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Tiffany Dong,* Ben Alencherry,* Susan Ospina, Milind Y Desai Section of Cardiovascular Imaging, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA*These authors contributed equally to this workCorrespondence: Milind Y Desai, Department of Cardiovascular Medicine, Miller Family Heart and Vascular Institute, Cleveland Clinic Main Campus J1-5, 9500 Euclid Avenue, Cleveland, OH, 44195, USA, Tel +1 216 445 5250, Fax +1 216 445 6155, Email desaim2@ccf.orgAbstract: Hypertrophic cardiomyopathy (HCM) is a condition with abnormal hypertrophy of the left ventricle in the absence of common causes. The most common form involves the basal septum and can lead to obstruction of the left ventricular outflow tract. Patients can experience exertional symptoms such as chest pain, dyspnea and syncope. Traditional treatment has included beta blockers and nondihydropyridine calcium channel blockers with second-line therapy being disopyramide. Recently, mavacamten, a cardiac myosin inhibitor, has demonstrated improvement in quantitative measures of obstruction and symptom relief to such a degree that patients were able to defer invasive management of the disease. This review focuses on the pharmacology of mavacamten, its clinical trial data and guidance on how to incorporate this drug into clinical practice. Furthermore, it discusses emerging therapies currently being investigated for HCM.Keywords: hypertrophic cardiomyopathy, mavacamten, septal reduction therapy, EXPLORER HCM, VALOR HCM

BACKGROUND: Abnormal papillary muscles (PM) are often found in hypertrophic cardiomyopathy (HCM). OBJECTIVE: To assess the relationship between morphological alterations of PM in patients with HCM and left ventricular outflow tract (LVOT) obstruction, using magnetic resonance imaging (MRI) and echocardiography. METHODS: Fifty-six patients with HCM (mean age 42 years (interquartile range 27, 51), 70% male) and 30 controls (mean age (42 (30, 53) years, 80% male) underwent MRI on a 1.5 T scanner (Siemens, Erlangen, Germany). Standard cine images were obtained in short-axis (base to apex), along with two-, three- and four-chamber views. The presence of bifid PM (none, one or both) and anteroapical displacement of anterolateral PM was recorded by MRI and correlated with resting LVOT gradients obtained by echocardiography. RESULTS: Double bifid PM (70% vs 17%) and anteroapical displacement of anterolateral PM (77% vs 17%) were more prevalent in patients with HCM than in controls (p<0.001). Subjects with anteroapically displaced PM and double bifid PM had higher resting LVOT gradients than controls (45 (6, 81) vs 12 (0, 12) mm Hg (p<0.01) and 42 (6, 64) vs 11 (0, 17) mm Hg (p = 0.02), respectively. In patients with HCM, the odds ratio of having significant (>/=30 mm Hg) peak resting gradient was 7.1 (95% CI 1.4 to 36.7) for anteroapically displaced anterolateral PM and 10.4 (95% CI 1.2 to 91.2) for double bifid PM (both p = 0.005), independent of septal thickness, use of beta-blockers and/or calcium blockers and resting heart rate. CONCLUSIONS: Patients with HCM with abnormal PM have a higher degree of resting LVOT gradient, which is independent of septal thickness. [ABSTRACT FROM AUTHOR]

