Previous studies have reported an inverse relationship between hospital septal myectomy (SM) volume and outcomes, without assessments of surgeon volume and SM outcomes. This Australia and New Zealand-based study sought to appraise the relationships between hospital volume, surgeon volume, and SM outcomes.

Data were collected from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons Database, from the time of inception of the Australian and New Zealand Society of Cardiac and Thoracic Surgeons Database (2001) until 1 January 2021. Hospitals were divided into the lowest (one to three cases), middle (four to six cases), and highest tertiles (more than six cases) based on their annual SM case volume.

This study cohort included 1,132 patients and 115 surgeons. The surgeon volume ranged from one to 91 cases in total. The overall 30-day mortality after SM was 2.2%, and the rate of new-onset complete heart block requiring permanent pacemaker was 7.5%. Concomitant mitral valve repair and mitral valve replacement were performed in 8.1% and 11.7% of patients, respectively. Concomitant mitral valve replacement was associated with increased mortality. Septal myectomy performed at low-volume centres had a significantly higher mortality rate (4.9%) than at the middle- (1.3%, p=0.002) and the high-volume centres (1.1%, p=0.004). Surgeons who performed SM on patients who subsequently died within 30 days of SM had a significantly lower case volume than surgeons who performed SM on patients who were alive.

This study highlights the importance of centre and surgeon case volume in outcomes after SM.

Real-world data on the effects of mavacamten on diastology and global longitudinal strain (GLS) in symptomatic patients with obstructive hypertrophic cardiomyopathy (oHCM) are limited. We share our experience with mavacamten over a 24-week period at an HCM Center of Excellence. Sixty-one adults with symptomatic oHCM who started on mavacamten between March 2023 and February 2024 were retrospectively identified. All patients had an electrocardiogram performed at each clinic visit, and 72-hour Holter monitoring was performed at 12- and 24-week visits. The mean age was 57.2 ± 14.5 years; 32 (51.6%) patients were female. Of the 61 patients, 45 completed a 24-week period and were the main subject of this study. After 6 months of treatment, the proportion of patients in Grade 1 diastolic dysfunction increased from 26.6% to 62.2%, p = 0.001, and the proportion in Grade 2 diastolic dysfunction decreased from 66.6% to 35.5%, p = 0.006; 26.7% (n = 12/45) of patients improved by 2 New York Heart Association functional classes and 46.7% (n = 21/45) by 1. GLS remained stable over time. At week 24, 35 of 45 patients (77.7%) had a left ventricular outflow tract gradient ≤30 mmHg. No arrhythmia burden or major side effects were reported. Left ventricular ejection fraction remained above 55% in all but 1 patient, who recovered within a month. In conclusion, our experience of significantly improved diastology and stable GLS after mavacamten treatment aligns with trial outcomes. Longitudinal investigations are needed to further assess the long-term impacts.

Hypertrophic cardiomyopathy remains underdiagnosed despite a growing number of effective treatment interventions that can improve care. Multimodality imaging has become integral to diagnosing and managing hypertrophic cardiomyopathy, providing a comprehensive assessment of the disease. In particular, it enhances the diagnostic accuracy and deepens the understanding of the mechanisms underlying patient symptoms, enabling targeted therapeutic approaches. Additionally, multimodality imaging allows for better risk stratification, assessment of therapy response, and guidance of interventions to deliver personalized medicine. The practical tools outlined in this review can help providers integrate multimodality imaging strategies to provide better care and improve the patient experience.

In hypertrophic cardiomyopathy (HCM), the determinants of exercise tolerance and the usefulness of exercise stress echocardiography (ESE) for predicting hard endpoints have not been fully investigated. We aimed to assess the key parameters of ESE for exercise tolerance and the factors predictive of cardiovascular events and new-onset atrial fibrillation (AF) in patients with HCM.

Seventy-four consecutive patients with HCM who underwent ESE and with an ejection fraction ≥50 % were enrolled. The primary endpoint was a composite of cardiovascular death, heart failure hospitalization, ventricular fibrillation or tachycardia, and ventricular assist device implantation. The secondary endpoint was new-onset AF.

The primary endpoint occurred in 13 patients. The left and right ventricular functions during exercise were responsible for decreased exercise tolerance. Peak exercise e' and tricuspid annular plane systolic excursion (TAPSE) significantly predicted increased primary outcome risk (hazard ratio 1.35, 95 % confidence interval 1.10-1.76, p = 0.003; hazard ratio 1.19, 95 % confidence interval 1.07-1.32, p = 0.002, respectively), and the results were consistent even after adjustment by maximum workload. These ESE parameters improved the prognostic model containing estimated glomerular filtration rate (eGFR) and left atrial (LA) volume index. In AF-naive patients (n = 58), LA volume, peak exercise LA reservoir strain, and left ventricular outflow tract (LVOT) pressure gradient predicted new-onset AF.

In patients with HCM, ESE parameters related to left and right ventricular function were responsible for low exercise tolerance. Furthermore, e' and TAPSE at peak workload could be useful for predicting cardiovascular events in addition to eGFR and LA volume index. LVOT pressure gradient and LA function during exercise predicted new-onset AF.

Hypertrophic cardiomyopathy (HCM) is a complex genetic disorder that has garnered significant attention because of its diverse manifestations, including arrhythmias and heightened risk of sudden cardiac death. Advances in precision diagnostics, such as genetic testing and cardiac imaging with late gadolinium enhancement, have refined HCM diagnosis, enabling targeted therapeutic and risk stratification approaches. AF, prevalent in HCM, exacerbates symptoms and stroke risk, while ventricular arrhythmias pose a direct threat to survival. Catheter ablation offers symptom relief in AF patients with HCM, yet recurrence remains high because of unique myocardial changes, highlighting the need for refined patient selection and long-term monitoring. The risk of sudden cardiac death in HCM, particularly in younger individuals, underscores the importance of precise risk stratification tools such as the European Society of Cardiology HCM Risk-SCD model. The expanding role of ICDs and emerging pharmacological agents, including myosin inhibitors, marks a shift toward more individualised management of HCM. This review integrates recent developments in arrhythmia management, targeted therapies and risk assessment, offering a comprehensive perspective on HCM tailored to improve clinical outcomes through a precision-medicine lens.

