Obstructive hypertrophic cardiomyopathy: from genetic insights to a multimodal therapeutic approach with mavacamten, aficamten, and beyond

Abstract

Background

A cardiac condition marked by excessive growth of heart muscle cells, hypertrophic cardiomyopathy (HCM) is a complex genetic disorder characterized by left ventricular hypertrophy, microvascular ischemia, myocardial fibrosis, and diastolic dysfunction. Obstructive hypertrophic cardiomyopathy (oHCM), a subset of HCM, involves significant obstruction in the left ventricular outflow tract (LVOT), leading to symptoms like dyspnea, fatigue, and potentially life-threatening cardiac events. With advancements in genetic understanding and the introduction of novel pharmacologic agents, including cardiac myosin inhibitors like mavacamten and aficamten, there is a paradigm shift in the therapeutic approach to oHCM.

Main body

The underlying mechanisms of HCM are closely tied to genetic mutations affecting sarcomere proteins, particularly those encoded by the MYH7 and MYBPC3 genes. These mutations lead to disrupted sarcomere function, resulting in hypertrophic changes and LVOT obstruction. While genetic heterogeneity is a hallmark of HCM, clinical diagnosis relies heavily on imaging techniques such as Echocardiography and cardiac magnetic resonance imaging to assess the extent of hypertrophy and obstruction. Current pharmacological management of obstructive HCM (oHCM) focuses on alleviating symptoms rather than modifying disease progression. Beta-blockers and calcium channel blockers are primary treatment options, although their effectiveness varies among patients. Recent clinical trials have highlighted the potential of novel cardiac myosin inhibitors, including mavacamten and aficamten, in enhancing exercise capacity, reducing LVOT obstruction, and improving overall cardiac function. These innovative agents represent a significant breakthrough in targeting the fundamental pathophysiological mechanisms driving oHCM. A comprehensive literature review was conducted, utilizing top-tier databases such as PubMed, Scopus, and Google Scholar, to compile an authoritative and up-to-date overview of the current advancements in the field. This review sheds light on the updated 2024 American Heart Association (AHA) guidelines for HCM management, emphasizing the treatment cascade and tailored management for each stage of oHCM. By introducing a new paradigm for personalized medicine in oHCM, this research leverages advanced genomics, biomarkers, and imaging techniques to optimize treatment strategies.

Conclusions

The introduction of cardiac myosin inhibitors heralds a new era in the management of oHCM. By directly targeting the molecular mechanisms underpinning the disease, these novel therapies offer improved symptom relief and functional outcomes. Ongoing research into the genetic basis of HCM and the development of targeted treatments holds promise for further enhancing patient care. Future studies should continue to refine these therapeutic strategies and explore their long-term benefits and potential in diverse patient populations. This review makes a significant contribution to the field by synthesizing the most recent AHA guidelines, emphasizing the crucial role of tailored management strategies in optimizing outcomes for patients with oHCM, and promoting the incorporation of cutting-edge genomics and imaging modalities to enhance personalized care.

Background

Hypertrophic cardiomyopathy (HCM) is a complex genetic disorder stemming from dysfunctional cardiac sarcomeres, leading to excessive contractile activation and altered calcium handling [1, 2]. The hallmark characteristics of HCM comprise ventricular wall remodeling, microvascular dysfunction, scar formation within the myocardium, and abnormal diastolic function resulting from impaired ventricular compliance [1–3]. Previously thought to be rare and highly lethal, HCM now affects an estimated 1 in 500 individuals, often following an autosomal dominant inheritance pattern [1, 4–7]. Pathogenic variations occur in genes like MYH7 and MYBPC3, altering sarcomeric protein relaxation and increasing contractility and energy requirements [1–3, 7]. About 60% of patients lack detectable sarcomeric variants, with some having a family history or polygenic etiology [8, 9]. The exact molecular pathways driving ventricular hypertrophy have yet to be fully elucidated.

A considerable majority of patients (around 67%) exhibit left ventricular outflow tract (LVOT) obstruction, which substantially impacts the presentation of symptoms and drives the progression of the disease [10]. The clinical presentation of HCM is remarkably heterogeneous, encompassing a broad spectrum of symptoms and disease expressions, with patients experiencing varying degrees of symptoms like dyspnea, palpitations, and fatigue [1, 11–13].

HCM has two main forms: obstructive hypertrophic cardiomyopathy (oHCM) and non-obstructive (nHCM). oHCM is characterized by a significant obstruction in the LVOT, with a resting gradient exceeding 30 mmHg. This condition leads to various symptoms, including breathing difficulties, fatigue during physical activity, chest discomfort, and even fainting or life-threatening cardiac events. Complications include syncope, atrial fibrillation, ventricular tachycardia, stroke, heart failure, and sudden death, which can be mitigated with implantable cardioverter defibrillator placement in high-risk patients [14–18].

The diagnostic process for HCM predominantly involves clinical assessment and imaging modalities such as Echocardiography (ECHO) and cardiac magnetic resonance (CMR) imaging, which enable the detection of left ventricular hypertrophy, given the constraints of genetic testing in accurately identifying the condition [1, 19]. A left ventricular wall thickness that surpasses expected values, particularly in those with a significant familial predisposition, should raise suspicion for HCM. Given the condition's diverse morphological presentations, which often involve hypertrophy beyond the basal septum, a thorough imaging workup is essential for accurate diagnosis. A comprehensive differential diagnosis is vital in evaluating patients suspected of having HCM, as various conditions, including hypertensive heart disease, aortic stenosis, amyloidosis, muscular dystrophies, Fabry's disease, and lysosomal storage disorders, can masquerade as HCM, necessitating careful consideration to avoid misdiagnosis [1, 19].

A thorough diagnostic evaluation is crucial to differentiate HCM from these conditions and ensure accurate diagnosis and management. The detection of an intracavitary gradient is a key differentiator between oHCM and nHCM, enabling clinicians to accurately classify patients into these distinct phenotypes A resting LVOT gradient exceeding 30 mmHg is generally considered indicative of obstruction in HCM. However, in patients with a gradient less than 50 mmHg, especially those with borderline or fluctuating measurements, additional provocative testing such as exercise stress ECHO may be necessary to assess for latent obstruction, which may manifest only under exertional conditions [1, 19]. To reveal a concealed higher gradient, diagnostic provocation tests such as amyl nitrate administration, Valsalva maneuver, or exercise ECHO may be employed. These tests can help uncover the true extent of obstruction, guiding accurate diagnosis and treatment decisions [1, 19].

Obstruction in HCM is characterized by distinct features, including the abnormal systolic anterior motion of the mitral valve, which yields a posteriorly directed mitral regurgitant jet. Furthermore, CMR imaging can serve as a valuable adjunct to ECHO in equivocal cases, providing enhanced anatomical definition of hypertrophic regions and subvalvular apparatus anomalies, as well as quantifying the extent of fibrosis through late gadolinium enhancement techniques. This multimodal approach can facilitate a more comprehensive understanding of HCM pathology and improve diagnostic accuracy [1, 19].

In the management of dynamic left ventricular (LV) obstruction in HCM, pharmacological interventions prioritize symptom management and relief, as there is no compelling evidence to suggest that they influence the natural history or disease trajectory. The focus of medical therapy is to enhance patient comfort and reduce symptoms, rather than alter the fundamental course of the condition [20]. In the pharmacological management of HCM, symptom response serves as the primary indicator of treatment success, rather than changes in the measured gradient, due to the variable nature of outflow tract obstruction. The treatment algorithm begins with non-vasodilating beta-blockers, followed by calcium channel blockers (verapamil or diltiazem) as secondary options. Patients who fail to respond to these medications may be considered for advanced therapies, including disopyramide, mavacamten, aficamten, or septal reduction. Conversely, medications that exacerbate outflow tract obstruction, such as pure vasodilators and high-dose diuretics, should be avoided. Low-dose diuretics, however, may be useful in combination with other medications for patients with persistent dyspnea or congestive symptoms. Septal reduction therapy (SRT) is reserved for patients with severe, drug-resistant symptoms and should be conducted exclusively in high-volume HCM centers with demonstrated expertise. Transaortic extended septal myectomy (ESM) stands out as a premier treatment option, delivering dependable and comprehensive gradient relief at any ventricular level, accompanied by a remarkably low mortality rate (< 1%) and an outstanding clinical success rate surpassing 90–95% [20–32]. ESM eliminates or reduces systolic anterior motion-mediated mitral regurgitation and its consequences. Long-term follow-up after ESM reveals survival rates equivalent to those of the general population, with rare instances of recurrent outflow tract obstruction, supporting the efficacy and sustainability of this surgical approach. ESM is the preferred treatment option when complex cardiac conditions or papillary muscle abnormalities coexist with HCM. Alcohol septal ablation, on the other hand, offers a less invasive alternative with a low risk of procedural mortality (< 1%), but its applicability is contingent upon favorable coronary anatomy. Although it offers the benefits of reduced hospitalization and avoidance of sternotomy, its efficacy is diminished in cases with severe gradients (≥ 100 mm Hg) and thicker septal dimensions (≥ 30 mm), and it is associated with an increased risk of permanent pacemaker implantation and repeat interventions [33]. Five-year survival is similar between alcohol septal ablation and myectomy, but 10-year survival is lower with alcohol septal ablation [34–37]. Table 1 shows the comparative efficacy of pharmacological Interventions for HCM.

