Faculty Bibliography

BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) increases risk of cardiovascular disease (CVD). Despite the high prevalence of MASLD among Hispanic populations, there is a scarcity of research on the associations between non-invasive markers of liver disease and incident CVD and all-cause mortality. In this study we investigated the association of liver related biomarkers with CVD events and all-cause mortality in a population based Hispanic/Latino cohort. METHODS:We included 15,216 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 years with no pre-existing CVD. The composite outcome combined incident CVD and all-cause mortality. Having "elevated ALT/AST" was defined as ALT > 40 IU/mL or AST > 37 IU/mL for males, and ALT or AST > 31 IU/mL for females. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) relating our composite outcome to elevated ALT/AST, FIB-4 and MASLD. Using interaction terms, we assessed whether the relationship between elevated ALT/AST and the composite outcome differed by MASLD status. RESULTS:The study population was 40 years old on average, 52.7% female and had 740 CVD or all-cause mortality events. Elevated FIB-4 had the strongest association with incident CVD or all-cause mortality (comparing FIB-4 > 2.67 versus ≤ 2.67, HR:3.47; CI:2.34-5.14). Elevated AST was found to be associated with incident CVD or all-cause mortality (HR:1.53; CI:1.14-2.05). MASLD was not associated with incident CVD or all-cause mortality (HR:1.14; CI: 0.94-1.40), but it was associated with incident CVD alone (HR:1.69; CI:1.19-2.39). The relationship between elevated ALT/AST and incident or all-cause mortality was modified by MASLD, such that the strongest association between elevated ALT/AST and incident CVD or all-cause mortality was in the absence of MASLD (HR:1.95; CI:1.20-3.18). CONCLUSIONS:Among Hispanic adults FIB-4 was strongly associated with CVD or all-cause mortality and among persons without MASLD, elevated ALT/AST were associated with CVD or all-cause mortality.

BACKGROUND:The clinical benefits of mavacamten in patients with obstructive hypertrophic cardiomyopathy previously treated with advanced therapies are not established. METHODS:Clinical and echocardiographic outcomes of patients treated with mavacamten for left ventricular outflow obstruction for at least 8 weeks were assessed based on prior treatment with one or more advanced therapies: disopyramide, septal myectomy, alcohol septal ablation, dual-chamber ventricular pacing with short atrioventricular delay; we also evaluated patients with left ventricular outflow obstruction that emerged as major driver of symptoms after aortic valve replacement. RESULTS:=0.31). CONCLUSIONS:Mavacamten is a safe and effective treatment for symptomatic left ventricular outflow obstruction in patients with obstructive hypertrophic cardiomyopathy resistant to previous advanced pharmacologic therapy, surgery, or alcohol septal ablation or who develop manifest left ventricular outflow obstruction after aortic valve replacement.