Context: Statins reduce low-density lipoprotein cholesterol (LDL-C) levels and slow progression of coronary atherosclerosis. However, no data exist describing the relationship between statin-induced changes in high-density lipoprotein cholesterol (HDL-C) and disease progression.Objective: To investigate the relationship between changes in LDL-C and HDL-C levels and atheroma burden.Design, Setting, and Patients: Post-hoc analysis combining raw data from 4 prospective randomized trials (performed in the United States, North America, Europe, and Australia between 1999 and 2005), in which 1455 patients with angiographic coronary disease underwent serial intravascular ultrasonography while receiving statin treatment for 18 months or for 24 months. Ultrasound analysis was performed in the same core laboratory for all of the studies.Main Outcome Measure: Relationship between changes in lipoprotein levels and coronary artery atheroma volume.Results: During statin therapy, mean (SD) LDL-C levels were reduced from 124.0 (38.3) mg/dL (3.2 [0.99] mmol/L) to 87.5 (28.8) mg/dL (2.3 [0.75] mmol/L) (a 23.5% decrease; P<.001), and HDL-C levels increased from 42.5 (11.0) mg/dL (1.1 [0.28] mmol/L) to 45.1 (11.4) mg/dL (1.2 [0.29] mmol/L) (a 7.5% increase; P<.001). The ratio of LDL-C to HDL-C was reduced from a mean (SD) of 3.0 (1.1) to 2.1 (0.9) (a 26.7% decrease; P<.001). These changes were accompanied by a mean (SD) increase in percent atheroma volume from 39.7% (9.8%) to 40.1% (9.7%) (a 0.5% [3.9%] increase; P = .001) and a mean (SD) decrease in total atheroma volume of 2.4 (23.6) mm3 (P<.001). In univariate analysis, mean levels and treatment-mediated changes in LDL-C, total cholesterol, non-HDL cholesterol, apolipoprotein B, and ratio of apolipoprotein B to apolipoprotein A-I were significantly correlated with the rate of atherosclerotic progression, whereas treatment-mediated changes in HDL-C were inversely correlated with atheroma progression. In multivariate analysis, mean levels of LDL-C (beta coefficient, 0.11 [95% confidence interval, 0.07-0.15]) and increases in HDL-C (beta coefficient, -0.26 [95% confidence interval, -0.41 to -0.10]) remained independent predictors of atheroma regression. Substantial atheroma regression (> or =5% reduction in atheroma volume) was observed in patients with levels of LDL-C less than the mean (87.5 mg/dL) during treatment and percentage increases of HDL-C greater than the mean (7.5%; P<.001). No significant differences were found with regard to clinical events.Conclusions: Statin therapy is associated with regression of coronary atherosclerosis when LDL-C is substantially reduced and HDL-C is increased by more than 7.5%. These findings suggest that statin benefits are derived from both reductions in atherogenic lipoprotein levels and increases in HDL-C, although it remains to be determined whether the atherosclerotic regression associated with these changes in lipid levels will translate to meaningful reductions in clinical events and improved clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), VALOR-HCM trial (Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy [URL: https://clinicaltrials.gov; Unique identifier: NCT04349072]) reported that mavacamten reduced the short-term need for septal reduction therapy (SRT). The current report examined the longer-term effect of mavacamten through end of treatment at week 128., Methods: A double-blind randomized placebo-controlled multicenter trial at 19 sites in the United States included symptomatic obstructive HCM patients referred for SRT (enrollment July 2020 through October 2021). The group initially randomized to mavacamten continued the drug for 128 weeks and the placebo to mavacamten group from week 16 to 128 (112-week exposure). Dose titrations were performed using echocardiographic left ventricular outflow tract gradient and left ventricular ejection fraction measurements. The principal end point was proportion of patients proceeding with SRT or remaining guideline-eligible at week 128., Results: At week 128, 17 of 108 (15.7%) patients in the total study sample met the composite end point (7 underwent SRT, 1 was SRT-eligible, and 9 SRT-status unevaluable). Additionally, 87 of 108 (80.5%) patients demonstrated ≥1 New York Heart Association class improvement by week 128, and 52 of 108 (48.1%) demonstrated ≥2, with a sustained reduction in resting and Valsalva left ventricular outflow tract gradients of 38.2 mm Hg and 59.4 mm Hg, respectively. Ninety-five of 108 (88%) patients transitioned to commercial mavacamten. Overall, 15 of 108 (13.8%) patients (5.41 per 100 patient-years) had an left ventricular ejection fraction <50% (2 with left ventricular ejection fraction ≤30%; 1 death). Of these, 12 of 15 (80%) continued treatment. New-onset atrial fibrillation occurred in 11 (10.2%) patients (4.55 per 100 patient-years)., Conclusions: In severely symptomatic obstructive HCM patients, sustained freedom from SRT was observed at 128 weeks, with nearly 90% patients remaining on long-term mavacamten.

Background: Mavacamten is the only cardiac myosin inhibitor approved by the US FDA for treatment of symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy (HCM) patients. Under the risk evaluation and mitigation strategy (REMS) program for mavacamten, patients are required to be monitored for development of systolic heart failure, and reduction of left ventricular ejection fraction (LVEF) to <50%. We report results from the mavacamten REMS database (28-Apr-2022 to 27-Feb-2024). Methods: Data on healthcare providers and pharmacy certification, patient monitoring (from Patient Status Forms, based partly on echocardiograms), and screening for drug interactions prior to each dispense were collected. Results: Of 6,299 patients who received ≥1 dose of mavacamten, 60.0% were women; 64.6% were >60 years of age. Of 5,573 patients with submitted Patient Status Forms, 256 (4.6%) developed LVEF <50% and 71 (1.3%) experienced heart failure requiring hospitalization (HFH). On the 29,111 status forms in these patients, each representing an assessment of an echocardiogram, LVEF <50% was reported on 276 (0.9%) and HFH was reported on 86 (0.3%). Of 1,929 patients with ≥1 year of treatment, 78 (4.0%) had an LVEF reduction to <50% and 4 (0.2%) experienced LVEF <50% + HFH but later resumed treatment. Of 3,228 patients initiated on 5 mg/day mavacamten and were treated for at least 6 months, 2,391 (74.1%) remained at 5 or 10 mg/day. At 3- and 6-months following mavacamten treatment initiation, 57.2% and 70.3%, respectively, demonstrated post-Valsalva LV outflow tract gradient <30 mmHg. Conclusions: We describe the feasibility and experience of the first 22 months of the REMS program for prescribing mavacamten in >6,000 symptomatic obstructive HCM patients. The need for temporary interruption for LVEF <50% was low, including for patients on therapy ≥1 year, with even fewer LVEF reductions associated with HFH.