Table 1.

This table compares the benefits and evidence of various drugs in treating HCM, including beta-blockers, calcium channel blockers, disopyramide, and cardiac myosin inhibitors

Treatment	Drug	Benefits	Evidence
Beta-blockers	Propranolol [47]	Symptom reduction and functional ability against a background of standard care [47]	Single-blind, placebo-controlled study [47]
	Metoprolol [48]	Reduces both resting and exercise-induced obstructed blood flow from the left heart chamber resulting in enhanced patient outcomes [48]	Insights from large patient databases and a meticulously planned, randomized, and placebo-controlled study featuring a crossover design [48]
Calcium Channel Blockers	Verapamil [49]	Upscales aerobic capacity and demonstrates similar efficacy to propranolol in comparison to placebo [49]	Randomized double-blind study [49]
	Diltiazem [50]	Enhances exercise endurance similarly to verapamil, while also alleviating symptoms [50].	Crossover trial with blinded evaluations [50]
Disopyramide [51]		Mitigates symptoms and cuts LVOT gradient in half [51]	Multi-institutional, observational research consortium [51]
Cardiac Myosin Inhibitors	Mavacamten [52]	Enhances overall cardiac well-being by boosting exercise tolerance, alleviating ventricular obstruction, and improving cardiac function in oHCM patients. Furthermore, it decreases the necessity for interventional procedures and minimizes signs of cardiac distress in nHCM patients [52]	Phases 1, 2, and 3 trials; Randomized placebo-controlled trials [52]
	Aficamten [32]	Boosts exercise capacity, reduces LVOT obstruction, and improves heart function, leading to a better NYHA classification [32].	Phase 2 trial [32]

oHCM: Obstructive Hypertrophic Cardiomyopathy, nHCM: non-obstructive Hypertrophic Cardiomyopathy, NYHA: New York Heart Association Classification

Historically, the risk of a sudden and lethal cardiac event has been perceived in pediatric patients with HCM has been evaluated using adult-based risk stratification tools, which may not be specifically applicable to the juvenile demographic due to differences in disease expression. However, recent research suggests that these adult-derived risk factors may not accurately predict sudden cardiac death (SCD) in pediatric patients, highlighting the need for more age-specific risk stratification approaches [34, 38–45].

Delivering comprehensive care for heart failure patients with HCM requires a unified, multidisciplinary effort, harnessing the skills of various healthcare experts. A team of specialists, including heart failure specialists, intensive care doctors, general practitioners, advanced practice providers, nurse specialists, medication management experts, patient advocates, movement and exercise specialists, and recovery and wellness experts, works together to provide seamless, coordinated support from diagnosis to treatment and recovery. In recent years (2022), treatment strategies for these patients were primarily focused on symptom management through pharmaceutical interventions or invasive procedures like septal reduction therapies, highlighting the need for innovative solutions. However, the advent of mavacamten, a pioneering drug designed to target the root causes of obstructive HCM, has introduced a novel therapeutic pathway. Mavacamten is associated with significant improvements in new york heart association (NYHA) symptomatic class and various hemodynamic and structural parameters. Its approval by the FDA [46] provides a crucial new option for treating patients with obstructive HCM and symptomatic heart failure, addressing a previously unmet need in this patient population.

A thorough insight of the pharmacodynamic and cardiovascular effects of mavacamten and aficamten is essential for personalized treatment planning, monitoring, and adjustment in patients with oHCM. Ongoing clinical investigations are expanding our knowledge of their applications in non-obstructive HCM and obstructive HCM patients who meet criteria for interventional procedures, paving the way for a deeper understanding of their therapeutic potential. This groundbreaking era of targeted HCM therapy holds tremendous promise for revolutionizing patient care and outcomes.

Pathogenesis of OHCM: unraveling genetic and molecular mechanisms

HCM is a cardiac condition where the left ventricular (LV) wall exhibits excessive growth, leading to enlarged dimensions in one or more segments of the myocardium [53, 54]. The mechanism underlying LVOT obstruction in HCM involves a complex interplay of anatomical factors. Hypertrophy of the basal interventricular septum and papillary muscles reduces the cross-sectional area of the LVOT, creating a narrowed pathway for blood to exit the LV [4, 7]. Concurrently, abnormalities of the mitral valve apparatus, such as elongated or redundant leaflet tissue and anterior displacement of the coaptation line, further compromise LVOT patency [55]. As the ventricle contracts, rapid ejection through the narrowed outflow tract generates Venturi forces, causing systolic anterior motion of the mitral valve (SAM) and mitral regurgitation [10, 56]. The anterior mitral valve leaflet is drawn into the outflow tract, creating a physical barrier to blood flow and exacerbating obstruction [19, 57]. This intricate mechanism ultimately leads to increased pressure gradients across the LVOT, compromising cardiac output and increasing the risk of heart failure and SCD [56, 57]. The development of HCM cannot be explained solely by external factors like hypertension, but is instead a complex condition driven by inherent cardiac abnormalities. Genetic mutations play a significant role, with up to 60% of cases caused by mutations in sarcomeric protein-encoding genes, inherited in an autosomal dominant pattern [53]. These mutations affect critical proteins like beta-myosin heavy chain, myosin-binding protein C, troponin I and T. Furthermore, 5–10% of HCM cases are associated with other genetic disorders, including rare conditions, such as genetic storage disorders, neurodegenerative disorders, and energy production disorders [54]. The expression of HCM is defined by a wide range of hypertrophy patterns, affecting different segments of the LV, including the septal, apical, and mid-cavity regions. As the disease progresses, the excessive hypertrophy can lead to a cascade of complications, such as LVOT obstruction, diastolic dysfunction, myocardial ischemia, and mitral regurgitation, which can substantially compromise cardiac function and amplify the risk of harmful effects [53, 54]. In obstructive HCM, the classic form, septal hypertrophy and systolic anterior movement of the anterior mitral valve combine to create a Venturi effect, causing LV outflow tract obstruction [53]. Other HCM morphologic variants can also lead to mid-cavity obstruction, highlighting the complexity of this condition [54]. Figure 1 shows Genetic and Pathophysiological Factors of HCM.

Fig. 1.

Pathogenesis, Genetic and Clinical Factors in HCM. LVO: Left Ventricular Outflow, OTO: Outflow Tract Obstruction, MR: Mitral Regurgitation, SAM: Systolic Anterior Motion, LVH: Left Ventricular Hypertrophy

The pathogenesis of HCM is a multifaceted and intricate process, involving a complex interplay of genetic, molecular, and cellular mechanisms. The diverse array of causal genes and mutations underlying HCM contributes to a heterogeneous landscape of disease manifestations, reflecting the intricate relationships between genotype, phenotype, and environmental factors. This complexity gives rise to a comprehensive collection of clinical presentations, characteristic profiles, and outcome measures, highlighting the need for personalized approaches to diagnosis, treatment, and management. These mechanisms can be categorized into four interlocking sets: primary defect, initial phenotypes, intermediate phenotypes, and tertiary effects. The primary defect is the mutation itself, triggering a cascade of downstream events. Initial phenotypes result directly from the mutation's impact on sarcomere protein structure and function [58–61]. Intermediate phenotypes represent molecular manifestations of these alterations, encompassing changes in signaling cascades, such as MAPK and TGFB1, and transcriptional reprogramming [62–72]. The downstream consequences of these molecular perturbations manifest as histological and pathological changes within the myocardium, resulting from the cascade of secondary molecular events [73–76].

The genetic mutations in HCM result in a variety of initial aberrations that disrupt sarcomere protein structure and function. These mutations instigate a series of transcriptional and translational alterations, leading to protein synthesis arrest, production of truncated polypeptides, and incorporation of aberrant proteins into the sarcomeric matrix. This triad of molecular malfunctions compromises the contractile function of cardiac muscle cells [58–61]. Aberrant protein incorporation within the sarcomeres impacts several aspects of acto-myosin function, including calcium-dependent regulation of cross-bridge dynamics. Mutations in the thin filament proteins increase Ca++ sensitivity of myofibrillar ATPase activity and force generation, further contributing to sarcomeric dysfunction [75–86]. Secondary molecular events, which include altered signaling cascades such as MAPK and TGFB1, ultimately lead to cardiac hypertrophy and characteristic morphological changes in HCM [62–72].

