Left ventricular outflow tract obstruction (LVOTO) represents a hallmark pathophysiologic mechanism in HCM, affecting approximately 70% of patients with gradients $\ge$30 mmHg at rest or with physical provocation [12]. The obstruction predominantly involves the systolic anterior motion (SAM) of the mitral valve (MV) leaflet, which contacts the hypertrophied interventricular septum (IVS) during systole, creating mechanical resistance to left ventricular (LV) ejection [8] (Fig. 1, Video 1). Ventricular loading conditions influence the dynamic nature of this obstruction. Increased contractility or decreased preload and afterload can exacerbate obstruction by reducing ventricular volume, making HCM with LVOTO a preload-dependent, afterload-sensitive condition [6]. This explains the characteristic variability in gradient severity with postural changes, exercise, pharmacologic agents, and physiologic maneuvers such as Valsalva or squatting, representing a mechanistic foundation for symptomatology and therapeutic interventions in obstructive HCM (oHCM) [6].

Mitral regurgitation (MR) in patients with HCM primarily occurs due to SAM of the MV, which is commonly attributed to the Venturi effect [13]. However, it can also result from intrinsic abnormalities of the mitral valve apparatus, such as excessive elongation of the anterior or posterior leaflets, and issues with the papillary muscles, including anomalous insertion or anterior displacement [2, 14]. Understanding these pathophysiological changes is crucial, as they can precede hypertrophic changes in the LV and may represent an early phenotypic manifestation of sarcomere mutations [15, 16]. For example, Velicki et al. [17] investigated patients with mutations in the MYBPC3 or MYH7 genes and found that those with MYH7 mutations exhibited more significant MV abnormalities and greater regurgitation compared to patients with MYBPC3 mutations. This genetic heterogeneity may account for the variability in valvular dysfunction observed across the HCM spectrum.

The etiology of MR also carries management implications, as study has demonstrated a significant reduction in MR after isolated septal myectomy without requiring additional MV surgery [18]. In contrast, those with intrinsic disease of the MV apparatus may require an additional MV repair procedure during septal myectomy [2, 18, 19]. Differentiation of the etiology of MR is therefore crucial for pre-procedural planning in patients undergoing septal reduction surgery. While SAM-mediated MR often presents with a posteriorly directed jet, its absence does not definitively rule in primary mitral valve disease due to its low negative predictive value [20, 21]. Conversely, central or anteriorly directed jets should prompt further investigation via transesophageal echocardiogram or cardiac magnetic resonance imaging to evaluate for structural abnormalities [2, 20].

As the disease progresses, many cellular and morphological changes drive diastolic dysfunction in HCM. This occurs due to impaired LV relaxation, increased myocardial stiffness, and left atrial myopathy [8, 20, 22]. Using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from healthy controls and HCM patients with diastolic dysfunction, Wu et al. [22] showed that diastolic calcium overload, slow calcium recycling, and increased myofilament calcium sensitivity collectively impaired diastolic relaxation times; thereby providing a molecular explanation for the utility of calcium channel blockers (CCBs) in the management of HCM. Myocardial stiffness in HCM, at the cellular level, results from hypertrophied and disorganized cardiomyocytes separated by interstitial fibrosis, leading to a shrinking LV cavity [6]. In severe cases, this may result in a restrictive physiology [2]. Lastly, left atrial myopathy contributes to the development of diastolic dysfunction by impairing LV filling [20]. A culmination of these three pathophysiologic mechanisms results in elevated LV diastolic pressures that increase markedly on exertion, resulting in symptoms of exertional dyspnea and exercise intolerance, especially in patients with concomitant atrial fibrillation (AF) [6].

The pathophysiology of myocardial ischemia in HCM is complex and involves multiple factors. One mechanism is coronary microvascular dysfunction (CMD), as evidenced by autopsy studies showing hypertrophy of intimal and/or medial layers of the coronary arterioles with resultant reduction in luminal cross-sectional area [23]. The consequent impairment of vasodilatory capacity leads to decreased myocardial blood flow (MBF) during periods of heightened physiological demand, such as exercise, severe hypertrophy, and significant LVOTO. Consequently, this creates a pronounced myocardial supply-demand mismatch and myocardial injury [23, 24, 25]. Therefore, if this mismatch persists, replacement fibrosis occurs and serves as an arrhythmogenic substrate associated with sudden cardiac death [24, 26].

