Safety and Efficacy of Metabolic Modulation With Ninerafaxstat in Patients With Nonobstructive Hypertrophic Cardiomyopathy.

BACKGROUND: In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics. OBJECTIVES: This study sought to evaluate the safety and efficacy of ninerafaxstat in nHCM. METHODS: Patients with hypertrophic cardiomyopathy and left ventricular outflow tract gradient <30 mm Hg, ejection fraction ≥50%, and peak oxygen consumption <80% predicted were randomized to ninerafaxstat 200 mg twice daily or placebo (1:1) for 12 weeks. The primary endpoint was safety and tolerability, with efficacy outcomes also assessed as secondary endpoints. RESULTS: A total of 67 patients with nHCM were enrolled at 12 centers (57 ± 11.8 years of age; 55% women). Serious adverse events occurred in 11.8% (n = 4 of 34) in the ninerafaxstat group and 6.1% (n = 2 of 33) of patients in the placebo group. From baseline to 12 weeks, ninerafaxstat was associated with significantly better VE/Vco2 (ventilatory efficiency) slope compared with placebo with a least-squares (LS) mean difference between the groups of -2.1 (95% CI: -3.6 to -0.6; P = 0.006), with no significant difference in peak VO2 (P = 0.90). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was directionally, though not significantly, improved with ninerafaxstat vs placebo (LS mean 3.2; 95% CI: -2.9 to 9.2; P = 0.30); however, it was statistically significant when analyzed post hoc in the 35 patients with baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary Score ≤80 (LS mean 9.4; 95% CI: 0.3-18.5; P = 0.04). CONCLUSIONS: In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a phase 3 study.

Mitral Leaflet Shortening as an Ancillary Procedure in Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Mitral leaflet elongation is common in hypertrophic cardiomyopathy (HCM), contributes to obstructive physiology, and presents a challenge to the dual surgical goals of abolition of outflow gradients and abolition of mitral regurgitation. Anterior leaflet shortening, performed as an ancillary surgical procedure during myectomy, is controversial. METHODS: This was a retrospective study of all patients undergoing myectomy from January 2010 to March 2020, with analysis of survival and echocardiographic results. The study compared outcomes of patients treated with myectomy and concomitant mitral leaflet shortening with patients treated with myectomy alone. Over this time, the technique for mitral shortening evolved from anterior leaflet plication to residual leaflet excision (ReLex). RESULTS: Myectomy was performed in 416 patients aged 57.5 ± 13.6 years, and 204 (49%) patients were female. Average follow-up was 5.4 ± 2.8 years. Survival follow-up was complete in 415 patients. Myectomy without valve replacement was performed in 332 patients, of whom 192 had mitral valve shortening (58%). Mitral leaflet plication was performed in 73 patients, ReLex in 151, and both procedures in 32. Hospital mortality for patients undergoing myectomy was 0.7%. At 8 years, cumulative survival was 95% for both the myectomy combined with leaflet shortening group and the myectomy alone group, with no difference in survival between the 2 groups. There was no difference in survival between the anterior leaflet plication and ReLex groups. Echocardiography 2.5 years after surgery showed a decrease in resting and provoked gradients, mitral regurgitation, and left atrial volume and no difference in key variables between patients who underwent ancillary leaflet shortening and patients who underwent myectomy alone. CONCLUSIONS: These results affirm that mitral shortening may be an appropriate surgical judgment for selected patients.

Clinical course of adults with co-occurring hypertrophic cardiomyopathy and hypertension: A scoping review.

Introduction: Hypertension affects approximately 50 % of patients with hypertrophic cardiomyopathy (HCM) but clinical course in adults with co-occurring HCM and hypertension is underexplored. Management may be challenging as routine anti-hypertensive medications may worsen obstructive HCM, the most common HCM phenotype. In this scoping review, we sought to synthesize the available literature related to clinical course and outcomes in adults with both conditions and to highlight knowledge gaps to inform future research directions. Methods: We searched 5 electronic databases (PubMed, CINAHL, Scopus, Embase, Web of Science) to identify peer-reviewed articles, 2011-2023. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Scoping Review (PRISMA-ScR) guideline. Results: Eleven articles met eligibility. Adults with both conditions were older and had higher rates of obesity and diabetes than adults with HCM alone. Results related to functional class and arrhythmia were equivocal in cross-sectional studies. Only 1 article investigated changes in medical therapy among adults with both conditions. Hypertension was a predictor of worse functional class, but was not associated with all-cause mortality, heart failure-related mortality, or sudden-death. No data was found that related to common hypertension-related outcomes, including renal disease progression, nor patient-reported outcomes, including quality of life. Conclusions: Our results highlight areas for future research to improve understanding of co-occurring HCM and hypertension. These include a need for tailored approaches to medical management to optimize outcomes, evaluation of symptom burden and quality of life, and investigation of hypertension-related outcomes, like renal disease and ischemic stroke, to inform cardiovascular risk mitigation strategies.