The tertiary phenotypes of HCM encompass the structural and histological changes that occur within the heart, including cardiac muscle fiber enlargement, cellular disorganization, and scar tissue formation [73, 74] .These changes arise as a result of the intermediary molecular events, ultimately giving rise to quaternary phenotypes, such as cardiac failure and arrhythmias.

Molecular genetics: the underlying principles

HCM is a classic example of a genetically determined condition, typically triggered by a lone genetic mutation, which can manifest with an autosomal dominant inheritance pattern, leading to a range of disease manifestations [82]. The variability in phenotype is partly due to the interaction between the causal mutation and other genetic and non-genetic factors. Approximately 60% of HCM patients have a clear family history of the diseases [87, 88]. While autosomal recessive and X-linked modes of inheritance have been reported, they are rare [87, 88]. X-linked inheritance often raises the possibility of phenocopy conditions, such as Fabry disease [89]. Phenocopy conditions also occur in syndromic conditions like Noonan syndrome and storage diseases like Anderson-Fabry disease [89–91].

Seminal work by Christine and Jonathan Seidman laid the foundation for the understanding of HCM's molecular genetic basis. The discovery of the p.Arg403Glu mutation in the MYH7 gene, encoding β-myosin heavy chain, in a French-Canadian family [83] paved the way for subsequent important discoveries [84]. Genetic analysis has uncovered a complex pattern of mutations in key sarcomere genes, underscoring the heterogeneous nature of HCM. The genes MYH7 and MYBPC3, essential for normal cardiac function, are the most frequently implicated, together accounting for around half of all inherited HCM cases [85]. Variants in the genes TNNT2, TNNI3, and TPM1, which play vital roles in regulating cardiac muscle contraction, are infrequent causes of HCM, responsible for a small fraction (less than 10%) of all cases [86, 92–94]. Moreover, variants in the genes ACTC1, MYL2, MYL3, and CSRP3 have been implicated as infrequent, but established, contributors to HCM, highlighting the genetic heterogeneity of this disease [88–90].

HCM is caused by rare mutations, primarily affecting genes encoding sarcomere and sarcomere-associated proteins. The predominant type of mutations identified in HCM-associated genes are missense mutations, which disrupt normal protein function by substituting a single amino acid in the protein sequence, thereby altering its structure and activity [95–97]. MYBPC3 stands out due to its high propensity for mutations that lead to protein disruption, including frameshift errors, which compromise protein integrity and function [95–97]. These frameshift mutations often lead to protein degradation through the nonsense-mediated decay pathway or the ubiquitin–proteasome system, resulting in haploinsufficiency [98, 99]. Additionally, rare deletion mutations have been reported in genes such as MYH7 and TNNT2 [98, 99].

Two notable mutations, the p.Arg502Trp in MYBPC3 and the p.Val762Asp in the same gene, have been reported in relatively high frequencies within specific populations. The p.Arg502Trp mutation is found in 1.5–3% of HCM patients [100–102], while the p.Val762Asp mutation is present in 3.9% of the Japanese population [103]. The increased frequency of mutations in these regions may point to the presence of genomic hotspots or a shared genetic heritage, which could explain the higher incidence of mutations linked to HCM [101]. This observation may be cohort-specific and not necessarily generalizable to all HCM populations, as the genetic landscape of HCM can vary significantly across different populations and studies [104–106].

HCM is characterized by genetic heterogeneity, primarily due to rare mutations in genes encoding sarcomere proteins. The elucidation of these mutations has significantly advanced our understanding of the disease, with MYH7 and MYBPC3 mutations being predominant, followed by less common mutations in genes like TNNT2, TNNI3, and TPM1. The identification of these mutations has not only improved our knowledge of HCM but also highlights the complexity and genetic diversity of the disease, paving the way for personalized diagnostic and therapeutic approaches.

Gene protein function tolerance to variation

HCM is linked to over 450 genetic mutations, mainly affecting cardiac muscle's sarcomere and myofilaments. Nevertheless, a significant proportion of HCM patients, approximately 66%, remain genetically unexplained, as only about one-third of patients test positive for a known disease-causing mutation [107]. Emerging technologies like CRISPR offer hope. A recent study successfully corrected HCM-causing mutations using endogenous DNA repair mechanisms. Gene editing may shift focus toward identifying pathogenic gene mutations and developing targeted therapies, potentially leading to a cure.

The heart's harmony relies on a symphony of genes, and research has identified 11 maestros that orchestrate cardiac muscle function: ACTN2, ANKRD1, CASQ2, CAV3, JPH2, LDB3, MYH6, MYLK2, NEXN, TNNC1, and VCL [108, 109]. These genetic virtuosos play pivotal roles in muscle structure, calcium signaling, and overall heart health. But how do they respond to genetic variations? By analyzing missense Z scores and loss-of-function probabilities (pLI), scientists can gauge their tolerance to changes.Some genes, like ACTN2 and JPH2, are perfectionists, with high intolerance to missense mutations (Z scores of 1.76 and 3.93, respectively) [109]. Even minor alterations could significantly impact their functions, like a single misplaced note in a melody. In contrast, genes like ANKRD1 and NEXN are more resilient, with negative Z scores (− 0.01 and − 1.32), suggesting they can adapt to genetic changes without severe functional consequences.The pLI values further highlight these differences. ACTN2, crucial for muscle structure, has a pLI of 1.0, indicating it is highly intolerant to loss-of-function mutations, like a missing beat in a rhythm. Conversely, MYH6 and MYLK2 have lower pLI values (0.00 and 0.22), suggesting they may tolerate such mutations better, like a flexible melody that can adapt to changes [108]. Table 2 presents a comprehensive overview of several genes, their associated proteins, functions, and their tolerance to genetic variation, as reflected by missense Z scores and loss-of-function (LoF) probabilities of loss-of function intolerance (pLI) [108, 109].

Table 2.

Outlines the key genes implicated in HCM, detailing the associated proteins, their functions, and the genes' tolerance to missense and loss-of-function (LoF) variations, providing insights into the molecular mechanisms underlying HCM

Gene	Protein and its associated biological function	Tolerance to variation
ACTN2	Alpha actinin 2,Z disc protein	Z score: 1.76; pLI: 1.0
ANKRD1	Ankyrin repeat domain 1,Suppressor of cardiac gene expression	Z score: − 0.01; pLI: 0.00
CASQ2	Calsequestrin 2,CBP	Missense (Z score): − 1.08; LoF (pLI): 0.00
CAV3	Caveolin 3,CAP	Z score: 1.19; pLI: 0.34
JPH2	Junctophilin 2,enables the efficient transmission of calcium-mediated signals within cells, facilitating vital cellular processes	Z score: 3.93; pLI: 0.01
LDB3	LIM domain-binding 3,Z disc protein	Z score: 0.32; pLI: 0.00
MYH6	Myosin heavy chain alpha,a protein that forms part of the sarcomere, with relatively low expression levels in adult hearts, but vital for supporting cardiac muscle contraction and relaxation	Z score: 2.87; pLI: 0.00
MYLK2	Myosin light chain kinase 2,catalyzes the phosphorylation of myosin light chain 2, a crucial regulatory step in cardiac muscle contraction and relaxation	Z score: 0.73; pLI: 0.22
NEXN	Nexilin,Z disc protein	Z score: − 1.32; pLI: 0.00
TNNC1	Cardiac troponin C,a calcium-sensitive regulator that controls myofilament function, enabling precise adjustments to cardiac muscle contraction and relaxation	Missense (Z score): 2.22; LoF (pLI): 0.51
VCL	Vinculin,Z disc protein	Z score: 3.11; pLI: 0.99

LoF: Loss-Of-Function, pLi: Probabilities of Loss-of-Function Intolerance, CBP: Calcium-binding protein, CAP: Caveolae-associated protein

The Z score for each gene represents the deviation of observed variants from the expected number in the ExAC database. A higher positive Z score suggests that the gene is less tolerant to variation. The pLI score reflects the probability of intolerance to Loss-of-Function (LoF) variants, with a score of 1 indicating complete intolerance [108, 109].

Circulating biomarkers in HCM: insights and implications

HCM is a complex condition characterized by polygenic and multifactorial inheritance patterns [110–112]. Recent epidemiological studies have highlighted an increase in its estimated prevalence from 1 in 500 [113] to approximately 1 in 200 individuals [114], underscoring its growing significance as a public health concern. While the overall clinical outcome is generally favorable, a distinct subgroup of patients is prone to developing severe and potentially catastrophic complications, including cardiac impairment, flow obstruction, heart rhythm disturbances, and potentially fatal cardiac incidents [115]. An in-depth analysis of the HCM Registry (HCMR) revealed significant differences in clinical and imaging profiles between patients with and without genetic sarcomere mutations [116].