With an estimated prevalence of 20%, AF is the most common sustained arrhythmia in patients with HCM [8]. The elevated LV filling pressures from progressive hypertrophy leading to left atrial dilation have been attributed to the development of AF. However, increasing evidence of a primary left atrial (LA) myopathy secondary to excessive fibrosis may also serve as a predisposing factor for AF [8, 27]. In contrast to atrial arrhythmias, the mechanism behind ventricular arrhythmias in HCM patients is multifaceted and involves both functional and structural abnormalities. Functionally, alterations in intracellular calcium and sodium homeostasis lead to prolonged action potentials in the diseased myocardium, increasing the susceptibility to early and delayed afterdepolarizations that can trigger ventricular arrhythmias [28, 29, 30]. Structurally, myocardial fibrosis, myocyte disarray, and CMD act as substrates for re-entry ventricular tachycardia, with precipitating factors including exercise and LVOTO [31]. Refer to section 6 for additional discussion on managing and preventing arrhythmic complications in HCM.

The mitochondrion has been of particular focus at the cellular level for HCM. Recent studies have demonstrated severe mitochondrial damage with additional downregulation of genes responsible for synthesizing creatinine kinase and adenosine triphosphate, suggesting a global energetic decompensation in HCM hearts [32, 33]. This energy deficit was further exacerbated, independent of hypertrophy or degree of fibrosis, during exercise in patients with HCM [34]. These findings underscore the importance of understanding the pathology of HCM at a cellular level to develop effective therapies.

HCM is predominantly diagnosed in an outpatient clinical setting [4, 5, 6]. Initial workup involves thoroughly assessing a patient’s personal history, obtaining a three-generational family history, and a focused physical exam. In obstructive or labile-obstructive disease variants, patients typically manifest with dyspnea, angina, presyncope, or syncope, with the latter being particularly prevalent among young athletes [6, 13, 35]. Individuals exhibiting a milder phenotype demonstrate attenuated symptomatology, with a subset remaining entirely asymptomatic [6, 13]. For these asymptomatic individuals, a meticulous physical exam and a detailed family history become instrumental in determining the necessity for additional diagnostic imaging. Cardinal examination findings include a leftward-displaced precordial impulse, brisk peripheral artery pulsations, and a pronounced fourth heart sound (S4) [6, 13]. Depending on the obstruction’s severity, a harsh mid-systolic murmur may be best heard between the left lower sternal border and the cardiac apex. A blowing high-pitched holosystolic apical murmur suggestive of mitral regurgitation may also be present [6, 13]. Lastly, augmentation of mid-systolic murmur intensity during preload-reducing maneuvers—specifically the Valsalva maneuver or orthostatic positioning—provides further diagnostic differentiation from aortic stenosis, reinforcing the diagnosis of HCM [35, 36].

The overall risk of SCD in HCM is relatively low and is estimated to be 0.5% per year [20]. However, the risk of SCD should be assessed based on the individual patient. For example, in a study of SCD among athletes of various ages, the sports with the highest incidence of SCD include basketball, football, and soccer. Moreover, a higher incidence rate was noted in Black male NCAA Division I college athletes compared to their high school counterparts [67, 68]. Risk stratification for SCD is a critical component in managing patients with HCM and has evolved considerably over the past several decades. Multiple clinical risk markers have been identified that stratify patients according to their level of risk for potentially life-threatening ventricular arrhythmias. These established risk factors include: family history of SCD in first-degree or close relatives $\le$50 years of age; massive LVH (wall thickness $\ge$30 mm in any segment); unexplained syncope, particularly when occurring within 6 months of evaluation; LVEF 50%; presence of apical aneurysm with transmural scar (Fig. 2, Video 2); extensive LGE on CMR ($\ge$15% of LV mass); and non-sustained ventricular tachycardia (NSVT) on ambulatory monitoring. Based on the 2024 AHA/ACC HCM Guideline, the presence of $\ge$1 of these major features may justify ICD placement for primary prevention (Class IIa recommendation) [2, 69]. Increased LA diameter has also been shown to correlate with an increase in the risk of SCD in one study, though evidence from further studies has been controversial [2, 20, 70]. Nevertheless, it has been added to the HCM risk-SCD calculator for estimating the 5-year risk of SCD, along with the LVOT gradient. However, the SCD risk estimate does not account for the newer factors (LVEF 50%, LGE, apical aneurysm) as their impact on the 5-year risk estimate is currently undetermined [2]. A growing body of literature demonstrates a consistent correlation between these factors and the resultant increase in risk of SCD, making it more likely for these findings to be integrated into a new scoring system [71, 72, 73]. Fig. 3 (Ref. [74, 75]) summarizes the risk stratification guidelines for SCD in HCM.

