Medical Treatment Strategies for Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic heart disease inherited in an autosomal dominant pattern with an estimated prevalence of 0.6% in the general population. Clinical manifestations of HCM vary considerably, with symptoms ranging from none or mild exercise intolerance to severe lifestyle-limiting symptoms, advanced heart failure, and sudden cardiac death. Current management options for HCM include lifestyle modifications, familial screening with genetic counseling, pharmacotherapy for symptom control, sudden cardiac death risk stratification with or without defibrillator implantation, septal reduction therapy, and, in some cases, heart transplantation. Only recently have strongly targeted medical therapies for HCM, such as myosin inhibitors, been studied in multicenter randomized controlled trials. In this report, we review the currently available medical treatments for HCM and the future directions of HCM pharmacotherapy, and we highlight important unmet needs in this population.

Two cardiac myosin inhibitors in the treatment of obstructive hypertrophic cardiomyopathy.

A key area of therapeutic progress in obstructive hypertrophic cardiomyopathy revolves around the emergence of cardiac myosin inhibitors, of which mavacamten and aficamten represent the first and second molecules. We summarize the key research evidence, including many similarities and potential differences between various clinical trials studying these molecules.

Promising therapies for adults with symptomatic obstructive hypertrophic cardiomyopathy: 2023 and beyond.

INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic heart disease with an estimated prevalence in the general population of 0.2% to 0.6%. Clinically, HCM can range from no symptoms to severe symptoms such as heart failure or sudden cardiac death. Currently, the management of HCM involves lifestyle modifications, familial screening, genetic counseling, pharmacotherapy to manage symptoms, sudden cardiac death risk assessment, septal reduction therapy, and heart transplantation for specific patients. Multicenter randomized controlled trials have only recently explored the potential of cardiac myosin inhibitors (CMIs) such as mavacamten as a directed pharmacological approach for managing HCM. AREAS COVERED: We will assess the existing medical treatments for HCM: beta-blockers, calcium channel blockers, disopyramide, and different CMIs. We will also discuss future HCM pharmacotherapy guidelines and underline this patient population's unfulfilled needs. EXPERT OPINION: Mavacamten is the first-in-class CMI approved by the FDA to target HCM pathophysiology specifically. Mavacamten should be incorporated into the standard therapy for oHCM in case of symptom persistence despite using maximally tolerated beta blockers and/or calcium channel blockers. Potential drug-drug interactions should be assessed before initiating this drug. More studies are needed on the use of CMIs in patients with kidney and/or liver failure and pregnant/breastfeeding patients.

Real-world experience with mavacamten in obstructive hypertrophic cardiomyopathy: Observations from a tertiary care center.

BACKGROUND: 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. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.

Novel Cardiac Myosin Inhibitor Therapy for Hypertrophic Cardiomyopathy in Adults: A Contemporary Review.

Hypertrophic cardiomyopathy (HCM) affects as many as 1 in 200 people in the adult population globally. Patients may present with exertional dyspnea, presyncope or syncope, atrial and ventricular arrhythmias, heart failure, and even sudden cardiac death. Current guideline-based therapy involves medical therapy for treatment of symptoms in milder forms of the disease and surgical or catheter-based septal reduction therapies in obstructive HCM. Until recently, there has existed a gap between these two approaches that is now being filled by a new class of drugs, cardiac myosin inhibitors, which directly target the underlying disease process in HCM. Current investigations examine the effects of two cardiac myosin inhibitors on reported symptoms, echocardiographic evidence of disease, and the associated need for septal reduction. This paper reviews the contemporary evidence for the use of cardiac myosin inhibitors in HCM in adults and highlights future directions for this exciting field of cardiovascular medicine.

Measurements of the Interventricular Septum and Mitral Leaflet Length in Hypertrophic Cardiomyopathy Patients Who Underwent Surgical Myectomy: A Prospective Comparative Multimodality Imaging Study.