Background: In hypertrophic cardiomyopathy, histologic findings like myocyte hypertrophy and disarray, interstitial fibrosis (IF), and small intramural coronary artery dysplasia (SICAD) result in left ventricular hypertrophy, diastolic dysfunction, arrhythmogenicity, and microvascular ischemia., Objectives: The authors sought to evaluate the association between histology and outcomes in obstructive hypertrophic cardiomyopathy (oHCM) patients undergoing surgical myectomy (SM)., Methods: The study included 1,722 symptomatic oHCM patients (mean age: 56 ± 14 years; 948 [55%] men) who underwent SM at a tertiary center between 2005 and 2018. The SM specimen was analyzed for presence and severity of: 1) myocyte hypertrophy; 2) myocyte disarray; 3) IF; and 4) SICAD. Histologic findings were graded as 0-3 (none, mild, moderate, and severe) and a score from 0-12 was calculated. Primary endpoint was a composite of death, appropriate defibrillator discharge, or cardiac transplantation during follow-up., Results: Moderate and severe histologic findings were distributed as follows: myocyte hypertrophy (1,341 [78%]); disarray (237 [14%]); IF (448 [26%]); and SICAD (258 [15%]). The mean total histologic score was 5.1 ± 1.4. At 5.1 ± 5.2 years, there were 352 (20%) primary events (317 [18%] deaths). On spline analysis, a total histology score of >5 was associated with primary events. On Kaplan-Meier analysis, patients with a histology score >5 had greater events vs those with a score ≤5 (147/598 [25%] vs 205/1124 [18%]; log-rank P value = 0.002). On multivariable Cox analysis, total histology score >5 (HR: 1.24 [95% CI: 1.03-1.54]; P = 0.03) was independently associated with higher primary events., Conclusions: In symptomatic oHCM patients undergoing SM, a higher histologic score was independently associated with long-term outcomes., Competing Interests: Funding Support and Author Disclosures Dr Desai acknowledges the Haslam family endowed chair in cardiovascular medicine. The current study was funded by unrestricted philanthropic gifts by the Ratner family, Stinson family, and Anderson family for Dr Desai’s research. Dr Desai is a consultant and has research agreements with Bristol Myers Squibb, Cytokinetics, Tenaya, Viz-AI, and Edgewise. Dr Gaballa, Mrs Ospina, and Dr Jadam have received salary support from unrestricted philanthropic gifts by the Haslam family, Ratner family, Stinson family, and Anderson family. No industry support was used to conduct this study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition that can lead to atrial fibrillation, heart failure, and sudden cardiac death in many individuals but mild clinical impact in others. The mechanisms underlying this phenotypic heterogeneity are not well defined. The aim of this study was to use plasma proteomic profiling to help illuminate biomarkers that reflect or inform the heterogeneity observed in HCM., Methods: The Olink antibody-based proteomic platform was used to measure plasma proteins in patients with genotype positive (sarcomeric) HCM participating in the HCM Registry. We assessed associations between plasma protein levels with clinical features, cardiac magnetic resonance imaging metrics, and the development of atrial fibrillation., Results: We measured 275 proteins in 701 patients with sarcomeric HCM. There were associations between late gadolinium enhancement with proteins reflecting neurohormonal activation (NT-proBNP [N-terminal pro-B-type natriuretic peptide] and ACE2 [angiotensin-converting enzyme 2]). Metrics of left ventricular remodeling had novel associations with proteins involved in vascular development and homeostasis (vascular endothelial growth factor-D and TM [thrombomodulin]). Assessing clinical features, the European Society of Cardiology sudden cardiac death risk score was inversely associated with SCF (stem cell factor). Incident atrial fibrillation was associated with mediators of inflammation and fibrosis (MMP2 [matrix metalloproteinase 2] and SPON1 [spondin 1])., Conclusions: Proteomic profiling of sarcomeric HCM identified biomarkers associated with adverse imaging and clinical phenotypes. These circulating proteins are part of both established pathways, including neurohormonal activation and fibrosis, and less familiar pathways, including endothelial function and inflammatory proteins less well characterized in HCM. These findings highlight the value of plasma profiling to identify biomarkers of risk and to gain further insights into the pathophysiology of HCM.

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Background: The early detection of transthyretin cardiac amyloidosis (ATTR-CM) is essential, with Tc-99m pyrophosphate scintigraphy (PYP scan) being a key diagnostic tool. Although a previously validated score has shown promise in predicting PYP scan positivity among patients with HFpEF, further evaluation in diverse cohorts is necessary. Objectives: To assess the effectiveness of the ATTR-CM score in predicting PYP scan positivity within our patient population. Methods: We analyzed patients referred for PYP with SPECT at the Cleveland Clinic from January 2012 to January 2020, all of whom had undergone echocardiography within the previous year. The ATTR-CM score was determined using the following criteria: Age (60-69, +2; 70-79, +3; ≥80, +4), sex (male, +2), hypertension (present, -1), left ventricular ejection fraction (LVEF <60%, +1), posterior wall thickness (≥12 mm, +1), and relative wall thickness (>0.57, +2). A score of ≥6 indicated high risk. Results: Among the 540 patients (32% female, 33% black), 27% had an LVEF <40%. The score demonstrated good discrimination by AUC, with consistent performance across different racial groups, sexes, and LVEF categories. For scores ≥6, sensitivity was lower in women and black patients; however, lowering the cutoff to 5 markedly improved sensitivity. Conclusions: The ATTR-CM score displayed consistently good performance by AUC across our cohort, including patients with HFrEF. Nevertheless, its sensitivity was reduced in black patients and women. Efforts to scale ATTR-CM diagnosis tools should be mindful of demographic differences in risk prediction models.