Regular assessment of biomarkers can facilitate early identification of disease progression, allowing for timely therapeutic interventions. Biomarkers can also guide genetic testing and family screening, as specific biomarker profiles may indicate a higher likelihood of genetic mutations. In summary, biomarkers have significantly advanced our understanding and management of HCM. Natriuretic peptides, cardiac troponins, and biomarkers of fibrosis provide critical insights into disease pathophysiology and treatment response. The potential of autoantibodies, genomic, proteomic, and metabolomic biomarkers is an exciting frontier, offering promise for future therapeutic innovations. Integrating biomarkers into clinical practice will facilitate personalized medicine, improve treatment outcomes, and enhance patient care in HCM (as shown in Fig. 2).

Fig. 2.

Comprehensive Biomarker Evaluation and Personalized Treatment Planning for oHCM, Cardiac Fibrosis and Function Assessment. BNP: B-type Natriuretic Peptide, NT-proBNP: N-terminal pro B-type Natriuretic Peptide, hs-cTnT: High-sensitivity Cardiac Troponin T, hs-cTnI: High-sensitivity Cardiac Troponin I, wVF: von Willebrand Factor

Elevations in natriuretic peptides, including brain-type natriuretic peptide (BNP), atrial natriuretic peptide, and N-terminal pro-B-type Natriuretic Peptide (NT-proBNP), serve as vital indicators of myocardial wall stress in HCM, enabling clinicians to gauge disease severity and monitor treatment efficacy [117]. BNP elevation is a marker of heightened cardiovascular vulnerability, predicting a higher likelihood of adverse events [118] and are predictive of NYHA functional class, the necessity for SRT [119], heart failure hospitalization [120], ventricular tachycardia [121], and mortality in patients undergoing septal myectomy [122]. NT-proBNP levels have shown correlations with LV mass, LV mass index, and late gadolinium enhancement (LGE) on CMR [123]. The HCMR data indicated that NT-proBNP levels were higher in mutation-positive patients and those with reduced LV systolic function and a resting LV outflow tract gradient ≥ 30 mmHg [124].

Cardiac troponin T and I are highly sensitive biomarkers of acute myocardial necrosis, associated with left ventricular (LV) mass, wall thickness, and fibrosis in HCM [123, 125–128]. High-sensitivity cardiac troponin T (hs-cTnT) levels serve as independent predictors of subsequent LV dysfunction and progression to end-stage HCM [129]. Elevated hs-cTnT levels also correlate with NYHA class, outflow obstruction, systolic dysfunction, and disease severity in HCM [130]. Concurrent elevations of BNP and hs-cTnT levels provides a robust predictive model for myocardial fibrosis and increased cardiovascular event risk [118, 125].

Myocardial fibrosis, a pivotal pathological process in HCM, leads to left ventricular (LV) stiffness and diastolic dysfunction. Biomarkers of fibrosis include procollagen type I carboxy-terminal, procollagen type III amino-terminal propeptide, and galectin-3 [131–137]. Galectin-3 levels are elevated in HCM patients, correlating with septal thickness, LV mass index, NYHA functional class, and sudden death risk [134–137]. Other emerging biomarkers, such as adiponectin, omentin-1, copeptin, midregional proadrenomedullin, and urotensin-II, show promise in predicting adverse outcomes, although further research is warranted [112, 115, 138–140].

The potential role of autoantibodies against self-antigens as biomarkers in HCM is gaining traction. One study reported higher concentrations of autoantibodies against muscarinic-2 and B1-adrenergic receptors in women and patients with a history of syncope, correlating with resting LV outflow tract gradient, maximal wall thickness, and interventricular septum thickness [95, 141]. Advancements in genomic, proteomic, and metabolomic biomarkers are ongoing, with studies demonstrating the up- or downregulation of microRNAs associated with LV hypertrophy, fibrosis, and cardiomyocyte apoptosis [142]. However, their ability to predict clinical outcomes remains to be fully established.

Biomarkers linked to LV outflow tract obstruction in HCM include vWF(von Willebrand factor), hs-cTnT, NT-proBNP, erythrocyte creatinine, and copeptin [124, 130, 140, 143–145]. These biomarkers are not only indicative of LV outflow tract obstruction but also predictive of adverse clinical outcomes, such as worsening NYHA class and atrial and ventricular arrhythmias. Elevated vWF levels have been shown to accurately discriminate between patients with obstructive and non-obstructive HCM and normalize after successful surgical myomectomy [143].

Furthermore, the EXPLORER-HCM trial demonstrated that high-sensitivity hs-cTnI and NT-proBNP levels significantly decreased in response to medical therapy [146]. The VANISH trial found that patients treated with valsartan exhibited improved cardiac structure and function, along with stable or reduced NT-proBNP levels [99]. Similarly, the VALOR-HCM trial indicated that mavacamten treatment resulted in reduced NT-proBNP and cTnI levels, alongside improved NYHA functional class [147].

Biomarkers play a vital role in monitoring disease progression in HCM, allowing for the early detection of changes in disease status, assessment of treatment response, and optimization of patient care through timely interventions and adjustments to management strategies. For instance, serial measurements of NT-proBNP and hs-cTnI can detect worsening cardiac function and predict adverse outcomes [148]. Additionally, galectin-3 levels may increase with advancing disease stages [137]. Regular assessment of these biomarkers could facilitate early identification of disease progression, allowing for timely therapeutic interventions.

Considering the heterogeneity of HCM, the identification of biomarkers is crucial for personalized medicine, enabling the tailoring of treatment strategies to individual patients and potentially leading to more effective and targeted management of the disease. For example, patients with elevated BNP levels might benefit from more aggressive medical therapy or earlier consideration of SRT [119]. Conversely, those with normal BNP levels may require less intensive monitoring and treatment. Biomarkers can also guide genetic testing and family screening, as specific biomarker profiles may indicate a higher likelihood of genetic mutations [126].

HCM management: a tailored strategy for each stage

Genetic testing has identified individuals with HCM-causing mutations who do not yet exhibit symptoms. This presents an opportunity to explore preventative measures. While gene editing technologies like CRISPR/Cas9 have shown promise in correcting HCM-causing mutations in human embryos, pharmacological approaches are more likely to enter clinical practice. For example, losartan, a TGF-β inhibitor, has prevented hypertrophy development in animal models [149, 150] and the VANISH trial demonstrated that valsartan can improve cardiac structure and function in individuals with early HCM phenotype, making Stage I: Pre-Phenotype Expression and Prevention a crucial period for intervention.

The quintessential HCM phenotype involves LVOTO (left ventricular outflow tract obstruction) caused by systolic anterior motion of the mitral valve. To manage LVOTO and associated symptoms, drugs with negative inotropic effects, such as beta-blockers (e.g., nadolol, metoprolol) [151, 152], non-dihydropyridine calcium channel blockers, and disopyramide, are commonly used, and are the mainstay of treatment for Stage II: Characteristic HCM with No Progression.

A significant proportion of patients (up to 15%) may exhibit the development of structural heart changes, including left ventricular fibrosis, which can compromise cardiac performance and lead to decreased diastolic and systolic function.. Attempts to target replacement fibrosis with anti-fibrotic drugs like spironolactone and losartan have been unsuccessful [149, 150] Ranolazine, an anti-anginal medication, may mitigate microvascular ischemia-driven fibrosis [153, 154] Cardiac resynchronization therapy has been considered in patients with systolic dysfunction, though data is limited, highlighting the challenges of managing Stage III: Adverse Remodeling.

A small proportion of HCM patients (5–8%) may experience significant left ventricular systolic impairment (EF < 50%), which carries a poor prognosis. In these cases, a comprehensive medical therapy approach, including angiotensin receptor-neprilysin inhibitors, beta-blockers, and SGLT2 inhibitors, should be considered to mitigate disease progression [1, 155]. For patients with refractory disease, more invasive options like LVAD (Left Ventricular Assist Device) implantation or cardiac transplantation may be required to provide adequate circulatory support and improve outcomes [156]. Across all stages, management of atrial fibrillation, a common complication, is crucial, with rhythm control preferred over rate control [1, 157] emphasizing the importance of Stage IV: Overt Systolic Dysfunction.

