ≤35% and NYHA functional class II–III symptoms despite optimal guideline-directed medical therapy. In contrast, HCM-specific guidelines recommend ICD placement for patients with LVEF <50%, reflecting the distinct outcomes of this disease.47 This distinction is clinically significant: nearly half of patients with HCM-LVSD experience SCD or aborted cardiac arrest.22

Conversely, HCM patients with preserved LVEF have other risk factors that heighten their need for ICD prophylaxis. These include a family history of HCM-related SCD before age 50 years, LV hypertrophy >30 mm, unexplained syncope or the presence of an apical aneurysm with transmural LGE. Additional considerations include non-sustained VT and extensive LGE (>20% LV mass), a surrogate for myocardial replacement fibrosis and arrhythmogenic risk. All the while, ICDs remain the cornerstone of secondary prevention in patients with a history of life-threatening ventricular tachyarrhythmias.

Cardiac Resynchronisation Therapy

Given the high prevalence of left bundle branch block (LBBB) in HCM, including in patients with prior SRT, current guidelines recommend CRT in HCM patients with LVEF <50%, NYHA functional class II–IV symptoms refractory to optimised medical therapy and LBBB.47 Rowin et al. found that 62% of patients with LVEF >35%, advanced heart failure symptoms and QRS >120 ms experienced symptom improvement 1 year post-CRT.2 Subsequently, 30% maintained NYHA functional class I–II, while another 30% relapsed into advanced heart failure by 3.4±2.2 years.2 Future studies are required to determine the most suitable candidates for ES-HCM CRT.

Left Ventricular Assist Device

LVADs are not particularly useful in HCM because of the small cavity size and considerable LV hypertrophy. These technical and physiological limitations have made LVAD implantation in HCM restrictive cardiomyopathy relatively uncommon. Despite these challenges, studies demonstrate that, when successfully implanted, LVAD outcomes such as 1- and 4-year survival or length of hospital stay are comparable to those in patients with dilated or ischaemic cardiomyopathy.60,61 However, those with very small LVs (<50 mm) did have significantly lower survival and perioperative complications such as right ventricular failure, infection, bleeding, stroke, renal dysfunction and arrhythmias did occur with increased frequency in the HCM-LVSD restrictive and HCM populations.61,62 Nevertheless, LVAD use as bridge-to-transplant in HCM patients does not increase the risk of waitlist mortality or delisting compared with ischaemic or non-ischaemic cardiomyopathies, but due to these challenges, upfront cardiac transplant is preferred over using an LVAD as a bridge.63

Transplantation

Cardiac transplantation remains the only definitive therapy for patients with ES-HCM.64 Recognising the historically poor outcomes associated with end-stage HCM under prior listing criteria, the Organ Procurement and Transplantation Network/United Network for Organ Sharing (UNOS) registry revised their cardiac transplant allocation system in 2018.65 This change was driven by the unique pathophysiological features of HCM, particularly the presence of fixed pulmonary hypertension, which previously excluded many patients from transplant eligibility.66 Since the policy update, there has been a meaningful reduction in waitlist time and an increase in transplant rates for HCM patients. Although HCM accounts for a small proportion of all transplant cases – 2.8% in the UNOS Registry – post-transplant outcomes are excellent, reaching 93% 1-year survival.67 Similar findings were reported in the Scientific Registry of Transplant Recipients, in which HCM comprised 2.1% of transplants and again demonstrated >90% 1-year survival.68

Longer-term outcomes are favourable as well. Five-year survival in HCM patients surpassed both ischaemic cardiomyopathy (82.5% versus 75.3%; p=0.01) and non-ischaemic cardiomyopathy (77.2%; p=0.04).68 Fortunately, the risk of graft rejection is not increased with HCM (HR 0.8 [95% CI, 0.2–3.1]; p=0.71) and recurrence in the transplanted heart has not been observed histologically.68,69 Moreover, a substantial survival benefit – averaging 10±8 years – has been documented in 79% of HCM patients with restrictive physiology.7 These data support the current class I recommendation for transplant evaluation in HCM patients with advanced heart failure.47