Hypertrophic cardiomyopathy (HCM) is associated with a significant risk of progression to heart failure (HF). Extensive experimental and clinical research has highlighted the therapeutic benefits of ranolazine in alleviating electrophysiological abnormalities and arrhythmias in the context of HCM and HF. Despite these findings, there is a shortage of studies examining the electromechanical responses of failing HCM cardiomyocytes to ranolazine and the impact of ranolazine dosage on outcomes across varying degrees of HF. This study aims to systematically address these issues.

A computational modeling approach was utilized to quantify alterations in electromechanical variables within failing HCM cardiomyocytes subsequent to ranolazine treatment. The model parameters were calibrated against extant literature data to delineate the spectrum of HF severities and the changes in ion channels following the administration of various doses of ranolazine.

The inhibition of the augmented late Na+ current in failing HCM cardiomyocyte with an adequate amount of ranolazine was found to be effective in alleviating electrophysiological abnormalities (e.g., prolongation of action potential (AP), Ca2+ overload in diastole), which contributed to improving the diastolic function of the cardiomyocyte, albeit with a modest negative effect on the systolic function. A threshold drug dose was identified for achieving a significant normalization of the overall electromechanical profile. The threshold drug dose for effective therapy was observed to be contingent upon the severity of HF and the status of certain key ion channels. Furthermore, it was determined that an increase of the drug dose beyond the threshold did not yield substantial additional improvements in the principal electromechanical variables.

The study demonstrated the presence of a threshold dose of ranolazine for effective treatment of failing HCM cardiomyocyte, and further established that this threshold is influenced by the severity of HF and the functional status of key ion channels. These findings may serve as theoretical evidence for comprehending the mechanisms underlying ranolazine's therapeutic efficacy in treating failing HCM hearts. Moreover, the study underscores the potential clinical value of personalized dosing strategies.

The online version contains supplementary material available at 10.1007/s12195-025-00842-5.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition with potentially serious manifestations. Management has traditionally comprised therapies to palliate symptoms and implantable cardioverter-defibrillators to prevent sudden cardiac death. The need for disease-modifying therapies has been recognized for decades. More recently, an increasing number of novel and repurposed therapies hypothesized to target HCM disease pathways have been evaluated, culminating in the recent regulatory approval of mavacamten, a novel oral myosin inhibitor. HCM poses several unique challenges for clinical trials, which are important to recognize when designing trials and interpreting findings. This manuscript discusses the key considerations in the context of recent and ongoing randomized trials, including the roles of genotype, phenotype and symptom status in patient selection, the evidence base for clinical and mechanistic outcome measurements, trial duration and sample size.

Hypertrophic cardiomyopathy (HCM) is an inherited condition characterized by left ventricular, non-dilated hypertrophy in the absence of another secondary underlying cause. There has been an ongoing increase in the diagnosis of HCM over the past couple of decades, prompting further work in the area of pharmacological and interventional therapies. This scoping review aimed to summarize the traditional therapeutic options for HCM and to explore emerging research on novel cardiac myosin inhibitors (CMIs) as a new option for pharmacologic management of HCM. A PRISMA search strategy was carried out to identify the pertinent literature on mavacamten and aficamten-two novel CMIs. Seventeen studies were included. Based on the results of the studies included in this review, cardiac myosin inhibitors have been proven to be a safe and efficacious second-line option for the management of HCM. In the foreseeable future, based on results of ongoing studies investigating patient outcomes and side-effect profile, CMIs may potentially play a larger role as part of standard treatment of HCM.

Unlike other suggested therapies, myosin inhibitors have been shown to change the course of hypertrophic cardiomyopathy by altering the contractile mechanics of cardiomyocytes. This meta-analysis sought to determine the efficacy of mavacamten and aficamten in hypertrophic cardiomyopathy.

The online databases were searched from inception to July 2024, including the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, ClinicalTrials.gov. The meta-analytical data were pooled using risk ratios (RRs) with 95% CI, standard mean difference (SMD) and SE.

A total of 6 randomised controlled trials with 826 hypertrophic cardiomyopathy patients (mean age±SD up to 59.8±14.2 years in intervention vs 60.9±10.5 years in placebo) were included in our study. Of these, 443 received a cardiac myosin inhibitor and 383 received a placebo. The resting left ventricular outflow tract (LVOT) gradient between the two groups was considerably improved by cardiac myosin inhibitors (MD -57.27; 95% CI -63.05 to -51.49). Significant differences were also observed in the post-Valsalva LVOT gradient between the two groups (MD -55.86; 95% CI -65.55 to -46.18). Significantly decreased left ventricle ejection fraction (LVEF) was also seen (MD -4.74; 95% CI -7.22 to -2.26). The New York Health Association (NYHA) class improvement between the two groups also changed significantly (RR 2.21; 95% CI 1.75 to 2.80). Cardiac myosin inhibitors also caused significant improvement in the Kansas City Cardiomyopathy Questionnaire in a Clinical Summary Score between the two groups (MD 7.71; 95% CI 5.37 to 10.05) and significant reduction in the N-terminal pro-B-type natriuretic peptide (SMD -13.27; 95% CI -17.51 to -9.03) and the cardiac troponin I (SMD -11.90; 95% CI -15.07 to -8.72).

According to our meta-analysis, cardiac myosin inhibitors significantly improve the resting and post-Valsalva LVOT gradient, reduce the LVEF and improve the NYHA class and cardiac biomarkers when compared with the placebo.

CRD52024586161.

In clinical trials, mavacamten reduced left ventricular outflow tract obstruction (LVOTO) and improved symptoms in patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). We aimed to share our real-world experience with the efficacy and safety of mavacamten in this patient population.

