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Compared to normal volunteers, coronary vasodilation reserve is reduced in patients with hypertrophic cardiomyopathy but not in rowing athletes with left ventricular hypertrophy. Positron emission tomography can provide complementary information to distinguish between the athlete's heart and hypertrophic cardiomyopathy. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To investigate the molecular genetic basis of the cause of disease in a family with hypertrophic cardiomyopathy. BACKGROUND--Mutation within the beta cardiac myosin heavy chain gene has been shown to be the pathogenetic mechanism underlying the disease in several families, though clear evidence of heterogeneity has been reported. PATIENTS--A family with a history of hypertrophic cardiomyopathy. RESULTS AND CONCLUSION--This paper reports a mutation at aminoacid position 908 within exon 23 of the beta cardiac myosin heavy chain gene, resulting in a conversion of a leucine to valine. This base substitution was identified in an individual with a confirmed family history but with equivocal symptoms of the disease. Inheritance of the mutation by his symptom free juvenile offspring demonstrates the application of the technique to presymptomatic diagnosis. [ABSTRACT FROM PUBLISHER]

BACKGROUND One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.) [ABSTRACT FROM AUTHOR]

Myocardial infarction in persons under the age of 45 years accounts for 6% to 10% of all myocardial infarctions in the United States. In this age group, it is predominantly a disease of men. Important risk factors include a family history of myocardial infarction before age 55 years, hyperlipidemia, smoking, and obesity. Unlike older patients, approximately half of young patients have single-vessel coronary disease, and in up to 20%, the cause is not related to atherosclerosis. Coronary angiography may be warranted in young patients with myocardial infarction to define the anatomy of the disease and to permit optimal management. [ABSTRACT FROM AUTHOR]

Obstructive hypertrophic cardiomyopathy (HCM) is associated with significant morbidity attributed to left ventricular outflow tract (LVOT) obstruction. Although alcohol septal ablation (ASA) is an established interventional treatment, mavacamten, a novel cardiac myosin inhibitor, has emerged as a noninvasive pharmacologic alternative. Understanding the comparative efficacy of these 2 treatments is important for optimizing patient care. This single-center retrospective study assessed the hemodynamic and functional changes in adult patients with obstructive HCM treated with ASA (n = 58) or mavacamten (n = 36) from July 2012 to May 2024. Outcomes, including changes in LVOT gradient, left ventricular ejection fraction, mitral regurgitation (MR) severity, and New York Heart Association (NYHA) class, were collected at baseline, 16 weeks, and after 32 weeks of treatment. ASA and mavacamten were associated with over 70% reductions in Valsalva-induced LVOT gradient and MR after 32 weeks. The maximal effect of ASA on LVOT gradient was observed at 16 weeks, whereas mavacamten's peak effect was noted after 32 weeks. MR severity improved similarly in both cohorts (p <0.01). Patients who underwent ASA had a poorer baseline NYHA functional class than their counterparts; however, each treatment significantly improved LVOT gradients (p <0.001) and average NYHA class after 32 weeks (p <0.001). The average left ventricular ejection fraction was comparable at baseline and after 32 weeks between the 2 groups. Patients treated with ASA were older than those treated with mavacamten (68.5 vs 60.8 years, p <0.001). In patients with obstructive HCM, ASA and mavacamten yield significant and comparable improvements in hemodynamics and functional status after 32 weeks., Competing Interests: Declaration of competing interest Dr. Baljash Cheema has served as a consultant for Caption Health, Inc and Viz.ai; speaker with honorarium from Bristol Myers Squibb; has served on an Advisory Board for Novo Nordisk; and is an advisor with equity interest in Healthspan, Inc and Zoe Biosciences. The remaining authors declare no conflicts of interest related to this study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aims: Long-term safety and efficacy of mavacamten in patients with obstructive