Review Article

Emerging Pharmacological and Invasive Therapies for Hypertrophic Cardiomyopathy with Obstructive Physiology

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Abstract

Hypertrophic cardiomyopathy is a prevalent condition characterised by ventricular hypertrophy, which results in left ventricular outflow obstruction in two-thirds of patients. Traditional pharmacological therapies, including β-blockers, calcium channel blockers and disopyramide, have been the cornerstone of symptom management but lack disease-modifying effects. The introduction of cardiac myosin inhibitors as the first therapy to directly target sarcomeric hypercontractility has dramatically changed clinical practice. However, several logistical factors presently limit the widespread adoption of cardiac myosin inhibitors, and their long-term side-effects and outcomes require ongoing investigation. Emerging pharmacological approaches, including EDG-7500 and gene therapies, aim to refine treatment strategies. For patients with refractory symptoms, invasive septal reduction therapies, including surgical myectomy and alcohol septal ablation, remain critical. Innovations such as radiofrequency ablation and septal scoring along the midline endocardium (SESAME) offer promising, minimally invasive alternatives. As treatment options expand, optimising patient selection, monitoring protocols and long-term outcomes remain essential to advancing care for patients with obstructive hypertrophic cardiomyopathy.

Keywords

Hypertrophic cardiomyopathy, cardiac myosin inhibitor, mavacamten, myectomy, myotomy, septal reduction therapy, radiofrequency ablation,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/cfr.2025.08

Disclosure: AM has received research grants from Pfizer, Ionis, Attralus and Cytokinetics, as well as consulting fees from Cytokinetics, BMS, BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, Akros, Lexeo, Prothena, BioMarin, AstraZeneca and Tenaya. DSK reports grant support from Amgen (via the Robert A. Winn Excellence in Clinical Trials Career Development Award), as well as support from the Wu-Tsai Human Performance Alliance (as a Clinician-Scientist Fellow), the Stanford Center for Digital Health (as a Digital Health Scholar), the Pilot Grant from the Stanford Center for Digital Health, National Institutes of Health (Grant no. 1L30HL170306) and the American Diabetes Association Pathway to Stop Diabetes Initiator Award (Grant no. 7-25-INI-11). ELC has no conflicts of interest to declare.

Correspondence: Ahmad Masri, Oregon Health & Science University, 3301 S. Bond Avenue, 7th floor, Portland, OR, 97239, US. E: masria@ohsu.edu

Copyright:

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

Hypertrophic cardiomyopathy (HCM) is common and frequently encountered in various clinical settings.1 Traditionally, HCM has been thought of as a monogenic disease but, due to frequent genotype-negative evaluations, a polygenic component has been proposed and continues to be evaluated.2 HCM is characterised by enhanced cardiac actin–myosin cross-bridge cycling, leading to hypercontractility, myocardial hypertrophy, myocardial fibrosis and diastolic dysfunction.3 HCM with obstructive physiology (oHCM) is the more common phenotype, occurring in up to two-thirds of patients, and results from the combination of hypercontractility, hypertrophy, a small left ventricular (LV) cavity and abnormal mitral valve leaflet length and subvalvular apparatus leading, most commonly, to LV outflow tract (LVOT) obstruction.1,3 HCM has a wide range of phenotypic presentations, including apical HCM, mid-ventricular HCM and septal variant with LVOT obstruction (here termed oHCM).

This narrative review explores traditional and emerging pharmacological and invasive interventions for oHCM, with an emphasis on the latter.

Pharmacological Therapies

Pharmacological therapies are the preferred initial therapy in symptomatic oHCM patients. For decades, β-blockers, calcium channel blockers (CCBs) and disopyramide were mainstay therapies, based largely on results from small and observational studies (Figure 1 and Table 1).1 The discovery of the super-relaxed state of cardiac myosin and the eventual introduction of cardiac myosin inhibitors (CMIs) as the first sarcomere-selective therapeutic approach in HCM represent pivotal moments in the care of patients with oHCM.4,5 The regulatory approval of the first CMI, mavacamten, for the treatment of symptomatic oHCM has dramatically changed clinical practice.6,7

Traditional Medical Therapies

Non-vasodilating β-blockers and non-dihydropyridine CCBs are recommended as first- and second-line therapies respectively for symptomatic patients with oHCM.1 In cardiomyocytes, β-blockers bind to β-adrenoceptors and CCBs inhibit L-type calcium channels, decreasing calcium entry during action potentials and subsequently reducing calcium release by the sarcoplasmic reticulum.8,9 A decrease in the amount of calcium available for binding troponin C subsequently leads to negative inotropy (Figure 1).9 In addition, β-blockers and CCBs act on receptors in cardiac nodal tissue to prolong diastolic filling (Figure 1 ).8,9 Collectively, the increase in LV filling and stroke volume has the potential to reduce the LVOT gradient and symptoms in oHCM patients. However, studies evaluating the physiological and symptomatic effects of these agents in oHCM are lacking. In fact, the recommendation for these agents as first-line therapy is based primarily on long-standing clinical use and expert consensus.1 Available studies examining their outcomes report variable degrees of LVOT reduction, with a substantial proportion of patients classified as non-responders.10–19 To date, there have been no adequately powered randomised and placebo-controlled multicentre clinical trials of these agents.

Disopyramide is a sodium channel blocker with negative inotropic effects that is recommended for oHCM patients with refractory symptoms despite the use of β-blockers and/or CCBs (Figure 1).1 Disopyramide exerts negative inotropic effects by reducing the calcium transient amplitude, thereby lowering calcium-mediated myofilament activation and decreasing force generation.20–22 This occurs through disopyramide’s combined inhibition of peak and late sodium currents, L-type calcium currents, delayed rectifier potassium channels and selective cardiac ryanodine receptors (RyRs).20 Disopyramide also shortens the action potential and stabilises RyRs, thereby reducing early and delayed afterdepolarisations, but there is limited evidence that it can mitigate arrhythmias in HCM.20–22 Although there are some data supporting its symptomatic benefit, the use of disopyramide in clinical practice is limited by inconsistent efficacy and side effects such as QTc prolongation, drug–drug interactions, systemic anticholinergic symptoms and tachyphylaxis.21,22

Although these conventional therapies can potentially improve symptoms for some patients, they do not directly target the pathophysiological mechanisms underlying HCM. Consequently, these treatments neither modify the natural progression of the disease nor consistently achieve symptom relief.