Traditional and novel risk factors for incident aortic stenosis in community-dwelling older adults.

OBJECTIVES: Calcific aortic stenosis (AS) is the most common valvular disease in older adults, yet its risk factors remain insufficiently studied in this population. Such studies are necessary to enhance understanding of mechanisms, disease management and therapeutics. METHODS: The Cardiovascular Health Study is a population-based investigation of older adults that completed adjudication of incident AS over long-term follow-up. We evaluated traditional cardiovascular risk factors or disease, as well as novel risk factors from lipid, inflammatory and mineral metabolism pathways, in relation to incident moderate or severe AS (including AS procedures) and clinically significant AS (severe AS, including procedures). RESULTS: Of 5390 participants (age 72.9±5.6 years, 57.6% female, 12.5% black), 287 developed moderate or severe AS, and 175 clinically significant AS, during median follow-up of 13.1 years. After full adjustment, age (HR=1.66 per SD (95% CI=1.45, 1.91)), male sex (HR=1.41 (1.06, 1.87)), diabetes (HR=1.53 (1.10, 2.13)), coronary heart disease (CHD, HR=1.36 (1.01, 1.84)), lipoprotein-associated phospholipase-A2 (LpPLA2) activity (HR=1.21 per SD (1.07, 1.37)) and sCD14 (HR=1.16 per SD (1.01, 1.34)) were associated with incident moderate/severe AS, while black race demonstrated an inverse association (HR=0.40 (0.24, 0.65)), and creatinine-based estimated glomerular filtration rate (eGFRcr) showed a U-shaped relationship. Findings were similar for clinically significant AS, although CHD and sCD14 fell short of significance, but interleukin-(IL) 6 showed a positive association. CONCLUSION: This comprehensive evaluation of risk factors for long-term incidence of AS identified associations for diabetes and prevalent CHD, LpPLA2 activity, sCD14 and IL-6, and eGFRcr. These factors may hold clues to biology, preventive efforts and potential therapeutics for those at highest risk.

Clinical course and outcomes in adults with co-occurring hypertrophic cardiomyopathy and hypertension: a scoping review protocol.

INTRODUCTION: Hypertension affects 40%-60% of adults with hypertrophic cardiomyopathy (HCM), the most common inherited cardiac condition. It can be a diagnostic confounder for HCM, contributing to delayed diagnosis. Clinically, treatment of co-occurring hypertension and HCM poses challenges as first-line and second-line antihypertensive medications are often contraindicated in HCM. The clinical course in adults with hypertension and HCM is also not well understood, and studies examining patient outcomes in this population are equivocal. In this paper, we aim to outline the protocol of a scoping review, a type of literature review, to systematically synthesise existing knowledge on adults with co-occurring HCM and hypertension, highlighting knowledge and evidence gaps, and identifying future research directions to optimise outcomes in this population. METHODS AND ANALYSIS: This review is guided by Arksey and O'Malley's conceptual framework on conducting scoping reviews. We will search five electronic databases (PubMed, CINAHL, Scopus, Embase and Web of Science) and reference lists of publications to identify eligible articles focusing on medical therapy, clinical course or outcomes in adults with HCM and hypertension, between 2011 and 2023. Our search strategy and presentation of results will be guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Scoping Review guideline. First, two independent reviewers will screen articles, by title and abstract, followed by a full-text screen to identify eligible articles. Relevant data will be extracted and synthesised. ETHICS AND DISSEMINATION: Ethical approval is not required for this review as it is a secondary data collection of published articles and does not involve human subject participation. We will present results of this review at relevant professional conferences and patient-centred educational events. Results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: https://osf.io/cy8qb/?view_only=98197f4850584e51807ff9b62533a706.