Background: Takotsubo cardiomyopathy (TC) is an established differential diagnosis of myocardial infarction with non-obstructive coronaries with significant interest but limited data on prognostication. We reviewed the characteristics and in-hospital outcomes and developed a novel risk score for TC., Methods: Using the National Inpatient Sample data from 2016 to 2020, we identified adult patients (≥18 years) with acute coronary syndrome (ACS) and TC. We divided the cohort into ACS with and without TC and retrieved baseline data. Multivariable regression analysis was conducted to identify factors associated with TC diagnosis and adverse outcomes, leading to the development of a risk-scoring system., Results: Among 7 219 004 adult ACS admissions, 78 214 (1.0%) were diagnosed with TC, with a mean age of 68.2 years, 64 526 (82.5%) being female and 5475 (7.0%, compared with 8.4% for other ACS) in-hospital mortality events. Factors significantly associated with TC were female sex (OR 6.78 (95% CI 6.47 to 7.09), p<0.001) and chronic heart failure (OR 1.60 (95% CI 1.54 to 1.66), p<0.001). A novel risk score was developed, including the following parameters: male sex, age >70 years, non-white race, hypertension, hyperlipidemia, history of coronary artery bypass grafting, history of percutaneous coronary intervention, cardiac arrhythmias, renal failure, cardiogenic shock and vasopressor use. The area under curves for in-hospital mortality was 0.716 in the derivation and 0.725 in the validation cohorts., Conclusions: TC remains a high-risk diagnosis in a minority of ACS cases, with mortality rates similar to other ACS causes. Our novel risk score offers a valuable tool for risk stratification in patients with TC, but external validation is needed to confirm its utility., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

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/m 2 per year [95% CI: 0.76-1.2 mL/m 2 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/m 2 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/m 2 (HR: 0.33 [95% CI: 0.15-0.72]; P = 0.006) but was not statistically significant among patients with LAVI <37 mL/m 2 (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., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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 (R 2 = 0.46, p <0.01 and R 2 = 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., Competing Interests: Declaration of competing interest Dr. Desai is a consultant and has research agreements with Bristol Myers Squibb, cytokinetics, Tenaya, Viz-AI, and Edgewise. Dr. Smedira is a consultant for Bristol Myers Squibb. No industry support was utilized in the conduct of this study. The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Funding Support and Author Disclosures The VALOR-HCM study was funded by Bristol Myers Squibb. Dr Desai has served as a consultant for Bristol Myers Squibb, Cytokinetics, Tenaya, Edgewise and Viz.AI; and has received research support (to Cleveland Clinic) from Bristol Myers Squibb, Cytokinetics, and Tenaya. Dr Owens has served as a consultant for Bristol Myers Squibb, Cytokinetics, Pfizer, Biomarin, Tenaya, Lexicon, Stealth, Edgewise, and Renovacor; and has received grant support for research from Bristol Myers Squibb. Ms Wolski works for C5 Research and is an employee of Cleveland Clinic, which received payments for current research from Bristol Myers Squibb. Dr Geske has served as a consultant for Bristol Myers Squibb. Dr Saberi has served as a consultant for Bristol Myers Squibb and Cytokinetics. Dr Wang has received research grants (to institution) from Bristol Myers Squibb, Cytokinetics, and Abbott Vascular; has served on a consulting/advisory board for Bristol Myers Squibb; has served on steering committees for Bristol Myers Squibb and Cytokinetics; and has received speaker fees from Bristol Myers Squibb. Dr Sherrid has served as a consultant for Bristol Myers Squibb and Cytokinetics. Dr. Cremer works for C5 Research; and is an employee of Cleveland Clinic, which received payments for current research from Bristol Myers Squibb. Dr Lakdawala has received consulting fees from Bristol Myers Squibb, Pfizer, Tenaya, Cytokinetics, and Akros; and has received research support from Bristol Myers Squibb and Pfizer. Dr Tower-Rader has served as a consultant for Bristol Myers Squibb and Cytokinetics. Dr Fermin has received consulting/speaker fees from Bristol Myers Squibb and BridgeBio; and has served as a consultant for Pfizer. Dr Naidu has served as a consultant for Bristol Myers Squibb and Cytokinetics. Dr Smedira has served as a consultant for Bristol Myers Squibb. Ms McErlean and Sewell work for C5 Research; and are employees of Cleveland Clinic, which received payments for current research from Bristol Myers Squibb. Dr Zhong is an employee of and has stock ownership in Bristol Myers Squibb. Dr Wyrwich was employed by and had stock ownership in Bristol Myers Squibb at the time of the study. Drs Lampl and Sehnert are employed by and have stock ownership in Bristol Myers Squibb. Dr Nissen works for C5 Research; and is an employee of Cleveland Clinic, which received payments for current research from Bristol Myers Squibb. Dr Spertus has consulted for Bristol Myers Squibb and Cytokinetics; and holds the copyright to the KCCQ. Dr Schaff has reported that he has no relationships relevant to contents of this paper to disclose.