Cardiac Myosin Inhibitors

The 2024 multisociety guidelines recommend CMIs as an alternative to disopyramide and invasive septal reduction therapy for oHCM patients with symptoms despite treatment with β-blockers and/or CCBs.1 CMIs are the first drug class designed to directly target the underlying pathophysiological mechanisms of HCM and the only HCM therapy with data from multiple placebo-controlled phase III clinical trials.23–27

The development of CMIs reflects the field’s growing understanding of myosin–actin interactions that contribute to the pathophysiology of oHCM. Myosin heavy chain heads shift between two states depending on the presence of ATP: a super-relaxed (SRX) state and a disordered-relaxed (DRX) state. The SRX state is characterised by myosin heads that are ‘off’ and unable to engage in actin–myosin cross-bridging. Meanwhile, in the DRX state, one of the myosin heads becomes available for binding. In HCM, a key mechanism driving aberrant sarcomere contraction is destabilisation of the SRX state.4 This increases myosin–actin cross-bridge formation and increases sarcomere force generation to produce hypercontractility.5 By selectively inhibiting cardiac myosin ATPase activity to stabilise the SRX state, CMIs decrease excessive myosin–actin cross-bridge formation to reduce hypercontractility and decrease LVOT obstruction to address symptoms (Figure 1 and Table 1).4,28 Our perspective on the clinical impact of CMIs is largely shaped by recent trials on mavacamten and aficamten.

Figure 1: Pharmacological Management of Hypertrophic Cardiomyopathy With Obstructive Physiology

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Table 1: Pharmacological Therapies for Hypertrophic Cardiomyopathy with Obstructive Physiology and Studied Outcomes

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Mavacamten

Mavacamten is the first and only commercially available CMI that is approved in North America, Asia, Europe, Australia and South America for the treatment of HCM with New York Heart Association (NYHA) functional class II–III symptoms.29 Mavacamten monitoring programs are dictated by the respective health and regulatory authorities. In the US, mavacamten is approved under a risk mitigation program. Mavacamten is started at a dose of 5 mg or lower with monitoring via an echocardiogram every 4 weeks, and the dose cannot be uptitrated the first 12 weeks.30 Subsequently, if the dose is stable, then the echocardiogram can be spaced out to every 12 weeks.30 However, whenever the dose is changed, an ad hoc 4-week echocardiogram is required.30 Any new decrease in LV ejection fraction (LVEF) below 50% requires at least a temporary interruption in therapy, with reinitiation of mavacamten at the next lower dose when LVEF recovers on a subsequent echocardiogram.30

Several randomised controlled trials support the efficacy of mavacamten.23,26,31 The phase III EXPLORER-HCM trial (NCT03470545) demonstrated that mavacamten can improve exercise capacity, reduce LVOT gradient and alleviate symptoms.23 A second phase III trial, VALOR-HCM (NCT04349072), showed that mavacamten therapy reduces the need for invasive septal reduction therapy in most patients.26 Substudies of EXPLORER-HCM showed favourable LV remodelling using imaging, with mavacamten contributing to significant positive myocardial remodelling effects, including an improvement in LV mass index, maximum LV wall thickness and left atrial volume index, which have the potential to reduce long-term cardiovascular events.24,32–34 Longer-term studies are needed to determine whether these findings translate to improved clinical outcomes.

Importantly, adverse events associated with mavacamten are mitigated through structured monitoring programs implemented in both clinical trials and commercial use. Permanent discontinuation due to mavacamten-related effects, such as LVEF <50%, heart failure, or prolonged QTc, has occurred in fewer than 5% of patients.23,25,26,35–39 However, mavacamten’s half-life and potential safety are dependent on metaboliser status.40 In addition, the relationship between mavacamten dose (pharmacokinetics) and its effect on LVEF (pharmacodynamics) is inconsistent, which leads to an unpredictable degree of LVEF reduction.36,41 This appears to be related to cumulative exposure to mavacamten. For example, the rate of developing LVEF <50% in EXPLORER-HCM was 5.6%, whereas the rate in its open-label extension was 8.7% even though that population included placebo-to-mavacamten crossover.39 Reassuringly, most patients with interrupted mavacamten therapy were able to restart mavacamten at the next lower dose, and the incidence of clinical heart failure in conjunction with LVEF <50% was low.23,26,31,36,38,42 In VALOR-HCM, which used echocardiogram-guided titration of mavacamten without monitoring of drug levels, up to 13.8% of patients had LVEF <50%, including two patients with LVEF <30% and one death that occurred in close proximity to such events.26 Furthermore, the rate of new-onset and recurrent AF is emerging as a potential side effect of mavacamten, and has thus become another important metric to monitor. Although AF is common in oHCM, and is expected to occur at a rate of 2–3% per year, the rates of new-onset AF seen with longer-term follow-up of mavacamten in the MAVA-LTE (NCT03723655) and VALOR-HCM trials (7.8% and 10.2%, respectively) are higher than expected and require further investigation.25,26,43

Recent data from the commercial use of mavacamten show somewhat similar conclusions from the clinical trials and their long-term extension studies.6,7,42 However, these analyses are fraught with bias towards patients who continue and restart mavacamten and frequent under-reporting of adverse events due to the lack of a requirement to submit data upon mavacamten discontinuation.42,44 Finally, the drug–drug interaction that can occur with mavacamten use requires significant monitoring and resources, and partly explains why the US Food and Drug Administration’s (FDA) risk mitigation program requires frequent pharmacy involvement.30

Aficamten

Aficamten is the second-in-class CMI. Aficamten binds to a distinct site compared to mavacamten and is currently under regulatory review for the indication of symptomatic oHCM.45 Compared with mavacamten, aficamten has a shorter half-life of 3.4 days and no significant drug–drug interactions.45

The pivotal phase III trial SEQUOIA-HCM (NCT05186818) demonstrated the efficacy and safety of aficamten in oHCM.27 In SEQUOIA-HCM, aficamten improved peak oxygen consumption to 1.74 ml/kg/min and over 95% of oHCM patients treated with aficamten experienced a clinically meaningful improvement in one or more of the following study measures: reduction in LVOT gradient, relief in symptom burden, improvement in exercise capacity and improvement in cardiac biomarkers.27,46 In addition, favourable LV remodelling was shown using both echocardiography and cardiac MRI.35

The collective evidence to date shows that aficamten’s properties result in a favourable safety profile. Aficamten studies in oHCM report a low rate (5.3%) of LVEF reduction to <50%, and downtitration rather than discontinuation of aficamten is safe in patients with LVEF 40–49%.27,46,47 In addition, the rate of AF is lower (2.4%) than that seen in VALOR-HCM and MAVA-LTE, but longer-term exposure data are required to enable more definitive conclusions.27

Challenges and Future Directions for Cardiac Myosin Inhibitors

As the use of CMIs continues to expand, several important considerations must be addressed. First, accurate diagnosis and phenotyping of HCM play a crucial role. Current data support the use of CMIs in sarcomeric oHCM. However, their efficacy in non-sarcomeric phenocopies, non-obstructive HCM, or less common variants of oHCM, including patients with apical or mid-ventricular obstruction, is not well studied.47,48 The potential role of CMIs in non-obstructive HCM is currently being investigated in ODYSSEY-HCM (NCT05582395) and the ACACIA-HCM trial (NCT06081894).