hypertrophic cardiomyopathy (HCM) are unknown. MAVA-LTE (NCT03723655) is an ongoing, 5-year, open-label extension study designed to evaluate the long-term effects of mavacamten., Methods: Participants from EXPLORER-HCM (NCT03470545) could enrol in MAVA-LTE upon study completion., Results: At the latest data cut-off, 211 (91.3%) of the 231 patients originally enrolled in MAVA-LTE still received mavacamten. Median (range) time on study was 166.1 (6.0-228.1) weeks; 185 (80.1%) and 99 (42.9%) patients had completed the Week 156 and 180 visits, respectively. Sustained reductions from baseline to Week 180 occurred in left ventricular outflow tract gradients [mean (standard deviation): resting, -40.3 (32.7) mmHg; Valsalva, -55.3 (33.7) mmHg], N-terminal pro B-type natriuretic peptide [median (interquartile range): -562 (-1162.5, -209) ng/L], and EQ-5D-5L score [mean (standard deviation): 0.09 (0.17)]. Mean left ventricular ejection fraction (LVEF) decreased from 73.9% (baseline) to 66.6% (Week 24) and 63.9% (Week 180). At Week 180, 74 (77.9%) of the 95 patients improved by at least one New York Heart Association class from baseline. Over 739 patient-years exposure, 20 patients (8.7%; exposure-adjusted incidence: 2.77/100 patient-years) experienced 22 transient reductions in LVEF to <50% resulting in temporary treatment interruption (all recovered LVEF of ≥50%). Five (2.2%) patients died (all considered unrelated to mavacamten)., Conclusions: Long-term mavacamten treatment resulted in sustained improvements in cardiac function and symptoms in patients with obstructive HCM, with no new safety concerns identified. Transient, reversible reductions in LVEF were observed in a small proportion of patients during long-term follow-up., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The current generation of large language models (LLMs) has limited chemical knowledge. Recently, it has been shown that these LLMs can learn and predict chemical properties through fine-tuning. Using natural language to train machine learning models opens doors to a wider chemical audience, as field-specific featurization techniques can be omitted. In this work, we explore the potential and limitations of this approach. We studied the performance of fine-tuning three open-source LLMs (GPT-J-6B, Llama-3.1-8B, and Mistral-7B) for a range of different chemical questions. We benchmark their performances against "traditional" machine learning models and find that, in most cases, the fine-tuning approach is superior for a simple classification problem. Depending on the size of the dataset and the type of questions, we also successfully address more sophisticated problems. The most important conclusions of this work are that, for all datasets considered, their conversion into an LLM fine-tuning training set is straightforward and that fine-tuning with even relatively small datasets leads to predictive models. These results suggest that the systematic use of LLMs to guide experiments and simulations will be a powerful technique in any research study, significantly reducing unnecessary experiments or computations., Competing Interests: K. M. J. and A. S. A. have been contractors for OpenAI (as part of the red teaming network). K. L. S. is a consultant for Transition Bio., (This journal is © The Royal Society of Chemistry.)

This study presents an elderly man with sequential hemodynamic obstructions caused by hypertrophic cardiomyopathy and aortic stenosis. Septal reduction therapy was performed to avoid outflow tract obstruction associated with potential future transcatheter aortic valve replacement. This case highlights the importance of resolving outflow tract obstruction during assessment of aortic valve disease., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Standard-of-care (SoC) medications for the treatment of obstructive hypertrophic cardiomyopathy (oHCM) are recommended as first-line therapy despite the lack of evidence from controlled clinical trials and well known off-target side effects., Objectives: We describe the impact of SoC therapy downtitration and withdrawal in patients already receiving aficamten in FOREST-HCM (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in Hypertrophic Cardiomyopathy; NCT04848506)., Methods: Patients receiving SoC therapy (beta-blocker, nondihydropyridine calcium-channel blocker, and/or