Despite the current guidelines, there remains conflicting evidence regarding screening criteria for genotype-positive, phenotype-negative individuals, given the phenotypically heterogeneous nature of HCM. Family members with identical mutations have been shown to display different phenotypic expression, which indicates the potential role of exogenous factors in disease development [76]. There is evidence that these patients have impaired myocardial relaxation and impaired energy metabolism, but the clinical implication of these findings on the disease onset or severity and the risk of sudden cardiac death remains unknown, which makes screening and treatment extremely challenging [76].

ICD therapy is an effective intervention for the primary prevention of lethal ventricular arrhythmias and SCD. However, due to the complexities associated with HCM, not all patients benefit from this treatment [77].

ICD selection has evolved from advocating “all-purpose” ICD systems toward a nuanced approach predicated on individualized patient characteristics and specific clinical scenarios. Single-chamber devices and subcutaneous ICDs (S-ICDs) represent reasonable options for most HCM patients without pacing requirements [78].

S-ICDs offer particular advantages for young patients with extended life expectancy who face a heightened cumulative risk of complications related to transvenous leads. Studies from the EFFORTLESS cohort illustrate these benefits, indicating a negligible risk of bloodstream infections, a low incidence of lead fractures, and an impressive 2-year estimate of 92.7% for freedom from procedural complications compared to traditional transvenous ICDs [78]. Furthermore, findings from the PRAETORIAN trial have shown that S-ICDs are non-inferior to transvenous ICDs in terms of inappropriate shocks among general ICD candidates. As a result, S-ICDs have gained popularity among patients with HCM without additional requirements [78, 79].

The nuanced approach stems from patient-specific clinical scenarios that warrant specific device selection, such as:

1. Left ventricular outflow tract obstruction: Transvenous systems may be preferred for oHCM patients, particularly if septal reduction procedures might be required, as these interventions carry a non-negligible risk of conduction defects (10% in ASA patients, 4.4% in SM patients) necessitating pacing capabilities [80]. Moreover, changes in QRS-T morphologies after septal reduction therapies (SRT) may result in T-wave oversensing and failure to recognize the stored QRS-T template, leading to inappropriate shocks [78]. Therefore, patients with oHCM who may require SRT in the future may benefit from transvenous ICD, rather than S-ICD, therapy upfront.

2. End-stage disease: Patients who develop “burnt out” HCM, characterized by advanced heart failure with reduced ejection fraction, face an annual event rate of 10% for life-threatening arrhythmias [78]. Given that left bundle branch block (LBBB) is prevalent in such cases, cardiac resynchronization therapy with a defibrillator (CRT-D) may offer more advantages than S-ICDs. This is especially relevant in patients exhibiting severe interventricular septal fibrosis on CMR, as this condition heightens concerns about potential heart block that may necessitate pacing [78].

3. Pediatric patients: High complication rates (approximately 9.5% per year) have been documented in children and adolescents with HCM, primarily involving inappropriate shocks (41%), lead malfunction, and lead stretching [78, 81]. As a result, S-ICDs may be a better alternative in this population. However, a significant limitation is their large size in relation to the transvenous ICD and the body size of the child (due to concern for device erosion in smaller patients) [2, 78, 81].