Second, there is currently no method to predict LVEF reduction and/or heart failure events. Initial exploratory data suggest that a history of AF and increased baseline index LV end-diastolic volume (>56 ml/m2) are associated with an increased risk of developing LVEF <50%.33 However, more expansive investigations into predictors of adverse outcomes associated with CMIs, especially mavacamten, are needed. A risk-mitigation strategy implemented by the European Medicines Agency involves assessing metaboliser status before initiating mavacamten.49 This approach aims to predict and reduce the likelihood of adverse events caused by excessive drug response or elevated drug levels. In addition, the emerging signal of increased burden of AF on mavacamten is concerning and requires further investigation.39

Finally, several logistical factors may limit the more widespread adoption of CMIs. The current list price of USD$89,500 for a year of treatment of mavacamten in the US is a challenge.50 In addition, the frequency of monitoring required for patients on mavacamten adds another layer of complexity and cost. Moreover, because of the complexities that relate to the use of mavacamten, HCM centres are typically tasked with prescribing it.

Pharmacotherapies in Early Development

CMIs mark a significant advance in the treatment of HCM, but they are still associated with side effects and logistical factors that limit their widespread use. Several novel pharmacotherapies in development, including EDG-7500, gene therapy and sotagliflozin, attempt to address the shortcomings of CMIs and have the potential to transform the field of HCM therapeutics.

EDG-7500 is a first-in-class selective cardiac sarcomere modulator designed to slow the rate of myocardial force generation in early systole and accelerate actin–myosin cross-bridge detachment in early diastole to improve ventricular filling. Unlike other pharmacotherapies, EDG-7500 was designed to preserve cardiac myosin function, and in vitro studies have shown that it does not affect myosin–actin proximity or cross-bridge reattachment rates.51

Data from studies in animal models show that EDG-7500 successfully slows early contraction and increases LV compliance to decrease LVOT obstruction.51–54 A reduction in LV systolic function below normal was not observed across multiple preclinical models, even at the highest exposure.51–54 Subsequently, a phase I study demonstrated that EDG-7500 was well tolerated in healthy subjects for 14 days in both the single ascending dose and multiple ascending dose cohorts.55 EDG-7500 had a half-life of approximately 30 hours, achieving steady-state concentrations within 4 days with once-daily dosing.55 Decreases in LVEF below 50% were not observed, even with increasing doses of EGD-7500 above the predicted target therapeutic exposure.55 CIRRUS-HCM, a multicentre open-label phase II trial, is currently underway to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of EDG-7500 in adults with oHCM and non-obstructive HCM.56,57 Unpublished preliminary data from CIRRUS-HCM show promising results, with a reduction in resting and Valsalva LVOT gradient by 67% and 55%, respectively, for three of five patients in the combined 100/200 mg cohorts.56

Sodium–glucose cotransporter (SGLT) inhibitors, particularly the dual SGLT1 and SGLT2 inhibitor sotagliflozin, are another class of medications under investigation for their therapeutic potential in HCM. Sotagliflozin has been shown to reduce adverse cardiovascular events in diabetic patients with heart failure, prompting interest in its role in HCM.58 In HCM, impaired fatty acid uptake and a metabolic shift from fatty acid oxidation (FAO) to glycolysis have been associated with the progression of LV hypertrophy.59,60 Preclinical studies have yielded mixed results regarding the effects of SGLT2 inhibition on cardiac hypertrophy.61,62 Early studies in a murine model of HCM indicate that SGLT2 inhibition increases the glucagon/insulin ratio in cardiomyocytes, thereby increasing FAO and glycolysis–glucose oxidation coupling, which, in turn, attenuates LV hypertrophy and fibrosis.63 In addition, there is some evidence that chronic pressure overload increases SGLT1 expression to generate cardiac hypertrophy and that SGLT1 inhibition can reverse pathological hypertrophy and LV failure.64 Conversely, a recent study suggests SGLT1 downregulation does not affect hyperglycaemia-related hypertrophy in diabetic hearts.63 These discrepancies may stem from variations in study designs and animal models, and further investigations are needed to understand the impact of sotagliflozin and other SGLT inhibitors on HCM. The phase III SONATA-HCM (NCT06481891) trial is currently investigating the effects of sotagliflozin on symptoms and function in HCM.65

Finally, gene therapy targeting common mutations in HCM is a rapidly evolving field that holds promise for transforming HCM care. Two strategies being explored are gene replacement and gene editing. Gene replacement involves using a viral vector, commonly adenovirus 9 (AAV9), to introduce functional copies of MYBPC3 DNA. In preclinical studies in mice lacking the MYBPC3 gene, TN-201 treatment reduced heart mass, increased cardiac ejection fraction and improved survival.66 At present, multiple biotechnology companies are studying this therapeutic option. MyPEAK1 (NCT05836259) is a phase Ib/II trial led by Tenaya Therapeutics that aims to study the safety of MYBPC3 gene therapy with TN-201. Preliminary data from three patients showed that TN-201 treatment resulted in increased concentration of TN-201 mRNA and MYBPC protein.67 However, the degree of RNA expression was lower than predicted from preclinical models.68 Although there are no reports of cardiotoxicity, all three patients experienced elevations in liver enzymes without evidence of liver injury, with one patient requiring corticosteroid injection.69 Meanwhile, preclinical studies exploring gene-editing therapies have demonstrated some success using the AAV9 system with cardiac-specific promoters to deliver clustered regularly interspaced short palindromic repeat (CRISPR)–Cas9 adenine base editing to correct the MYH7 c1208G>A (p.Arg403Gln) mutation in mouse models.69–71 These studies showed a wide range of transcript correction (from 26% to 68%) owing to study design and the specific cardiac cell types targeted.69–71

Although initial preclinical data underscore the potential of gene therapies, several challenges limit their use in humans. The delivery method and unintended off-target effects pose a challenge because the unintentional consequences of gene therapies can be hazardous.71 In addition, the body’s immune system may be triggered by the introduction of foreign genetic material.72 In a recent gene therapy trial for Duchenne muscular dystrophy, a patient experienced a severe immune response to the AAV9 vector that ultimately led to their death.72 The adverse event was attributed to the immune response elicited by the viral vector, not the gene-editing technology itself.72

Invasive Therapies

Septal reduction therapies are invasive strategies to relieve LVOT obstruction in patients with oHCM whose symptoms are refractory to medical therapy (Table 2). Current standard-of-care approaches include surgical myectomy and alcohol septal ablation (ASA).1 Robust evidence supports surgical myectomy and ASA as an effective means to reduce septal thickness and LVOT obstruction, thereby improving symptoms in patients with oHCM (Table 2).73,74–77 However, these approaches have notable limitations. Recent advances in minimally invasive techniques, such as radiofrequency ablation and septal scoring along the midline endocardium (SESAME), have expanded the therapeutic landscape.