Transesophageal echocardiography (TEE) plays an important role for real-time procedural guidance during surgical smyectomy (SM) for hypertrophic obstructive cardiomyopathy (HOCM). We aimed to compare (1) interventricular septum (IVS) thickness using 2- (2D) and 3-dimensional (3D) intraoperative TEE and preoperative cardiac magnetic resonance (CMR) and (2) mitral valve (MV) leaflet length using 2D, 3D TEE, automatic quantification of mitral valve (AMVQ) and preoperative CMR. We prospectively studied 50 patients with HOCM (age 59 ± 12 years, 44% men) who underwent SM during 2018 to 2019. The maximal basal, mid, and distal anteroseptum (AS) and inferoseptum (IS) were measured by multiplanar 3D reconstruction on TEE and by short-axis imaging on preoperative CMR and classified as mild (≤18 mm), moderate (18 to 25 mm), or severe (≥25 mm) groups based on AS and IS thickness on CMR. MV leaflet lengths were evaluated by preoperative CMR and intraprocedural 2D TEE, zoom 3D TEE, and AMVQ (EchoPAC, General Electric, Wisconsin). There was a moderate correlation between AS and IS thickness on 3D TEE and CMR (R2 = 0.46, p <0.01 and R2 = 0.41, p <0.01, respectively), with 3D TEE showing an average overestimation of 3.8 and 4.7 mm versus CMR. The 3D TEE overestimated 14 patients (56%) with mild thickness as moderate and 5 patients (22%) with moderate thickness as severe. Assuming 3D TEE as the gold standard, the closest correlation for anterior mitral leaflet length was with CMR (average overestimation by CMR of 0.5 mm [root mean square deviation (RMSE%) 17]), intermediate correlation with 2D TEE (average deviation of 0.6 mm [RMSE% 21]) and no correlation with AMVQ (average deviation of 0.7 mm [RMSE% 24]). In conclusion, 3D TEE overestimates IVS thickness versus CMR in patients with HOCM who underwent SM, with greater discrepancy in those with thinner IVS. There are significant differences in MV lengths measured using different imaging techniques.

Incidence, Risk Factors, and Outcomes Associated With Permanent Pacemaker Implantation Following Tricuspid Valve Surgery.

BACKGROUND: Data regarding permanent pacemaker (PPM) implantation following tricuspid valve surgery (TVS) are limited. We sought to evaluate its incidence, risk factors, and outcomes. METHODS AND RESULTS: Medicare beneficiaries who underwent TVS from 2013 to 2020 were identified. Patients who underwent TVS for endocarditis were excluded. The primary exposure of interest was new PPM after TVS. Outcomes included all-cause mortality and readmission with endocarditis or heart failure on follow-up. Among the 13 294 patients who underwent TVS, 2518 (18.9%) required PPM placement. Risk factors included female sex (relative risk [RR], 1.26 [95% CI, 1.17-1.36], P<0.0001), prior sternotomy (RR, 1.12 [95% CI, 1.02-1.23], P=0.02), preoperative second-degree heart block (RR, 2.20 [95% CI, 1.81-2.69], P<0.0001), right bundle-branch block (RR, 1.21 [95% CI, 1.03-1.41], P=0.019), bifascicular block (RR, 1.43 [95% CI, 1.06-1.93], P=0.02), and prior malignancy (RR, 1.23 [95% CI, 1.01-1.49], P=0.04). Tricuspid valve (TV) replacement was associated with a significantly higher risk of PPM implantation when compared with TV repair (RR, 3.20 [95% CI, 2.16-4.75], P<0.0001). After a median follow-up of 3.1 years, mortality was not different in patients who received PPM compared with patients who did not (hazard ratio [HR], 1.02 [95% CI, 0.93-1.12], P=0.7). PPM placement was not associated with a higher risk of endocarditis but was associated with a higher risk of heart failure readmission (HR, 1.28 [95% CI, 1.14-1.43], P<0.001). CONCLUSIONS: PPM implantation frequently occurs after TVS, notably in female patients and patients undergoing TV replacement. Although mortality is not increased, it is associated with higher rates of heart failure rehospitalization.

A Multicenter Evaluation of the Impact of Therapies on Deep Learning-based Electrocardiographic Hypertrophic Cardiomyopathy Markers.