This retrospective, single-centre study included patients with symptomatic oHCM from March 2023 to November 2023. Inclusion criteria were oHCM, age >18 years, significant LVOTO (gradient >50 mmHg at rest or with Valsalva), New York Heart Association (NYHA) class ≥II despite maximally tolerated medical therapy, and left ventricular ejection fraction (LVEF) >55%. Patients were evaluated by echocardiography, NYHA class, electrocardiography and Holter monitor on each monthly visit for 3 months. A total of 31 patients were included in this study. The mean (SD) age was 58 (16.5) years, and 14 (45%) were female. Mean provoked left ventricular outflow tract gradient (LVOTG) reduced by -49.4 mmHg (P < 0.001) at 4 weeks, -59.2 mmHg (P < 0.001) at 8 weeks, and -60.8 mmHg (P < 0.001) at 12 weeks. Twenty-six of the 31 patients (83.8%) achieved an LVOTG ≤30 mmHg at Week 12. No major side effects were reported. Sixty-seven percent experienced ≥2 NYHA class improvements, LVEF remained above 55% and no dose titration was made.

Our real-world experience aligns with established mavacamten trial outcomes. Continuous vigilance and longitudinal investigations are needed to further assess potential long-term impacts.

An improved understanding of the natural history in NYHA functional class I patients with obstructive hypertrophic cardiomyopathy (oHCM) is needed.

Using a multicenter registry (SHaRe [Sarcomeric Human Cardiomyopathy Registry]), this study described the natural history in patients with oHCM who were classified as NYHA functional class I at the initial visit compared with patients classified as NYHA functional class II and reported baseline characteristics associated with incident clinical events.

Incident events assessed included a composite of NYHA functional class III to IV symptoms, left ventricular ejection fraction <50%, atrial fibrillation, stroke, ventricular arrhythmias, septal reduction therapy, ventricular assist device or transplantation, or death. Factors associated with incident events were determined using Kaplan-Meier, Cox proportional hazards, and restricted cubic spline models.

Of 7,964 patients with HCM in SHaRe, 1,239 patients with oHCM met inclusion criteria; 598 were in NYHA functional class I at the initial visit (age 48 ± 17 years; 31.1% female; peak gradient, 75 ± 40 mm Hg). At 5-year follow-up, the composite event rate of NYHA functional class I patients was 28% compared with 44% (P < 0.001) in 641 NYHA functional class II patients with oHCM (age 54 ± 16 years; 46.5% female; peak gradient, 83 ± 39 mm Hg). Left atrial (LA) diameter ≥45 mm (HR: 1.56 [95% CI: 1.14-2.12]; P = 0.005), female sex (HR: 1.61 [95% CI: 1.16-2.24]; P = 0.003), and older age (HR: 1.21 per 10 years [95% CI: 1.09-1.34]; P < 0.001), but not the magnitude of left ventricular outflow tract obstruction, were associated with a higher risk of the composite outcome in NYHA functional class I patients.

Although NYHA functional class I patients with oHCM fared better than NYHA functional class II patients, more than one-fourth experienced adverse events over 5-year follow-up, especially if they were older, female, and/or had LA enlargement. Strategies to reduce the rate of clinical outcomes in NYHA functional class I patients warrant further study.

Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder. It is characterized by left ventricular hypertrophy and impaired cardiac function, with forms categorized into obstructive (oHCM) and nonobstructive (nHCM). Traditional treatments address symptoms but not the underlying disease mechanism, highlighting the need for novel therapies. Cardiac myosin inhibitors such as mavacamten and aficamten present potential new treatment options.

A meta-analysis of randomized controlled trials (RCTs) was conducted following PRISMA guidelines. Studies comparing cardiac myosin inhibitors with placebo were reviewed, and outcomes related to NYHA functional class, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), LVOT gradients, and left ventricular ejection fraction (LVEF) were analyzed.

Six RCTs involving 826 participants demonstrated that mavacamten and aficamten significantly improved NYHA functional class and KCCQ-CSS scores. The incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) was similar between the treatment and control groups, indicating a comparable safety profile.

Cardiac myosin inhibitors are effective in improving cardiac function and reducing LVOT obstruction in HCM patients. They offer a promising alternative to current treatments, with a safety profile comparable to placebo. Further research is needed to confirm long-term benefits.

Hypertrophic cardiomyopathy (HCM) with or without left ventricular outflow tract (LVOT) obstruction is a common primary myocardial disease, with a prevalence of 1:500. It is characterized by thickening of the myocardium. Its diagnostic evaluation includes history-taking and physical examination, genetic studies, transthoracic echocardiography, and cardiac MRI. When optimally treated, it carries a mortality of less than 1% per year.

This review is based on pertinent publications retrieved by a selective literature search, including the current guidelines.

In symptomatic patients with high LVOT gradients (≥ 50 mm Hg), the treatment of first choice is pharmacotherapy with nonvasodilating beta-blockers or non-dihydropyridine-type calcium channel antagonists. Common side effects include bradycardia and hypotension, and there is a risk of AV nodal blockade. Both substance classes lower the LVOT gradient. Beta-blockers alleviate dyspnea and improve patients' quality of life. Verapamil can increase physical resilience. A further option is mavacamten, a myosin inhibitor that gained approval in Germany in mid-2023: it, too, lowers the LVOT gradient and improves quality of life. In 7-10% of patients, there is a reversible reduction of the left ventricular ejection fraction to less than 50%. Septal reduction treatments can be considered if drug therapy fails. Attention must also be paid to the management of sequelae such as atrial fibrillation, malignant arrhythmias, and mitral valve insufficiency.

Patients with HCM have a near-normal life expectancy if the disease is diagnosed early and treated according to the guidelines. The treatment of HCM and HOCM (hypertrophic obstructive cardiomyopathy) have been studied in no more than a few clinical trials, and randomized studies with clinical endpoints are needed.

Septal reduction therapy (SRT) provides substantial symptomatic improvement in patients with obstructive hypertrophic cardiomyopathy (HCM). However, long-term disease course after SRT and predictors of adverse outcomes have not been systematically examined.