disopyramide) were eligible for protocol-guided SoC downtitration and withdrawal at the discretion of the investigator and after achieving a stable dose of aficamten for ≥4 weeks. Successful SoC withdrawal was defined as at least a 50% dose-reduction in ≥1 medication. Adverse events (AEs) were prospectively evaluated 1 to 2 weeks after any SoC withdrawal., Results: Of 145 patients with oHCM who were followed for at least 24 weeks (mean age 60.5 ± 13.2 years; 44.8% female; 42% NYHA functional class III), 136 (93.8%) were receiving ≥1 SoC therapy; of those, 64 (47%) had an attempt at withdrawal, with 59 (92.2%) successful. Thirty-eight (64.4%) patients completely discontinued ≥1 medication, and 27 (45.8%) achieved aficamten monotherapy with 2 later restarting a SoC medication. There were no significant differences in baseline characteristics on day 1 in FOREST-HCM in those with a SoC-withdrawal vs no-withdrawal attempt. In patients who underwent successful SoC therapy withdrawal, NYHA functional class improved by ≥1 class in 79.2% from baseline, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score improved to 83.0 ± 15.8 points, and resting and Valsalva left ventricular outflow tract gradient improved to 14.3 ± 10.9 and 32.9 ± 21.4 mm Hg, respectively. N-terminal pro-B-type natriuretic peptide levels improved to a median of 220.0 pg/mL (Q1-Q3: 102.0-554.0.0 pg/mL) and high-sensitivity troponin I improved to a median of 6.0 ng/L (Q1-Q3:3.5-10.7 ng/L). Downtitration and withdrawal of SoC therapy did not impact these results (all P values for change were >0.05), and these changes were similar in patients who did not undergo SoC therapy withdrawal. There were no serious AEs attributed to SoC withdrawal and treatment emergent AEs were similar between groups., Conclusions: In FOREST-HCM, one-half of the patients with oHCM attempted downtitration and withdrawal of SoC medications while receiving aficamten treatment, with infrequent instances of resumption of SoC. Stopping and dose reduction of SoC medications were well tolerated with no adverse consequences in clinical measures of efficacy (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in Hypertrophic Cardiomyopathy [FOREST-HCM]; NCT04848506)., Competing Interests: Funding Support and Author Disclosures The FOREST-HCM trial is funded by Cytokinetics, Incorporated. Dr Masri has received consulting/advisor fees from Tenaya, Attralus, Cytokinetics, Bristol Myers Squibb, Eidos, Pfizer, Haya, Lexion, BioMarin, Alexion, and Ionis; and has received research grants from Ionis, Pfizer, Cytokinetics, and Attralus. Dr Choudhury has received advisor fees from Cytokinetics. Dr Barriales-Villa has received consulting/advisor fees from MyoKardia/Bristol Myers Squibb. Dr Elliott has received consulting fees from Bristol Myers Squibb, Pfizer, and Cytokinetics; has received speaker fees from Pfizer; and has received an unrestricted grant from Sarepta. Dr Maron has received consulting/advisor fees from Imbria, Edgewise, and Biomarin; and has received steering committee fees for SEQUIOA-HCM from Cytokinetics, Incorporated. Dr Nassif has received research and grant support from AstraZeneca and Cytokinetics; and has received consulting/advisory fees from Vifor and Cytokinetics. Dr Oreziak has received investigator fees from Cytokinetics and MyoKardia/Bristol Myers Squibb. Dr Owens has received consulting/advisor fees from Bristol Myers Squibb; and has received research grants from Bristol Myers Squibb, Cytokinetics, Novartis, and Actelion Pharmaceuticals. Dr Saberi has received consulting fees from Bristol Myers Squibb and Cytokinetics. Dr Tower-Rader has received research grants from Bristol Myers Squibb and Cytokinetics. Dr Rader has received consulting fees/honoraria from Medtronic, Cytokinetics, Bristol Myers Squibb, and Recor. Dr Garcia-Pavia has received Speakers Bureau fees from Bristol Myers Squibb, Pfizer, BridgeBio, Ionis, AstraZeneca, NovoNordisk, Intellia, and Alnylam; has received consulting fees from Bristol Myers Squibb, Cytokinetics, Rocket Pharma, Lexeo Therapeutics, Pfizer, BridgeBio, Daiichi-Sankyo, Neurimmune, Alnylam, AstraZeneca, Novo Nordisk, Attralus, Intellia, Idoven, General Electric, and Alexion; and has received research/educational support to his institution from Pfizer, BridgeBio, NovoNordisk, AstraZeneca, Intellia, and