Cardiac Myosin Inhibitors

Mavacamten and aficamten are two CMIs that reduce actin–myosin cross-bridge formation and the hypercontractile state characteristic of HCM. Clinical trials have demonstrated excellent functional and symptomatic improvements. In EXPLORER-HCM, mavacamten improved exercise capacity, symptoms, patient-reported outcomes and LV outflow tract gradients.70 Long-term follow-up from VALOR-HCM confirmed sustained improvements and reduction in the need for SRT.71 In SEQUOIA-HCM and MAPLE-HCM, aficamten improved the same metrics that were improved with mavacamten, with a lower incidence of systolic dysfunction than previously seen.72,73 While these medications are expected to provide favourable structural remodelling and prevent further deterioration of the underlying phenotype, long-term data to that effect are still needed.74,75 In addition, CMIs are contraindicated in patients with HCM-LVSD. However, it is important not to equate systolic reduction to the spontaneous development of HCM-LVSD. It is very clear that the LVEF reduction seen using CMIs is a type of exaggerated pharmacodynamic effect that is reversible once the CMI is stopped or downtitrated.

Future Directions: Prevention of Left Ventricular Systolic Dysfunction and Restrictive Cardiomyopathy

Given the established link between myocardial fibrosis and declining cardiac function, anti-fibrotic strategies have long been of interest. Early studies, such as a 2005 randomised trial by Kawano et al., showed that valsartan could suppress plasma procollagen type I carboxyterminal peptide, a fibrosis biomarker.76 In 2013, Shimada et al. demonstrated modest reductions in LGE with losartan over 1 year.77 However, this benefit was not replicated in patients with extensive fibrosis.78 As a result, preventive efforts have shifted upstream, focusing on genotype-positive, LVH-negative individuals before irreversible remodelling occurs.13,23,79,80

Targeting the cardiac sarcomere with CMIs offers promise in disrupting the maladaptive remodelling cascade. While short-term cardiac MRI studies are very encouraging, longer-term studies are needed to examine this further.74,75

Conclusion

The historically poor prognosis associated with HCM-LVSD is being reshaped by emerging multinational registry data. Contemporary management has transformed the outcomes of patients with ES-HCM. However, there remains significant unmet need given that the only definitive therapy is cardiac transplant.