According to the 2024 Guidelines [20] genetic testing is suggested for individuals with a family history of HCM or those exhibiting symptoms suggestive of HCM, to uncover potential genetic mutations that may be driving the condition [20]. ECHO is the primary mean of diagnosing and tracking HCM, offering essential information for patient care and management. CMR imaging is recommended for further evaluation of HCM in select cases. Exercise stress testing is recommended to assess functional capacity and detect potential cardiac complications. Implantable cardioverter-defibrillators (ICDs) are recommended for primary prevention of SCD in high-risk patients. Cardiac resynchronization therapy (CRT) is recommended for patients with systolic dysfunction and conduction disturbances [20]. Figure 3 shows a tailored strategy for each stage in HCM management.

Fig. 3.

HCM Management Cascade According to 2024 Guidelines. HCM: Hypertrophic Cardiomyopathy; LVOTO: Left Ventricular Outflow Tract Obstruction; ICDs: Implantable Cardioverter-Defibrillators

Overview of Mavacamten's global therapeutic impact

Mavacamten's global reach, spanning regulatory approvals in North America, Europe, and parts of Asia, has yielded promising real-world outcomes. Its safety and efficacy have been consistently demonstrated across trials and post-approval use, benefiting diverse patient demographics. This increased availability alleviates the therapeutic gap for undiagnosed or untreated patients, particularly in regions historically lacking access to cutting-edge cardiovascular therapies [158].

Mavacamten represents a paradigm-shifting treatment modality specifically tailored for patients experiencing debilitating symptoms of NYHA class II or III obstructive HCM. The approval of mavacamten is firmly grounded in the compelling evidence generated by the EXPLORER-HCM trial, a seminal investigation that unequivocally demonstrated the medication's superior clinical efficacy and safety profile in this distinct patient cohort. This comprehensive and randomized study showcased mavacamten's exceptional efficacy in alleviating symptoms, enhancing physical performance, and reducing the reliance on invasive procedures among patients with oHCM [159].

The translation of mavacamten from clinical trials to real-world practice has demonstrated substantial therapeutic benefit, characterized by improved clinical outcomes and a stable safety profile across varied patient demographics. This increased accessibility has bridged a critical gap in cardiovascular disease management, providing relief to a substantial number of undiagnosed or untreated patients worldwide, especially in areas with limited access to specialized therapies [158].

Mechanism of action of Mavacantem

Preclinical studies have unveiled mavacamten's unique mechanism of action, which involves modulating the myosin-actin interaction to reduce hypercontractility and its associated detrimental effects [160–163]. This myosin ATPase inhibitor induces a conformational shift in the myosin population, favoring a relaxed, energy-conserving state dissociated from actin, which in turn decreases cross-bridge formation and slows disease progression and symptom severity (as shown in Fig. 4) [161–164]. A cutting-edge approach counterbalances the deleterious effects of HCM-related mutations, which lead to overactive myosin heads and resultant energetic, structural, and clinical dysfunction. By harmonizing myosin head activity, this method reduces sarcomeric hyperexcitability and myocardial overcontraction, culminating in a profound improvement in cardiac function and overall cardiac well-being [161, 164–167]. By reducing LVOT obstruction, left ventricular filling pressure, maximal force, Ca2 + sensitivity, myocardial energy demands, and diastolic dysfunction, mavacamten showcases its potential as a comprehensive treatment for oHCM. Research in a feline model of oHCM has demonstrated mavacamten's efficacy in inhibiting myosin ATPase and reducing outflow tract obstruction, paving the way for further investigation into its disease-modifying effects on the structural abnormalities characteristic of oHCM. Mavacamten's pharmacokinetic profile is marked by high oral bioavailability (85%), unaffected by food intake, and extensive binding to plasma proteins (97%) [163, 168]. Metabolism is primarily mediated by CYP2C19, with secondary contribution from CYP3A4, and elimination occurs predominantly through renal excretion (over 80%), with the remaining fraction excreted via the gastrointestinal tract [168].

Fig. 4.

Mechanism of Action of Mavacamten in HCM. HCM: Hypertrophic Cardiomyopathy; ATPase: Adenosine Triphosphatase

Exploring mavacamten: an in-depth analysis of clinical trials

Notably, the EXPLORER-HCM trial validated mavacamten's effectiveness in enhancing cardiopulmonary function and alleviating symptoms in oHCM patients. These findings highlight mavacamten's potential to significantly improve therapeutic outcomes in this challenging condition. The pharmacokinetic profile of mavacamten was thoroughly assessed in Phase 1 trials, which revealed rapid absorption and extensive metabolism via cytochrome P450 enzymes, particularly CYP2C19 and CYP3A4.The terminal half-life of the drug varies with CYP2C19 metabolic status, ranging from 6 to 23 days. Additionally, the use of CYP2C19 and CYP3A4 inducers or inhibitors can impact mavacamten's systemic exposure, necessitating careful consideration when co-administering medications that affect these enzymes [168, 169].

The PIONEER-HCM trial [170], a 12-week Phase 2 study examined the safety and efficacy of an investigational treatment in 21 patients with symptomatic oHCM. The open-label trial featured two separate cohorts: Cohort A started with a daily dose of 10 or 15 mg, with possible dose adjustments at week 4 to achieve a predetermined 15–20% reduction in resting LVEF from baseline, while Cohort B initiated treatment at a lower dose (2 mg/day) and could increase to 5 mg/day if the resting LVOT gradient did not decrease by more than 50% from baseline [170].

Results from the PIONEER-HCM trial indicated significant reductions in post-exercise LVOT gradients at Week 12, with Cohort A showing a mean change of − 89.5 mmHg and Cohort B -25.0 mmHg [170]. Further analysis revealed significant enhancements in secondary endpoints, including pressure gradients at rest and during Valsalva maneuvers, aerobic capacity (peak oxygen consumption), ventilatory efficiency (VE/VCO2 slope), and symptom severity (dyspnea scores). A therapeutic window of plasma concentrations (350–695 ng/mL) was identified, where substantial reductions in LVOT obstruction occurred without compromising left ventricular ejection fraction (> 50%). However, higher plasma levels (> 695 ng/mL) led to more marked declines in left ventricular ejection fraction, ranging from 34 to 49% [170]. Most reported adverse events were transient and did not appear to be related to the study medication, indicating that the treatment was well-tolerated by participants.

Participants from the PIONEER-HCM trial were subsequently invited to join the PIONEER-OLE open-label extension study [171], where mavacamten was initiated at 5 mg/day post-washout. Dosages were adjusted to achieve a plasma concentration of 250–500 ng/mL, resulting in sustained improvements in LVOT obstruction, NYHA functional class, and NT-proBNP levels at 48 weeks [171]. Long-term follow-up at 3 years demonstrated continued improvements in cardiovascular hemodynamics, symptoms, and quality of life. Additionally, AI-enhanced electrocardiography (AI-ECG) analysis showed decreasing mean HCM scores over time, reflecting improvements in ECG morphology. These improvements positively correlated with reductions in Valsalva LVOT gradients and NT-proBNP levels, indicating favorable disease status measures [172].

Building on the encouraging results from the PIONEER-HCM study, mavacamten advanced to the crucial Phase 3 EXPLORER-HCM study, a comprehensive global investigation involving 251 individuals with oHCM, characterized by preserved left ventricular ejection fraction (> 55%) and significant functional impairment, across 68 sites in 13 countries [52, 165]. Participants, mostly on beta-blocker or calcium channel blocker therapy, were initiated on mavacamten at 5 mg/day, with dose adjustments at Weeks 8 and 14 to achieve targeted therapeutic endpoints [165]. The primary endpoint at Week 30 was a composite measure of exercise capacity and symptom burden, focusing on peak oxygen consumption and NYHA class improvements [52]. The results demonstrated significant efficacy of mavacamten compared to placebo, with marked improvements in LVOT gradients, NYHA class, and patient-reported outcomes such as KCCQ-CSS and HCMSQ-SoB scores [52]. Mavacamten showed a positive effect on biomarkers of cardiac stress and injury, with NT-proBNP and hs-cTnI levels suggesting a decrease in cardiac strain [52]. Beyond these established benefits, the innovation of mavacamten lies in its Proprietary functional mechanism. As a selective cardiac myosin inhibitor, mavacamten directly targets the underlying pathophysiology of oHCM by reducing myocardial contractility and thereby decreasing LVOT obstruction. This targeted approach contrasts with traditional therapies that primarily address symptoms rather than the root cause of the disease. The integration of advanced pharmacokinetic monitoring and AI-enhanced diagnostic tools in the ongoing management of patients underscores mavacamten's role in personalized medicine. Table 3 This detailed examination aggregates and scrutinizes the findings from clinical trials targeting HCM, facilitating a comparative evaluation of treatment benefits and risks to guide therapeutic decision-making.

Table 3.