Alnylam. Dr Olivotto has received Speakers Bureau fees from Bristol Myers Squibb, Amicus, and Genzyme; has received consulting/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, Rocket Pharma, and Lexeo; and has received research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, Chiesi, and Boston Scientific. Dr Wang has received Speakers Bureau fees from Bristol Myers Squibb; has received consulting/advisor fees from Bristol Myers Squibb and Cytokinetics; and has received research grants from Bristol Myers Squibb, Cytokinetics, and Abbott Vascular. Drs Heitner, Jacoby, Kupfer, Malik, Melloni, Meng, and Wei are employees of and hold stock in Cytokinetics Incorporated. Dr Sherrid has received consulting fees/honoraria from Pfizer Inc; and has served as a consultant for Cytokinetics Inc without payment. 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: Aficamten is a cardiac myosin inhibitor that mitigates left ventricular outflow gradients in obstructive hypertrophic cardiomyopathy (oHCM). The clinical efficacy of aficamten across multiple outcome domains in oHCM has not been fully defined., Objectives: This responder analysis from the SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) trial characterizes the clinical impact of aficamten., Methods: Patients who were symptomatic of oHCM were randomized to aficamten (n = 142) or placebo (n = 140) daily for 24 weeks. Outcomes assessed included the proportion of patients with complete hemodynamic response (rest and Valsalva gradient <30 mm Hg and <50 mm Hg, respectively), relief in limiting symptoms (≥1 improvement in NYHA functional class and/or ≥10-point change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score), enhanced exercise capacity (≥1.5 mL/kg/min change in peak oxygen uptake), and ≥50% reduction in N-terminal pro-B-type natriuretic peptide. Eligibility for septal reduction therapy was also evaluated., Results: At 24 weeks, patients treated with aficamten vs placebo showed significant improvement in limiting symptoms (71% vs 42%), were more likely to have complete hemodynamic response (68% vs 7%), demonstrated enhanced exercise capacity (47% vs 24%), and showed a decrease ≥50% in N-terminal pro-B-type natriuretic peptide (84% vs 8%) (P ≤ 0.002 for all). An improvement in ≥1 of these outcome measures was achieved in 97% of patients treated with aficamten (vs 59% placebo), including 23% on aficamten who achieved all 4 outcomes compared with none in placebo. Among 32 patients receiving aficamten and 29 patients receiving placebo who were eligible for septal reduction therapy, 28 (88%) from the aficamten group were no longer eligible at 24 weeks compared with 15 (52%) from the placebo group (P = 0.002)., Conclusions: Treatment with aficamten was associated with substantial improvements across a broad range of clinically relevant efficacy measures. These results underscore the wide-ranging potential of aficamten for treatment of patients with symptomatic oHCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults with oHCM [SEQUOIA-HCM]; NCT05186818)., Competing Interests: Funding Support and Author Disclosures The SEQUOIA-HCM study was funded by Cytokinetics, Incorporated. Dr Maron has received consultant/advisor fees from Imbria, Edgewise, and BioMarin; and has received steering committee fees for SEQUIOA-HCM from Cytokinetics. Dr Masri has received consultant/advisor fees from Tenaya, Attralus, Cytokinetics, Bristol Myers Squibb, and Ionis; and has received research grants from Ionis, Akcea, Pfizer, Ultromics, and the Wheeler Foundation. Dr Nassif has received research and grant support from AstraZeneca and Cytokinetics; and has received consulting/advisory fees from Vifor and Cytokinetics. Dr Barriales-Villa has received consultant/advisor fees from MyoKardia/Bristol Myers Squibb. Dr Arad has received consulting and lecture fees from Bristol Myers Squibb. Dr Cardim has received consultant/advisor fees from Cytokinetics, Bristol Myers Squibb, Pfizer, Menarini, Boehinger Ingelheim, and Bial. Dr Coats has received speaker fees from Alnylam and Roche; and has received advisor fees from Cytokinetics. Dr Düngen has received grants from Novartis, CSL Behring, and Cytokinetics. Dr Garcia-Pavia has received speakers’ bureau fees from Pfizer, AstraZeneca, Novo Nordisk, Ionis, Bridgebio, Bristol Myers Squibb, Intelllia, and