Background: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), the VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) trial showed that mavacamten reduced the eligibility for septal reduction therapy with sustained improvement in left ventricular outflow tract gradients. Mavacamten also resulted in favorable cardiac remodeling, including improvement in biomarkers (eg, N-terminal pro-B-type natriuretic peptide and troponin T). However, the impact of mavacamten on left atrial (LA) function is unknown., Objectives: The aim of this study was to assess serial changes in LA strain measures in patients enrolled in the VALOR-HCM trial., Methods: VALOR-HCM included 112 symptomatic patients with obstructive HCM (mean age 60 years; 51% male). Patients assigned to receive mavacamten at baseline (n = 56) continued therapy for 56 weeks and those assigned to placebo transitioned to mavacamten (n = 52) from week 16 to week 56. Echocardiographic LA strain (reservoir, conduit, and contraction) was measured by using a vendor-neutral postprocessing software., Results: At baseline, the mean LA volume index (LAVI) and LA strain values (conduit, contraction, and reservoir) were 41.3 ± 16.5 mL/m 2 , -11.8% ± 6.5%, -8.7% ± 5.0%, and 20.5% ± 8.7%, respectively (all worse than reported normal). LAVI significantly improved by -5.6 ± 9.7 mL/m 2 from baseline to week 56 (P < 0.001). There was a significant (P < 0.05) improvement in absolute LA strain values from baseline to week 56 (conduit [-1.7% ± 6%], contraction [-1.2% ± 4.5%], and reservoir [2.8% ± 7.7%]). Patients originally receiving placebo had no differences in LA measurements up to week 16. There was no significant improvement in LA strain values (conduit [-0.9% ± 3.8%], contraction [-0.4% ± 3.4%], and reservoir [1.4% ± 6.1%]; all; P = NS) from baseline to week 56 in patients with history of atrial fibrillation., Conclusions: In VALOR-HCM, mavacamten resulted in an improvement in LAVI and LA strain at week 56, suggesting sustained favorable LA remodeling and improved function, except in the atrial fibrillation subgroup. Whether the advantageous LA remodeling associated with long-term treatment with mavacamten results in a favorable impact on the observed high burden of atrial tachyarrhythmias in HCM remains to be proven. (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy [VALOR-HCM]; NCT04349072)., Competing Interests: Funding Support and Disclosures Bristol Myers Squibb policy on data sharing is provided at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html. The VALOR-HCM study was funded by Bristol Myers Squibb. Dr Desai has received consulting fees from Bristol Myers Squibb, Cytokinetics, Tenaya, Edgewise, and Viz.AI; and has done research support to Cleveland Clinic from Bristol Myers Squibb, Cytokinetics, and Tenaya. Drs Wolski and Nissen work for the Cleveland Clinic Coordinating Center for Clinical Research and are employees of the Cleveland Clinic, which received payments for the current research from Bristol Myers Squibb. Dr Geske has received consulting fees from Bristol Myers Squibb. Dr Owens has received consulting fees from Bristol Myers Squibb, Cytokinetics, Pfizer, BioMarin, Tenaya, Lexicon, Stealth, Edgewise, Renovacor; and has received grant support for research from Bristol Myers Squibb. Dr Saberi has received consulting fees from Bristol Myers Squibb and Cytokinetics. Dr Wang has received research grants (to institution) from Bristol Myers Squibb, Cytokinetics, and Abbott Vascular; has been on the consulting/advisory board from Bristol Myers Squibb; has held steering committee roles for Bristol Myers Squibb and Cytokinetics; and has received speaker fees from Bristol Myers Squibb. Dr Lakdawala has received consulting fees from Bristol Myers Squibb, Pfizer, Tenaya, Cytokinetics, and Akros; and has received research support from Bristol Myers Squibb and Pfizer. Drs Sherrid, Tower-Rader, and Naidu have received consulting fees from Bristol Myers Squibb and Cytokinetics. Dr Fermin has received consulting and speaker fees from Bristol Myers-Squibb and BridgeBio; and has received consulting fees from Pfizer. Drs Lampl and Sehnert are employed and have stock ownership at Bristol Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Apical hypertrophic cardiomyopathy (aHCM) is a distinct variant characterized by predominant hypertrophy of the left ventricle apex., Objectives: This study sought to describe aHCM patients' characteristics and develop a risk score for aHCM patients., Methods: A total of 462 patients (age 58 ± 15 years, 68% male) diagnosed with aHCM were included. The primary endpoint was death, appropriate defibrillator discharge, or need for cardiac transplantation. Variables showing potential association with the composite endpoint were considered to develop an aHCM-specific risk score., Results: At baseline, 67% patients were asymptomatic and 69% had no risk factors for sudden death. On echocardiography, the mean left ventricle ejection fraction, left atrial volume index, and right ventricular systolic pressure were 64% ± 8%, 36 ± 15 ml/m 2 , and 32 ± 10 mm Hg, respectively, with 51(11%) demonstrating