Comparative Summary of Clinical Studies on HCM

Study (reference)	PIONEER HCM [170, 171]	EXPLORER HCM [165, 166]	VALOR-ACH [147]
Study configuration	Open-label, non-randomized	Double-blind, randomized	Double-blind, randomized
Participant count	21	251	112
Study length (weeks)	12	30	16
Heart failure severity	II/III	II/III	III/IV
Daily dose (mg)	2–20	2.5–15	2.5–15
Main study objective	Exercise-induced LVOT gradient improvement	Enhanced physical performance and reduced symptom severity	Assessing persistent qualification for SRT
Major findings	LVOT obstruction shows a significant decrease	Reduced LVOT obstruction	Decreased reliance on SRT
	Exercise capacity and breathing efficiency improve substantially	Increased exercise tolerance	Improved LVOT obstruction with reduced gradients
	Heart failure symptoms alleviate, leading to a lower NYHA classification	Improved heart failure classification (NYHA)	Enhanced heart failure symptoms with lower NYHA classification
	Breathlessness severity decreases, as indicated by lower NRS scores	Lower levels of biomarkers (NT-proBNP and hs-cTnI) indicating reduced cardiac stress	Significant reduction in biomarkers (NT-proBNP and hs-cTnI) indicating improved cardiac health
	Overall health and well-being exhibit notable enhancement	Improved heart relaxation and filling (diastolic function)	Overall improvement in health and well-being

Safety analysis revealed manageable adverse events, with temporary drug discontinuation occurring in a few cases due to LVEF considerations, though most patients completed the trial [52]. Subgroup analyses suggested consistent benefits across various patient characteristics, emphasizing mavacamten's potential as a viable treatment option for oHCM [165, 173]. Mavacamten's robust performance in EXPLORER-HCM supports its role in improving cardiopulmonary function and symptom management in oHCM patients, offering promise for enhanced therapeutic outcomes in this challenging condition.

Dosage and administration

Oral administration of mavacamten is achieved through capsules offered in various dosages, including 2.5 mg, 5 mg, 10 mg, and 15 mg. The suggested starting point for treatment is a single daily dose of 5 mg. [170]. Dose adjustments may occur at weeks 4, 8, and 12 following treatment initiation, with a maximum approved daily dose of 15 mg. The target plasma concentration ranges from 350 ng/mL to 700 ng/mL, and achieving steady-state levels and therapeutic effects may take several weeks [170]. Regular assessment of the patient's clinical status, left ventricular ejection fraction (LVEF), and LVOT gradient is essential before dose titration [170]. Table 4 shows the mavacamten dosing regimen [170].

Table 4.

Dosage (mg) and administration recommendations for mavacamten, including starting dose, titration options, and maximum daily dose

Dosage (mg)	Administration	Recommended Use
2.5	Oral capsule	–
5	Oral capsule	Starting dose, may titrate
10	Oral capsule	Titration possible
15	Oral capsule	Maximum daily dose

Mavacamten management strategies and criteria, as observed in the EXPLORER-HCM and VALOR-HCM trials, involve a uniform starting dose of 5 mg, with subsequent adjustments based on specific clinical indicators. Dose reduction is considered if mavacamten plasma concentrations fall within a certain range (700–1,000 ng/mL) in EXPLORER-HCM, while VALOR-HCM adds an additional criterion of a Valsalva LVOT gradient below 30 mm Hg by week 4. Upward titration is guided by achieving a resting LVEF of 50% or higher, mavacamten plasma levels below 350 ng/mL, and a Valsalva LVOT gradient of 30 mm Hg or higher at specified intervals. Temporary discontinuation is warranted if LVEF drops below 50%, mavacamten plasma concentrations exceed 1000 ng/mL, or QTcF prolongation occurs. These criteria highlight the importance of close monitoring and personalized treatment adjustments to optimize mavacamten therapy in patients with HCM [147, 174]. Table 5 shows the comparison of dosing criteria for mavacamten in EXPLORER-HCM and VALOR-HCM clinical trials, including starting dose, down-titration, up-titration, and temporary discontinuation criteria [147, 174].

Table 5.

Mavacamten Dosing Criteria in HCM Clinical Trials

Characteristic	EXPLORER-HCM (Day 1 to Week 30)	VALOR-HCM (Day 1 to Week 16)
Initial dose of mavacamten	5 mg	5 mg
Criteria for dose reduction	Mavacamten plasma levels between 700 and 1000 ng/mL at any visit	Mavacamten plasma levels between 700 and 1000 ng/mL, or Valsalva LVOT gradient under 30 mm Hg at Week 4
Criteria for dose increase	Resting LVEF at least 50%, Mavacamten plasma levels under 350 ng/mL, and Valsalva LVOT gradient at least 30 mm Hg at Weeks 8 and 14	Resting LVEF at least 50%, Mavacamten plasma levels under 350 ng/mL, and Valsalva LVOT gradient at least 30 mm Hg at Weeks 8 and 12
Temporary stoppage criteria	Resting LVEF below 50%, Mavacamten plasma levels at or above 1000 ng/mL, or QTcF prolongation	Resting LVEF below 50%

HCM: Hypertrophic Cardiomyopathy, LVEF: Left Ventricular Ejection Fraction, LVOT: Left Ventricular Outflow Tract, QTcF: QT interval corrected for heart rate using Fridericia's formula

Adverse effects

Key safety considerations include dizziness (27%) and syncope (6%), which were commonly reported adverse events in clinical trials [165, 170]. Additionally, mavacamten may cause a decrease in left ventricular ejection fraction (LVEF), with up to 10% reduction reported. This decrease can lead to temporary treatment discontinuation, as seen in 3.6% of patients in the EXPLORER-HCM trial and 3.6% in the VALOR-HCM trial. Other Mavacamten may cause various adverse effects, including cardiovascular issues (stress cardiomyopathy, arrhythmias, chest pain), respiratory symptoms (shortness of breath), and general complaints (headache, fatigue, leg swelling). Regular surveillance of patients is vital to identify and manage potential side effects, enabling timely adjustments to treatment plans and optimizing patient outcomes [165, 170]. Pharmacists play a crucial role in reviewing patient regimens for potential drug interactions, and patients are required to undergo regular echocardiograms during therapy [46, 52]. Although mavacamten is frequently administered alongside beta-blockers or non-dihydropyridine calcium channel blockers, it is not considered a frontline therapy for oHCM, particularly in light of recent studies that underscore the benefits of beta-blockers [151].

Incorporating Mavacamten into treatment plans for NYHA class II/III HCM

Contrary to previous guidelines [1], the latest treatment cascade for HCM from the American Heart Association (AHA) and American College of Cardiology (ACC) now includes cardiac myosin inhibitors (CMIs) as a treatment option [20]. As shown in Fig. 5, this updated approach reflects the latest recommendations, which differ from the 2023 study [175]. CMIs are now incorporated into the treatment algorithm, offering a new option for managing HCM. Mavacamten treatment has been linked to enhanced NYHA symptom classification and notable improvements in various hemodynamic and structural parameters. The FDA's approval of mavacamten for use in patients with oHCM and symptomatic heart failure offers a novel treatment option for this specific heart failure population, providing a fresh therapeutic approach to manage their condition. Mavacamten's capacity to substantially diminish the symptom burden, thus providing a valuable therapeutic window for patients who might otherwise face the prospect of surgery.While clinical trials have highlighted short-term side effects, the long-term effects, including impacts on lactation, pregnancy, and left ventricular ejection fraction (LVEF), warrant further investigation [175, 176]. The intensive monitoring required for mavacamten and its projected economic costs pose practical challenges [46, 175]. Furthermore, certain patient groups, including those with atrial fibrillation or advanced liver or kidney disease, were excluded from major trials, leaving uncertainties about mavacamten's safety in these populations [147, 165, 170]. As such, future research must address these gaps, particularly in diverse patient populations with coexisting conditions.

Fig. 5.

Management Algorithm for HCM. SCD: Sudden Cardiac Death, ICD: Implantable Cardioverter Defibrillator, HCM: Hypertrophic Cardiomyopathy, AV: Atrioventricular

Mavacamten's integration into clinical practice will be contingent upon various clinical considerations, including the effectiveness of established medical therapy, patient suitability for SRT, and tolerance to mavacamten. The FDA's approval of mavacamten for treating oHCM with progressive symptoms [46] is poised to significantly impact the treatment algorithm for oHCM patients. Currently, mavacamten is only available through the Risk Evaluation and Mitigation Strategy (REMS) program, ensuring careful monitoring and safe administration of the medication. Figure 6 shows clinical applications of mavacamten.

Fig. 6.