Alnylam; has received consulting/advisor fees from Pfizer, Alnylam, MyoKardia/Bristol Myers Squibb, Cytokinetics, Neuroimmune, Intellia, Ionis, Bridgebio, Lexeo, Rocket, Attralus, and AstraZeneca; and has received research/educational grants to his institution from Pfizer, AstraZeneca, Novo Nordisk, BridgeBio, and Alnylam. Dr Hagège has received consulting/advisor fees from Alnylam, Amicus Therapeutics, Bayer, MyoKardia/Bristol Myers Squibb, Pfizer, and Sanofi Genzyme; and has received steering committee fees for SEQUOIA-HCM from Cytokinetics. Dr Januzzi is funded in part by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; has served as a board member for Imbria Pharmaceuticals; has served as a Director at Jana Care; has received grant support from Abbott, Applied Therapeutics, HeartFlow, Innolife, and Roche Diagnostics; has received consulting fees from Abbott, Beckman, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Novartis, Pfizer, Merck, Roche Diagnostics, and Siemens; and has participated in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, CVRx, Intercept, and Takeda. Dr Lee has received research grants through his institution from AstraZeneca, Boehringer Ingelheim, and Roche Diagnostics; has been a member of a Clinical Endpoints Committee for Bayer; and has been a member of the Trial Steering Committee for Cytokinetics. Dr Lewis has received research funding from the National Institutes of Health (R01-HL 151841, R01-HL131029, and R01-HL159514), American Heart Association (15GPSGC-24800006), Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, and SoniVie; has received honoraria for advisory boards from Pfizer, Merck, Boehringer Ingelheim, Novartis, American Regent, Cyclerion, Cytokinetics, and Amgen; and has received royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Michels has received consulting/advisor fees from Bristol Myers Squibb, Cytokinetics, and Pfizer; and has received research grant funding from Bristol Myers Squibb. Dr Olivotto has received speakers’ bureau fees from Bristol Myers Squibb, Amicus, and Sanofi Genzyme; has received consulting/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, Rocket Pharma, and Lexeo; and has received research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, Chiesi, and Boston Scientific. Dr Oreziak has received investigator fees from Cytokinetics and MyoKardia/Bristol Myers Squibb. Dr Owens has received consulting/advisor fees from Cytokinetics, Bristol Myers Squibb/MyoKardia. Dr Spertus is the principal investigator of grants from the NIH, Abbott Vascular, and the American College of Cardiology Foundation; has received consulting fees from Janssen, Novartis, Amgen, Myokardia, AstraZeneca, Bayer, and Merck; has served on the Scientific Advisory Board of United Healthcare and the Board of Directors for Blue Cross Blue Shield of Kansas City; owns the copyright to the KCCQ, SAQ, and PAQ; and has an equity interest in Health Outcomes Sciences. Dr Solomon has received consulting/advisor fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, DiNAQOR, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health; and has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI. Dr Tfelt-Hansen has received consulting fees from Leo Pharma, MicroPort, and Johnson and Johnson. Ms van Sinttruije is a patient advisory committee member and a SEQUOIA-HCM Steering Committee member for Cytokinetics. Dr Watkins has received consulting/advisor fees from Cytokinetics, BioMarin, and BridgeBio. Drs Jacoby, Heitner, Kupfer, Malik, and Meng and Ms Wohltman are employees of Cytokinetics Incorporated and hold stock in Cytokinetics. 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: This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with nonobstructive hypertrophic cardiomyopathy (nHCM)., Methods: Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤ 30 mmHg, left ventricular ejection fraction [LVEF] ≥ 60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] > 300 pg/mL) received aficamten 5-15 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks., Results: We enrolled 41 patients (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥ 1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP levels (56%; P < 0.001) and high-sensitivity cardiac troponin I (22%; P < 0.005). Modest reductions in LVEF (mean ± SD) of -5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF < 50% (range: 41%-48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study., Conclusions: Aficamten administration for symptomatic nHCM was generally safe and was associated with improvements in heart failure symptoms and cardiac biomarkers., Trial Registration: ClinicalTrials.gov Identifier: NCT04219826., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Purpose In previously performed studies, retinopathy of prematurity (ROP) has been shown to occur postpartum. As a result, mechanical ventilation and oxygen dependence were eventually connected to the development of ROP in these preterm children, and ROP prevalence is on the rise globally. Despite various improvements in childcare, ROP still tends to arise due to various risk factors associated with the disease. So, clinically the research was performed to determine the clinical and epidemiological profile of ROP. Materials and methods A total of 268 participants were to be enrolled in the study. It was an observational, cross-sectional study carried out at Department of Ophthalmology and Neonatal Intensive Care Unit in Veer Surendra Sai Institute of Medical Sciences and Research Centre, Burla, Sambalpur, Odisha, India. Ethical approval was provided on 30 November 2019. Results Overall 123 (46%) infants out of 268 infants developed retinopathy of prematurity. Majorly, the infants had stage 1 and stage 2 ROP. Most of the infants were male. Birth weight in ROP patients was 1000 g or less in 54% of infants, 1000-1500 g in 46% of infants and >1500 g in 33% of infants. Gestational age was found to be a predictor of retinopathy of prematurity. The adverse events that were found to be associated with retinopathy of prematurity were sepsis (53%), respiratory distress syndrome (RDS) (54.6%), intraventricular haemorrhage (IVH) (60%), anaemia (61.5%). Conclusion It has been observed that babies with higher birth weights and older gestations are also susceptible to developing ROP. Therefore, the greater birth weight newborns up to 1750 g and older gestational age babies >34 weeks should also be included in the screening criteria, especially if they have risk factors such as oxygen supplementation, sepsis, RDS, and anaemia., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Vimsar Institutional Research & Ethics Committee issued approval 19215/Dt.30.11.19/IST-228/19. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sahu et al.)

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., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

Background: In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics., Objectives: This study sought to evaluate the safety and efficacy of ninerafaxstat in nHCM., Methods: Patients with hypertrophic cardiomyopathy and left ventricular outflow tract gradient <30 mm Hg, ejection fraction ≥50%, and peak oxygen consumption <80% predicted were randomized to ninerafaxstat 200 mg twice daily or placebo (1:1) for 12 weeks. The primary endpoint was safety and tolerability, with efficacy outcomes also assessed as secondary endpoints., Results: A total of 67 patients with nHCM were enrolled at 12 centers (57 ± 11.8 years of age; 55% women). Serious adverse events occurred in 11.8% (n = 4 of 34) in the ninerafaxstat group and 6.1% (n = 2 of 33) of patients in the placebo group. From baseline to 12 weeks, ninerafaxstat was associated with significantly better V E /Vco 2 (ventilatory efficiency) slope compared with placebo with a least-squares (LS) mean difference between the groups of -2.1 (95% CI: -3.6 to -0.6; P = 0.006), with no significant difference in peak VO 2 (P = 0.90). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was directionally, though not significantly, improved with ninerafaxstat vs placebo (LS mean 3.2; 95% CI: -2.9 to 9.2; P = 0.30); however, it was statistically significant when analyzed post hoc in the 35 patients with baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary Score ≤80 (LS mean 9.4; 95% CI: 0.3-18.5; P = 0.04)., Conclusions: In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a phase 3 study., Competing Interests: Funding Support and Author Disclosures Imbria Pharmaceuticals contributed significant funding to this study. Dr Neubauer acknowledges support from the Oxford NIHR Biomedical Research Centre and the Oxford British Heart