Background: Artificial intelligence-enhanced electrocardiography (AI-ECG) can identify hypertrophic cardiomyopathy (HCM) on 12-lead ECGs and offers a novel way to monitor treatment response. While the surgical or percutaneous reduction of the interventricular septum (SRT) represented initial HCM therapies, mavacamten offers an oral alternative. Objective: To evaluate biological response to SRT and mavacamten. Methods: We applied an AI-ECG model for HCM detection to ECG images from patients who underwent SRT across three sites: Yale New Haven Health System (YNHHS), Cleveland Clinic Foundation (CCF), and Atlantic Health System (AHS); and to ECG images from patients receiving mavacamten at YNHHS. Results: A total of 70 patients underwent SRT at YNHHS, 100 at CCF, and 145 at AHS. At YNHHS, there was no significant change in the AI-ECG HCM score before versus after SRT (pre-SRT: median 0.55 [IQR 0.24-0.77] vs post-SRT: 0.59 [0.40-0.75]). The AI-ECG HCM scores also did not improve post SRT at CCF (0.61 [0.32-0.79] vs 0.69 [0.52-0.79]) and AHS (0.52 [0.35-0.69] vs 0.61 [0.49-0.70]). Among 36 YNHHS patients on mavacamten therapy, the median AI-ECG score before starting mavacamten was 0.41 (0.22-0.77), which decreased significantly to 0.28 (0.11-0.50, p <0.001 by Wilcoxon signed-rank test) at the end of a median follow-up period of 237 days. Conclusions: The lack of improvement in AI-based HCM score with SRT, in contrast to a significant decrease with mavacamten, suggests the potential role of AI-ECG for serial monitoring of pathophysiological improvement in HCM at the point-of-care using ECG images.

Trends and Outcomes Associated With Bariatric Surgery and Pharmacotherapies With Weight Loss Effects Among Patients With Heart Failure and Obesity.

BACKGROUND: Utilization patterns of bariatric surgery among older patients with heart failure (HF), and the associations with cardiovascular outcomes, are not well known. METHODS: Medicare beneficiaries with HF and at least class II obesity from 2013 to 2020 were identified with Medicare Provider Analysis and Review 100% inpatient files and Medicare 5% outpatient files. Patients who underwent bariatric surgery were matched to controls in a 1:2 ratio (matched on exact age, sex, race, body mass index, HF encounter year, and HF hospitalization rate pre-surgery/matched period). In an exploratory analysis, patients prescribed pharmacotherapies with weight loss effects (semaglutide, liraglutide, naltrexone-bupropion, or orlistat) were identified and matched to controls with a similar strategy in addition to HF medical therapy data. Cox models evaluated associations between weight loss therapies (as a time-varying covariate) and mortality risk and HF hospitalization rate (calculated as the rate of HF hospitalizations following index HF encounter per 100 person-months) during follow-up. RESULTS: Of 298 101 patients with HF and body mass index ≥35 kg/m2, 2594 (0.9%) underwent bariatric surgery (45% men; mean age, 56.2 years; mean body mass index, 51.5 kg/m2). In propensity-matched analyses over a median follow-up of 4.7 years, bariatric surgery was associated with lower risk of all-cause mortality (HR, 0.55 [95% CI, 0.49-0.63]; P<0.001), greater reduction in HF hospitalization rate (rate ratio, 0.72 [95% CI, 0.67-0.77]; P<0.001), and lower atrial fibrillation risk (HR, 0.78 [95% CI, 0.65-0.93]; P=0.006). Use of pharmacotherapies with weight loss effects was low (4.8%), with 96.3% prescribed GLP-1 (glucagon-like peptide-1) agonists (semaglutide, 23.6%; liraglutide, 72.7%). In propensity-matched analysis over a median follow-up of 2.8 years, patients receiving pharmacotherapies with weight loss effects (versus matched controls) had a lower risk of all-cause mortality (HR, 0.82 [95% CI, 0.71-0.95]; P=0.007) and HF hospitalization rate (rate ratio, 0.87 [95% CI, 0.77-0.99]; P=0.04). CONCLUSIONS: Bariatric surgery and pharmacotherapies with weight loss effects are associated with a lower risk of adverse outcomes among older patients with HF and obesity; however, overall utilization remains low.

Long-term outcome of bicuspid aortic valve repair using figure-of-8 hitch-up stitches.