Histopathology of the Mitral Valve Residual Leaflet in Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Mitral valve (MV) elongation is a primary hypertrophic cardiomyopathy (HCM) phenotype and contributes to obstruction. The residual MV leaflet that protrudes past the coaptation point is especially susceptible to flow-drag and systolic anterior motion. Histopathological features of MVs in obstructive hypertrophic cardiomyopathy (OHCM), and of residual leaflets specifically, are unknown. OBJECTIVES: The purpose of this study was to characterize gross, structural, and cellular histopathologic features of MV residual leaflets in OHCM. On a cellular-level, we assessed for developmental dysregulation of epicardium-derived cell (EPDC) differentiation, adaptive endocardial-to-mesenchymal transition and valvular interstitial cell proliferation, and genetically-driven persistence of cardiomyocytes in the valve. METHODS: Structural and immunohistochemical staining were performed on 22 residual leaflets excised as ancillary procedures during myectomy, and compared with 11 control leaflets from deceased patients with normal hearts. Structural components were assessed with hematoxylin and eosin, trichrome, and elastic stains. We stained for EPDCs, EPDC paracrine signaling, valvular interstitial cells, endocardial-to-mesenchymal transition, and cardiomyocytes. RESULTS: The residual leaflet was always at A2 segment and attached by slack, elongated and curlicued, myxoid chords. MV residual leaflets in OHCM were structurally disorganized, with expanded spongiosa and increased, fragmented elastic fibers compared with control leading edges. The internal collagenous fibrosa was attenuated and there was collagenous tissue overlying valve surfaces in HCM, with an overall trend toward decreased leaflet thickness (1.09 vs 1.47 mm, P = 0.08). No markers of primary cellular processes were identified. CONCLUSIONS: MV residual leaflets in HCM were characterized by histologic findings that were likely secondary to chronic hemodynamic stress and may further increase susceptibility to systolic anterior motion.

How common is hypertrophic cardiomyopathy really?: Disease prevalence revisited 27 years after CARDIA.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous albeit treatable cardiac disease of variable severity, with the potential for heart failure, atrial fibrillation and arrhythmic sudden death, characterized by otherwise unexplained left ventricular (LV) hypertrophy and affecting all ages and races. Over the last 30 years, several studies have estimated the prevalence of HCM in the general population, employing echocardiography and cardiac magnetic resonance imaging (CMR), as well electronic health records and billing databases for clinical diagnosis. The estimated prevalence in the general population based on the disease phenotype of LV hypertrophy by imaging is 1:500 (0.2%). This prevalence was initially proposed in 1995 in the population-based CARDIA study employing echocardiography, and more recently confirmed by automated CMR analysis in the large UK Biobank cohort. The 1:500 prevalence appears most relevant to clinical assessment and management of HCM. These available data suggest that HCM is not a rare condition but likely underdiagnosed clinically and by extrapolation potentially affects about 700,000 Americans and possibly 15 million people worldwide.

Weight loss in hypertrophic cardiomyopathy: A clinical case series.

Background: Obesity is prevalent among patients with hypertrophic cardiomyopathy (HCM). Obese HCM patients have greater wall thickness, LV mass, worse hemodynamic function and NYHA class. Weight loss may favorably influence the HCM phenotype. Case summary: We describe six patients with hypertrophic cardiomyopathy who lost weight through diet and lifestyle changes (n = 4) or bariatric surgery (n = 2). Radiographic imaging, with cardiac MRI or CT scan, was performed before and after their weight loss. There was a mean decrease in LV mass and indexed LV mass, and a mean numerical decrease in mean wall thickness in up to 14 out of 18 LV segments. There was also NYHA class reduction in symptoms. Discussion: In this case series, we have shown that substantial weight loss in HCM patients can be associated with a decrease in LV mass, wall thickness and improvement in symptoms. These observations indicate the potential for positive remodeling of the heart by weight loss. Prospective studies of the benefits of weight loss in HCM are needed.

Apical Aneurysms and Mid-Left Ventricular Obstruction in Hypertrophic Cardiomyopathy.