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References

  1. Marstrand P, Han L, Day SM, et al. Hypertrophic cardiomyopathy with left ventricular systolic dysfunction: insights from the SHaRe registry. Circulation 2020;141:1371–83. 
    Crossref | PubMed
  2. Rowin EJ, Maron BJ, Carrick RT, et al. Outcomes in patients with hypertrophic cardiomyopathy and left ventricular systolic dysfunction. J Am Coll Cardiol 2020;75:3033–43. 
    Crossref | PubMed
  3. Kubo T, Sugiura K, Tokita Y, et al. Contemporary clinical characteristics and management patterns in hypertrophic cardiomyopathy: insights from baseline enrolment data in a nationwide prospective Japanese registry. Heart 2025;111:885–92. 
    Crossref | PubMed
  4. Musumeci B, Tini G, Biagini E, et al. Clinical characteristics and outcome of end stage hypertrophic cardiomyopathy: role of age and heart failure phenotypes. Int J Cardiol 2024;400:131784. 
    Crossref | PubMed
  5. Wasserstrum Y, Larrañaga-Moreira JM, Martinez-Veira C, et al. Hypokinetic hypertrophic cardiomyopathy: clinical phenotype, genetics, and prognosis. ESC Heart Fail 2022;9:2301–12. 
    Crossref | PubMed
  6. Harris KM, Spirito P, Maron MS, et al. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation 2006;114:216–25. 
    Crossref | PubMed
  7. Pasqualucci D, Fornaro A, Castelli G, et al. Clinical spectrum, therapeutic options, and outcome of advanced heart failure in hypertrophic cardiomyopathy. Circ Heart Fail 2015;8:1014–21. 
    Crossref | PubMed
  8. Kubo T, Gimeno JR, Bahl A, et al. Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype. J Am Coll Cardiol 2007;49:2419–26. 
    Crossref | PubMed
  9. Biagini E, Spirito P, Rocchi G, et al. Prognostic implications of the Doppler restrictive filling pattern in hypertrophic cardiomyopathy. Am J Cardiol 2009;104:1727–31. 
    Crossref | PubMed
  10. Marian AJ, Braunwald E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res 2017;121:749–70. 
    Crossref | PubMed
  11. Xiao Y, Yang KQ, Yang YK, et al. Clinical characteristics and prognosis of end-stage hypertrophic cardiomyopathy. Chin Med J (Engl) 2015;128:1483–9. 
    Crossref | PubMed
  12. Kelly M, Semsarian C. Multiple mutations in genetic cardiovascular disease: a marker of disease severity? Circ Cardiovasc Genet 2009;2:182–90. 
    Crossref | PubMed
  13. Ho CY. Hypertrophic cardiomyopathy: preclinical and early phenotype. J Cardiovasc Transl Res 2009;2:462–70. 
    Crossref | PubMed
  14. Seferović PM, Polovina M, Bauersachs J, et al. Heart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019;21:553–76. 
    Crossref | PubMed
  15. Gartzonikas IK, Naka KK, Anastasakis A. Current and emerging perspectives on pathophysiology, diagnosis, and management of hypertrophic cardiomyopathy. Hellenic J Cardiol 2023;70:65–74. 
    Crossref | PubMed
  16. Spudich JA. Three perspectives on the molecular basis of hypercontractility caused by hypertrophic cardiomyopathy mutations. Pflugers Arch 2019;471:701–17. 
    Crossref | PubMed
  17. Baudenbacher F, Schober T, Pinto JR, et al. Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. J Clin Invest 2008;118:3893–903. 
    Crossref | PubMed
  18. Bai F, Weis A, Takeda AK, et al. Enhanced active cross-bridges during diastole: molecular pathogenesis of tropomyosin’s HCM mutations. Biophys J 2011;100:1014–23. 
    Crossref | PubMed
  19. Musumeci B, Tini G, Russo D, et al. Left ventricular remodeling in hypertrophic cardiomyopathy: an overview of current knowledge. J Clin Med 2021;10:1547. 
    Crossref | PubMed
  20. Spindler M, Saupe KW, Christe ME, et al. Diastolic dysfunction and altered energetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy. J Clin Invest 1998;101:1775–83. 
    Crossref | PubMed
  21. Ashrafian H, Redwood C, Blair E, Watkins H. Hypertrophic cardiomyopathy:a paradigm for myocardial energy depletion. Trends Genet 2003;19:263–8. 
    Crossref | PubMed
  22. Kawarai H, Kajimoto K, Minami Y, et al. Risk of sudden death in end-stage hypertrophic cardiomyopathy. J Card Fail 2011;17:459–64. 