Patient Selection for Invasive Therapies

The multisociety 2024 HCM guidelines recommend septal reduction therapies (SRT) for patients with resting or provoked LVOT gradient ≥50 mmHg with NYHA class III/IV symptoms despite optimal medical therapies.1 Age and comorbidities are also factored into assessment of surgical candidacy. Myectomy is often favoured in patients with concomitant cardiac conditions requiring invasive intervention, such as papillary muscle disease or valvular pathologies.1,78–80 Skilled surgeons can frequently address multiple pathologies in a single operation with minimally added perioperative risk and potentially lower rates of postoperative complications.81–83 In patients who are deemed not surgical candidates, ASA has traditionally been used to alleviate LVOT obstruction. Advances in targeting alternative coronary branches, including septal perforators not originating from the left anterior descending artery, have expanded its applicability.84 However, ASA is ineffective in patients who have unsuitable coronary artery anatomy, massive LV hypertrophy, severely elevated LVOT gradients and concomitant abnormal mitral valve or papillary muscle anatomy.85–87 Due to the frequency of complete heart block, ASA also has a significant postoperative complication of permanent pacing.76,88 In addition, although these approaches are established and extensively studied in oHCM, they are less well-established in other phenotypes of HCM, such as apical and mid-ventricular HCM.89 Limitations of ASA and the invasive nature of septal myectomy have promoted evaluation of newer invasive techniques that are more robust than ASA but avoid the burden of open-heart surgery.

Radiofrequency Ablation

Radiofrequency ablation (RFA) is a newer innovation in minimally invasive therapies. RFA creates a focal lesion that can achieve a similar reduction in LVOT gradient as ablating a larger amount of myocardium (Table 2).90–92 RFA allows for greater precision compared with alcohol ablation, with decreased risks of conduction system injury and inadequate debulking, as well as better targeting of anatomy that is not confined by the coronary artery anatomy.90–92 Studies on RFA have varied in their approach and use of imaging modalities to ensure precision of the ablation target.93–99

Endocardial RFA of septal hypertrophy (ERASH) is one of the earlier RFA therapies, and involves applying high-frequency currents directly to endocardial tissue of the septum to cause localised tissue necrosis.97,100 Although ERASH did not achieve as large a reduction in septal thickness and LVOT gradient as surgical myectomy, it had a similar effect on symptom improvement.100,101 Percutaneous intramyocardial septal RFA (PIMSRA) is a more recent RFA approach that uses an echocardiography-guided electrode needle inserted transapically into the septal myocardial tissue to deliver high-frequency currents for targeted tissue ablation.94,97 Similar to ERASH, initial studies for PIMSRA have demonstrated success in its ability to reduce septal hypertrophy, decrease LVOT gradient and improve clinical symptoms in the majority of patients.93,96,97,101

The rate of intraoperative and 30-day mortality of RFA across several studies is approximately 1–2%, comparable to overall mortality rates of ASA and surgical myectomy.70–73,75–77,85 Method-specific complications include a paradoxical increase in LVOT gradient due to localised tissue oedema, occurring in up to 9% of patients based on one study of ERASH.100 Pericardial effusion is the most common complication of PIMSRA, likely due to injury of a coronary vein from the transapical approach.93 For both RFA methods, the development of postoperative arrhythmias and the need for pacemaker implantation are less frequent than after ASA, because RFA allows for greater precision when targeting areas of therapeutic effect.92,99 However, based on early studies, compared with myectomy, RFA carries an increased risk of high-grade atrioventricular block requiring pacemaker implantation.91,100 There is insufficient data to compare ventricular and/or atrial tachyarrhythmia rates between RFA and other septal reduction therapies.

Despite the theoretical advantages of RFA due to its targeted approach, its efficacy and safety are not as well studied as surgical myectomy or ASA, and RFA studies generally have smaller cohorts and a shorter follow-up duration.93,95–97,99,100 Data on specific haemodynamic or anatomical traits that predict the success of RFA compared with ASA or surgical myectomy remain limited, complicating the decision-making process among available septal reduction therapies. This knowledge gap underscores the need for further research to compare the efficacy and safety profiles of RFA to standard therapies and to identify patient-specific factors that optimise outcomes.

Septal Scoring Along the Midline Endocardium

SESAME is a recent development in transcatheter therapies.102 SESAME involves using a catheter guided by echocardiography and fluoroscopy to electrosurgically lacerate the myocardium to achieve septal myotomy (Table 2).102 SESAME addresses several shortcomings of ASA and RFA, with decreased risks of geographic miss, inadequate debulking and injury to the conduction system.103,104

Table 2: Invasive Therapies for the Management of Hypertrophic Cardiomyopathy With Obstructive Physiology and Studied Outcomes

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The few available studies on SESAME have demonstrated successful reduction of septal thickness, enlargement of the LVOT area and symptom improvement in the majority of patients.102,103 The decline in residual LVOT gradients occurred progressively as septal myotomy continued to widen for at least 1 month postoperatively.103 Although initial results are promising, further research is needed to examine the degree of progressive septal splay over a longer follow-up period, as well as the impact of ablation depth on long-term outcomes.

Complication rates of SESAME are high relative to other septal reduction therapies, which is expected considering the early and evolving experience with this technique. In the largest study on SESAME to date, 30% of 76 patients experienced a major complication, such as significant bleeding, iatrogenic myocardial perforation or the need for a permanent pacemaker.103 The intraoperative mortality rate was 2.6%, which is higher than mortality rates of ASA and myectomy at high-volume centres, but comparable to those at lower-volume centres.78,103–105 SESAME’s high complication rates likely reflect its early stages of development in addition to the technical challenges of the technique. Adequate training of proceduralists will likely be a barrier to its widespread adoption.

Ongoing Developments in Septal Reduction Therapies and Future Directions

One technique in early development is high-intensity focused ultrasound, which is a growing area of interest for oHCM therapeutics that uses ultrasound energy for localised tissue ablation with the potential to generate deeper and larger areas of ablation compared with other minimally invasive septal reduction therapies.106–108 One study on live canines provides proof of concept, but no in-human trials have been published yet.106 Another technique being studied is localised ionising radiation for septal ablation.109 The first-in-human study showed promising outcomes without any serious adverse events reported.109 However, larger trials, such as the NIRA-HOCM (NCT0415316), are needed to establish the efficacy and safety of this technique.

Although the landscape of septal reduction therapies has evolved dramatically in the past few decades, surgical myectomy still offers superior outcomes, especially in patients with greater baseline LVOT gradients, and lower complication rates compared with its less invasive alternatives.75–77,110 However, as minimally invasive techniques continue to be refined to improve target precision and ensure adequate debulking, they could potentially expand access to septal reduction therapies to patients who are not surgical candidates, in addition to offering patients less invasive options.

In the era of CMIs, it is necessary to consider their potential impact on the field of septal reduction therapies. Septal reduction therapies are typically reserved for severely symptomatic patients and do not directly address the underlying pathophysiology of the disease. Moreover, CMIs may offer increased access for patients who are not surgical candidates or do not want invasive therapies, and CMI outcomes are not operator dependent. Given the potential impact of CMIs on this field, further exploration into non-invasive strategies is essential to advance the boundaries of septal reduction therapies.