BACKGROUND: Apical left ventricular (LV) aneurysms in hypertrophic cardiomyopathy (HCM) are associated with adverse outcomes. The reported frequency of mid-LV obstruction has varied from 36% to 90%. OBJECTIVES: The authors sought to ascertain the frequency of mid-LV obstruction in HCM apical aneurysms. METHODS: The authors analyzed echocardiographic and cardiac magnetic resonance examinations of patients with aneurysms from 3 dedicated programs and compared them with 63 normal controls and 47 controls with apical-mid HCM who did not have aneurysms (22 with increased LV systolic velocities). RESULTS: There were 108 patients with a mean age of 57.4 ± 13.5 years; 40 (37%) were women. A total of 103 aneurysm patients (95%) had mid-LV obstruction with mid-LV complete systolic emptying. Of the patients with obstruction, 84% had a midsystolic Doppler signal void, a marker of complete flow cessation, but only 19% had Doppler systolic gradients ≥30 mm Hg. Five patients (5%) had relative hypokinesia in mid-LV without obstruction. Aneurysm size is not bimodal but appears distributed by power law, with large aneurysms decidedly less common. Comparing mid-LV obstruction aneurysm patients with all control groups, the short-axis (SAX) systolic areas were smaller (P < 0.007), the percent SAX area change was greater (P < 0.005), the papillary muscle (PM) areas were larger (P < 0.003), and the diastolic PM areas/SAX diastolic areas were greater (P < 0.005). Patients with aneurysms had 22% greater SAX PM areas compared with those with elevated LV velocities but no aneurysms (median: 3.00 cm2 [IQR: 2.38-3.70 cm2] vs 2.45 [IQR: 1.81-2.95 cm2]; P = 0.004). Complete emptying occurs circumferentially around central PMs that contribute to obstruction. Late gadolinium enhancement was always brightest and the most transmural apical of, or at the level of, complete emptying. CONCLUSIONS: The great majority (95%) of patients in the continuum of apical aneurysms have associated mid-LV obstruction. Further research to investigate obstruction as a contributing cause to apical aneurysms is warranted.

The Associations of Aortic Valve Sclerosis, Aortic Annular Increased Reflectivity, and Mitral Annular Calcification with Subsequent Aortic Stenosis in Older Individuals: Findings from the Cardiovascular Health Study.

BACKGROUND: Although aortic valve sclerosis (AVS) is well described as preceding aortic stenosis (AS), the associations of AS with antecedent mitral annular calcification (MAC) and aortic annular increased reflectivity (AAIR) have not been characterized. In a population-based prospective study, the authors evaluated whether MAC, AAIR, and AVS are associated with the risk for incident AS. METHODS: Among participants of the Cardiovascular Health Study free of AS at the 1994-1995 visit, the presence of MAC, AAIR, AVS, and the combination of all three was evaluated in 3,041 participants. Cox proportional-hazards regression was used to assess the association between the presence of calcification and the incidence of moderate or severe AS in three nested models adjusting for factors associated with atherosclerosis and inflammation both relevant to the pathogenesis of AS. RESULTS: Over a median follow-up period of 11.5 years (interquartile range, 6.7-17.0 years), 110 cases of incident moderate or severe AS were ascertained. Strong positive associations with incident moderate or severe AS were found for all calcification sites after adjustment for the main model covariates: AAIR (hazard ratio [HR], 2.90; 95% CI, 1.95-4.32; P < .0005), AVS (HR, 2.20; 95% CI, 1.44-3.37; P < .0005), MAC (HR, 1.67; 95% CI, 1.14-2.45; P = .008), and the combination of all three (HR, 2.50; 95% CI, 1.65-3.78; P < .0005). In a secondary analysis, the risk for AS increased with the number of sites at which calcification was present. CONCLUSIONS: In a large cohort of community-dwelling elderly individuals, there were strong associations between each of AAIR, AVS, MAC, and the combination of the three and incident moderate or severe AS. The novel finding that AAIR had a particularly strong association with incident AS, even after adjusting for other calcification sites, suggests its value in identifying individuals at risk for AS and potential inclusion in routine assessment by transthoracic echocardiography.

Sex differences in the prognostic value of troponin and D-dimer in COVID-19 illness.