Non-vasodilating beta-blockers (BBs) are regarded as first-line therapy for symptomatic oHCM [2, 35, 82]. They work by increasing LV filling time and volume (negative chronotropy) while decreasing the contractile force (negative inotropy), attenuating dynamic LVOTO and mitigating associated symptoms [2, 35, 82]. Although these drugs are widely used, there is a surprising lack of studies assessing their effectiveness, with the majority being underpowered and not randomized [82]. For example, all the studies on BBs found significant variability in LVOT gradient reduction, limited improvement in symptoms, and a stark proportion of non-responders, raising the need for larger randomized trials to better understand the role of these medications, especially in non-responders [82]. BB dosing is individualized, with medications uptitrated until a patient achieves symptomatic relief. However, if patients continue to have suboptimal response despite maximum dosing, non-dihydropyridine CCBs, such as verapamil or diltiazem, can be substituted [2, 35, 82]. CCBs also work by providing negative inotropic and chronotropic effects; however, they pose the risk of exacerbating outflow gradients in some patients. In fact, verapamil is specifically contraindicated for patients with severely elevated resting gradients ($>$100 mmHg), hypotension, and severe dyspnea at rest [2, 82].

Regarding treating asymptomatic carriers, it is crucial to continue close clinical surveillance to monitor for symptom onset or for the presence of additional risk factors, which might warrant further management. Pharmacotherapy should be utilized to provide symptomatic relief and improve quality of life, but the role of medical therapy in asymptomatic carriers is currently not recommended and remains a topic of ongoing investigation. Overmedicalization of asymptomatic carriers poses an additional financial and psychosocial burden on these patients.

Disopyramide serves as an additional treatment option for patients with oHCM who remain symptomatic despite first-line pharmacotherapy [2]. Because it can enhance conduction through the atrioventricular (AV) node, potentially facilitating rapid ventricular rates during AF, disopyramide should only be administered with BBs or CCBs [2].

As a class I antiarrhythmic agent, disopyramide possesses potent negative inotropic effects. Recent studies have demonstrated that it influences multiple ion channels, reduces the inward calcium current, and stabilizes the ryanodine receptor. This stabilization subsequently leads to diminished calcium release from the sarcoplasmic reticulum. Furthermore, disopyramide inhibits the late inward sodium current, which is often elevated in HCM and contributes to early and late afterdepolarizations. This mechanism may help mitigate the risk of ventricular arrhythmias in these patients [83, 84].

Disopyramide’s cost-effectiveness allows better access for patients of lower socioeconomic backgrounds, unlike the significantly more expensive mavacamten discussed in section 7.3 [76, 77, 78]. Fig. 4 (Ref. [2, 85, 86, 87, 88, 89, 90]) summarizes the overall management of patients with symptomatic HCM.

Mavacamten is a first-in-class reversible cardiac myosin inhibitor that, unlike negative inotropes, exhibits a novel mechanism of action through selective modulation of the sarcomeric contractile apparatus [91].

At the molecular level, mavacamten acts as an inhibitor of the $\beta$-cardiac myosin adenosine triphosphatase (ATPase). ATP typically binds to the myosin head and is hydrolyzed by ATPase into adenosine diphosphate (ADP), allowing the myosin head to form a cross-bridge with actin and initiate a power stroke [85, 91]. By inhibiting ATPase, mavacamten increases the number of myosin heads in a relaxed, energy-sparing state (ATP bound) while decreasing the number of myosin heads in a power-generating state (ADP bound). As a result, it reduces cardiac hypercontractility by lowering the frequency of actin-myosin cross-bridge formation [85, 91].

In the landmark phase 3 EXPLORER-HCM randomized controlled trial, mavacamten demonstrated significant efficacy in HCM patients with LVOT obstruction. This pivotal trial enrolled 251 patients with symptomatic oHCM (NYHA class II–III, and LVOT gradient $\ge$50 mmHg at rest or with provocation) randomized to mavacamten or placebo [86]. After 30 weeks of treatment, mavacamten produced a remarkable improvement through an increase in peak oxygen consumption (pVO₂) by $\ge$1.5 mL/kg/min along with a $\ge$1 reduction in NYHA class, or $\ge$3 mL/kg/min increase in pVO₂ without worsening of NYHA class in 37% of patients [85, 86]. Finally, long-term extension data from the EXPLORER-HCM study (MAVA-LTE) revealed a substantial improvement in LVOT gradients, achieving non-obstructive levels in 82.7% of patients. Furthermore, by the conclusion of the 3.5-year period, 67.4% of patients had returned to NYHA I status [87].