Conclusion

The past decade has seen substantial advances in HCM therapies with the rise of CMIs and minimally invasive therapies. Although traditional pharmacological treatments remain the first-line therapy for symptomatic patients, this is likely to change as more robust evidence on CMIs accumulates. Emerging options, including sarcomere modulators and non-invasive reduction therapies, aim to address the limitations of existing treatments. Future efforts should focus on areas of unmet need, including treating special populations, expanding access, developing clinical tools to facilitate decision-making and studying the impact of available therapies on the risk of arrhythmia and sudden cardiac death.

References

  1. Ommen SR, Ho CY, Asif IM, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guideline for the management of hypertrophic cardiomyopathy: a report of the American Heart Association/American College of Cardiology joint committee on clinical practice guidelines. J Am Coll Cardiol 2024;83:2324–2405. 
    Crossref | PubMed
  2. Harper AR, Goel A, Grace C, et al. Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. Nat Genet 2021;53:135–42. 
    Crossref | PubMed
  3. Marian AJ, Braunwald E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res 2017;121:749–70. 
    Crossref | PubMed
  4. Anderson RL, Trivedi DV, Sarkar SS, et al. Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers. Proc Natl Acad Sci U S A 2018;115:E8143–52. 
    Crossref | PubMed
  5. Lehman SJ, Crocini C, Leinwand LA. Targeting the sarcomere in inherited cardiomyopathies. Nat Rev Cardiol 2022;19:353–63. 
    Crossref | PubMed
  6. Desai MY, Hajj-Ali A, Rutkowski K, et al. Real-world experience with mavacamten in obstructive hypertrophic cardiomyopathy: observations from a tertiary care center. Prog Cardiovasc Dis 2024;86:62–8. 
    Crossref | PubMed
  7. Kim DS, Chu EL, Keamy-Minor EE, et al. One-year real-world experience with mavacamten and its physiologic effects on obstructive hypertrophic cardiomyopathy. Front Cardiovasc Med 2024;11:1429230. 
    Crossref | PubMed
  8. Baker JG, Kemp P, March J, et al. Predicting in vivo cardiovascular properties of β-blockers from cellular assays: a quantitative comparison of cellular and cardiovascular pharmacological responses. FASEB J 2011;25:4486–97. 
    Crossref | PubMed
  9. Shah K, Seeley S, Schulz C, et al. Calcium channels in the heart: disease states and drugs. Cells 2022;11:943. 
    Crossref | PubMed
  10. Toshima H, Koga Y, Nagata H, et al. Comparable effects of oral diltiazem and verapamil in the treatment of hypertrophic cardiomyopathy. Double-blind crossover study. Jpn Heart J 1986;27:701–15. 
    Crossref | PubMed
  11. Taha M, Dahat P, Toriola S, et al. Metoprolol or verapamil in the management of patients with hypertrophic cardiomyopathy: a systematic review. Cureus 2023;15:e43197. 
    Crossref | PubMed
  12. Rosing DR, Kent KM, Maron BJ, Epstein SE. Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy. Circulation 1979;60:1208–13. 
    Crossref | PubMed
  13. Frank MJ, Abdulla AM, Watkins LO, et al. Long-term medical management of hypertrophic cardiomyopathy: usefulness of propranolol. Eur Heart J 1983;4(Suppl F):155–64. 
    Crossref | PubMed
  14. Dybro AM, Rasmussen TB, Nielsen RR, et al. Randomized trial of metoprolol in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2021;78:2505–17. 
    Crossref | PubMed
  15. Dybro AM, Rasmussen TB, Nielsen RR, et al. Metoprolol improves left ventricular longitudinal strain at rest and during exercise in obstructive hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2023;36:196–204. 
    Crossref | PubMed
  16. Dybro AM, Rasmussen TB, Nielsen RR, et al. Effects of metoprolol on exercise hemodynamics in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2022;79:1565–75. 
    Crossref | PubMed
  17. Bonow RO, Rosing DR, Bacharach SL, et al. Effects of verapamil on left ventricular systolic function and diastolic filling in patients with hypertrophic cardiomyopathy. Circulation 1981;64:787–96. 
    Crossref | PubMed
  18. Pinto G, Chiarito M, Puscas T, et al. Comparative influences of beta blockers and verapamil on cardiac outcomes in hypertrophic cardiomyopathy. Am J Cardiol 2025;235:9–15. 
    Crossref | PubMed
  19. Gilligan DM, Chan WL, Joshi J, et al. A double-blind, placebo-controlled crossover trial of nadolol and verapamil in mild and moderately symptomatic hypertrophic cardiomyopathy. J Am Coll Cardiol 1993;21:1672–9. 
    Crossref | PubMed
  20. Coppini R, Ferrantini C, Pioner JM, et al. Electrophysiological and contractile effects of disopyramide in patients with obstructive hypertrophic cardiomyopathy: a translational study. JACC Basic Transl Sci 2019;4:795–813. 
    Crossref | PubMed
  21. Sherrid MV, Barac I, McKenna WJ, et al. Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005;45:1251–8. 
    Crossref | PubMed
  22. Adler A, Fourey D, Weissler-Snir A, et al. Safety of outpatient initiation of disopyramide for obstructive hypertrophic cardiomyopathy patients. J Am Heart Assoc 2017;6:e005152. 
    Crossref | PubMed
  23. Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2020;396:759–69. 
    Crossref | PubMed
  24. Cremer PC, Geske JB, Owens A, et al. Myosin inhibition and left ventricular diastolic function in patients with obstructive hypertrophic cardiomyopathy referred for septal reduction therapy: insights from the VALOR-HCM study. Circ Cardiovasc Imaging 2022;15:e014986. 
    Crossref | PubMed
  25. Rader F, Oręziak A, Choudhury L, et al. Mavacamten treatment for symptomatic obstructive hypertrophic cardiomyopathy: interim results from the MAVA-LTE study, EXPLORER-LTE cohort. JACC Heart Fail 2024;12:164–77. 
    Crossref | PubMed
  26. Desai MY, Wolski K, Owens A, et al. Mavacamten in patients with hypertrophic cardiomyopathy referred for septal reduction: week 128 results from VALOR-HCM. Circulation 2025;151:1378–90. 
    Crossref | PubMed
  27. Maron MS, Masri A, Nassif ME, et al. Aficamten for symptomatic obstructive hypertrophic cardiomyopathy. N Engl J Med 2024;390:1849–61. 