Data from 13 high clinical volume HCM centers from the international SHARE (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Patients were followed from the time of SRT until last follow-up or occurrence of heart failure (HF) composite outcome (cardiac transplantation, implantation of a left ventricular assist device, left ventricular ejection fraction <35%, development of New York Heart Association class III or IV symptoms), ventricular arrhythmias composite outcome (sudden cardiac death, resuscitated cardiac arrest, or appropriate implantable cardioverter defibrillator therapy), or HCM-related death. Cox proportional hazards models were used to identify predictors of outcome.

Of the 10 225 patients in SHARE, 1832 (18%; 968 [53%] male) underwent SRT, including 455 (25%) with alcohol septal ablation and 1377 (75%) with septal myectomy. The periprocedural 30-day mortality rate was 0.4% (8 of 1832) and 1499 of 1565 (92%) had a maximal left ventricular outflow tract gradient <50 mm Hg at 1 year. After 6.8 years (range, 3.4-9.8 years; 12 565 person-years) from SRT, 77 (4%) experienced HCM-related death (0.6% per year), 236 (13%) a composite HF outcome (1.9% per year), and 87 (5%) a composite ventricular arrhythmia outcome (0.7% per year). Among adults, older age at SRT was associated with a higher incidence of HCM death (hazard ratio, 1.22 [95 CI, 1.1-1.3]; P<0.01) and the HF composite (hazard ratio, 1.14 [95 CI, 1.1-1.2] per 5-year increase; P<0.01) in a multivariable model. Female patients also had a higher risk of the HF composite after SRT (hazard ratio, 1.4 [95 CI, 1.1-1.8]; P<0.01). De novo atrial fibrillation occurred after SRT in 387 patients (21%). Among pediatric patients followed for a median of 13 years after SRT, 26 of 343 (16%) developed the HF composite outcome, despite 96% being free of recurrent left ventricular outflow tract obstruction.

Successful short- and long-term relief of outflow tract obstruction was observed in experienced multidisciplinary HCM centers. A subset of patients progressed to develop HF, but event-free survival at 10 years was 83% and ventricular arrhythmias were rare. Older age, female sex, and SRT during childhood were associated with a greater risk of developing HF.

New postprocessing software facilitates 3-dimensional (3D) echocardiographic determination of mitral annular (MA) and neo-left ventricular outflow tract (neo-LVOT) dimensions in patients undergoing transcatheter mitral valve replacement (TMVR).

This study aims to test the accuracy of 3D echocardiographic analysis as compared to baseline computed tomography (CT).

A total of 105 consecutive patients who underwent TMVR at 2 tertiary care centers between October 2017 and May 2023 were retrospectively included. A virtual valve was projected in both baseline CT and 3D transesophageal echocardiography (TEE) using dedicated software. MA dimensions were measured in baseline images and neo-LVOT dimensions were measured in baseline and postprocedural images. All measurements were compared to baseline CT as a reference. The predicted neo-LVOT area was correlated with postprocedural peak LVOT gradients.

There was no significant bias in baseline neo-LVOT prediction between both imaging modalities. TEE significantly underestimated MA area, perimeter, and medial-lateral dimension compared to CT. Both modalities significantly underestimated the actual neo-LVOT area (mean bias pre/post TEE: 25.6 mm2, limit of agreement: -92.2 mm2 to 143.3 mm2; P < 0.001; mean bias pre/post CT: 28.3 mm2, limit of agreement: -65.8 mm2 to 122.4 mm2; P = 0.046), driven by neo-LVOT underestimation in the group treated with dedicated mitral valve bioprosthesis. Both CT- and TEE-predicted-neo-LVOT areas exhibited an inverse correlation with postprocedural LVOT gradients (r2 = 0.481; P < 0.001 for TEE and r2 = 0.401; P < 0.001 for CT).

TEE-derived analysis provides comparable results with CT-derived metrics in predicting the neo-LVOT area and peak gradient after TMVR.

The efficacy and safety profile of mavacamten, a cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathy (HCM) is not well-established, prompting the need for an updated meta-analysis. The authors conducted an extensive search across multiple electronic databases, including Embase, MEDLINE (via Pubmed), and CENTRAL, to identify randomized controlled trials (RCTs) assessing the efficacy and safety of mavacamten in HCM. Review Manager 5.4 (Revman) was employed to pool risk ratios (RR) and mean differences (MD). Our literature search yielded 4 RCTs with a total of 503 patients. Mavacamten was found to be associated with higher rates of greater than or equal to 1 New York Heart Association (NYHA) class improvement (RR 2.20, 95% CI: 1.48-3.28; I2=51%) and change from baseline in the Kansas City Cardiomyopathy Questionnaire- Clinical Summary Score (KCCQ-CSS) (MD 7.50, 95% CI: 3.44-11.55; I2 =50%). Mavacamten was also associated with improved resting left ventricular outflow tract (LVOT) gradient (MD -38.33, 95% CI: -49.38 to -27.28; I2 =75%), Valsalva LVOT gradient (MD -48.08, 95% CI: -62.21 to -33.96; I2 =78%), post-exercise LVOT gradient (MD -37.1, 95% CI: -44.37 to -29.84; I2 =0%), LVMI (MD -16.91, 95% CI: -28.29 to -5.54; I2 =88%), and lower rates of septal reduction therapy (SRT) (RR 0.30, 95% CI: 0.22-0.40; I2 =0%). There were no significant differences between mavacamten and placebo regarding the composite functional outcome, greater than or equal to 1 treatment-emergent adverse event, greater than or equal to 1 serious adverse event, and atrial fibrillation. The authors; findings suggest that mavacamten contributes to improvements in NYHA class, KCCQ-CSS scores, and LVOT gradients while reducing the incidence of SRT in patients with HCM.

The aim of this study was to investigate whether the H2FPEF score, which was developed to improve the diagnosis of heart failure (HF) with preserved ejection fraction, is associated with HF outcomes in patients with hypertrophic cardiomyopathy (HCM).