Since the discovery of mavacamten, several trials have been conducted to elucidate its benefits across various patient populations. The VALOR-HCM study enrolled 112 patients who fit the criteria for septal reduction therapy, defined by an LVOT gradient of $\ge$50 mmHg at rest or during provocation. These patients were randomized in a double-blind manner to receive either a placebo or mavacamten, which was titrated from a starting dose of 5 mg to a maximum dose of 15 mg daily. The study’s primary endpoint was the proportion of patients who either proceeded with septal reduction therapy or remained eligible for it according to guidelines after 16 weeks of treatment. At the conclusion of the study, only 17.9% (10 out of 56) of the mavacamten patients underwent septal reduction therapy, compared to 76.8% (43 out of 56) of those in the placebo group. Long-term data further supported the effectiveness of mavacamten, as 89% (96 out of 108) of patients continued to take the medication without needing septal reduction therapy. This suggests that mavacamten can reduce the need for surgery through medical management alone [92, 93]. Additional exploratory analysis from this study also revealed similar and sustained longitudinal benefits from mavacamten in all patients irrespective of genotype status [94].

The EXPLORER-CN study randomized 81 Chinese patients with oHCM to mavacamten or placebo and found a significant improvement in Valsalva LVOT gradient in the mavacamten arm [95].

It should be noted that the effects of mavacamten have only been found to be beneficial in HCM patients with LVOTO, as major landmark trials (i.e., EXPLORER-HCM, VALOR-HCM) have specifically included LVOTO patients and excluded those with mid-ventricular obstruction. As discussed in section 10, the ODYSSEY-HCM trial sought to address the role of mavacamten in non-obstructive HCM patients (including those with mid-ventricular obstruction or apical HCM). However, a recent update from the study investigators reveals no significant improvement in peak oxygen consumption or patient-reported quality of life [96, 97, 98]. Altogether, these trials showcase the significant symptomatic and hemodynamic benefits of mavacamten in patients with LVOTO and underscore its potential to provide a better quality of life for HCM patients. Fig. 5 showcases the effects of mavacamten on the LVOT gradient in the same patient pre- and post-therapy.

The principal safety concern with mavacamten is its negative inotropic effect, manifesting as a reduction in LVEF. In the EXPLORER-HCM trial, 7 patients (5.4%) receiving mavacamten experienced LVEF 50%, necessitating temporary dose reduction or treatment interruption, with all cases resolving after protocol-directed interventions [86]. Therefore, the 2024 ACC/AHA HCM Guideline recommends discontinuing mavacamten for patients who develop an LVEF of 50% and fail to recover [2]. Hence, rigorous echocardiographic surveillance should be performed, particularly during dose titration and in patients with borderline systolic function. The United States Food & Drug Administration (FDA) recommends obtaining a TTE every 4 weeks for the first 12 weeks after initiating mavacamten. After this initial period, routine TTEs should be performed every 6 months per recent updates, assuming the LVEF and LVOT gradients remain stable (LVEF $\ge$55% and LVOT gradient 30 mmHg) [99].

If treatment is halted due to LVEF dropping below 50%, it is recommended to repeat TTEs every 4 weeks until LVEF exceeds 50%. Once LVEF is stable, treatment can be restarted at half the previous dose, with an uptitration after two TTEs obtained 4 weeks apart from each other show a stable LVEF [99].

Aficamten, like mavacamten, is a selective cardiac myosin inhibitor that modulates sarcomere function by reducing actin-myosin cross-bridge formation [88]. However, there are key differences between the two. Aficamten was specifically designed with a shallow dose-response curve, meaning that increases in dosage lead to only modest reductions in LVEF. This feature provides it with a broader therapeutic window compared to mavacamten [88]. Additionally, aficamten has a shorter half-life of 3.4 days, whereas mavacamten has a half-life of 7 to 9 days. This shorter half-life facilitates more rapid titration and allows for quicker reversibility after dose adjustments [85].