an apical aneurysm. Baseline cardiac magnetic resonance, performed in 246 (53%) patients, demonstrated delayed gadolinium enhancement in 170 (71%) patients (mean percentage of 4.9% ± 6.6%). At age 6.3 ± 4.8 years, the composite events occurred in 80 (17%, death in 62 [13%]) patients. The aHCM-specific risk score, incorporating age, apical aneurysm, left atrial volume index, serum creatinine, and right ventricular systolic pressure, demonstrated good discrimination (C-statistic = 0.75) with an expected to observed ratio of 1.02 and a calibration slope of 0.91. The risk score ranged between 0 and 8 points, with a higher score associated with higher composite events., Conclusions: aHCM constituted 6.8% of our overall HCM cohort with a composite event rate of 2.8%/year. The aHCM risk score provided good discrimination in predicting the composite primary endpoint, with a higher score associated with a higher rate of events., Competing Interests: The current study was funded by unrestricted philanthropic gifts by the Ratner family, Stinson family, and Anderson family for Dr Desai’s research. Dr Hajj-Ali, Dr Gaballa, Mrs Ospina, and Dr Jadam have received salary support from unrestricted philanthropic gifts by the Haslam family, Ratner family, Stinson family, and Anderson family. Dr Desai is a consultant and has research agreements with Bristol Myers Squibb, Cytokinetics, Tenaya, Viz-AI, and Edgewise. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy, VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) demonstrated that mavacamten reduces the need for septal reduction therapy with sustained improvement in left ventricular (LV) outflow tract gradients and symptoms. Global longitudinal strain (GLS), a measure of regional myocardial function, is a more sensitive marker of systolic function. In VALOR-HCM, we assessed serial changes in LV and right ventricular (RV) strain., Methods: VALOR-HCM included 112 patients with symptomatic obstructive hypertrophic cardiomyopathy (mean, 60 years; 51% male; LV ejection fraction, 68%). Patients assigned to mavacamten at baseline continued the drug for 56 weeks (n=56) and those assigned to placebo (n=52) transitioned to mavacamten from weeks 16 to 56 (40-week exposure). LV-GLS and RV-GLS assessment was performed using a vendor-neutral software. Non-foreshortened apical (4-, 3-, and 2-chamber) views were used to obtain peak LV-GLS. RV focused 4-chamber view was used to calculate RV 4-chamber and free wall strain. A more negative strain value is favorable., Results: At baseline, the mean LV-GLS, RV 4-chamber, and free wall strain values were -14.7%, -22.2%, and -16.8%, respectively (all worse than reported normal means). In the total study sample, LV-GLS significantly improved from baseline to week 56 ( P =0.02). Twelve patients had transient reduction in LV ejection fraction (<50%) requiring temporary drug interruption (including 3 permanent discontinuations). The LV-GLS in this subgroup was worse at baseline versus total study population (-11.4%), with no significant worsening from baseline through week 56 ( P =0.64). Both free wall and 4-chamber RV-GLS remained unchanged from baseline to week 56 ( P =0.62 and P =0.56, respectively)., Conclusions: In VALOR-HCM, treatment with mavacamten improved LV-GLS from baseline through week 56 (with no significant worsening of LV-GLS in patients with a reduction in LV ejection fraction ≤50%), suggesting a favorable long-term impact on regional LV systolic function. Additionally, there was no detrimental impact on RV systolic function., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04349072., Competing Interests: Dr Desai reports consulting for Bristol Myers Squibb, Cytokinetics, Tenaya, Edgewise, and viz.AI and research support to Cleveland Clinic from Bristol Myers Squibb, Cytokinetics, and Tenaya. Dr Owens reports consulting for Bristol Myers Squibb, Cytokinetics, Pfizer, Biomarin, Tenaya, Lexicon, Stealth, Edgewise, and Renovacor and grant support for research from BMS. Dr Saberi reports consulting for Bristol Myers Squibb and Cytokinetics. Dr Lakdawala has received consulting incomes from Bristol Myers Squibb, Pfizer, Tenaya, Cytokinetics, and Akros and research support from Bristol Myers Squibb and Pfizer. Dr Wang reports research grants (to institution) from Bristol Myers Squibb, Cytokinetics, and Abbott Vascular; being on the consulting/advisory board from Bristol Myers Squibb; being on the steering committee for Bristol Myers Squibb and Cytokinetics; and speaker fees from Bristol Myers Squibb. Drs Naidu, Sherrid, and Tower-Rader report consulting for Bristol Myers Squibb and Cytokinetics. Dr Geske reports consultation with Bristol Myers Squibb. Dr Fermin reports conflicts from Bristol Myers Squibb (consulting, speaking), Pfizer (consulting), and BridgeBio (consulting, speaking). Drs Gaballa, Cremer, Popovic, and Yokushi report no conflicts of interest. Dr Nissen and Wang work for C5 Research and are employees of Cleveland Clinic, which received payments for current research from Bristol Myers Squibb. Drs Lampl and Sehnert are employed by and have stock ownership at Bristol Myers Squibb.