    Crossref | PubMed
  28. Grillo MP, Erve JCL, Dick R, et al. In vitro and in vivo pharmacokinetic characterization of mavacamten, a first-in-class small molecule allosteric modulator of beta cardiac myosin. Xenobiotica 2019;49:718–33. 
    Crossref | PubMed
  29. Bristol-Myers Squibb. Camzyos™ (mavacamten) capsules. 2024. https://www.camzyoshcp.com (accessed 15 January 2025).
  30. Bristol-Myers Squibb. CAMZYOS® (mavacamten) capsules for oral use. [Pamphlet] 2025. http://packageinserts.bms.com/pi/pi_camzyos.pdf (accessed 15 January 2025).
  31. Masri A, Lester SJ, Stendahl JC, et al. Long-term safety and efficacy of mavacamten in symptomatic obstructive hypertrophic cardiomyopathy: interim results of the Pioneer-OLE study. J Am Heart Assoc 2024;13:e030607. 
    Crossref | PubMed
  32. Desai MY, Okushi Y, Wolski K, et al. Mavacamten-associated temporal changes in left atrial function in obstructive HCM: insights from the VALOR-HCM trial. JACC Cardiovasc Imaging 2025;18:251–62. 
    Crossref | PubMed
  33. Desai MY, Okushi Y, Gaballa A, et al. Serial changes in ventricular strain in symptomatic obstructive hypertrophic cardiomyopathy treated with mavacamten: insights from the VALOR-HCM trial. Circ Cardiovasc Imaging 2024;17:e017185. 
    Crossref | PubMed
  34. Saberi S, Cardim N, Yamani M, et al. Mavacamten favorably impacts cardiac structure in obstructive hypertrophic cardiomyopathy: EXPLORER-HCM cardiac magnetic resonance substudy analysis. Circulation 2021;143:606–8. 
    Crossref | PubMed
  35. Masri A, Cardoso RN, Abraham TP, et al. Effect of aficamten on cardiac structure and function in obstructive hypertrophic cardiomyopathy: SEQUOIA-HCM CMR substudy. J Am Coll Cardiol 2024;84:1806–17. 
    Crossref | PubMed
  36. Heitner SB, Jacoby D, Lester SJ, et al. Mavacamten treatment for obstructive hypertrophic cardiomyopathy: a clinical trial. Ann Intern Med 2019;170:741–8. 
    Crossref | PubMed
  37. Desai MY, Owens A, Geske JB, et al. Myosin inhibition in patients with obstructive hypertrophic cardiomyopathy referred for septal reduction therapy. J Am Coll Cardiol 2022;80:95–108. 
    Crossref | PubMed
  38. Desai MY, Owens A, Wolski K, et al. Mavacamten in patients with hypertrophic cardiomyopathy referred for septal reduction: week 56 results from the VALOR-HCM randomized clinical trial. JAMA Cardiol 2023;8:968–77. 
    Crossref | PubMed
  39. Garcia-Pavia P, Oręziak A, Masri A, et al. Long-term effect of mavacamten in obstructive hypertrophic cardiomyopathy. Eur Heart J 2024;45:5071–83. 
    Crossref | PubMed
  40. McGurk KA, Bilgehan N, Ware JS. Pharmacogenetic influences over mavacamten pharmacokinetics: considerations for the treatment of individuals with hypertrophic cardiomyopathy. Circulation 2024;149:1786–8. 
    Crossref | PubMed
  41. Bende G, Zheng N, Wang YH, et al. Center for Drug Evaluation and Research. Application number: 214998Orig1s000. Clinical pharmacology review: mavacamten. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/214998Orig1s000ClinPharmR.pdf (accessed 17 February 2025).
  42. Desai MY, Seto D, Cheung M, et al. Mavacamten: real-world experience from 22 months of the risk evaluation and mitigation strategy (REMS) program. Circ Heart Fail 2025;18:e012441. 
    Crossref | PubMed
  43. Rowin EJ, Link MS, Maron MS, Maron BJ. Evolving contemporary management of atrial fibrillation in hypertrophic cardiomyopathy. Circulation 2023;148:1797–811. 
    Crossref | PubMed
  44. Masri A, Lakdawala NK. Stop dreaming: mavacamten REMS data are here. Circ Heart Fail 2025;18:e012545. 
    Crossref | PubMed
  45. Chuang C, Collibee S, Ashcraft L, et al. Discovery of aficamten (CK-274), a next-generation cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathy. J Med Chem 2021;64:14142–52. 
    Crossref | PubMed
  46. Maron MS, Masri A, Nassif ME, et al. Impact of aficamten on disease and symptom burden in obstructive hypertrophic cardiomyopathy: results from SEQUOIA-HCM. J Am Coll Cardiol 2024;84:1821–31. 
    Crossref | PubMed
  47. Masri A, Barriales-Villa R, Elliott P, et al. Safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy: a 36-week analysis from FOREST-HCM. Eur J Heart Fail 2024;26:1993–8. 
    Crossref | PubMed
  48. Ho CY, Mealiffe ME, Bach RG, et al. Evaluation of mavacamten in symptomatic patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2020;75:2649–60. 
    Crossref | PubMed
  49. European Medicines Agency. Annex I: summary of product characteristics. [Camyzos pamphlet] 2023. https://www.ema.europa.eu/en/documents/product-information/camzyos-epar-product-information_en.pdf (accessed 17 February 2025).
  50. Reuters. FDA approves Bristol Myers’ oral heart disease drug. 2022. https://www.reuters.com/business/healthcare-pharmaceuticals/fda-approves-bristol-myers-heart-disease-drug-2022-04-29/ (accessed 18 December 2024).
  51. Del Rio CL, Rupert C, Tolley J, et al. Abstract 15612: EDG-7500, a novel cardiac sarcomere regulator that preserves intrinsic myosin-motor function, improves cardiac function and reserve in a minipig model of hypertrophic cardiomyopathy. Circulation 2023;148(Suppl 1):A15612. 
    Crossref
  52. Emter C, Lehman S, Lee L, et al. Abstract 4142919: chronic administration of EDG-7500, a novel sarcomere modulator, prevents increases in cardiac mass, T1 relaxation time, and left ventricular end diastolic pressure in a Yucatán mini-pig model of genetic non-obstructive hypertrophic cardiomyopathy. Circulation 2024;150(Suppl 1):A4142919. 
    Crossref
  53. Kaplan JL, Lehman S, Duvall M, et al. EDG-7500 (EDG-002), A first-in-class targeted sarcomere regulator that preserves intrinsic myosin-motor function, normalizes systolic function and eliminates LVOT obstruction in cats with hypertrophic cardiomyopathy. Presented at: American College of Cardiology (ACC) 72nd Annual Scientific Sessions, New Orleans, Louisiana, 4–6 March 2023. Poster 1066-13.
  54. Evanchik M, Emter C, Del Rio C, et al. Abstract We094: acute administration of the novel cardiac sarcomere modulator EDG-7500, improves ventricular filling while preserving LVEF in dogs with pacing induced left-ventricular systolic dysfunction. Circ Res 2024;135(Suppl 1):AWe094. 