The SEQUOIA-HCM trial was the first major landmark trial to explore the efficacy of aficamten among 142 of the 282 patients enrolled with symptomatic oHCM across multiple clinically relevant endpoints [88]. At the 6-month mark, 58.5% of patients had improvement in their baseline NYHA class by $\ge$1, 49.3% had an LVOT gradient of 30 mmHg with a rapid reduction of at least 20 mmHg in the first 2 weeks, and 47% of patients had a significant improvement in exercise capacity—even in severely symptomatic NYHA III or IV patients [88, 89]. Following a 4-week washout period, patients returned to their baseline echocardiographic parameters but experienced a worsening of their health status, further demonstrating rapid pharmacologic reversal of the drug and potentially creating the problem of medication reliance in the future [100]. Lastly, in contrast to the EXPLORER-HCM trial which suggested a reduction in the benefits of mavacamten in patients taking BBs, the benefits of aficamten were similar regardless of BB use and independent of the presence of a pathogenic sarcomere gene variant [88]. Additional head-to-head studies are required to compare mavacamten and aficamten in a long-term setting to determine which generation of myosin inhibitors is superior.

SM is an open-heart intervention characterized by median sternotomy, cardiopulmonary bypass, aortic cross-clamping, and a transaortic approach for the excision of a segment of the IVS to alleviate the LVOTO [101, 102]. The classic Morrow procedure, introduced in the 1960s, has evolved from a straightforward excision of the basal IVS from the aortic valve annulus to a more extensive septal excision. This modern technique extends well beyond the mitral-septal contact point and involves the midventricular septum, reaching up to the level of the papillary muscles [101]. Myectomy, therefore, reliably results in the immediate and typically permanent elimination of outflow obstruction, with normalization of LV pressures and preservation of systolic function via the enlargement of the LVOT cross-sectional area and subsequent redirection of blood flow away from the anteriorly displaced MV seen in SAM. Fig. 6 and Video 3A,3B showcase the immediate results of a patient’s outflow tract gradient pre- and post-myectomy. During SM, a comprehensive evaluation via intra-, and post-operative transesophageal echocardiogram (TEE) may be done to assess the hemodynamic implications of the procedure, including the persistence of the LVOT gradient. Should such gradients remain problematic, re-establishment of cardiopulmonary bypass may be warranted to facilitate a more extensive myectomy [101].

Optimal candidates for SM include symptomatic (NYHA III–IV) patients with oHCM who have additional structural diseases that require intervention. These conditions may include anomalous insertion of the papillary muscle, severe elongation of the anterior or posterior mitral leaflet (greater than 30 mm), multivessel CAD, and valvular aortic stenosis [2, 101]. Additionally, patients with AF who might benefit from intraoperative pulmonary vein isolation or a maze procedure should also be considered for SM [2]. NYHA class II patients with significant pulmonary hypertension secondary to LVOTO or associated MR, poor exercise capacity, and children and young adults with severely elevated LVOT gradients of $>$100 mmHg should also be considered for SM in highly experienced centers (Class IIb level of evidence per 2024 ACC/AHA HCM Guideline) [2]. Lastly, while it may be tempting to replace the mitral valve for MR during SM, studies have shown that valve replacement, as opposed to valve repair or a valve-sparing approach, leads to a $>$10-fold increase in hospital mortality and length of stay compared to isolated SM [2, 18, 103].

In general, SM, when done at comprehensive HCM centers, carries exceptional success rates of $>$90% to 95%, with an overall estimated procedural mortality of 1% [2, 104]. However, it is not without its complications. Conduction abnormalities are common in patients after SM, with a 38% risk of developing an LBBB and a 2.3% risk of developing complete heart block (CHB) [105]. On the other hand, the risks of ventricular septal defect (VSD), aortic regurgitation (AR), ventricular arrhythmias, cardiac tamponade, and stroke were found to be 1% in the modern era [104, 106].

The importance of performing SM at comprehensive and highly skilled HCM centers is underscored when comparing the outcomes of these specialized centers with those of lower-volume facilities. For instance, data from the Mayo Clinic, which analyzed over 3000 SM procedures conducted between 1993 and 2016, revealed impressive results. Specifically, there was less than a 1% risk of post-operative death, a 2% chance of CHB that required the insertion of a pacemaker, and an iatrogenic risk of ventricular septal defect of 0.3% [107]. Additionally, 90% of severely symptomatic patients experienced an improvement of more than 2 NYHA classes, leading to a significant relief from their symptoms [107].

