BackgroundIn 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.MethodsWe 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.ResultsAt 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%.ConclusionsIn 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.

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 = 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.

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.

Background: Radiation-associated cardiac disease (RACD) has significant long-term mortality and morbidity, often requiring cardiac surgery(CS). Hypothesis: We sought to study factors associated with longer-term survival in RACD patients and develop a specific risk score associated with 5-year survival following CS. Methods: This was an observational cohort study of 351 patients with documented RACD (252 [72%] had mantle radiation for lymphoma at a mean of 18 years prior), who underwent CS at a tertiary care center between 1991-2018. Clinical characteristics were collected, and Society of Thoracic Surgeons (STS) score was calculated. The primary endpoint was mortality. Multivariable analysis for 5-year mortality was performed using age, sex, history of lymphoma, New York Heart Association class, prior cardiac surgery, atrial fibrillation, constriction, chronic pulmonary disease, serum creatinine, left ventricular ejection fraction, right ventricular systolic pressure and valvular surgery(aortic, mitral or tricuspid). Results: Clinical characteristics are shown in Figure 1. Mean follow-up was 6.2±4.6 years&5-year mortality occurred in 123 (35%) patients (7 [2%] in-hospital deaths). Cox 5-year survival analysis results are shown in Figure 2A. A receiver operator curve analysis for 5-year mortality showed an area under curve of 0.70 (95% confidence interval 0.64-76, p<0.001). Subsequently, a 5-year risk score (0-7 points) was generated (Figure 2 A); with an increasing risk of mortality at 5 years, based on increasing risk score (Figure 2C). Cardiac reoperation was not associated with worse outcomes. Conclusion: RACD patients undergoing CTS have a high rate of 5-year mortality, despite a low baseline STS score&perioperative mortality. A novel RACD-specific risk score (incorporating higher age, abnormal renal/pulmonary, constrictive pericarditis&need for concomitant mitral valve surgery) provides good discrimination for 5-year survival&could be used for shared-decision making.

BACKGROUND:In obstructive hypertrophic cardiomyopathy, myectomy improves symptoms, quality of life, and left ventricular (LV) outflow tract gradients. We prospectively evaluated the temporal changes in various echo parameters after myectomy. METHODS AND RESULTS:In 173 adults with obstructive hypertrophic cardiomyopathy (53±10 years, 63% men) who underwent myectomy between March 2017 and June 2020, clinical and blinded echo assessment (before and at 12±6 months follow-up) was performed prospectively (SPIRIT-HCM [Quality of Life and Functional Capacity Following Septal Myectomy in Obstructive Patients With Hypertrophic Cardiomyopathy]). Changes in echocardiographic parameters (left atrial volume index, E/e', LV outflow tract gradients, along with average LV global longitudinal strain on apical 2-, 3-, and 4-chamber views and regional LV strain from apical 4-chamber view) were measured in 126 patients. There was significant improvement in left atrial volume index (-6.9 mL/m2 [95% CI, 4-9.7]), E/e' (-2.9 [95% CI, -2.7 to -4.1]) and peak LV outflow tract gradient (-94 mm Hg [95% CI -87 to -100]) from baseline to follow-up (both P<0.001). There was no improvement in basal (0.91% [95% CI, -0.15 to 1.97], P=0.09) and midseptal (-0.98% [95% CI, -1.93 to 0.02], P=0.05) LV strain, worsening in apical septal strain (-4.5% [95% CI, -5.9 to -3.0], P<0.001) and an improvement in LV free wall strain (2.3% [95% CI, 0.67-3.9], P<0.001), with no change in overall LV-global longitudinal strain (0.47% [95% CI, -0.43 to 1.37], P=0.30). There was no correlation between change in LV-global longitudinal strain and change in 6-minute walk time (r=0.12, P=0.24) or Kansas City Cardiomyopathy Questionnaire summary score change (r=0.02, P=0.85), whereas it was significantly associated with change in E/e' (r=0.29, P=0.003). CONCLUSIONS:In patients with obstructive hypertrophic cardiomyopathy, myectomy improved various echocardiography parameters at 1-year; however, LV-global longitudinal strain remained unchanged. REGISTRATION:URL: https://clinicaltrials.gov; Unique identifier: NCT03092843.