BACKGROUND:Disopyramide, used in obstructive hypertrophic cardiomyopathy (oHCM) for its negative inotropic properties mediated by its reduction in cytosolic calcium, has been recommended for decades as an option to relieve resistant obstruction. Aficamten is a selective cardiac myosin inhibitor that reduces hypercontractility directly by reducing myosin-actin interaction. OBJECTIVES/OBJECTIVE:This study aims to investigate the safety and efficacy of concomitant use and withdrawal of disopyramide in patients with symptomatic oHCM receiving aficamten. METHODS:Patients with oHCM enrolled in REDWOOD-HCM Cohort 3 (open-label), SEQUOIA-HCM (placebo-controlled), and FOREST-HCM (open-label) were analyzed. The authors identified 4 groups, each with patients symptomatic despite background therapy with disopyramide who received: 1) disopyramide plus aficamten and subsequent aficamten withdrawal per protocol (Diso-Afi Withdrawal); 2) disopyramide plus placebo (Diso-Pbo); 3) aficamten plus disopyramide with subsequent disopyramide withdrawal (Afi-Diso Withdrawal); and 4) continued both disopyramide and aficamten (Diso+Afi Continuous). Assessments were performed at baseline, after aficamten or placebo add-on therapy, and after washout (except at week 24 for Diso+Afi Continuous group). RESULTS:Overall, 50 unique patients from 3 trials enrolled, resulting in 93 subjects (segments) across 4 groups: Diso-Afi Withdrawal (n = 29), Diso-Pbo (n = 20), Afi-Diso Withdrawal (n = 17), and Diso+Afi Continuous (n = 27); mean disopyramide dose was 331 ± 146 mg/d. The addition of aficamten to disopyramide alleviated left ventricular outflow tract (LVOT) obstruction (resting: change [Δ] in least squares mean -27.0 ± 3.6, Valsalva: Δ least squares mean -39.2 ± 5.0, both P < 0.0001), symptoms (≥1 NYHA functional class improvement: 77.8% [95% CI: 61.0-94.5]; P < 0.0001; Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score: 12.3 ± 3.3 [P < 0.001]), and reduced N-terminal pro-B-type natriuretic peptide ratio: 0.35 [95% CI: 0.26-0.48]; P < 0.0001, and there was no significant change with placebo. Withdrawal of aficamten while on disopyramide resulted in return of LVOT obstruction, worsening of symptoms, and increase in NT-proBNP to baseline values. Conversely, withdrawal of disopyramide while on aficamten did not impact efficacy. There were no safety events associated with aficamten or disopyramide withdrawal, and no episodes of atrial fibrillation after disopyramide withdrawal. CONCLUSIONS:In this cohort of patients with symptomatic oHCM with persistent LVOT obstruction, combination therapy with aficamten and disopyramide was safe and well tolerated but did not enhance clinical efficacy vs aficamten alone. For such oHCM patients, aficamten treatment may be considered with an option to discontinue disopyramide. (Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM [REDWOOD-HCM]; NCT04219826) (Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [SEQUOIA-HCM]; NCT05186818) (Open-label Extension Study to Evaluate the Long-term Safety and Tolerability of Aficamten in Adults With HCM [FOREST-HCM]; NCT04848506).

BACKGROUND:Calcific aortic valve disease (CAVD), and ensuing severe aortic stenosis (AS), is the foremost valvular disorder of aging, yet preventive therapies are lacking. A better understanding of the molecular underpinnings of aortic valve calcification (AVC) is necessary to develop pharmacologic interventions. METHODS AND RESULTS/RESULTS:=0.009). CONCLUSIONS:This study of older adults newly identified and largely replicated associations of 3 circulating proteins with calcific aortic valve disease, of which the relationship of plasma KLKB1 may have a causal basis. Additional investigation is necessary to determine if KLKB1 could be harnessed for calcific aortic valve disease therapeutics.

Hypertrophic cardiomyopathy is a common but underrecognized cardiac disorder characterized by a heterogenous phenotype that includes increased left ventricular thickness, outflow obstruction, diastolic dysfunction, and arrhythmia. Hypertrophic cardiomyopathy is often heritable and associated with pathogenic variants in sarcomeric genes. While not curable, an integrated approach involving medical, interventional, and surgical care can have a considerable impact on disease burden, quality of life, and mortality. This review provides a practical overview of important topics in hypertrophic cardiomyopathy, including evaluation of differential diagnosis, imaging, provocation of left ventricular outflow obstruction, treatment of obstructive and nonobstructive hypertrophic cardiomyopathy with negative inotropic therapy and myosin inhibition, as well as surgical and interventional approaches to septal reduction and mitral valve intervention.

BACKGROUND:Disopyramide is used to treat heart failure symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM) with known medium-term efficacy and safety, while long-term outcomes are unknown. METHODS AND RESULTS/RESULTS:=0.51). Ventricular tachyarrhythmias and left ventricular systolic dysfunction were uncommon (n=3 and n=1) and were not attributed to disopyramide. Death on disopyramide was exceedingly rare (n=3 [5%]) and non-HCM-related occurring at age ≥90 years. CONCLUSIONS:In patients with obstructive HCM, disopyramide is safe and effective at relieving heart failure symptoms from outflow obstruction in a subgroup of patients who were maintained on disopyramide for >5 years.