Objective: To maximize successful repair of bicuspid aortic valves by adding figure-of-8 hitch-up stitches at commissures. Methods: From 2000 to 2022, bicuspid aortic valve repair was performed on 1112 patients at Cleveland Clinic, with 367 patients receiving figure-of-8 hitch-up stitches along with classical techniques, including Cabrol suture, cusp plication, raphe resection, and valve-sparing root replacement. Operative outcomes, repair durability, and survival were assessed in the figure-of-8 hitch-up stitches cohort, and outcomes were compared among 195 balancing-score-matched patient pairs who underwent bicuspid aortic valve repair with and without figure-of-8 hitch-up stitches. Results: Patients who underwent bicuspid aortic valve repair with figure-of-8 stitches had an operative mortality of 0.3% (1 of 367) and in-hospital reoperation for aortic valve dysfunction of 1.1% (4 of 367). At 10 years, prevalence of severe aortic regurgitation was 8.6%, mean gradient 24 mm Hg, freedom from aortic valve reoperation 75%, and survival 98%. In matched cohorts, operative mortality was similar (0.51% vs 0%; P > .9) as were morbidities, including in-hospital reoperation due to aortic valve dysfunction (1.0% vs 1.5%; P > .9). Comparable long-term outcomes were observed at 10 years (prevalence of severe aortic regurgitation of 8.7% vs 5.0% [P = .11], mean gradient 18 vs 17 mm Hg [P = .40]; freedom from aortic valve reoperation 80% vs 81% [P = .73]; and survival 99.5% vs 94.6% [P = .18]). Conclusions: Figure-of-8 hitch-up stitch is a safe bicuspid aortic valve repair technique. It increases the likelihood of a successful repair without increasing risk of cusp tear and achieves satisfactory long-term survival and durability when added to classical repair techniques.

Ambient Air Pollution Exposure and Adverse Outcomes Among Medicare Beneficiaries With Heart Failure.

BACKGROUND: Exposure to fine particulate matter (<2.5 um, particulate matter with an aerodynamic diameter <2.5 microns [PM2.5]) has been implicated in atherogenesis. Limited data in animal studies suggest that PM2.5 exposure leads to myocardial fibrosis and increased incidence of heart failure (HF). Whether PM2.5 is associated with adverse outcomes in patients with preexisting HF has not been widely studied. METHODS AND RESULTS: In this retrospective cohort study, Medicare patients hospitalized with first HF between 2013 and 2020 were identified from the Medicare Provider Analysis and Review Part A 100% files. Patients were linked with integrated estimates of ambient PM2.5 obtained at 1×1 km using the zip code of participants' residence. The study outcomes were all-cause death, HF, and all-cause readmissions burden. A total of 2 599 525 patients were included in this study, with 6 321 731 person-years of follow-up. Mean PM2.5 was 7.3±1.7 µg/m3. Each interquartile range of PM2.5 was associated with 0.9% increased hazard of all-cause death, 4.5% increased hazard of first HF readmission, 3.1% increased risk of HF hospitalization burden, and 5.2% increase in all-cause readmission burden, after adjusting for 11 sociodemographic and medical factors. Subgroup analyses showed that the effects were more pronounced at levels <7 µg/m3 and in patients aged <75 years, Asians, and those residing in rural areas. CONCLUSIONS: Ambient air pollution is associated with higher risk of adverse events in Medicare beneficiaries with established HF. These associations persist below the National Air Quality Standards (12 µg/m3), supporting that no threshold effect exists for health effects of air pollution exposure.

Longitudinal Assessment of Left Atrial Remodeling in Patients With Chronic Severe Aortic Regurgitation.