Background: Patient reported outcomes (PRO) can assess quality of life (QOL) in obstructive hypertrophic cardiomyopathy (oHCM). In symptomatic oHCM patients, we sought to study the correlation between various PROs, their association with physician reported New York Heart Association (NYHA) class and changes after surgical myectomy. Methods: We prospectively studied 173 symptomatic oHCM patients undergoing myectomy (age 51 years, 62% men) between 3/17-6/20. PROs, including a) Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score b) Patient-Reported Outcomes Measurement Information System [PROMIS] c) Duke Activity Status Index [DASI] & d) European QOL score [EQ-5D], along with NYHA class, 6-min walk test (6MWT) distance and peak left ventricular outflow tract gradient (PLVOTG) were recorded at baseline and 12 month follow-up. Results: The median baseline PRO scores (KCCQ summary, PROMIS physical, PROMIS mental, DASI, EQ-5D) were 50, 67, 63, 25, 50, 37, 44, 25 and 0.61, respectively; 6MWT distance was 366 m. There were significant correlations between various PROs (r-values between 0.66 and 0.92, p < 0.001), but only modest correlations with 6MWT and provokable LVOTG (r-values between 0.2 and 0.5, p < 0.01). At baseline, 35-49% patients in NYHA class II had PROs worse than median, while 30-39% patients in NYHA Class III/IV had PROs better than median. At follow-up, a 20 point improvement in KCCQ summary score was observed in 80%, 4 point improvement in DASI score in 83%, 4 point improvement in PROMIS physical score 86% and a 0.04 point improvement in EQ-5D in 85%); along with improvements in NYHA class (67% in Class I) and peak LVOTG (median 13 mmHg) and 6MWT (median distance 438 m). Conclusions: In a prospective study of symptomatic oHCM patients, surgical myectomy significantly improved PROs, LVOT obstruction, and functional capacity, with a high correlation between various PROs. However, there was high rate of discordance between PROs and NYHA class.

BACKGROUND Obstructive hypertrophic cardiomyopathy (oHCM) is increasingly being diagnosed in elderly patients.OBJECTIVES The authors sought to study long-term outcomes of septal reduction therapies (SRT) in Medicare patients with oHCM, and hospital volume-outcome relation.METHODS Medicare beneficiaries aged >65 years who underwent SRT, septal myectomy (SM) or alcohol septal ablation (ASA), from 2013 through 2019 were identified. Primary outcome was all-cause mortality, and secondary outcomes included heart failure (HF) readmission and need for redo SRT in follow-up. Overlap propensity score weighting was used to adjust for differences between both groups. Relation between hospital SRT volume and short-term and long-term mortality was studied.RESULTS The study included 5,679 oHCM patients (SM = 3,680 and ASA =1,999, mean age 72.9 vs 74.8 years, women 67.2% vs 71.1%; P < 0.01). SM patients had fewer comorbidities, but after adjustment, both groups were well balanced. At 4 years (IQR: 2-6 years), although there was no difference in long-term mortality between SM and ASA (HR: 0.87; 95% CI: 0.74-1.03; P = 0.1), on landmark analysis, SM was associated with lower mortality after 2 years of follow-up (HR: 0.72; 95% CI: 0.60-0.87; P < 0.001) and had lower need for redo SRT. Both reduced HF readmissions in follow-up vs 1 year pre-SRT. Higher-volume centers had better outcomes vs lower-volume centers, but 70% of SRT were performed in low-volume centers.CONCLUSIONS SRT reduced HF readmission in Medicare patients with oHCM. SM is associated with lower redo and better long-term survival compared with ASA. Despite better outcomes in high-volume centers, 70% of SRT are performed in low-volume U.S. centers. (J Am Coll Cardiol 2023;81:105-115)(c) 2023 by the American College of Cardiology Foundation.