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., (© 2024. The Author(s).)

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., Competing Interests: Declaration of competing interest Dr. Desai is a consultant and has research agreements with Bristol Myers Squibb, Cytokinetics, Tenaya, Viz-AI and Edgewise. No industry support was utilized in the conduct of this study. Dr. Emery is a consultant for Bristol Myers Squibb. Others have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diastolic dysfunction plays a major role in precipitating congestive heart failure in patients with hypertrophic cardiomyopathy (HCM). In many such patients, symptoms are unmasked only during exercise because left ventricular (LV) filling pressure is normal at rest but increase with exercise. We sought to establish whether abnormal postexercise diastolic parameters are associated with reduced exercise capacity in patients with HCM. We examined 590 patients with asymptomatic/minimally symptomatic HCM (age 54 ± 14 years, 57% men, body mass index 30 ± 6 kg/m 2 , 84% on β blockers) with HCM by 2-dimensional and Doppler echocardiography at rest and after maximal treadmill exercise echocardiography (TSE). A complete echocardiogram (including LV ejection fraction, LV thickness, LV outflow tract [LVOT] gradient, degree of mitral regurgitation) was recorded. Diastolic parameters (septal and lateral [e'] velocities of the mitral annulus, peak early [E] and late [A] mitral inflow velocity, E/A ratio, E/e', right ventricular systolic pressure [RVSP], and left atrial volume index) were recorded at rest and after TSE. Exercise functional capacity was recorded and divided into <85% or >85% of age-gender predicted metabolic equivalents (AGP-METs). After maximal exercise, 32% patients had at least moderate mitral regurgitation, mean LVOT gradient was 61 ± 59 mm Hg, E/A ratio was 1.2 ± 1.0, average E/e' ratio 12.9 ± 1.0, and peak RVSP was 36 ± 15 mm Hg. Only 42% of patients achieved >85% of AGP-METs; the mean METs was 7 ± 3. On multivariable logistic regression analysis, higher body mass index (odds ratio [OR] 1.05), β-blocker use (OR 2.58), higher left atrial volume index (OR 1.02), higher peak stress LVOT gradient (LVOTG) (OR 1.06), peak stress E/e' (OR 1.04), and higher RVSP (OR 1.03) were independently associated with <85% AGP-METs achieved (all p <0.05). In conclusion, in patients with asymptomatic/minimally symptomatic HCM who underwent TSE, there is a significant and independent association between abnormal diastolic response to exercise and reduced exercise capacity in HCM. Incorporating diastolic parameters during stress echocardiography could provide incremental diagnostic utility in deciphering the exact etiology of dyspnea in such patients., Competing Interests: Declaration of competing interest Dr. Milind Desai is a consultant and has research agreements with Bristol Myers Squibb, Cytokinetics, Tenaya, Viz-AI, and Edgewise. No industry support was utilized in the conduct of this study. The remaining authors have no competing interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Male and female patients with hypertrophic cardiomyopathy (HCM) differ in physiologic characteristics and hemodynamics. Little is known about gender-related differences in left atrial (LA) strain and exercise capacity. The aim of this study was to assess the gender-related differences in the relationship between exercise capacity and cardiac function including LA function in patients with HCM., Methods: Five hundred and thirty-two patients with HCM undergoing exercise stress echocardiography and cardiopulmonary exercise testing (CPET) were prospectively recruited between October 2015 and April 2019 as part of a cohort study in a quaternary referral center. To reduce potential confounding factors, propensity score (PS) matching was performed in 420 patients. LA strain mechanics were evaluated using speckle-tracking echocardiography., Results: The majority of patients were male, comprising 58% of the total. Female HCM patients were older (54±14 vs . 50±15 years, P=0.002). After PS matching, percent-predicted peak VO 2 was similar between the genders (67.5%±20.7% vs . 65.8%±21.8%, P=0.41), even though female HCM patients had lower peak VO 2 (17.7±5.9 vs . 24.1±8.3 mL/kg/min, P<0.001). Left ventricular (LV) diastolic function was worse for female HCM patients. This is shown by worse E/e' ratio (15.0±5.9 vs . 12.9±6.4, P<0.001) and larger LA volume in respect to LV (0.88±0.35 vs . 0.74±0.31, P<0.001), compared with male HCM patients. The gender-related differences in LA reservoir strain were more evident for patients aged 60 years and older (27.5%±8.8% vs . 30.9%±9.1%, P=0.03). LA reservoir strain was found to have a significant association with exercise capacity in both male and female HCM patients (for females, β=0.27, P=0.001; for males, β=0.27, P<0.001), independent of LV diastolic dysfunction and stroke volume., Conclusions: Gender-related differences in LA reservoir strain were increasingly evident for older HCM patients aged 60 years and older. LA reservoir strain was an independent determinant of percent-predicted peak VO 2 in male and female patients, underpinning the importance of LA function in determining exercise capacity in HCM., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-147/coif). N.G.S. receives consulting fees from Bristol-Myers Squibb. M.Y.D. receives consulting fees from Cytokinetics, Inc. and Bristol-Myers Squibb. The other authors have no conflicts of interest to declare., (2024 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Objective: Valve-sparing aortic root replacement for proximal aortic dilation with aortic regurgitation is associated with excellent outcomes. Modified aortic reimplantation entails reducing the anulus size to the expected size for sex and body surface area and creating neosinuses to preserve the aortic valve. We present our mid- and late-term outcomes with the modified technique, including a single-surgeon's experience over the past 2 decades., Methods: From January 2002 to January 2024, 528 patients underwent modified aortic reimplantation for aortic aneurysm or dilation; 491 were included in this study. End points included time-related mortality and postoperative morbidities, including aortic valve reintervention and longitudinal aortic regurgitation grade., Results: There were no operative deaths. Survival at 30 days, 1 year, and 15 years were 100%, 99.6%, and 87%, respectively. Postoperative stroke occurred in 4 patients (0.81%) and reoperation for bleeding in 7 (1.4%). Moderate or severe aortic valve regurgitation was seen in 6.2% and 10% of patients at 1 and 10 years, respectively. Aortic valve mean gradients were 7.0 and 7.5 mm Hg at 1 and 10 years, respectively. Freedom from reintervention on the aortic valve was 99.9%, 99%, and 95% at 30 days, 1 year, and 15 years, respectively., Conclusions: Modified aortic reimplantation technique is a reliable and reproducible technique with excellent mid- and long-term outcomes in survival and freedom from reintervention. The results advocate for modified reimplantation in patients with enlarged aortic roots, especially in younger patients with connective tissue disorder., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Exposure to fine particulate matter (<2.5 um, particulate matter with an aerodynamic diameter <2.5 microns [PM 2.5 ]) has been implicated in atherogenesis. Limited data in animal studies suggest that PM 2.5 exposure leads to myocardial fibrosis and increased incidence of heart failure (HF). Whether PM 2.5 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 PM 2.5 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 PM 2.5 was 7.3±1.7 μg/m 3 . Each interquartile range of PM 2.5 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/m 3 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/m 3 ), supporting that no threshold effect exists for health effects of air pollution exposure.