BACKGROUND: Male sex, elevated troponin levels, and elevated D-dimer levels are associated with more complicated COVID-19 illness and greater mortality; however, while there are known sex differences in the prognostic value of troponin and D-dimer in other disease states, it is unknown whether they exist in the setting of COVID-19. OBJECTIVE: We assessed whether sex modified the relationship between troponin, D-dimer, and severe COVID-19 illness (defined as mechanical ventilation, ICU admission or transfer, discharge to hospice, or death). METHODS: We conducted a retrospective cohort study of patients hospitalized with COVID-19 at a large, academic health system. We used multivariable regression to assess associations between sex, troponin, D-dimer, and severe COVID-19 illness, adjusting for demographic, clinical, and laboratory covariates. To test whether sex modified the relationship between severe COVID-19 illness and troponin or D-dimer, models with interaction terms were utilized. RESULTS: Among 4,574 patients hospitalized with COVID-19, male sex was associated with higher levels of troponin and greater odds of severe COVID-19 illness, but lower levels of initial D-dimer when compared with female sex. While sex did not modify the relationship between troponin level and severe COVID-19 illness, peak D-dimer level was more strongly associated with severe COVID-19 illness in male patients compared to female patients (males: OR=2.91, 95%CI=2.63-2.34, p<0.001; females: OR=2.31, 95%CI=2.04-2.63, p<0.001; p-interaction=0.005). CONCLUSION: Sex did not modify the association between troponin level and severe COVID-19 illness, but did modify the association between peak D-dimer and severe COVID-19 illness, suggesting greater prognostic value for D-dimer in males with COVID-19.

Subcutaneous versus transvenous implantable defibrillator in patients with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiomyopathy. The implantable cardioverter-defibrillator (ICD) is important for prevention of sudden cardiac death (SCD) in patients at high risk. In recent years, the subcutaneous implantable cardioverter-defibrillator (S-ICD) has emerged as a viable alternative to the transvenous implantable cardioverter-defibrillator (TV-ICD). The S-ICD does not require intravascular access; however, it cannot provide antitachycardia pacing (ATP) therapy. OBJECTIVE: The purpose of this study was to assess the real-world incidence of ICD therapy in patients with HCM implanted with TV-ICD vs S-ICD. METHODS: We compared the incidence of ATP and shock therapies among all HCM patients with S-ICD and TV-ICD enrolled in the Boston Scientific ALTITUDE database. Cumulative Kaplan-Meier incidence was used to compare therapy-free survival, and Cox proportional hazard ratios were calculated. We performed unmatched as well as propensity match analyses. RESULTS: We included 2047 patients with TV-ICD and 626 patients with S-ICD, followed for an average of 1650.5 ± 1038.5 days and 933.4 ± 550.6 days, respectively. Patients with HCM and TV-ICD had a significantly higher rate of device therapy compared to those with S-ICD (32.7 vs 14.5 therapies per 100 patient-years, respectively; P <.001), driven by a high incidence of ATP therapy in the TV-ICD group, which accounted for >67% of therapies delivered. Shock incidence was similar between groups, both in the general and the matched cohorts. CONCLUSION: Patients with HCM and S-ICD had a significantly lower therapy rate than patients with TV-ICD without difference in shock therapy, suggesting potentially unnecessary ATP therapy. Empirical ATP programming in patients with HCM may be unbeneficial.

Aortic valve imaging using 18F-sodium fluoride: impact of triple motion correction.

BACKGROUND: Current 18F-NaF assessments of aortic valve microcalcification using 18F-NaF PET/CT are based on evaluations of end-diastolic or cardiac motion-corrected (ECG-MC) images, which are affected by both patient and respiratory motion. We aimed to test the impact of employing a triple motion correction technique (3 × MC), including cardiorespiratory and gross patient motion, on quantitative and qualitative measurements. MATERIALS AND METHODS: Fourteen patients with aortic stenosis underwent two repeat 30-min PET aortic valve scans within (29 ± 24) days. We considered three different image reconstruction protocols; an end-diastolic reconstruction protocol (standard) utilizing 25% of the acquired data, an ECG-gated (four ECG gates) reconstruction (ECG-MC), and a triple motion-corrected (3 × MC) dataset which corrects for both cardiorespiratory and patient motion. All datasets were compared to aortic valve calcification scores (AVCS), using the Agatston method, obtained from CT scans using correlation plots. We report SUVmax values measured in the aortic valve and maximum target-to-background ratios (TBRmax) values after correcting for blood pool activity. RESULTS: Compared to standard and ECG-MC reconstructions, increases in both SUVmax and TBRmax were observed following 3 × MC (SUVmax: Standard = 2.8 ± 0.7, ECG-MC = 2.6 ± 0.6, and 3 × MC = 3.3 ± 0.9; TBRmax: Standard = 2.7 ± 0.7, ECG-MC = 2.5 ± 0.6, and 3 × MC = 3.3 ± 1.2, all p values ≤ 0.05). 3 × MC had improved correlations (R2 value) to the AVCS when compared to the standard methods (SUVmax: Standard = 0.10, ECG-MC = 0.10, and 3 × MC = 0.20; TBRmax: Standard = 0.20, ECG-MC = 0.28, and 3 × MC = 0.46). CONCLUSION: 3 × MC improves the correlation between the AVCS and SUVmax and TBRmax and should be considered in PET studies of aortic valves using 18F-NaF.