Patients with HCM and preserved left ventricular ejection fraction (LVEF ≥50%) were included from a multicentre registry and the H2FPEF score was calculated. Patients were divided into three groups: low (0-1), intermediate (2-5) and high (6-9) H2FPEF score. The primary combined endpoint was a composite of all-cause death and HF admissions, while the secondary endpoints were all-cause death and HF admissions separately. A total of 955 patients were included (age 51 ± 17 years, 310 [32.5%] female). Patients with a high H2FPEF score (n = 105) were more often female, and presented with more symptoms and comorbidities. On echocardiography, patients with a high H2FPEF score had lower LVEF, more impaired diastolic function and more frequently left ventricular outflow tract obstruction. During follow-up (median 90 months [interquartile range 49-176]), 103 (11%) patients died and 57 (6%) patients had a first HF hospitalization. Event-free survival rate for the primary combined and secondary endpoints was lower for patients with an intermediate and high H2FPEF score. On multivariate Cox regression analysis, female sex (hazard ratio [HR] 1.670, 95% confidence interval [CI] 1.157-2.410; p = 0.006), Asian ethnicity (HR 6.711, 95% CI 4.076-11.048; p < 0.001), ischaemic heart disease (HR 1.732, 95% CI 1.133-2.650; p =  0.011), left atrial diameter (HR 1.028, 95% CI 1.005-1.051; p = 0.016) and intermediate (HR 2.757, 95% CI 1.612-4.713; p < 0.001) or high H2FPEF score (HR 3.689, 95% CI 1.908-7.134; p < 0.001) were independently associated with the primary combined endpoint.

The H2FPEF score is independently associated with HF outcome in patients with HCM and may be considered for risk stratification.

Mavacamten is a selective, allosteric, reversible cardiac myosin inhibitor that has been developed for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). A population pharmacokinetic (PopPK) model was developed to characterize mavacamten pharmacokinetics (PK) and the variation in mavacamten exposure associated with intrinsic and extrinsic factors. Data from 12 clinical studies (phases 1, 2, and 3) were used. Evaluable participants were those who had at least one mavacamten concentration measurement with associated sampling time and dosing information. The base model included key covariates: body weight, cytochrome P450 isozyme 2C19 (CYP2C19) phenotype with respect to PK, and formulation. The final model was generated using stepwise covariate testing and refinement processes. Simulations were performed to evaluate PK: apparent clearance (CL/F); apparent central and peripheral volumes of distribution; and steady-state average, trough, and maximum concentrations. Overall, 9244 measurable PK observations from 497 participants were included. A two-compartment model structure was selected. After stepwise covariate model building and refinement, additional covariates included were: specified mavacamten dose, omeprazole or esomeprazole administration, health/disease status, estimated glomerular filtration rate, fed status, and sex. The final PopPK model accurately characterized mavacamten concentrations. At any given dose, CYP2C19 phenotype was the most influential covariate on exposure parameters (e.g., median CL/F was reduced by 72% in CYP2C19:poor metabolizers compared with the reference participant [CYP2C19:normal metabolizer]). CL/F was also approximately 16% higher in women than in men but lower in participants receiving concomitant omeprazole or esomeprazole (by 33% and 42%, respectively) than in participants not receiving such concomitant therapy.

In symptomatic obstructive hypertrophic cardiomyopathy (oHCM) patients, mavacamten is commercially approved to help improve left ventricular (LV) outflow tract (LVOT) gradients, symptoms, and reduce eligibility for septal reduction therapy (SRT) under the risk evaluation and mitigation strategy (REMS) program. We sought to prospectively report the initial real-world clinical experience with the use of commercially available mavacamten in a multi-hospital tertiary healthcare system.

We studied the first 150 consecutive oHCM patients (mean age 65 years, 53% women, 83% on betablockers and 61% in New York Heart Association [NYHA] class III) who were initiated on 5 mg of mavacamten with dose titrations using symptom assessment and echocardiographic measurements of LVOT gradient and LV ejection fraction (LVEF) measurements. We measured changes in NYHA class, LVEF, LVOT gradients (resting and Valsalva) at baseline, 4, 8 and 12 weeks.

At 261 ± 143 days (range of 31-571 days), 69 (46%) patients had ≥1 NYHA class, and 27 (18%) additional patients had ≥2 NYHA class improvement. The mean Valsalva LVOT gradient decreased from 72 ± 43 mmHg at baseline to 29 ± 31 mmHg at 4 weeks, 29 ± 28 mmHg at 8 weeks and 30 ± 29 mmHg at 12 weeks (p < 0.001). At baseline, 100% patients had Valsalva LVOT gradients ≥30 mmHg, which reduced to 29% at 4 weeks, 28% at 8 weeks and 30% at 12 weeks. In 40 patients who reported no symptomatic improvement, the mean Valsalva LVOT gradient decreased from 73 ± 39 mmHg at baseline to 34 ± 27 mmHg at 4 weeks, 35 ± 28 mmHg at 8 weeks and 30 ± 24 mmHg at 12 weeks (P < 0.001). The mean LVEF at baseline was 66 ± 6% and changed to 64 ± 5% at 4 weeks, 63 ± 5% at 8 weeks and 62 ± 7% at 12 weeks (p < 0.0001). No patient underwent SRT, developed LVEF ≤30% or developed heart failure requiring admission. Three (2%) patients needed temporary interruption of mavacamten due to LVEF<50%.

In a real-world study in symptomatic oHCM patients at a multi-hospital tertiary care referral center, we demonstrate the efficacy and safety, along with the logistic feasibility of prescribing mavacamten under the REMS program.

Patients with refractory, symptomatic left ventricular (LV) mid-cavity obstructive (LVMCO) hypertrophic cardiomyopathy have few therapeutic options. Right ventricular pacing is associated with modest hemodynamic and symptomatic improvement, and LV pacing pilot data suggest therapeutic potential. We hypothesized that site-specific pacing would reduce LVMCO gradients and improve symptoms.