Competing Interests: Funding Support and Author Disclosures The current study was funded by unrestricted philanthropic gifts by the Ratner family, Stinson family, and Anderson family for Dr Desai’s research. Dr Desai is a consultant and has research agreements with Bristol Myers Squibb, Cytokinetics, Tenaya, Viz-AI and Edgewise; and is the Haslam Family Endowed Chair in Cardiovascular Medicine. Mrs Rutkowski and Mrs Ospina have received salary support from unrestricted philanthropic gifts by the Haslam family, Ratner family, Stinson family, and Anderson family. Dr Smedira is a consultant for Bristol Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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., Competing Interests: Declaration of interests M.Y.D. is a consultant for and has research agreements with Bristol Myers Squibb, Cytokinetics, Tenaya, Viz.ai, and Edgewise. E.B. has research grants through his institution from AstraZeneca, Daiichi Sankyo, Merck, and Novartis and consults with Amgen, Bristol Myers Squibb, Boehringer Ingelheim/Lilly, Cardurion, Edgewise, and Verve., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of interest: None relevant for current document. M.Y.D. is a consultant and has research agreements with Bristol Myers Squibb, Tenaya, Cytokinetics, and VizAI.

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.

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.

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., Competing Interests: Declaration of competing interest Dr. Desai reports financial support was provided by Bristol Myers Squibb Co. The remaining author has no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

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/m 2 , 2594 (0.9%) underwent bariatric surgery (45% men; mean age, 56.2 years; mean body mass index, 51.5 kg/m 2 ). 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., Competing Interests: Disclosures Dr Desai is a consultant at Medtronic, Cytokinetics, Tenaya, and Bristol Myers Squibb. Dr Patel has served as a consultant at Novo Nordisk. Dr Aminian received research support and honorarium from Medtronic and Ethicon. He is on the executive steering committee of a trial sponsored by Eli Lilly. Dr Keshvani has served as a consultant for HeartSciences and Tricog Inc. Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc, and Sanofi. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Lincoff has received honoraria or served as a consultant for Novo Nordisk, Eli Lilly, Akebia, Alnylam, Ardelyx, Becton Dickinson, Brainstorm Cell, Cadrenal, Endologix, Fibrogen, GlaxoSmithKline, Intarcia, Medtronic, Neovasc, Provention Bio, and ReCor and has received research funding to his institution from AbbVie, AstraZeneca, CSL Behring, Eli Lilly, Esperion, and Novartis. Dr Van Spall receives research funding from the Canadian Institutes of Health Research and education program funding from Boehringer Ingelheim and Novartis. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Novo Nordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, and Siemens Healthcare Diagnosticsand Us2.ai; and serves as cofounder and non-executive director of Us2.ai. Dr Butler has served as a consultant for Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Daxor Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Roche, Secretome, Sequana, SQ Innovation, Tenex, and Vifor. Dr Nissen reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from Abbvie, AstraZeneca, Amgen, Arrowhead, Bristol Myers Squibb, Eli Lilly, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, Pfizer, and Silence Therapeutics. Dr Nissen is involved in these clinical trials but receives no personal remuneration for his participation. Dr Pandey has received research support from the National Institute of Health. Dr Pandey has received grant funding from Applied Therapeutics and Gilead Sciences; has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Axon Therapies, Medtronic, Edward Lifesciences, Science37, Novo Nordisk, Bayer, Merck, Sarfez Pharmaceuticals, and Emmi Solutions; and has received nonfinancial support from Pfizer and Merck. Dr Pandey is also a consultant for Palomarin Inc with stock compensation. The other authors report no conflicts.

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., Competing Interests: Dr Desai has consultant and research agreements with Bristol Myers Squibb, Tenaya, and Cytokinetic, and is a consultant for Medtronic. Dr Vargo is a speaker for Edwards Lifesciences and a consultant for Artivion and Cellphire. Dr Roselli is a consultant, investigator, and speaker for Artivion, Edwards Lifesciences, WL Gore, Medtronic, and Terumo Aortic; a speaker for Cook Medical, Corcym, and JenaValve; and has a license with Artivion. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2024 The Author(s).)