    Crossref | PubMed
  23. Olivotto I, Cecchi F, Poggesi C, Yacoub MH. Patterns of disease progression in hypertrophic cardiomyopathy: an individualized approach to clinical staging. Circ Heart Fail 2012;5:535–46. 
    Crossref | PubMed
  24. Olivotto I, Cecchi F, Gistri R, et al. Relevance of coronary microvascular flow impairment to long-term remodeling and systolic dysfunction in hypertrophic cardiomyopathy. J Am Coll Cardiol 2006;47:1043–8. 
    Crossref | PubMed
  25. Galati G, Leone O, Pasquale F, et al. Histological and histometric characterization of myocardial fibrosis in end-stage hypertrophic cardiomyopathy: a clinical-pathological study of 30 explanted hearts. Circ Heart Fail 2016;9:e003090. 
    Crossref | PubMed
  26. Cannon RO, Rosing DR, Maron BJ, et al. Myocardial ischemia in patients with hypertrophic cardiomyopathy: contribution of inadequate vasodilator reserve and elevated left ventricular filling pressures. Circulation 1985;71:234–43. 
    Crossref | PubMed
  27. Maron BJ, Spirito P. Implications of left ventricular remodeling in hypertrophic cardiomyopathy. Am J Cardiol 1998;81:1339–44. 
    Crossref | PubMed
  28. Olivotto I, Maron BJ, Appelbaum E, et al. Spectrum and clinical significance of systolic function and myocardial fibrosis assessed by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. Am J Cardiol 2010;106:261–7. 
    Crossref | PubMed
  29. Chan RH, Maron BJ, Olivotto I, et al. Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation 2014;130:484–95. 
    Crossref | PubMed
  30. Maron BJ, Rowin EJ, Casey SA, Maron MS. How hypertrophic cardiomyopathy became a contemporary treatable genetic disease with low mortality: shaped by 50 years of clinical research and practice. JAMA Cardiol 2016;1:98–105. 
    Crossref | PubMed
  31. Coppini R, Ferrantini C, Yao L, et al. Late sodium current inhibition reverses electromechanical dysfunction in human hypertrophic cardiomyopathy. Circulation 2013;127:575–84. 
    Crossref | PubMed
  32. Castiglione V, Aimo A, Todiere G, et al. Role of imaging in cardiomyopathies. Card Fail Rev 2023;9:e08. 
    Crossref | PubMed
  33. Rapezzi C, Aimo A, Barison A, et al. Restrictive cardiomyopathy: definition and diagnosis. Eur Heart J 2022;43:4679–93. 
    Crossref | PubMed
  34. Maurizi N, Olivotto I, Maron MS, et al. Lifetime clinical course of hypertrophic cardiomyopathy: outcome of the historical Florence cohort over 5 decades. JACC Adv 2023;2:100337. 
    Crossref | PubMed
  35. Biagini E, Coccolo F, Ferlito M, et al. Dilated-hypokinetic evolution of hypertrophic cardiomyopathy: prevalence, incidence, risk factors, and prognostic implications in pediatric and adult patients. J Am Coll Cardiol 2005;46:1543–50. 
    Crossref | PubMed
  36. Rowin EJ, Maron BJ, Kiernan MS, et al. Advanced heart failure with preserved systolic function in nonobstructive hypertrophic cardiomyopathy: under-recognized subset of candidates for heart transplant. Circ Heart Fail 2014;7:967–75. 
    Crossref | PubMed
  37. Rowin EJ, Maron BJ, Haas TS, et al. Hypertrophic cardiomyopathy with left ventricular apical aneurysm: implications for risk stratification and management. J Am Coll Cardiol 2017;69:761–73. 
    Crossref | PubMed
  38. Olivotto I, Cecchi F, Casey SA, et al. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation 2001;104:2517–24. 
    Crossref | PubMed
  39. Zhang Y, Xie W, Dai Y, et al. Influencing and prognostic factors of end-stage hypertrophic cardiomyopathy. ESC Heart Fail 2024;11:4028–37. 
    Crossref | PubMed
  40. Nguyen A, Schaff HV, Ommen SR, et al. Late health status of patients undergoing myectomy for obstructive hypertrophic cardiomyopathy. Ann Thorac Surg 2021;111:1867–75. 
    Crossref | PubMed
  41. Shloido E, Popov K, Chernyshov S, Kashtanov M. National experience of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: a long-term multicenter retrospective study. Indian Heart J 2024;76:390–7. 
    Crossref | PubMed