Patients with symptomatic-drug-refractory LVMCO were recruited for a randomized, blinded trial of personalized prescription of pacing (PPoP). Multiple LV and apical right ventricular pacing sites were assessed during an invasive hemodynamic study of multisite pacing. Patient-specific pacing-site and atrioventricular delays, defining PPoP, were selected on the basis of LVMCO gradient reduction and acceptable pacing parameters. Patients were randomized to 6 months of active PPoP or backup pacing in a crossover design. The primary outcome examined invasive gradient change with best-site pacing. Secondary outcomes assessed quality of life and exercise following randomization to PPoP.

A total of 17 patients were recruited; 16 of whom met primary end points. Baseline New York Heart Association was 3±0.6, despite optimal medical therapy. Hemodynamic effects were assessed during pacing at the right ventricular apex and at a mean of 8 LV sites. The gradients in all 16 patients fell with pacing, with maximum gradient reduction achieved via LV pacing in 14 (88%) patients and right ventricular apex in 2. The mean baseline gradient of 80±29 mm Hg fell to 31±21 mm Hg with best-site pacing, a 60% reduction (P<0.0001). One cardiac vein perforation occurred in 1 case, and 15 subjects entered crossover; 2 withdrawals occurred during crossover. Of the 13 completing crossover, 9 (69%) chose active pacing in PPoP configuration as preferred setting. PPoP was associated with improved 6-minute walking test performance (328.5±99.9 versus 285.8±105.5 m; P=0.018); other outcome measures also indicated benefit with PPoP.

In a randomized placebo-controlled trial, PPoP reduces obstruction and improves exercise performance in severely symptomatic patients with LVMCO.

URL: https://clinicaltrials.gov/study; Unique Identifier: NCT03450252.

Hypertrophic cardiomyopathy is an important cause of heart failure and arrhythmias, including sudden death, with a major impact on the healthcare system. Genetic causes and different phenotypes are now increasingly being identified for this condition. In addition, specific medications, such as myosin inhibitors, have been recently shown as potentially able to modify its symptoms, hemodynamic abnormalities and clinical course. Our article aims to provide a comprehensive outline of the epidemiology, diagnosis and treatment of hypertrophic cardiomyopathy in the current era.

Hypertrophic cardiomyopathy (HCM) has long been considered to be a high-risk cardiac condition for which exercise was thought to increase the risk of sudden cardiac death (SCD). This was founded in part by initial autopsy studies reporting HCM to be a leading medical cause of SCD among young athletes. Most forms of competitive sport and exercise were therefore thought to increase the risk of SCD to a prohibitive level. Resultant expert consensus guideline recommendations universally restricted athletes with HCM from participation in moderate- to vigourous-intensity sport and exercise in a binary "yes" or "no" clinical decision making process with the goal of reducing the risk of sports-related SCD. HCM is, however, a heterogeneous genetic condition with variable penetrance and risk. The degree to which sports and exercise increases the risk of SCD at an individual patient level continues to be an area of clinical uncertainty. Emerging data and clinical experience from the past several decades have provided important new insights into exercise-related risks and have brought into question the appropriateness of overly restrictive binary clinical decision making for exercise recommendations in HCM. This includes an improved understanding of the overall prevalence of HCM in the general population, improved observational estimates of the risk of SCD related to continued sport and exercise participation, and a general shift toward improved patient-centred approaches to care through shared decision making processes. The rules by which the game is played may be changing for athletes with HCM.

Hypertrophic Cardiomyopathy (HCM) is a complex cardiac condition characterized by hypercontractility of cardiac muscle leading to a dynamic obstruction of left ventricular outlet tract (LVOT). Mavacamten, a first-in-class cardiac myosin inhibitor, is increasingly being studied in randomized controlled trials. In this meta-analysis, we aimed to analyse the efficacy and safety profile of Mavacamten compared to placebo in patients of HCM.

We carried out a comprehensive search in PubMed, Cochrane, and clinicaltrials.gov to analyze the efficacy and safety of mavacamten compared to placebo from 2010 to 2023. To calculate pooled odds ratio (OR) or risk ratio (RR) at 95% confidence interval (CI), the Mantel-Haenszel formula with random effect was used and Generic Inverse Variance method assessed pooled mean difference value at a 95% CI. RevMan was used for analysis. P<0.05 was considered significant.

We analyzed five phase 3 RCTs including 609 patients to compare mavacamten with a placebo. New York Heart Association (NYHA) grade improvement and KCCQ score showed the odds ratio as 4.94 and 7.93 with p<0.00001 at random effect, respectively. Cardiac imaging which included LAVI, LVOT at rest, LVOT post valsalva, LVOT post-exercise, and reduction in LVEF showed the pooled mean differences for change as -5.29, -49.72, -57.45, -36.11, and -3.00 respectively. Changes in LVEDV and LVMI were not statistically significant. The pooled mean difference for change in NT-proBNP and Cardiac troponin-I showed 0.20 and 0.57 with p<0.00001. The efficacy was evaluated in 1) A composite score, which was defined as either 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction, or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening and 2) changes in pVO2, which was not statistically significant. Similarly, any treatment-associated emergent adverse effects (TEAE), treatment-associated serious adverse effects (TSAE), and cardiac-related adverse effects were not statistically significant.

Mavacamten influences diverse facets of HCM comprehensively. Notably, our study delved into the drug's impact on the heart's structural and functional aspects, providing insights that complement prior findings. Further large-scale trials are needed to evaluate the safety profile of Mavacamten.

Ogden syndrome is an exceptionally rare X-linked disease caused by mutations in the NAA10 gene. Reported cases of this syndrome are approximately 20 children and are associated with facial dysmorphism, growth delay, developmental disorders, congenital heart disease, and arrhythmia.

We present the clinical profile of a 3-year-old girl with Ogden syndrome carrying a de novo NAA10 variant [NM_003491:c.247C>T, p.(Arg83Cys)]. During infancy, she exhibited features such as left ventricular hypertrophy, protruding eyeballs, and facial deformities.

Clinical diagnosis included Ogden syndrome, congenital heart disease (obstructive hypertrophic cardiomyopathy, left ventricular outflow tract obstruction, mitral valve disease, tricuspid valve regurgitation), tonsillar and adenoidal hypertrophy, and speech and language delay.