Similarly, Tufts Medical Center reported favorable outcomes for 482 SM procedures performed from 2003 to 2016. They recorded a post-operative mortality rate of 0.8%, with 94% of patients improving to NYHA Class I or II, owing to substantial reductions in LVOT gradients and a decrease in associated mitral regurgitation [108].

In contrast, a recent study from the National Readmission Database, which tracked patients receiving septal reduction therapy from 2010 to 2019, found that those who underwent SM at low-volume centers faced double the risk of complications, such as needing a pacemaker (11.8% compared to 6.9%). These patients also had higher rates of composite in-hospital mortality and 30-day readmissions (21.7% versus 11.8%) [109].

The significant disparities between low- and high-volume HCM centers highlight the critical need to refer patients to specialized institutions to ensure better outcomes.

ASA is a therapeutic option for adult patients with symptomatic oHCM refractory to maximal pharmacological intervention, particularly in those for whom surgical intervention is contraindicated or confers prohibitive risk due to significant comorbidities or advanced age [2]. This percutaneous interventional procedure involves the targeted delivery of alcohol via a catheter-based approach to a selectively engaged septal perforator artery, inducing a precisely controlled septal myocardial infarction [110]. Appropriate targets for ASA are determined by several factors, including the presence of basal-predominant hypertrophy, an adequate diameter of the septal artery (ranging from 1.25 mm to 2.5 mm), and the absence of concurrent surgical indications [110]. Notably, septal measurements of less than 2.5 mm are associated with a greater likelihood of benefiting from alcohol septal ablation. In contrast, cases exhibiting massive or diffuse septal hypertrophy extending into the mid-ventricle are better addressed through surgical resection, which effectively eliminates all hemodynamic gradients across the entire septal length [110].

Before initiating an ASA procedure, a transvenous pacemaker is typically positioned to mitigate the significant risk of conduction abnormalities, which ranges from 8% to 15%. The most prevalent conduction disorders observed in this context include right bundle branch block (RBBB), which occurs in approximately 50% to 70% of patients, and transient intraprocedural CHB resulting from tissue edema secondary to localized myocardial infarction [110]. Post-procedural improvements in gradients are not immediate, and the full benefits from ASA may take up to 1 year [110].

In centers with requisite expertise, ASA demonstrates a favorable procedural safety profile with perioperative mortality rates comparable to SM at approximately 1% [2]. However, longitudinal outcomes data reveal a significant divergence in survival trajectories, with SM conferring superior long-term survival at the 10-year follow-up interval (8.2% mortality) compared to ASA cohorts (26.1% mortality) [2, 111, 112]. Refer to Table 3 (Ref. [8, 104, 105, 110, 113, 114]) for the comparison between ASA and SM.

In addition to SM and ASA, there are several emerging minimally invasive techniques for HCM management. Percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) was evaluated in the largest cohort study involving 200 patients with drug-refractory symptomatic oHCM, and a significant overall reduction in the LVOT gradient was noted. However, 4% of patients continued to experience exertional chest pain or dyspnea despite the procedure. Additionally, 5.5% of patients developed permanent RBBB, while 1% experienced LBBB. Notably, no patients required permanent pacemaker implantation after the procedure. These findings suggest that PIMSRA may be an effective option for treating LVOT obstruction and providing symptomatic relief [115]. Additional procedures include transapical beating-heart septal myectomy, a minimally invasive technique for septal reduction that does not require cardiopulmonary bypass or a median sternotomy. Another option is the thoracoscopic Morrow procedure, which has also been demonstrated to provide significant symptomatic relief using a minimally invasive surgical approach [116, 117]. These emerging techniques offer favorable treatment options with minimized surgical trauma, and larger studies with long-term data will be needed to compare the efficacy of the minimally invasive techniques against the traditional SM and ASA procedures.