Mavacamten used in non-oHCM cases under different clinical scenarios. ASA: Alcohol Septal Ablation, SRT: Septal Reduction Therapy, BB: Beta-Blockers, CCB: Calcium Channel Blockers

Aficamten for OHCM

Aficamten, a cutting-edge myosin inhibitor, is being investigated as a potential breakthrough treatment for HCM, a condition characterized by abnormal thickening of the heart muscle. By targeting the underlying pathophysiology of HCM, aficamten aims to provide a novel and effective therapeutic strategy for patients with this disease [177]. Aficamten's pharmacokinetic properties are noteworthy, featuring a shorter half-life than mavacamten, enabling faster titration to optimal doses. Additionally, aficamten achieves steady-state concentrations within a relatively short period of two weeks, and its wide therapeutic window suggests a favorable balance between efficacy and safety, providing clinicians with flexibility in dosing and minimizing the risk of adverse reactions [177]. In the phase II REDWOOD-HCM trial, high-dose aficamten demonstrated a favorable safety profile and led to a remarkable 93% response rate, defined as a final resting LVOT gradient ≤ 30 mmHg and Valsalva LVOT gradient ≤ 50 mmHg, compared to 8% in the placebo arm [178].

Aficamten has been shown to reduce myosin ATPase activity and contractility in preclinical studies [177]. Although its effects on the super-relaxed (SRX) state of myosin are unknown, aficamten binds to the ATP-binding pocket, similar to blebbistatin, suggesting a distinct myosin off-state [177]. Preliminary data indicate that aficamten reduces cardiac contractility in vivo, similar to mavacamten, in healthy rats, beagle dogs, and a transgenic mouse model of HCM [179–181]. Pharmacokinetic assessments reveal faster kinetics than mavacamten, with a predicted human half-life of 2.8 days and actual half-life of 3.4 days, and no significant effect on cytochrome P450 [177, 182].

Preliminary results from the REDWOOD-HCM trial demonstrate thataficamten treatment leads to a substantial reduction in resting LVOT gradients and plasma NT-proBNP levels, demonstrating superiority over placebo. Notably, aficamten is well-tolerated, with a benign side effect profile and no reported serious adverse events, indicating a positive benefit-risk ratio and potential as a valuable therapeutic agent [183]. A phase 2 open-label trial evaluated aficamten's safety and efficacy in non-HCM patients. Symptomatic patients received aficamten for 10 weeks, with doses adjusted based on left ventricular ejection fraction (LVEF). Results showed 55% of patients experienced significant symptom improvement, with 29% becoming asymptomatic. Quality of life and cardiac biomarkers (NT-proBNP and troponin I) also improved. Modest LVEF reductions occurred, with three patients experiencing asymptomatic decreases below 50% (resolved after washout). One patient with a history of SCD experienced a fatal arrhythmia [178] (see discussion below). Aficamten therapy for symptomatic nHCM demonstrated a favorable safety profile and was linked to significant improvements in heart failure symptoms and cardiac biomarkers [178].

Discussion

The recently updated guidelines for HCM diagnosis and treatment reflect a significant shift in clinical practice, incorporating novel research insights and innovative care approaches to enhance patient outcomes. Recent revisions have integrated contemporary strategies for management and treatment, poised to transform the field and yield improved patient outcomes. This update heralds a new era in the clinical approach to this complex condition, and its implications warrant thorough examination and consideration in future research and practice [20].

The standard of care for oHCM has remained largely unchanged for decades [1] with recent update adding more contemporary strategies for management and treatment [20], relying on beta-blockers [184] and/or non-dihydropyridine calcium channel blockers to alleviate symptoms by slowing heart rate and mildly decreasing contractility [1]. Disopyramide, an antiarrhythmic, may be added to enhance negative inotropic effects, but its use is often limited by anticholinergic side effects. Despite their widespread use, these medications have limited efficacy, supported mainly by observational studies, and fail to decipher the molecular pathways underlying oHCM to develop effective interventions driving the disease. SRT, including septal myectomy [185] or alcohol septal ablation [186], is restricted to treatment-refractory patients, but its use is hampered by operator expertise requirements and may not suit patients with comorbidities or preferences for non-invasive options. This significant unmet need for effective and safe medical management of oHCM has sparked a pressing demand for innovative solutions.

A phase 2 trial (NCT01912534) demonstrated valsartan's efficacy in early-stage sarcomeric HCM, improving left ventricular wall thickness and diastolic function (composite z-score + 0.231; P = 0.001). This complements recent studies on novel cardiac myosin inhibitors, mavacamten and aficamten, showing improved symptoms and reduced LVOT obstruction in obstructive HCM [187] .Furthermore, the TEMPO study, a double-blind, placebo-controlled, randomized trial, highlighted metoprolol's efficacy in oHCM. Metoprolol significantly reduced LVOT gradients at rest and during exercise, and improved symptom relief, with fewer patients in higher NYHA and CCS classes, and improved quality of life scores (KCCQ-OSS). However, metoprolol did not significantly affect maximum exercise capacity, underscoring its limitations in certain clinical scenarios [151].

As of the 2024 guidelines of management oHCM, cardiac myosin inhibitors are an integral part in the management of the disease [20]. Mavacamten, a pioneering selective cardiac myosin inhibitor, revolutionizes the treatment landscape by targeting the core pathophysiological mechanism of oHCM [1], offering a disease-specific approach that tackles the root cause of the disease.

By targeting the underlying pathophysiology, mavacamten offers a crucial alternative for patients refractory to conventional therapies. Emerging evidence highlights its efficacy in symptom alleviation and potential to delay or prevent SRT. However, its use requires careful management due to the risk of LV systolic dysfunction, necessitating a Risk Evaluation and Mitigation Strategy (REMS) program. This innovative approach ensures provider certification, patient education, and comprehensive oversight, Creating a framework for the development of a new treatment algorithm in oHCM [46, 52].

Figure 7 illustrates the mechanism of action of myosin inhibitors like mavacamten across three distinct states of sarcomere function: Normal, HCM, and HCM with mavacamten treatment. In a healthy sarcomere, the interaction between actin and myosin filaments is well-balanced, facilitating optimal muscle contractility and relaxation, thereby ensuring normal cardiac function. Conversely, in HCM sarcomeres, an excessive formation of actin-myosin cross-bridges results in hypercontractility and impaired relaxation, disrupting normal cardiac function and altering myocardial energetics. Mavacamten's intervention in HCM sarcomeres reduces the number of actin-myosin cross-bridges, mitigating hypercontractility and enhancing relaxation. This restoration of normal muscle dynamics also improves myocardial energetics, underscoring mavacamten's therapeutic potential in managing HCM. The transitions between these states accentuate the impact of HCM on sarcomere function and mavacamten's corrective effects, emphasizing its role in rebalancing cardiac muscle performance [163, 164, 175].

Fig. 7.

Shows the transition from a normal sarcomere to an HCM sarcomere and the effects of mavacamten treatment on contractility, relaxation, and myocardial energetics

Meanwhile, Aficamten has been found to decrease the activity of myosin ATPase in bovine cardiac myofibrils and reduce contractility in rat primary cardiomyocytes [177]. While its impact on the super-relaxed (SRX) state of myosin remains unknown, aficamten has been shown to interact with the ATP-binding site of myosin [177], suggesting a distinct mechanism of action. Table 6 shows a comparative analysis for sarcomeric contractile inhibitors in HCM.

Table 6.

Summarizes the mechanisms of action, clinical trial outcomes, and efficacy of sarcomeric contractile inhibitors, including mavacamten and aficamten, in treating HCM

Type	Drug	Target	Mechanism	Contractility	Clinical Trials	Outcomes
Sarcomeric contractile inhibitors	Mavacamtem	Myosin heavy chain-β [171]	Stabilizes SRX state of myosin [169]	Reduced myosin head availability [163]	EXPLORER-HCM [146, 165, 188], PIONEER-HCM [170], MAVERICK-HCM [189, 190]	Improved peak oxygen consumption, NYHA class, reduced LVOT-obstruction [146, 165, 170, 188, 189, 190]
	Aficamten [178]	Myosin heavy chain-β [177]	Slows phosphate release from myosin [32]	Stabilizes weak actin-binding myosin [177]	REDWOOD-HCM [178]	Therapy led to significant symptom alleviation and biomarker improvement in over half of non-oHCM patients, with nearly a third achieving complete symptom resolution [178]

HCM: Hypertrophic Cardiomyopathy, LVOT: Left Ventricular Outflow Tract, NYHA: New York Heart Association, nHCM: non-obstructive Hypertrophic Cardiomyopathy SRX: super relaxed state. Clinical trials: EXPLORER-HCM, PIONEER-HCM, MAVERICK-HCM, REDWOOD-HCM