  42. Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003;348:295–303. 
    Crossref | PubMed
  43. Choi YJ, Lee HJ, Park JS, et al. Left ventricular global longitudinal strain as a prognosticator in hypertrophic cardiomyopathy with a low-normal left ventricular ejection fraction. Eur Heart J Cardiovasc Imaging 2023;24:1374–83. 
    Crossref | PubMed
  44. Guttmann OP, Rahman MS, O’Mahony C, et al. Atrial fibrillation and thromboembolism in patients with hypertrophic cardiomyopathy: systematic review. Heart 2014;100:465–72. 
    Crossref | PubMed
  45. Debonnaire P, Joyce E, Hiemstra Y, et al. Left atrial size and function in hypertrophic cardiomyopathy patients and risk of new-onset atrial fibrillation. Circ Arrhythm Electrophysiol 2017;10:e004052. 
    Crossref | PubMed
  46. Beyhoff N, Agnel OP, Fenski M, et al. Left atrial reservoir strain predicts atrial fibrillation in hypertrophic cardiomyopathy: insights from the NHLBI HCM registry. JACC Cardiovasc Imaging. 2025:S1936-878X(25)00403-6. 
    Crossref | PubMed
  47. Writing Committee Members, Ommen SR, Ho CY, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guideline for the management of hypertrophic cardiomyopathy: a report of the American Heart Association/American College of Cardiology joint committee on clinical practice guidelines. J Am Coll Cardiol 2024;83:2324–405. 
    Crossref | PubMed
  48. Masri A, Kanj M, Thamilarasan M, et al. Outcomes in hypertrophic cardiomyopathy patients with and without atrial fibrillation: a survival meta-analysis. Cardiovasc Diagn Ther 2017;7:36–44. 
    Crossref | PubMed
  49. Maron BJ, Olivotto I, Bellone P, et al. Clinical profile of stroke in 900 patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;39:301–7. 
    Crossref | PubMed
  50. Choi YJ, Kim B, Rhee TM, et al. Augmented risk of ischemic stroke in hypertrophic cardiomyopathy patients without documented atrial fibrillation. Sci Rep 2022;12:15785. 
    Crossref | PubMed
  51. Guttmann OP, Pavlou M, O’Mahony C, et al. Prediction of thrombo-embolic risk in patients with hypertrophic cardiomyopathy (HCM Risk-CVA). Eur J Heart Fail 2015;17:837–45. 
    Crossref | PubMed
  52. Maurizi N, Antiochos P, Owens A, et al. Long-term outcomes after septal reduction therapies in obstructive hypertrophic cardiomyopathy: insights from the SHARE registry. Circulation 2024;150:1377–90. 
    Crossref | PubMed
  53. Green EM, Wakimoto H, Anderson RL, et al. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science 2016;351:617–21. 
    Crossref | PubMed
  54. Haraf R, Habib H, Masri A. The revolution of cardiac myosin inhibitors in patients with hypertrophic cardiomyopathy. Can J Cardiol 2024;40:800–19. 
    Crossref | PubMed
  55. Santangeli P, Di Biase L, Themistoclakis S, et al. Catheter ablation of atrial fibrillation in hypertrophic cardiomyopathy: long-term outcomes and mechanisms of arrhythmia recurrence. Circ Arrhythm Electrophysiol 2013;6:1089–94. 
    Crossref | PubMed
  56. Rowin EJ, Hausvater A, Link MS, et al. Clinical profile and consequences of atrial fibrillation in hypertrophic cardiomyopathy. Circulation 2017;136:2420–36. 
    Crossref | PubMed
  57. Doi Y, Kitaoka H. Hypertrophic cardiomyopathy in the elderly: significance of atrial fibrillation. J Cardiol 2001;37(Suppl 1):133–8.
    PubMed
  58. Lyu SQ, Zhu J, Wang J, et al. The efficacy and safety of direct oral anticoagulants compared with vitamin K antagonist in patients with hypertrophic cardiomyopathy and atrial fibrillation. Thromb J 2024;22:2. 
    Crossref | PubMed
  59. Maron MS, Rowin EJ, Maron BJ. The paradigm of sudden death prevention in hypertrophic cardiomyopathy. Am J Cardiol 2024;212S:S64–76. 
    Crossref | PubMed
  60. Topilsky Y, Pereira NL, Shah DK, et al. Left ventricular assist device therapy in patients with restrictive and hypertrophic cardiomyopathy. Circ Heart Fail 2011;4:266–75. 
    Crossref | PubMed
  61. Patel SR, Saeed O, Naftel D, et al. Outcomes of restrictive and hypertrophic cardiomyopathies after LVAD: an INTERMACS analysis. J Card Fail 2017;23:859–67. 