Introduction: The 2D echocardiographic features of radiation-associated cardiac disease (RACD) are well-described including aorto-mitral curtain thickness. However, the 3D speckle tracking echocardiographic strain patterns and their predictive risk for all-cause mortality are not well known in RACD. Methods: We studied 441 patients with RACD (63.7 ± 13.4 y; 62.4% female) seen in our institution. Echocardiographic strain patterns of their initial echocardiograms were reviewed. 3D strain analysis using TOMTEC was performed for left ventricle (LV), right ventricle (RV), and left atrium (LA). Primary outcome was all-cause mortality. We constructed 3 Cox regression models: (1) unadjusted; (2) minimally adjusted for age and sex; (3) adjusted for 42 covariates including CV risk factors, cancer history, cardiac treatments, and cardiac function. Results: During a median 6.8 (95%CI 5.7-7.4) years follow-up, 245 patients died. In the unadjusted model, all LV, RV, and LA strain metrics (except for RV free wall strain) were significantly associated with all-cause death. After comprehensive adjustment for 42 covariates, the strain metrics (except for left atrial contraction strain) remained significantly associated with mortality. The strongest predictor for mortality was reduced LV GLS (HR 0.93, 95%CI 0.89-0.96; p <0.001). Conclusions: Abnormal strain patterns in patients with RACD were associated with increased all-cause mortality independently from other known risk factors. Abnormal strain is a distinct feature of radiation-induced cardiac disease, possibly indicating the mechanism of radiation associated cardiac disease. (JED and TSK are first Co-authors)

IntroductionHypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder leading to hypertrophy of the left ventricle excluding other etiologies. Patients can experience exertional chest pain, dyspnea, syncope or even sudden cardiac death (SCD). Traditional medical management consists of beta blockers (BB), nondihydropyridine calcium channel blockers and disopyramide. Mavacamten, a novel cardiac myosin inhibitor, has recently been shown to improve both quantitative and qualitative measures of obstructive HCM allowing some patients to defer septal reduction therapy.Areas coveredThis review delves into the pharmacotherapy of mavacamten, the evidence behind this first-in-class drug for HCM, guidance for clinical usage, and possible future uses for cardiac myosin inhibitors.Expert opinionMavacamten should be incorporated into the standard armamentarium of medications used to treat obstructive HCM. PIONEER-HCM, EXPLORER-HCM and VALOR-HCM demonstrated improvements in peak LVOT gradient both at rest and post-exercise, cardiac biomarkers, New York Heart Association (NYHA) functional class and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. Unlike other medications utilized for treatment, mavacamten can delay or even obviate the need for septal reduction therapy.

Background: Few studies have systematically assessed quality of life (QOL) in hypertrophic cardiomyopathy (HCM) patients not meeting the septal reduction therapy (SRT) threshold, but require avoiding isometric exertion and weightlifting. We prospectively studied a newly developed QOL instrument to examine the associations between patient characteristics and self-reported QOL scores in HCM patients not anticipated to undergo SRT for at least 6 months. Methods: A single-center, prospective sample of 51 adult HCM patients (54±14 years, mean interventricular septum thickness = 1.7±0.4cm, 65% with left ventricular outflow tract (LVOT) obstruction, mean provokable LVOT gradient 65±42 mmHg, 59% men) completed a baseline 70-item QOL instrument, adapted from validated QOL questionnaires. All patients signed informed consent. Results: Mean self-reported QOL scores (on a 5-point Likert scale with higher scores indicating higher QOL) were as follows: physical function (3.5±1), depression (3.7±1), anxiety (3.6±1), post-traumatic stress disorder (PTSD) (3.7±1), social function (4.1±1), spiritual acceptance of diagnosis (3.8±1), self-efficacy (4±1), and resilience (4±1). Men vs. women reported higher physical function (3.9±1 vs. 2.9±1), less depression (4±1 vs. 3.3±1), less anxiety (3.8±1 vs. 3.3±1), and higher social function (4.3±0.7 vs. 3.8±1) (all p<0.05). Patients with obstructive HCM reported lower physical function scores (3.3±0.8) vs. non-obstructive HCM (3.8±0.8), p=0.03. Symptomatic patients reported lower physical function (3.2±0.8 vs. 4.3±0.5), social function (3.8±0.8 vs. 4.5±0.6) and worse depression (3.5±0.7 vs. 4.3±0.6), anxiety (3.4±0.8 vs. 4.1±0.7) and PTSD (3.5±0.8 vs. 4.3±0.9) scores (all p<0.01). Presence of an implantable cardioverter defibrillator (ICD) was associated with lower vs. higher physical (2.9±0.4 vs. 3.5±1) and social function (3.6±1 vs. 4.1±1) (all p<0.05). Conclusion: In HCM patients not requiring SRT, higher physical function scores were significantly associated with a better self-perceived overall health. Being a woman, having LVOT obstruction, presence of a defibrillator and presence of symptoms was significantly associated with worse perceived physical and social function.