BACKGROUND/UNASSIGNED:There is controversy about risk of malignant arrhythmias and stroke in patients with apical aneurysms in hypertrophic cardiomyopathy (HCM). OBJECTIVES/UNASSIGNED:The aim of this study was to estimate the associations of aneurysm size and major HCM risk factors with the incidence of lethal and potentially lethal arrhythmias and to estimate incidence of unexplained stroke. METHODS/UNASSIGNED:In 108 patients (age 57.4 ± 13.5 years, 37% female) from 3 HCM centers, we assessed American Heart Association/American College of Cardiology guidelines risk factors and initial aneurysm size by echocardiography and cardiac magnetic resonance imaging and assessed outcomes after median 5.9 (IQR: 3.7-10.0) years. RESULTS/UNASSIGNED:and also without risk factors VT, VF, or SCD occurred in only 2.5%. Clinical atrial fibrillation (AF) was prevalent, occurring in 49 (45%). Stroke was commonly associated with AF. Stroke without conventional cause had an incidence of 0.5%/year. Surgery in 19% was effective in reducing symptoms. VT ablation and surgery were moderately effective in preventing recurrent VT. CONCLUSIONS/UNASSIGNED:Risk factors and aneurysm size were associated with subsequent VT, VF, or SCD. Patients with aneurysms in the lowest tercile of size have a low cumulative 5-year risk. Clinical AF occurred frequently. Stroke prevalence in absence of known stroke etiologies is uncommon and comparable to risk of severe bleeding.

BACKGROUND:Latent left ventricular outflow tract obstruction (LVOTO) is an important cause of symptoms in patients with hypertrophic cardiomyopathy (HCM) but can be challenging to provoke. OBJECTIVES AND METHODS/OBJECTIVE:To examine the value of postprandial resting and stress echocardiography and utilization of invasive or enhanced drug therapies (surgical myectomy, alcohol septal ablation, disopyramide, and mavacamten) in patients with postprandial LVOTO. Consecutive HCM patients without LVOTO underwent routine and postprandial echocardiography at rest, with provocation (Valsalva and standing) and after symptom-limited treadmill stress. RESULTS:Among 252 patients (mean age, 58 years, 39% women), postprandial LVOT gradients were higher compared with routine echocardiography at rest (median, 9.0 [0-38.0] vs 0 [0-14.0] mm Hg; P < .0001) and with provocation (18.5 [0-70.3] vs 1.5 [0-41.0] mm Hg; P < .0001). Postprandial exercise stress echocardiogram (PPXSE) gradients were higher in a subset of 44 patients who underwent both postprandial and fasting stress echocardiography (47.0 [5.3-81.0] vs 17.5 [0-46.0] mm Hg; P < .0001). In total, 49 (19.5%) patients achieved the ≥50 mm Hg threshold under routine conditions (rest/provocation); 90 (35.7%) additional patients achieved postprandial gradients ≥50 mm Hg (rest/provocation/exercise), 38 (15.1%) with PPXSE alone. A total of 71 patients were treated with 91 invasive or enhanced drug therapies, 32 (45.1%) of whom had gradients ≥50 mm Hg only after eating (rest/provocation) and 8 (11.3%) only with PPXSE, with symptom relief in the majority. CONCLUSIONS:Postprandial echocardiography was useful at unmasking LVOTO in more than one-third of patients who did not have high gradients otherwise. Eating before echocardiography is a powerful provocative tool in the evaluation of patients with HCM.

Ventricular arrhythmias are commonly associated with hypertrophic cardiomyopathy with and without midventricular obstruction. Although the overall prognosis is relatively good with an annual mortality rate <1%, the propensity to potentially fatal ventricular arrhythmias (ventricular tachycardia) is the most feared complication. Electrical storms are a severe manifestation of ventricular arrhythmias, with poor outcomes. In this report, we present a case of a young patient with non-obstructive hypertrophic cardiomyopathy who presents after a syncopal episode and is found to have an electric storm that is refractory to medical therapy.