    Crossref | PubMed
  62. Sreenivasan J, Kaul R, Khan MS, et al. Left ventricular assist device implantation in hypertrophic and restrictive cardiomyopathy: a systematic review. ASAIO J 2021;67:239–44. 
    Crossref | PubMed
  63. Yagi N, Seguchi O, Mochizuki H, et al. Implantation of ventricular assist devices in hypertrophic cardiomyopathy with left ventricular systolic dysfunction. ESC Heart Fail 2021;8:5513–22. 
    Crossref | PubMed
  64. Brufau-Cochs M, Ramos-Jovani M, Lopez Sainz A, et al. Predictive factors for requiring heart transplantation in patients with hypertrophic cardiomyopathy: data from a referral center. Eur Heart J 2021;42(Suppl 1):ehab724.1779. 
    Crossref
  65. Uccellini K. Review board guidance for hypertrophic and restrictive cardiomyopathy exception requests. Rockville, MD: Health Resources & Services Administration. https://optn.transplant.hrsa.gov/media/2637/thoracic_guidance_review_board_hcm_rcm_201806.pdf (accessed 28 February 2025).
  66. Liang LW, Lumish HS, Sewanan LR, et al. Advanced heart failure therapies for hypertrophic cardiomyopathy: state-of-the-art review and an updated analysis from UNOS. JACC Heart Fail 2023;11:1473–80. 
    Crossref | PubMed
  67. Jedeon Z, Konstantinidis I, Patel N, et al. Heart transplant outcomes in adults with hypertrophic cardiomyopathy: a contemporary analysis. J Heart Lung Transplant 2024;43:S230–1. 
    Crossref
  68. Zuñiga Cisneros J, Stehlik J, Selzman CH, et al. Outcomes in patients with hypertrophic cardiomyopathy awaiting heart transplantation. Circ Heart Fail 2018;11:e004378. 
    Crossref | PubMed
  69. Lee MS, Zimmer R, Kobashigawa J. Long-term outcomes of orthotopic heart transplantation for hypertrophic cardiomyopathy. Transplant Proc 2014;46:1502–5. 
    Crossref | PubMed
  70. 70. Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2020;396(10253):759-769. 
    Crossref | PubMed
  71. Desai MY, Owens A, Wolski K, et al. Mavacamten in patients with hypertrophic cardiomyopathy referred for septal reduction: week 56 results from the VALOR-HCM randomized clinical trial. JAMA Cardiol 2023;8:968–77. 
    Crossref | PubMed
  72. Maron MS, Masri A, Nassif ME, et al. Aficamten for symptomatic obstructive hypertrophic cardiomyopathy. N Engl J Med 2024;390:1849–61. 
    Crossref | PubMed
  73. Garcia-Pavia P, Maron MS, Masri A, et al. Aficamten or metoprolol monotherapy for obstructive hypertrophic cardiomyopathy. N Engl J Med 2025;393:949–60. 
    Crossref | PubMed
  74. Saberi S, Cardim N, Yamani M, et al. Mavacamten favorably impacts cardiac structure in obstructive hypertrophic cardiomyopathy: EXPLORER-HCM cardiac magnetic resonance substudy analysis. Circulation 2021;143:606–8. 
    Crossref | PubMed
  75. Masri A, Cardoso RN, Abraham TP, et al. Effect of aficamten on cardiac structure and function in obstructive hypertrophic cardiomyopathy: Sequoia-HCM CMR substudy. J Am Coll Cardiol 2024;84:1806–17. 
    Crossref | PubMed
  76. Kawano H, Toda G, Nakamizo R, et al. Valsartan decreases type I collagen synthesis in patients with hypertrophic cardiomyopathy. Circ J 2005;69:1244–8. 
    Crossref | PubMed
  77. Shimada YJ, Passeri JJ, Baggish AL, et al. Effects of losartan on left ventricular hypertrophy and fibrosis in patients with nonobstructive hypertrophic cardiomyopathy. JACC Heart Fail 2013;1:480–7. 
    Crossref | PubMed
  78. Axelsson A, Iversen K, Vejlstrup N, et al. Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2015;3:123–31. 
    Crossref | PubMed
  79. Ho CY, Day SM, Axelsson A, et al. Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial. Nat Med 2021;27:1818–24. 
    Crossref | PubMed
  80. Moradi A, Khoshniyat S, Nzeako T, et al. The future of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene therapy in cardiomyopathies: a review of its therapeutic potential and emerging applications. Cureus 2025;17:e79372. 
    Crossref | PubMed
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