Dosing and safety profile of aficamten in symptomatic obstructive hypertrophic cardiomyopathy: results from from SEQUOIA‐HCM

Background: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA‐HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). Methods and Results: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5–20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site‐interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8–24), and washout (weeks 24–28), and included major adverse cardiac events, new‐onset atrial fibrillation, implantable cardioverter‐defibrillator discharges, LVEF <50%, and treatment‐emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5‐, 10‐, 15‐, and 20‐mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by −0.9% (95% CI, −1.3 to −0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per‐protocol dose reduction for site‐interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment‐emergent adverse events were similar between treatment groups, including atrial fibrillation. Conclusions: A site‐based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA‐HCM

A Case of Muscular Dystrophy with Dilated Cardiomyopathy: Do Not Forget Your Basics

Introduction: Becker muscular dystrophy (BMD) is an X-linked recessive disorder with dystrophin mutation. Dilated Cardiomyopathy (DCM) is a leading cause of death in BMD patients. Herein, we are presenting a patient with BMD that initially sought medical attention for acute onset of systolic heart failure that highlights the importance of careful clinical assessment and appropriate work up. Case Report: A 29-year-old male with medical history of asthma presented to the hospital with progressive dyspnea and leg swelling. He was diagnosed with DCM with an LVIDD of 6.5 cm and LV ejection fraction of 20-25% by echocardiogram. Coronary angiogram revealed no coronary artery disease. Initial blood work and electrocardiogram are below (Figure). Cardiac MRI showed severely reduced biventricular systolic function with near circumferential, sub-epicardial to mid-myocardial delayed gadolinium enhancement (Figure). Initial differential diagnosis included prior myocarditis vs. burnt out sarcoidosis. It was subsequently noted that patient began recurrently falling with muscle weakness from age 20 years with chronically elevated AST and CK. His exam was notable for atrophy of the bilateral quadriceps muscles, decreased muscular strength and bilateral calves hypertrophy. Electromyography showed evidence of chronic proximal and distal myopathy, predominantly affecting the lower extremity. Skeletal muscle biopsy showed fascicular atrophy and hypertrophy, focal endomyosial fibrosis and an increase of central nuclei without evidence of inflammation or granuloma which was most suggestive of a muscular dystrophy. Genetic testing was then completed and showed hemizygous dystrophin mutation confirming diagnosis of BMD. BMD has a diffuse phenotype and should be considered in young patients with cardiomyopathy and chronically elevated CK and AST. A thorough clinical history, exam, and CMR can assist in directing need for skeletal muscle biopsy and subsequent genetic testing

Ventricular Assist Device Patient Phenotypes: What Attributes Describe Long Term Survival?

Purpose: Presently, 50% of patients on LVAD support are alive on therapy at 5 years. While preoperative (preop) variables can predict short term (ST) survival, correlates of long term (LT) survival remain poorly characterized. Using Intermacs-STS, we aim to identify preop and postoperative correlates of LT survival. Methods: Patients (n=16474) undergoing LVAD implant (2012-18) in Intermacs-STS were categorized as ST (survival ≤1 year postoperative, n=7483), mid-term (MT, 1-3 years, n=5976) and LT (\u3e3 years, n=3015) survivors. Pre-implant characteristics and events during support were compared between the three groups to identify mortality correlates. Results: Compared with patients dying in the ST, LT survivors were more likely to be younger, not listed for transplant, with higher BSA and VAS scores and several lower risk preop characteristics but differences between MT and LT survivors were not clinically significant (table). On multi-variable analysis, patients suffering post-LVAD stroke (HR 1.42, image), any major infection (HR 1.13), pump related infection (HR 1.19), and/or device malfunction (HR=1.22) (all p\u3c0.001) were less likely to live \u3e1 year, as were patients with a history of pulmonary disease (HR 1.19, 0.01), cancer (HR 1.26, p=0.01), CABG (HR 1.24, p\u3c0.001), hepatitis (HR 1.54, p=0.002) and active smoking (1.44, p \u3c0.001). Conclusion: The preop clinical features of ST and LT survivors vary significantly. Preop characteristics mainly select out early deaths, failing to accurately characterize survival after 1 year. LT survival is heavily influenced by device complications and pre-existing medical co-morbidities