Foundation Centre of Research Excellence. Dr Valkovic is supported by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (#221805/Z/20/Z), and also acknowledges the support from the Oxford BHF Centre of Research Excellence and from the Slovak Grant Agencies VEGA (#2/0004/23) and APVV (#21-0299). Dr Samat was supported by a doctoral scholarship funded by the Ministry of Higher Education Malaysia and National University of Malaysia. Dr Maron has served on the steering committee for SEQUOIA-HCM; and has received consultant/advisor fees from Cytokinetics, Imbria, and Edgewise. Dr Mahmod has served as an investigator for SEQUOIA-HCM, FOREST-HCM (Cytokinetics), and EMPA-VISION (Boehringer Ingelheim). Dr Massera has received consulting fees from Sanofi, Tenaya Therapeutics, and Chiesi Pharmaceuticals. Dr Cresci has served on the data monitoring committee for the SEQUOIA-HCM, MAPLE-HCM, and ACACIA-HCM trials (Cytokinetics). Dr Martinez has served on the steering committee for ACACIA-HCM; and has received consultant/advisor fees from Cytokinetics and BMS. Dr Masri has received research grants from Pfizer, Ionis, Attralus, and Cytokinetics; and has received consultancy/advisory fees from Cytokinetics, BMS, Eidos/BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, Akros, Prothena, BioMarin, AstraZeneca, and Tenaya. Dr Adler is currently the chief medical officer and head of research at Lexeo Therapeutics; has equity holdings in Lexeo Therapeutics, Rocket Pharmaceuticals, and Papillion Therapeutics; and has served on advisory boards for Cytokinetics and Kiniksa Pharmaeuticals. Dr Wever-Pinzon has received speaker fees from Bristol Myers Squibb. Dr Lewis has received research support and/or served as a consultant for the National Institutes of Health, American Reagent, Amgen, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Cardiage, Cytokinetics, Edwards, Imbria, Lilly, Merck, Novartis, NXT, Pfizer, and Rivus. Drs Chamberlin and Patel are salaried employees of Imbria Pharmaceuticals. Dr Yavari has served as a consultant for Imbria Pharmaceuticals; and is an employee of Weatherden Ltd. Dr Dehbi has received consulting fees from Imbria Pharmaceuticals. Dr Sarwar has received consulting fees from Imbria Pharmaceuticals and Ultromics. Dr Udelson has served as a member of the data and safety monitoring committee for the trial and has received consulting fees from Imbria Pharmaceuticals., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Many cardiomyopathy-associated FLNC pathogenic variants are heterozygous truncations, and FLNC pathogenic variants are associated with arrhythmias. Arrhythmia triggers in filaminopathy are incompletely understood., Methods and Results: We describe an individual with biallelic FLNC pathogenic variants, p.Arg650X and c.970-4A>G, with peripartum cardiomyopathy and ventricular arrhythmias. We also describe clinical findings in probands with FLNC variants including Val2715fs87X, Glu2458Serfs71X, Phe106Leu, and c.970-4A>G with hypertrophic and dilated cardiomyopathy, atrial fibrillation, and ventricular tachycardia. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated. The FLNC truncation, Arg650X/c.970-4A>G, showed a marked reduction in filamin C protein consistent with biallelic loss of function mutations. To assess loss of filamin C, gene editing of a healthy control iPSC line was used to generate a homozygous FLNC disruption in the actin binding domain. Because filamin C has been linked to protein quality control, we assessed the necessity of filamin C in iPSC-CMs for response to the proteasome inhibitor bortezomib. After exposure to low-dose bortezomib, FLNC- null iPSC-CMs showed an increase in the chaperone proteins BAG3, HSP70 (heat shock protein 70), and HSPB8 (small heat shock protein B8) and in the autophagy marker LC3I/II. FLNC null iPSC-CMs had prolonged electric field potential, which was further prolonged in the presence of low-dose bortezomib. FLNC null engineered heart tissues had impaired function after low-dose bortezomib., Conclusions: FLNC pathogenic variants associate with a predisposition to arrhythmias, which can be modeled in iPSC-CMs. Reduction of filamin C prolonged field potential, a surrogate for action potential, and with bortezomib-induced proteasome inhibition, reduced filamin C led to greater arrhythmia potential and impaired function.