The girl was considered to have hypertrophic cardiomyopathy (HCM) and received oral metoprolol as a treatment for HCM at our hospital. The drug treatment effect was not ideal, and her hypertrophy myocardial symptoms were aggravated and she had to be hospitalized for surgery.

The girl underwent a modified Morrow procedure under cardiopulmonary bypass and experienced a favorable postoperative recovery. No pulmonary infections or significant complications were observed during this period. The patient's family expressed satisfaction with the treatment process.

The case emphasizes the HCM of Odgen syndrome, and early surgery should be performed if drug treatment is ineffective.

We aimed to assess the overall clinical impact of cardiac myosin inhibitors in hypertrophic cardiomyopathy (HCM). We performed a meta-analysis of published trials assessing the effect of cardiac myosin inhibitors (mavacamten and aficamten) on resting and Valsalva left ventricular outflow tract (LVOT) gradients and functional capacity in symptomatic HCM. The co-primary outcomes were mean percent change (mean difference [MD]) from baseline in LVOT gradient at rest and Valsalva LVOT gradient and the proportion of patients achieving New York Heart Association class improvement ≥1. The secondary outcomes included the mean percent change from baseline N-terminal pro-B-type natriuretic peptide, troponin I, and left ventricular ejection fraction (LVEF). A total of 4 studies (all randomized controlled trials, including 3 mavacamten-focused and 1 aficamten-focused trials) involving 463 patients were included in the meta-analysis. Compared with placebo, the cardiac myosin inhibitor group demonstrated statistically significant differences in the baseline percent change in mean LVOT gradient at rest (MD -62.48, confidence interval [CI] -65.44 to -59.51, p <0.00001) and Valsalva LVOT gradient (MD -54.21, CI -66.05 to -42.36, p <0.00001) and the proportion of patients achieving New York Heart Association class improvement ≥1 (odds ratio 3.43, CI 1.90 to 6.20, p <0.0001). Regarding the secondary outcomes, the intervention group demonstrated statistically significant reductions in mean percent change from baseline in N-terminal pro-B-type natriuretic peptide (MD -69.41, CI -87.06 to -51.75, p <0.00001), troponin I (MD, -44.19, CI -50.59 to -37.78, p <0.00001), and LVEF (MD -6.31, CI -10.35, -2.27, p = 0.002). In conclusion, cardiac myosin inhibitors may confer clinical and symptomatic benefits in symptomatic HCM at the possible expense of LVEF. Further trials with large sample sizes are needed to confirm our findings.

Anterior mitral valve leaflet (AMVL) elongation is detectable in overt and subclinical hypertrophic cardiomyopathy (HCM). We sought to investigate the dynamic motion of the aorto-mitral apparatus to understand the behaviour of the AMVL and the mechanisms of left ventricular outflow tract obstruction (LVOTO) predisposition in HCM.

Cardiovascular magnetic resonance imaging using a 1.5 Tesla scanner was performed on 36 HCM sarcomere gene mutation carriers without left ventricular hypertrophy (G+LVH-), 31 HCM patients with preserved ejection fraction carrying a pathogenic sarcomere gene mutation (G+LVH+), and 53 age-, sex-, and body surface area-matched healthy volunteers. Dynamic excursion of the aorto-mitral apparatus was assessed semi-automatically on breath-held three-chamber cine steady-state free precession images. Four pre-defined regions of interest (ROIs) were tracked: ROIPMVL: hinge point of the posterior mitral valve leaflet; ROITRIG: intertrigonal mitral annulus; ROIAMVL: AMVL tip; and ROIAAO: anterior aortic annulus. Compared with controls, normalized two-dimensional displacement-vs.-time plots in G+LVH- revealed subtle but significant systolic anterior motion (SAM) of the AMVL (P < 0.0001) and reduced longitudinal excursion of ROIAAO (P = 0.014) and ROIPMVL (P = 0.048). In overt and subclinical HCM, excursion of the ROITRIG/AMVL/PMVL was positively associated with the burden of left ventricular fibrosis (P < 0.028). As expected, SAM was observed in G+LVH+ together with reduced longitudinal excursion of ROITRIG (P = 0.049) and ROIAAO (P = 0.008).

Dyskinesia of the aorto-mitral apparatus, including SAM of the elongated AMVL, is detectable in subclinical HCM before the development of LVH or left atrial enlargement. These data have the potential to improve our understanding of early phenotype development and LVOTO predisposition in HCM.

The current ACC/AHA guidelines on hypertrophic cardiomyopathy (HCM) caution that alcohol septal ablation (ASA) might be less effective in patients with left ventricular outflow tract obstruction (LVOTO) ≥ 100 mm Hg.

We used a multinational registry to evaluate the outcome of ASA patients according to baseline LVOTO.

A total of 1346 ASA patients were enrolled and followed for 5.8 ± 4.7 years (7764 patient-years). The patients with baseline LVOTO ≥ 100 mm Hg were significantly older (61 ± 14 years vs 57 ± 13 years; P < 0.01), more often women (60% vs 45%; P < 0.01), and had a more pronounced HCM phenotype than those with baseline LVOTO < 100 mm Hg. There were no significant differences in the occurrences of 30-day major cardiovascular adverse events in the 2 groups. After propensity score matching (2 groups, 257 pairs of patients), the long-term survival was similar in both groups (P = 0.10), the relative reduction of LVOTO was higher in the group with baseline LVOTO ≥ 100 mm Hg (82 ± 21% vs 73 ± 26%; P < 0.01), but the residual resting LVOTO remained higher in this group (23 ± 29 mm Hg vs 13 ± 13 mm Hg; P < 0.01). Dyspnoea (NYHA functional class) at the most recent clinical check-up was similar in the 2 groups (1.7 ± 0.7 vs 1.7 ± 0.7; P = 0.85), and patients with baseline LVOTO ≥ 100 mm Hg underwent more reinterventions (P = 0.02).