BACKGROUND: There are significant sex and age differences in left ventricular (LV) remodeling that may lead to disparity in outcomes when used to inform the timing of aortic regurgitation (AR) intervention. OBJECTIVES: The aim of this study was to examine whether left atrial (LA) parameters might represent better criteria than LV parameters to inform the timing of AR intervention. METHODS: Using data on patients with moderate to severe or severe AR with serial echocardiography (2010-2016), the longitudinal trends in left atrial volume index (LAVI) and left atrial reservoir strain (LAr) were evaluated by sex and age. The incremental utility of these parameters in predicting adverse events over LV parameters was also determined. RESULTS: In 525 patients (25.7% women) with 1,687 echocardiograms over a median follow-up period of 2.0 years (Q1-Q3: 1.0-3.6 years), there was significant increase in LAVI (1.0 mL/m2 per year [95% CI: 0.76-1.2 mL/m2 per year]) and decrease in LAr (-1.3% per year [95% CI: -1.6% to -0.92%]), without a significant interaction by sex or age category (P for interaction ≥ 0.17). In addition, both LAVI and LAr were significant predictors of adverse events independent of LV parameters. The optimal discriminatory thresholds were 37 mL/m2 for LAVI and 35% for LAr. These thresholds were similar across categories of sex and age. Within the relatively short-term follow-up, surgery was associated with survival benefit among patients with LAVI ≥37 mL/m2 (HR: 0.33 [95% CI: 0.15-0.72]; P = 0.006) but was not statistically significant among patients with LAVI <37 mL/m2 (HR: 0.46 [95% CI: 0.18-1.17]; P = 0.09). Similarly, surgery was associated with survival for the subgroup with LAr ≤35% but not among those with LAr >35%. CONCLUSIONS: Unlike LV remodeling, LA remodeling demonstrates a similar rate of progression between categories of sex and age among patients with AR. In addition, LA parameters provide incremental prognostic value over LV parameters.

Guidelines for the Evaluation of Prosthetic Valve Function With Cardiovascular Imaging: A Report From the American Society of Echocardiography Developed in Collaboration With the Society for Cardiovascular Magnetic Resonance and the Society of Cardiovascular Computed Tomography.

In patients with significant cardiac valvular disease, intervention with either valve repair or valve replacement may be inevitable. Although valve repair is frequently performed, especially for mitral and tricuspid regurgitation, valve replacement remains common, particularly in adults. Diagnostic methods are often needed to assess the function of the prosthesis. Echocardiography is the first-line method for noninvasive evaluation of prosthetic valve function. The transthoracic approach is complemented with two-dimensional and three-dimensional transesophageal echocardiography for further refinement of valve morphology and function when needed. More recently, advances in computed tomography and cardiac magnetic resonance have enhanced their roles in evaluating valvular heart disease. This document offers a review of the echocardiographic techniques used and provides recommendations and general guidelines for evaluation of prosthetic valve function on the basis of the scientific literature and consensus of a panel of experts. This guideline discusses the role of advanced imaging with transesophageal echocardiography, cardiac computed tomography, and cardiac magnetic resonance in evaluating prosthetic valve structure, function, and regurgitation. It replaces the 2009 American Society of Echocardiography guideline on prosthetic valves and complements the 2019 guideline on the evaluation of valvular regurgitation after percutaneous valve repair or replacement.

Survival and repair durability in patients undergoing concomitant aortic valve reimplantation and mitral valve repair.

Objective: The study objective was to determine repair durability and survival in patients with and without connective tissue disorders undergoing concomitant aortic valve reimplantation and mitral valve repair. Methods: From 2002 to 2019, 68 patients underwent concomitant aortic valve reimplantation and mitral valve repair, including 27 patients with Marfan syndrome (39.7%). Follow-up echocardiograms were analyzed using nonlinear multiphase mixed-effects cumulative logistic regression. The regurgitation grade over time was estimated by averaging patient-specific profiles. Survival and freedom from reoperation were estimated by the Kaplan-Meier method. Results: At 7 years, 11% of patients had aortic insufficiency greater than mild (severe in 2 patients). There was no difference in greater than mild aortic insufficiency between patients with or without Marfan syndrome (P = .37). Twenty percent of patients had progressed to mitral regurgitation greater than mild (severe in only 1 patient). The prevalence of recurrent mitral regurgitation was higher in those without Marfan syndrome, with greater than mild regurgitation increasing to 24% by 2 years and remaining constant thereafter (P = .04). Freedom from reoperation on the aortic valve or mitral valve was 83% at 10 years and did not differ between Marfan syndrome groups. There were no cases of perioperative mortality. Survival at 5 and 10 years was 94% and 87%, respectively, without a difference between those with and without Marfan syndrome. Conclusions: Patients can undergo a total repair strategy using combined aortic valve reimplantation and mitral valve repair procedures with a low risk of mortality and complications, with favorable freedom from both residual valve regurgitation and reoperation.