    Crossref
  55. Dufton C, Evanchik M, Daniel DD, et al. EDG-7500, a first-in-class cardiac sarcomere modulator, demonstrates favorable tolerability, safety, and pharmacokinetics in healthy adults. J Card Fail 2025;31:345. 
    Crossref
  56. Koch K, Evanchik M, Owens A, Semigran M. EGD-7500: phase 1 & phase 2 CIRRUS-HCM development program update. 2024. https://s204.q4cdn.com/663829792/files/doc_presentations/2024/09/EDG-7500-HV-and-CIRRUS-Part-A-Disclosure_vFinal.pdf (accessed 17 February 2025).
  57. Dufton C, Evanchik M, Emery L, et al. CIRRUS-HCM: an open-label study to evaluate the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of EDG-7500 in adults with hypertrophic cardiomyopathy. Presented at: HFSA Annual Scientific Meeting, Atlanta, Georgia, 27–30 September 2024.
  58. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2021;384:129–39. 
    Crossref | PubMed
  59. Zhao M, Li N, Zhou H. SGLT1: a potential drug target for cardiovascular disease. Drug Des Devel Ther 2023;17:2011–23. 
    Crossref | PubMed
  60. Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci 2020;5:632–44. 
    Crossref | PubMed
  61. Sacchetto C, Sequeira V, Bertero E, et al. Metabolic alterations in inherited cardiomyopathies. J Clin Med 2019;8:2195. 
    Crossref | PubMed
  62. Li Y, Xu G. Sodium glucose cotransporter 1 (SGLT1) inhibitors in cardiovascular protection: mechanism progresses and challenges. Pharmacol Res 2022;176:106049. 
    Crossref | PubMed
  63. Sherratt SC, Weindorf AV, Libby P, et al. Abstract 16947: sotagliflozin, a dual SGLT 1 and 2 inhibitor, has high membrane affinity and hydrocarbon core location compared with empagliflozin. Circulation 2023;148(Suppl 1):A16947. 
    Crossref
  64. Lin H, Guan L, Meng L, et al. SGLT1 knockdown attenuates cardiac fibroblast activation in diabetic cardiac fibrosis. Front Pharmacol 2021;12:700366. 
    Crossref | PubMed
  65. Greer-Short A, Greenwood A, Leon EC, et al. AAV9-mediated MYBPC3 gene therapy with optimized expression cassette enhances cardiac function and survival in MYBPC3 cardiomyopathy models. Nat Commun 2025;16:2196. 
    Crossref | PubMed
  66. Baka T, Moore J, Qin F, et al. Abstract 15515: SGLT2 inhibitor empagliflozin increases fatty acid oxidation, coupling between glycolysis and glucose oxidation, and decreases left ventricular hypertrophy in mice with hypertrophic cardiomyopathy due to myosin R403Q mutation. Circulation 2023;148(Suppl 1):A15515. 
    Crossref
  67. Tenaya Therapeutics, Inc. Tenaya therapeutics reports promising early data from MyPEAK™-1 Phase 1b/2 clinical trial of TN-201 for treatment of MYBPC3-associated hypertrophic cardiomyopathy. 2024. https://investors.tenayatherapeutics.com/news-releases/news-release-details/tenaya-therapeutics-reports-promising-early-data-mypeaktm-1/ (accessed 18 February 2025).
  68. Reichart D, Newby GA, Wakimoto H, et al. Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice. Nat Med 2023;29:412–21. 
    Crossref | PubMed
  69. Nie J, Han Y, Jin Z, et al. Homology-directed repair of an MYBPC3 gene mutation in a rat model of hypertrophic cardiomyopathy. Gene Ther 2023;30:520–7. 
    Crossref | PubMed
  70. Chai AC, Cui M, Chemello F, et al. Base editing correction of hypertrophic cardiomyopathy in human cardiomyocytes and humanized mice. Nat Med 2023;29:401–11. 
    Crossref | PubMed
  71. Strong A. CRISPR gene editing therapies for hypertrophic cardiomyopathy. Nat Med 2023;29:305–6. 
    Crossref | PubMed
  72. Lek A, Wong B, Keeler A, et al. Death after high-dose rAAV9 gene therapy in a patient with Duchenne’s muscular dystrophy. N Engl J Med 2023;389:1203–10. 
    Crossref | PubMed
  73. Maurizi N, Antiochos P, Owens A, et al. Long-term outcomes after septal reduction therapies in obstructive hypertrophic cardiomyopathy: insights from the SHARE Registry. Circulation 2024;150:1377–90. 
    Crossref | PubMed
  74. Maron MS, Rastegar H, Dolan N, et al. Outcomes over follow-up ≥10 years after surgical myectomy for symptomatic obstructive hypertrophic cardiomyopathy. Am J Cardiol 2022;163:91–7. 
    Crossref | PubMed
  75. Osman M, Kheiri B, Osman K, et al. Alcohol septal ablation vs myectomy for symptomatic hypertrophic obstructive cardiomyopathy: systematic review and meta-analysis. Clin Cardiol 2019;42:190–7. 
    Crossref | PubMed
  76. Singh K, Qutub M, Carson K, et al. A meta analysis of current status of alcohol septal ablation and surgical myectomy for obstructive hypertrophic cardiomyopathy. Catheter Cardiovasc Interv 2016;88:107–15. 
    Crossref | PubMed
  77. Sorajja P, Valeti U, Nishimura RA, et al. Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation 2008;118:131–9. 
    Crossref | PubMed
  78. Veselka J, Jensen MK, Liebregts M, et al. Long-term clinical outcome after alcohol septal ablation for obstructive hypertrophic cardiomyopathy: results from the Euro-ASA registry. Eur Heart J 2016;37:1517–23. 
    Crossref | PubMed
  79. Minakata K, Dearani JA, Nishimura RA, et al. Extended septal myectomy for hypertrophic obstructive cardiomyopathy with anomalous mitral papillary muscles or chordae. J Thorac Cardiovasc Surg 2004;127:481–9. 
    Crossref | PubMed
  80. Hong JH, Schaff HV, Nishimura RA, et al. Mitral regurgitation in patients with hypertrophic obstructive cardiomyopathy: implications for concomitant valve procedures. J Am Coll Cardiol 2016;68:1497–504. 
    Crossref | PubMed
  81. Teo EP, Teoh JG, Hung J. Mitral valve and papillary muscle abnormalities in hypertrophic obstructive cardiomyopathy. Curr Opin Cardiol 2015;30:475–82. 
    Crossref | PubMed
  82. Di Tommaso L, Stassano P, Mannacio V, et al. Asymmetric septal hypertrophy in patients with severe aortic stenosis: the usefulness of associated septal myectomy. J Thorac Cardiovasc Surg 2013;145:171–5. 
    Crossref | PubMed
  83. Kayalar N, Schaff HV, Daly RC, et al. Concomitant septal myectomy at the time of aortic valve replacement for severe aortic stenosis. Ann Thorac Surg 2010;89:459–64. 