Evaluation of a New Aptamer-Based Array for Soluble Suppressor of Tumorgenicity (ST2) and N-terminal Pro-B-Type Natriuretic Peptide (NTproBNP) in Heart Failure Patients

Background: Recent advances in multi-marker platforms offer faster data generation, but the fidelity of these methods compared to the ELISA is not established. We tested the correlation and predictive performance of SOMAscan vs. ELISA methods for NTproBNP and ST2. Methods: Patients ≥ 18 years with heart failure and ejection fraction < 50% were enrolled. We tested the correlation between SOMA and ELISA for each biomarker and their association with outcomes. Results: There was good correlation of SOMA vs. ELISA for ST2 (ρ = 0.71) and excellent correlation for NTproBNP (ρ = 0.94). The two versions of both markers were not significantly different regarding survival association. The two ST2 assays and NTproBNP assays were similarly associated with all-cause mortality and cardiovascular mortality. These associations remained statistically significant when adjusted for MAGGIC risk score (all p < 0.05). Conclusion: SOMAscan quantifications of ST2 and NTproBNP correlate to ELISA versions and carry similar prognosis. Graphical abstract: [Figure not available: see fulltext.

Survival and Predictors of Mortality in Patients Undergoing RVAD Explant in IMACS.

Purpose: Survival in patients requiring RVAD support is known to be poor. However, outcomes in those undergoing subsequent RVAD explant and predictors of mortality remain unknown. Methods: Of 16482 patients in IMACS, 723 patients had an isolated RVAD (n=29) or BiVAD (n=694) in place. Using Kaplan Meier methods, survival was estimated for the LVAD-only cohort and within the subgroup of RVAD/BiVAD patients with and without RVAD explant. Correlates of mortality in the RVAD explant group were identified with Cox multivariable regression. Results: Within the BiVAD group, 240 patients (33%) had an RVAD explant. Of these, 221 (92%) were performed for RV recovery, 17 (7.1%) for device malfunction and 2 (0.8%) were for other reasons. Survival at 1Y was 53±2.0% in the BiVAD group vs. 82±0.3% in LVAD-only patients (p\u3c0.0001). Within the BiVAD group, patients undergoing RVAD explant had equivalent survival (1Y=54±2.5%) to those with ongoing BiVAD support (1Y=52±3.4%, p=0.54). BiVAD patients who died after RVAD explant were older, more likely to be BTT, and had higher preimplant creatinine (table). On multivariable analysis, older age, higher preimplant pulmonary systolic pressure, explant for RVAD dysfunction, and BTT indication predicted death after RVAD explant (table). Within the subgroup of BTT BiVAD (n=51) patients undergoing RVAD explant, survival was only 62% at 3 months. Conclusion: Patients undergoing RVAD explant, even for RV-recovery, have very poor survival. Patients who are transplant eligible with signs of RVAD dysfunction should be given urgent listing status. Rather than RVAD explant, BTT patients with signs of RV recovery may be better served with transplant

Heart transplant recipients with confirmed 2019 novel coronavirus infection: The Detroit experience

A chronic immunosuppressed state as in solid organ transplant recipients is a reported risk factor for the novel 2019 coronavirus infection. Patients with a history of orthotopic heart transplant (OHT) at a tertiary care transplant center in Detroit, Michigan were retrospectively reviewed from March until May 2020. Clinical parameters and outcomes of 5 OHT recipients and one combined heart-lung recipient with confirmed SARS-CoV-2 were obtained. The cohort was predominately African American males with median age of 59 years (interquartile range, 48.25-73.25). All patients were classified as having mild-moderate disease; none required intubation or ICU admission with no deaths. The most common presenting symptoms were fever and shortness of breath 83% (n = 5), followed by cough and chills 67% (n = 4). All admitted patients (n = 5) received hydroxychloroquine and 3 received high-dose steroids. Antimetabolites were held for 2 patients (33.3%). The calcineurin inhibitor trough goal was decreased in only 1 patient; 3 other patients, without change in goal, required calcineurin inhibitor dosage reduction. Two patients requiring readmission presented 7 and 23 days after initial symptoms onset. In conclusion, our experience with OHT patients infected by the SARS-CoV-2 virus did not have an elevated risk of severe infection. Impact of modifying immunosuppression remains unclear