Introduction: We sought to study prevalence of conduction disease and permanent pacemaker (PPM) in patients presenting with radiation-associated cardiac disease (RACD) and its impact on long-term survival. Methods: We studied 699 patients with documented RACD (prior chest radiotherapy at a mean of 22 years prior) evaluated at a single center from 1998-2018. Conduction abnormalities and PPM at baseline were recorded, along with cardiac procedures performed during follow-up. Death was the primary endpoint. Results: Patients were divided into 4 groups: 1) no procedure during follow-up 2) 1 valve or coronary artery bypass grafting (CABG) or 1-valve+CABG surgery 3) Multivalve+/-CABG+/-aortic/pericardial surgery and 4)Trans catheter aortic valve replacement (TAVR). Relevant characteristics and outcomes are shown in Table. In total, 183 patients had a PPM (82 [45%] implanted during follow-up). Over a mean follow-up of 5±4 years (range 0-21 years), 370 patients (53%) patients died. On survival analysis, presence of PPM (HR 1.26 [1.03-1.54], p=0.03) was independently associated with higher long-term mortality; 109 (60%) patients with PPM died in the long-term vs. those without261 (51%, log-rank p-value=0.03). Conclusion: RACD patients have a high rate of mortality during longer-term follow-up, despite a low calculated preoperative risk. In addition, they have a high rate of conduction abnormalities with a high proportion requiring PPM, including at baseline, irrespective of need for a cardiac procedure. Presence of a PPM was independently associated with long-term risk of mortality.

Introduction: Health-related quality of life (QOL) outcomes in thoracic aortopathy (TA) patients who have not yet met the surgical threshold, but need significant lifestyle/weightlifting restrictions, are not well understood. We prospectively studied a newly developed QOL instrument to examine the associations between patient characteristics and self-reported QOL scores in TAA patients not anticipated to undergo aortic intervention for at least 6 months. Methods: All 128 adult TA patients (57±10 years, mean thoracic aortic diameter = 4.4±0.3cm, 77% male) were recruited prospectively as a single center and completed a baseline QOL instrument. The 70-item QOL instrument was adapted from validated QOL questionnaires. All patients signed informed consent. Results: Mean QOL scores for the eight scales of the instrument (range, 0 to 5, with 5 reflecting best function/QOL) were self-reported and as follows: physical function (4.2±0.8), depression (3.9±0.8), anxiety (3.8±0.9), post-traumatic stress disorder (PTSD) (4.1±0.9), social function (4.4±0.6), spiritual acceptance of diagnosis (3.6±0.7), self-efficacy (4.2±0.7), and resilience (4.1±0.6). Higher physical function score was associated with higher emotional (β=0.67, p<0.001) and social function (β=0.52, p<0.001) scores. Higher physical function (β=0.535), less depression (β=0.47), less anxiety (β=0.45), less PTSD (β =0.43), and higher social function (β=0.281) scores were all significant predictors of higher perceived overall health (all p<0.001). The degree of TA dilatations had no significant association with lower social function (β=-0.89, p=0.65), lower self-efficacy (β=-2.73, p=0.21), or lower resilience. Conclusion: In TA patients not requiring aortic surgery, higher physical, emotional, and social function scores were significantly associated with self-perceived overall health. However, the actual size had no significant association with these metrics. Further research is needed to elucidate trends of patient-reported QOL and their correlation to clinical/imaging changes.