    Crossref | PubMed
  84. Imori Y, Takano H, Kitamura M, et al. Percutaneous transluminal septal myocardial ablation for hypertrophic obstructive cardiomyopathy through non-left anterior descending septal perforators. Heart Vessels 2020;35:647–54. 
    Crossref | PubMed
  85. Liebregts M, Vriesendorp PA, Mahmoodi BK, et al. A systematic review and meta-analysis of long-term outcomes after septal reduction therapy in patients with hypertrophic cardiomyopathy. JACC Heart Fail 2015;3:896–905. 
    Crossref | PubMed
  86. Sorajja P, Binder J, Nishimura RA, et al. Predictors of an optimal clinical outcome with alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Catheter Cardiovasc Interv 2013;81:E58–67. 
    Crossref | PubMed
  87. Gragnano F, Pelliccia F, Guarnaccia N, et al. Alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy: a contemporary perspective. J Clin Med 2023;12:2810. 
    Crossref | PubMed
  88. Agarwal S, Tuzcu EM, Desai MY, et al. Updated meta-analysis of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy. J Am Coll Cardiol 2010;55:823–34. 
    Crossref | PubMed
  89. Hughes RK, Knott KD, Malcolmson J, et al. Apical hypertrophic cardiomyopathy: the variant less known. J Am Heart Assoc 2020;9:e015294. 
    Crossref | PubMed
  90. Canzi CC, do Prado Júnior ER, da Silva Menezes Júnior A, et al. Radiofrequency ablation in patients with obstructive hypertrophic cardiomyopathy: a systematic review and meta-analysis. Am Heart J Plus 2022;24:100229. 
    Crossref | PubMed
  91. Yang H, Yang Y, Xue Y, Luo S. Efficacy and safety of radiofrequency ablation for hypertrophic obstructive cardiomyopathy: a systematic review and meta-analysis. Clin Cardiol 2020;43:450–8. 
    Crossref | PubMed
  92. Crossen K, Jones M, Erikson C. Radiofrequency septal reduction in symptomatic hypertrophic obstructive cardiomyopathy. Heart Rhythm 2016;13:1885–90. 
    Crossref | PubMed
  93. Zhou M, Ta S, Hahn RT, et al. Percutaneous intramyocardial septal radiofrequency ablation in patients with drug-refractory hypertrophic obstructive cardiomyopathy. JAMA Cardiol 2022;7:529–38. 
    Crossref | PubMed
  94. Xie X, Chen S, Cui Y, et al. Midterm outcomes of percutaneous intramyocardial septal radiofrequency ablation for hypertrophic cardiomyopathy: a single-center, observational study. J Am Heart Assoc 2024;13:e034080. 
    Crossref | PubMed
  95. Liu Q, Qiu H, Jiang R, et al. Selective interventricular septal radiofrequency ablation in patients with hypertrophic obstructive cardiomyopathy: who can benefit? Front Cardiovasc Med 2021;8:743044. 
    Crossref | PubMed
  96. Liu L, Li J, Zuo L, et al. Percutaneous intramyocardial septal radiofrequency ablation for hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 2018;72:1898–909. 
    Crossref | PubMed
  97. Lawrenz T, Borchert B, Leuner C, et al. Endocardial radiofrequency ablation for hypertrophic obstructive cardiomyopathy: acute results and 6 months’ follow-up in 19 patients. J Am Coll Cardiol 2011;57:572–6. 
    Crossref | PubMed
  98. Kong L, Zhao Y, Pan H, et al. A modified endocardial radiofrequency ablation approach for hypertrophic obstructive cardiomyopathy guided by transthoracic echocardiography: a case series. Ann Transl Med 2021;9:1006. 
    Crossref | PubMed
  99. Cooper RM, Shahzad A, Hasleton J, et al. Radiofrequency ablation of the interventricular septum to treat outflow tract gradients in hypertrophic obstructive cardiomyopathy: a novel use of CARTOSound® technology to guide ablation. Europace 2016;18:113–20. 
    Crossref | PubMed
  100. Lawrenz T, Lawin D, Radke K, Stellbrink C. Acute and chronic effects of endocardial radiofrequency ablation of septal hypertrophy in HOCM. J Cardiovasc Electrophysiol 2021;32:2617–24. 
    Crossref | PubMed
  101. Jiang T, Huang B, Huo S, et al. Endocardial radiofrequency ablation vs. septal myectomy in patients with hypertrophic obstructive cardiomyopathy: a systematic review and meta-analysis. Front Surg 2022;9:859205. 
    Crossref | PubMed
  102. Greenbaum AB, Khan JM, Bruce CG, et al. Transcatheter myotomy to treat hypertrophic cardiomyopathy and enable transcatheter mitral valve replacement; first-in-human report of SESAME (SEptal Scoring Along the Midline Endocardium). Circ Cardiovasc Interv 2022;15:e012106. 
    Crossref | PubMed
  103. Greenbaum AB, Ueyama HA, Gleason PT, et al. Transcatheter myotomy to reduce left ventricular outflow obstruction. J Am Coll Cardiol 2024;83:1257–72. 
    Crossref | PubMed
  104. Khan JM, Bruce CG, Greenbaum AB, et al. Transcatheter myotomy to relieve left ventricular outflow tract obstruction: the septal scoring along the midline endocardium procedure in animals. Circ Cardiovasc Interv 2022;15:e011686. 
    Crossref | PubMed
  105. Kim LK, Swaminathan RV, Looser P, et al. Hospital volume outcomes after septal myectomy and alcohol septal ablation for treatment of obstructive hypertrophic cardiomyopathy: US nationwide inpatient database, 2003–2011. JAMA Cardiol 2016;1:324–32. 
    Crossref | PubMed
  106. Rong S, Woo K, Zhou Q, et al. Septal ablation induced by transthoracic high-intensity focused ultrasound in canines. J Am Soc Echocardiogr 2013;26:1228–34. 
    Crossref | PubMed
  107. Takei Y, Muratore R, Kalisz A, et al. In vitro atrial septal ablation using high-intensity focused ultrasound. J Am Soc Echocardiogr 2012;25:467–72. 
    Crossref | PubMed
  108. Engel DJ, Muratore R, Hirata K, et al. Myocardial lesion formation using high-intensity focused ultrasound. J Am Soc Echocardiogr 2006;19:932–7. 
    Crossref | PubMed
  109. Li X, Zhu Z, Liu J, et al. Septal radioablation therapy for patients with hypertrophic obstructive cardiomyopathy: first-in-human study. Eur Heart J Open 2023;3:oead052. 
    Crossref | PubMed
  110. Nguyen A, Schaff HV, Hang D, et al. Surgical myectomy versus alcohol septal ablation for obstructive hypertrophic cardiomyopathy: a propensity score-matched cohort. J Thorac Cardiovasc Surg 2019;157:306–315.e3. 
    Crossref | PubMed
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