After propensity matching, ASA patients with baseline LVOTO ≥ 100 mm Hg had similar survival and dyspnoea as patients with baseline LVOTO < 100 mm Hg, but their residual LVOTO and risk of repeated procedures were higher.

Accurate identification of hypertrophic cardiomyopathy (HCM) patients at high risk of sudden cardiac death (SCD) event is challenging. The objective of this study was to validate the three SCD risk stratifications recommended by the 2014 European Society of Cardiology (ESC) guideline, the 2020 American Heart Association /American College of Cardiology (AHA/ACC) guideline, and the 2022 ESC guideline in Chinese patients with HCM. Our study population are made up of a cohort of 856 HCM patients without prior SCD events. The endpoint was defined as SCD or equivalent events (successful resuscitation after cardiac arrest or appropriate ICD shock for ventricular tachycardia or ventricular fibrillation). During a median follow-up of 43 months, SCD endpoints occurred in 44 (5.1%) patients. A total of 34 (77.3%) patients suffering from SCD events were classified correctly into high-risk groups by the 2020 AHA/ACC guideline, 27(61.4%) by the 2022 ESC guideline, and 13 (29.6%) by the 2014 ESC guideline. The C-statistic of the 2020 AHA/ACC guideline was 0.68 (95% CI, 0.60-0.76), which performed better than the 2022 ESC guideline (0.65: 95% CI, 0.56-0.73), and the 2014 ESC guideline (0.58: 95% CI, 0.48-0.67). The 2020 AHA/ACC guideline displayed better discrimination for SCD risk stratification in Chinese HCM patients than the other two guidelines, with a higher sensitivity but lower specificity.

Despite the progress made in risk stratification, sudden cardiac death and heart failure remain dreaded complications for hypertrophic cardiomyopathy (HCM) patients. Myocardial ischaemia is widely acknowledged as a contributor to cardiovascular events, but the assessment of ischaemia is not yet included in HCM clinical guidelines. This review aims to evaluate the HCM-specific pro-ischaemic mechanisms and the potential prognostic value of imaging for myocardial ischaemia in HCM. A literature review was performed using PubMed to identify studies with non-invasive imaging of ischaemia (cardiovascular magnetic resonance, echocardiography, and nuclear imaging) in HCM, prioritising studies published after the last major review in 2009. Other studies, including invasive ischaemia assessment and post-mortem histology, were also considered for mechanistic or prognostic relevance. Pro-ischaemic mechanisms in HCM reviewed included the effects of sarcomeric mutations, microvascular remodelling, hypertrophy, extravascular compressive forces and left ventricular outflow tract obstruction. The relationship between ischaemia and fibrosis was re-appraised by considering segment-wise analyses in multimodal imaging studies. The prognostic significance of myocardial ischaemia in HCM was evaluated using longitudinal studies with composite endpoints, and reports of ischaemia-arrhythmia associations were further considered. The high prevalence of ischaemia in HCM is explained by several micro- and macrostructural pathological features, alongside mutation-associated energetic impairment. Ischaemia on imaging identifies a subgroup of HCM patients at higher risk of adverse cardiovascular outcomes. Ischaemic HCM phenotypes are a high-risk subgroup associated with more advanced left ventricular remodelling, but further studies are required to evaluate the independent prognostic value of non-invasive imaging for ischaemia.

Mavacamten has shown clinical benefits in global studies for patients with obstructive hypertrophic cardiomyopathy (oHCM), but evidence in the Asian population is lacking.

To evaluate the safety and efficacy of mavacamten compared with placebo for Chinese patients with symptomatic oHCM.

This phase 3, randomized, double-blind, placebo-controlled clinical trial was conducted at 12 hospitals in China. Between January 4 and August 5, 2022, patients with oHCM and a left ventricular outflow tract (LVOT) gradient of 50 mm Hg or more and New York Heart Association (NYHA) class II or III symptoms were enrolled and received treatment for 30 weeks.

Patients were randomized 2:1 to receive mavacamten (starting at 2.5 mg once daily) or placebo for 30 weeks.

The primary end point was change in Valsalva LVOT peak gradient from baseline to week 30. Left ventricular outflow tract gradients and left ventricular ejection fraction (LVEF) were assessed by echocardiography, while left ventricular mass index (LVMI) was determined by cardiac magnetic resonance imaging. Analysis was performed on an intention-to-treat basis.

A total of 81 patients (mean [SD] age, 51.9 [11.9] years; 58 men [71.6%]) were randomized. Mavacamten demonstrated a significant improvement in the primary end point compared with placebo (least-squares mean [LSM] difference, -70.3 mm Hg; 95% CI, -89.6 to -50.9 mm Hg; 1-sided P < .001). Similar trends were demonstrated for resting LVOT peak gradient (LSM difference, -55.0 mm Hg; 95% CI, -69.1 to -40.9 mm Hg). At week 30, more patients receiving mavacamten than placebo achieved a Valsalva LVOT peak gradient less than 30 mm Hg (48.1% [26 of 54] vs 3.7% [1 of 27]), less than 50 mm Hg (59.3% [32 of 54] vs 7.4% [2 of 27]), and NYHA class improvement (59.3% [32 of 54] vs 14.8% [4 of 27]). Greater improvements were also observed with mavacamten regarding the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (LSM difference, 10.2; 95% CI, 4.4-16.1), N-terminal pro-B-type natriuretic peptide level (proportion of geometric mean ratio, 0.18; 95% CI, 0.13-0.24), high-sensitivity cardiac troponin I level (proportion of geometric mean ratio, 0.34; 95% CI, 0.27-0.42), and LVMI (mean difference, -30.8 g/m2; 95% CI, -41.6 to -20.1 g/m2). Safety and tolerability were similar between mavacamten and placebo. No patients experienced LVEF less than 50%.

Mavacamten significantly improved Valsalva LVOT gradient vs placebo for Chinese patients. All secondary efficacy end points were also improved. Mavacamten was well tolerated with no new safety signals. This study supports the efficacy and safety of mavacamten in diverse populations, including Chinese patients.

ClinicalTrials.gov Identifier: NCT05174416.