Adverse cardiac mechanics and incident coronary heart disease in the Cardiovascular Health Study.

OBJECTIVES: Speckle-tracking echocardiography enables detection of abnormalities in cardiac mechanics with higher sensitivity than conventional measures of left ventricular (LV) dysfunction and may provide insight into the pathogenesis of coronary heart disease (CHD). We investigated the relationship of LV longitudinal strain, LV early diastolic strain rate (SR) and left atrial (LA) reservoir strain with long-term CHD incidence in community-dwelling older adults. METHODS: The association of all three strain measures with incidence of non-fatal and fatal CHD (primary outcome of revascularisation, non-fatal and fatal myocardial infarction) was examined in the population-based Cardiovascular Health Study using multivariable Cox proportional hazards models. Follow-up was truncated at 10 years. RESULTS: We included 3313 participants (mean (SD) age 72.6 (5.5) years). During a median follow-up of 10.0 (25th-75th percentile 7.7-10.0) years, 439 CHD events occurred. LV longitudinal strain (HR=1.25 per SD decrement, 95% CI 1.09 to 1.43) and LV early diastolic SR (HR=1.31 per SD decrement, 95% CI 1.14 to 1.50) were associated with a significantly greater risk of incident CHD after adjustment for potential confounders. By contrast, LA reservoir strain was not associated with incident CHD (HR=1.06 per SD decrement, 95% CI 0.94 to 1.19). Additional adjustment for biochemical and echocardiographic measures of myocardial stress, dysfunction and remodelling did not meaningfully alter these associations. CONCLUSION: We found an association between echocardiographic measures of subclinically altered LV mechanics and incident CHD. These findings inform the underlying biology of subclinical LV dysfunction and CHD. Early detection of asymptomatic myocardial dysfunction may offer an opportunity for prevention and early intervention.

Mitral annular calcification in hypertrophic cardiomyopathy.

BACKGROUND: Changes in mitral valve anatomy contribute to left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM). Mitral annular calcification (MAC) is common among patients with HCM but its implications are currently unknown. METHODS: We tested the hypothesis that echocardiographic MAC would be associated with anterior displacement of the mitral valve and LVOTO in a cohort of 304 patients with HCM aged ≥ 60 years (mean [SD] age 71.6 [7.7] years, 52% women). RESULTS: MAC was present in 141 (46%) patients. The mean (SD) MAC offset distance was 9.8 (4.8) mm. A higher proportion of those with MAC compared to those without MAC had SAM (84.2 vs. 63.8%, p < 0.001) and LVOTO (80.9 vs. 57.9%, p < 0.001). In patients with MAC, the septal-mitral valve distance was shorter compared to those without (19.4 [4.0] vs 21.5 [4.9] mm, p < 0.001). The mitral valve position ratio was greater in those with MAC compared to those without (1.00 [0.79, 1.22] vs. 0.86 [0.67, 1.05], p < 0.001) denoting greater anterior displacement, especially in those with MAC and LVOTO. After multivariable adjustment, MAC offset distance was associated with LVOTO (OR 1.16 [95% CI 1.07, 1.28] per mm, p = 0.001). Over a median follow-up of 2.7 years, 42 (29.8%) patients with MAC underwent surgery to relieve LVOTO, with no deaths. CONCLUSION: This study adds MAC to the known geometrical alterations of the mitral valve that predispose to LVOTO and suggests that surgical relief of LVOTO in the presence of MAC is safe when performed by an experienced surgeon.