The three clinical trials previously discussed consistently demonstrate mavacamten's effectiveness and relative safety for oHCM patients already receiving standard treatments. This cardiac myosin inhibitor has demonstrated a comprehensive benefit profile, including alleviation of cardiac obstruction, enhanced cardiac function, and significant improvements in physical performance, overall well-being, and symptom management. Additionally, it has shown a broad improvement in various clinical metrics, patient-reported outcomes, and biomarkers. Notably, this cardiac myosin inhibitor has decreased the necessity for invasive procedures in severely symptomatic oHCM patients who were already receiving optimal medical treatment for 16–32 weeks. The PIONEER-HCM and EXPLORER-HCM trials utilized pharmacokinetic monitoring to tailor treatment and optimize outcomes. Mavacamten's impact on cardiac structure and function was further explored in sub-studies within EXPLORER-HCM. A CMR sub-study [146] revealed that mavacamten achieved a remarkable reduction in left ventricular mass index, maximum LV wall thickness, and left atrial volume index (LAVI) compared to placebo after 30 weeks, with sustained improvements at 96 weeks [191]. An echocardiographic sub-study [166] demonstrated that mavacamten led to a significantly higher rate of complete resolution of systolic anterior motion and mitral regurgitation (MR) compared to placebo, with strong correlations between serum NT-proBNP level reduction and echocardiographic parameters. These findings confirm mavacamten's ability to improve cardiac structure and function in patients with oHCM.

The medical research trial demonstrated that mavacamten treatment led to substantial enhancements in patient outcomes, including comprehensive well-being and total symptom burden. The KCCQ-OSS showed a mean increase from baseline to Week 30, with the mavacamten group exhibiting a notably higher rise (14.9) compared to the placebo group (5.4; P < 0.0001). Benefits were observed across all domains, including symptom severity, physical functioning, social functioning, and overall quality of life, although these gains were not maintained post-treatment. Additionally, an analysis employing the EQ-5D-5L index score and EQ-VAS revealed that patients receiving mavacamten experienced relatively significant advancements in both measures at Week 30 compared to placebo, indicating notable progress in health-related quality of life and overall well-being [192–194]. These clinical trial results demonstrate that mavacamten yields significant enhancements in patient well-being and quality of life for individuals with oHCM. Notably, the transition of 13 patients from the initial study to a long-term extension study paved the way for investigating the sustained safety and efficacy of cardiac myosin inhibitors in symptomatic oHCM [170]. Over a median follow-up of 201 weeks, mavacamten consistently demonstrated significant improvements, including substantial reductions in LVOT gradients and enhanced diastolic function metrics. Additionally, there were notable decreases in NT-proBNP levels, reflecting reduced myocardial wall stress [165, 166, 195]. These results highlight mavacamten's potential as a promising long-term treatment for obstructive HCM, supported by stable clinical outcomes and manageable safety profiles observed over extended monitoring periods [195].

The VALOR-HCM trial revealed a significant breakthrough in the treatment of symptomatic oHCM, demonstrating that mavacamten surpasses placebo in reducing high-sensitivity cardiac troponin I (hs‐cTnI) by 50% and NT‐proBNP by 80% (P < 0.01) [146]. This pioneering study also uncovered a crucial link between changes in left ventricular (LV) mass index, as assessed by CMR, and hs‐cTnI levels. Moreover, the VANISH trial's findings showed that early intervention with valsartan, an angiotensin receptor blocker, leads to improved cardiac structure, function, and remodeling outcomes, accompanied by stable or reduced NT‐proBNP levels over a 2-year period, compared to placebo [187]. Building on this success, the VALOR-HCM trial further demonstrated that mavacamten significantly reduces the need for SRT and improves NYHA functional class, outperforming placebo in both regards [147].

As far as clinical trials of aficamten are concerned, this phase 3 double-blind trial demonstrated a significant improvement in peak oxygen uptake among patients with symptomatic oHCM [32]. Aficamten, a novel oral agent targeting cardiac myosin, demonstrated efficacy in reducing LVOT gradients by modulating excessive cardiac contractility, resulting in improved exercise capacity and symptom alleviation. In a 24-week randomized controlled trial, 282 participants received either aficamten or placebo, with dose titration guided by serial echocardiographic assessments. This study design enabled a thorough evaluation of aficamten's safety and efficacy profile, providing valuable insights into its potential as a treatment for cardiac conditions characterized by hypercontractilit [32]. Aficamten significantly improved peak oxygen uptake (1.8 ml/kg/min vs. 0.0 ml/kg/min with placebo) and all 10 secondary endpoints, including quality of life, functional capacity, and pressure gradients [32]. Notably, the safety profile of aficamten was comparable to placebo, suggesting a favorable risk–benefit profile [32]. These findings support aficamten as a promising treatment option for patients with symptomatic obstructive HCM, offering improved exercise tolerance and reduced symptoms. As far as clinical trials of aficamten are concerned, this study provides robust evidence for its efficacy and safety, paving the way for further investigation into its long-term benefits and potential as a game-changer in HCM management.

For patients with refractory symptoms on initial therapy, mavacamten emerges as a pivotal secondary treatment option before considering surgical myectomy or SRT [1]. This innovative approach to refractory therapy leverages mavacamten's ability to target the underlying hypercontractility in HCM, offering a less invasive yet effective alternative to traditional surgical interventions. The efficacy of mavacamten in postponing or circumventing invasive procedures has been vividly demonstrated in trials such as VALOR-HCM [147]. This trial showcased mavacamten's capacity to substantially diminish the symptom burden, thus providing a valuable therapeutic window for patients who might otherwise face the prospect of surgery.While clinical trials have highlighted short-term side effects, the long-term effects, including impacts on lactation, pregnancy, and left ventricular ejection fraction (LVEF), warrant further investigation [175, 176]. The need for close surveillance and the expected high costs of mavacamten therapy create substantial practical and economic challenges [46, 175]. Furthermore, certain patient groups, including those with atrial fibrillation or advanced liver or kidney disease, were excluded from major trials, leaving uncertainties about mavacamten's safety in these populations [147, 165, 170]. As such, future research must address these gaps, particularly in diverse patient populations with coexisting conditions.

Mavacamten's therapeutic potential stretches beyond oHCM to include nHCM and diastolic heart failure,with current clinical trials investigating its effectiveness and safety in these additional indications [196]. Clinical trials of aficamten have demonstrated its promise in improving exercise tolerance and reducing symptoms in symptomatic oHCM patients [32], providing robust evidence for its efficacy and safety. These findings pave the way for further investigation into its long-term benefits and potential as a game-changer in HCM management, potentially leading to broader therapeutic uses and solidifying mavacamten's role as a versatile and innovative treatment in the cardiovascular domain.

Conclusion

OHCM is a complex condition characterized by LVOT obstruction and impaired myocardial energetics, leading to significant morbidity and mortality. The findings of this research emphasize the need for a holistic strategy in addressing oHCM, bringing together genetic knowledge, innovative therapies, and tailored management plans.

The advent of novel therapeutics such as mavacamten and aficamten represents a significant milestone in the treatment landscape of oHCM. These myosin inhibitors have shown promising results in improving symptoms, functional capacity, and overall quality of life for patients. Mavacamten, in particular, has demonstrated efficacy in reducing the need for invasive septal reduction therapies, marking a paradigm shift in non-surgical intervention options.

This study highlights the critical impact of genetic diagnosis and informed decision-making in identifying at-risk individuals and tailoring personalized treatment plans. Emerging therapies, including other myosin inhibitors and adjunctive pharmacologic agents, continue to be explored, offering hope for more targeted and effective management of oHCM. The integration of genetic understanding with innovative therapies such as mavacamten and aficamten, alongside traditional management approaches, provides a comprehensive framework for optimizing outcomes in patients with oHCM. Continued research and clinical trials are essential to further refine these strategies and improve the prognosis for individuals affected by this challenging condition.

Abbreviations

HCM

Hypertrophic cardiomyopathy

oHCM

Obstructive hypertrophic cardiomyopathy

LVOT

Left ventricular outflow tract

LV

Left ventricle

NYHA

New York Heart Association

CMR

Cardiac magnetic resonance imaging

SRT

Septal reduction therapy

ESM

Extended septal myectomy

SCD

Sudden cardiac death

FDA

Food and drug administration

Author contributions

K.S and A.R did the conceptualization. S.L,M.K,M.U.R and S.M.I.A conducted the literature search and screening. Drafting of the manuscript was done by M.K, S.L, A.R, K.S and N.R M.U.R performed the editing and supervision. All authors have read and agreed to the final version of the manuscript.

Funding

The authors received no extramural funding for the study.

Availability of data and materials

Data available within the article. The authors confirm that the data supporting the findings of this study are available within the article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no potential conflicts of interest concerning the research, authorship, and/or publication of this article.