In HCM patients with systolic dysfunction, defined as a LVEF of less than 50%, guideline-directed medical therapy (GDMT) should be initiated promptly according to the 2022 ACC/AHA Heart Failure Guideline. HCM patients with LVEF 35% are especially at a high risk of ventricular arrhythmias and death [2]. An ischemic evaluation should be performed in the setting of new systolic dysfunction to assess for concomitant etiologies such as obstructive coronary artery disease. Additionally, harmful ionotropic agents (verapamil, diltiazem, disopyramide) and cardiac myosin inhibitors should be discontinued in patients with LVEF 50%; ICD implantation for primary prevention of SCD should also be considered in this cohort. Most importantly, CPET should be performed to assess parameters of functional limitations such as peak oxygen consumption, minute ventilation to CO₂ production, and ventilatory anaerobic threshold, and to refer the appropriate subset of patients for heart transplantation consideration [2]. As per the United Network for Organ Sharing data, the survival rates for HCM patients after heart transplant are 85%, 75%, and 61% at 1, 5, and 10 years, respectively [118]. Therefore, given these decent survival rates post-transplant, patients with severe or refractory HCM not meeting criteria for SRT with NYHA III/IV symptoms despite maximally tolerated GDMT should be considered for heart transplantation, with consideration of a left ventricular assist device as a bridge to transplantation [2].

Previously thought to be a benign condition without a significant increase in mortality risk, recent data suggest that 1 in 3 patients with apical HCM (aHCM) may experience adverse life events such as malignant ventricular arrhythmias, SCD, and heart failure [119]. Recent data also reveals a mortality rate ranging from 0.5% to 4.8%, similar to that of typical HCM patients [119, 120]. In the absence of large randomized clinical trials, medical therapy in patients with aHCM is largely limited and primarily based on the management of classic HCM [120]. However, surgical options such as transapical myectomy and the novel transapical beating-heart septal myectomy may significantly benefit long-term survivability [120]. Lastly, while risk scores have been made to predict adverse events such as death, need for transplant, or ICD shocks, additional research is required to account for newer predictors of outcomes such as LGE [71].

The risk of stroke is significantly higher in patients with HCM, and in cases of AF, anticoagulation is highly recommended regardless of the CHADS2-VASc score. Per the 2024 ACC/AHA HCM Guideline, direct-acting oral anticoagulants are the first-line option, and Vitamin K antagonists are the second-line treatment option. Regarding management, utilizing BBs, verapamil, or diltiazem as rate control agents is acceptable. In cases of poorly tolerated AF, a rhythm control strategy can be pursued with amiodarone, which is considered an effective agent in HCM patients. Alternatively, catheter ablation can be considered in patients with severely symptomatic AF, but HCM patients have twice the risk of relapse when compared to patients without HCM, likely due to a higher degree of electrophysiologic and structural remodeling noted in these patients [121].

As per the 2024 ACC/AHA HCM Guideline, HCM patients should be counseled to engage in mild to moderate intensity recreational exercise to optimize their cardiovascular health and enhance their overall quality of life. The decision to participate in vigorous-intensity exercise, especially for athletes, relies on an individualized shared decision-making approach between the patient and an HCM expert, with extensive consideration of the potential risks and benefits. ICD implantation solely for participation in competitive sports is not recommended unless patients meet the clinical criteria described in Section 6.

Families affected by HCM bear a significant psychological burden that affects not only the diagnosed individual but also their relatives. Research has shown that asymptomatic gene-positive relatives, known as silent gene carriers, face various psychological challenges. These include shock, worry, and uncertainty about their disease status, which can lead to anxiety and depression, ranging from minimal to severe levels [122]. Additionally, relatives of silent gene carriers often seek genetic testing primarily out of concern for their loved ones rather than personal benefit [122]. Moreover, the interpretation of positive gene results among silent carriers varies widely, with some patients viewing themselves as carriers without personal risk.

In contrast, others believe they have a serious heart condition, resulting in heightened anxiety and paranoia [122]. This unhealthy thought process leads to significant behavioral changes in some patients and influences career choices, physical activity, insurance decisions, and family planning [122]. Therefore, it is essential to provide adequate counseling and clearly communicate the meaning of genetic test results and their implications to patients to alleviate any psychological burden faced by families navigating this complex disease.