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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]

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 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), NT-proBNP (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 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.)

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.

Polymicrobial infections are the leading causes of complications incurred from injuries that burn patients develop. Such patients admitted to the hospital have a high risk of developing hospital-acquired infections, with longer patient stays leading to increased chances of acquiring such drug-resistant infections. Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis are the most common multidrug-resistant (MDR) Gram-negative bacteria identified in burn wound infections (BWIs). BWIs caused by viruses, like Herpes Simplex and Varicella Zoster, and fungi-like Candida spp. appear to occur occasionally. However, the preponderance of infection by opportunistic pathogens is very high in burn patients. Variations in the causative agents of BWIs are due to differences in geographic location and infection control measures. Overall, burn injuries are characterized by elevated serum cytokine levels, systemic immune response, and immunosuppression. Hence, early detection and treatment can accelerate the wound-healing process and reduce the risk of further infections at the site of injury. A multidisciplinary collaboration between burn surgeons and infectious disease specialists is also needed to properly monitor antibiotic resistance in BWI pathogens, help check the super-spread of MDR pathogens, and improve treatment outcomes as a result.

Background: This study aims to understand and describe the clinical impact of SARS-CoV-2 (COVID-19) infection in patients with Hypertrophic Cardiomyopathy (HCM)., Methods: A data repository of over 6.6 million patients in a large metropolitan (Chicago IL) healthcare system was queried to identify adults with a history of HCM and COVID-19 infection between 2019 and 2021. Propensity score-matched analysis was performed based on age, sex, BMI, and elements of the cardiovascular history, including tobacco use, hypertension, hyperlipidemia, myocardial injury, and heart failure., Results: Individuals with HCM and COVID-19 infection had more total hospitalizations (41.6 v 23 per 100 persons, p < 0.01), more heart-failure-related hospitalizations (24.2 v 8.7 per 100-persons, p < 0.01), more non-ST elevation myocardial injury (NSTEMI) hospitalizations (8.6 v 4.6 per 100-persons, p < 0.01), and increased mortality (10.8 v 5 per 100-persons, p < 0.01) compared to HCM patients without a history of COVID-19 infection. Patients with HCM and COVID-19 were also noted to have a higher peak CRP when compared to those without prior COVID-19 (Inter-quartile range of 9.0-106.9 v 1.8-21.3, p < 0.01)., Conclusions: In patients with HCM, COVID-19 infection is associated with increased incidence of myocardial injury, increased number of total and heart-failure specific hospitalizations, and increased mortality.

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.)

Although not as well studied as the bacterial component of the human microbiota, the commensal fungi or mycobiota play important roles in maintaining our health by augmenting our immune system. This mycobiota is also associated with various fatal diseases like opportunistic mycoses, and even cancer, with different cancers having respective type-specific mycobiota. The different fungal species which comprise these different intratumoral mycobiota play important roles in cancer progression. The aim of this review paper is to decipher the association between mycobiota and cancer, and shed light on new avenues in cancer diagnosis, and the development of new anti-cancer therapeutics.

Patients with obstructive hypertrophic cardiomyopathy (oHCM) have increased risk of arrhythmia, stroke, heart failure, and sudden death. Contemporary management of oHCM has decreased annual hospitalization and mortality rates, yet patients have worsening health-related quality of life due to impaired exercise capacity and persistent residual symptoms. Here we consider the design of clinical trials evaluating potential oHCM therapies in the context of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). This large, phase 3 trial is now fully enrolled (N = 282). Baseline characteristics reflect an ethnically diverse population with characteristics typical of patients encountered clinically with substantial functional and symptom burden. The study will assess the effect of aficamten vs placebo, in addition to standard-of-care medications, on functional capacity and symptoms over 24 weeks. Future clinical trials could model the approach in SEQUOIA-HCM to evaluate the effect of potential therapies on the burden of oHCM. (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM [SEQUOIA-HCM]; NCT05186818)., Competing Interests: Funding Support and Author Disclosures The SEQUOIA-HCM trial is funded by Cytokinetics, Incorporated. Representatives of Cytokinetics have been involved in the design and conduct of the study reported in this manuscript. Dr Coats has received speaker fees from Alnylam and Roche, and advisory fees from Cytokinetics. Dr Maron has received consultant/advisor fees from Imbria and Takeda, and Steering Committee fees for SEQUOIA-HCM from Cytokinetics, Incorporated. Dr Olivotto has received Speakers Bureau fees from Boston Scientific, Amicus, and Novartis; consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, and Rocket Pharma; and research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, and Boston Scientific. Dr Lee has received research grants to his institution from AstraZeneca and Boehringer Ingelheim, and Clinical Endpoint Committee fees from Bayer. Dr Arad has received consultant and lecture fees from Bristol Myers Squibb. Dr Cardim is on the advisory boards for Bristol Myers Squibb and Cytokinetics. Dr Düngen has received grants from Novartis, CSL Behring, and Cytokinetics. Dr Garcia-Pavia has received Speakers Bureau fees from Pfizer, AstraZeneca, NovoNordisk, Bristol Myers Squibb, BridgeBio, Ionis, and Alnylam; consultant/advisor fees from Pfizer, Alnylam, MyoKardia/Bristol Myers Squibb, Cytokinetics, Neurimmune, BridgeBio, Attralus, Intellia, Rocket Pharma, Lexeo Therapeutics, and AstraZeneca; and research/educational grants to his institution from Pfizer, BridgeBio, NovoNordisk, AstraZeneca, and Alnylam. Dr Hagège has received consultant/advisor fees from Alnylam, Amicus Therapeutics, Bayer, MyoKardia/Bristol Myers Squibb, Pfizer, and Sanofi Genzyme; and Steering Committee fees for SEQUOIA-HCM from Cytokinetics, Incorporated. 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; honoraria for advisory boards from Pfizer, Merck, Boehringer Ingelheim, Novartis, American Regent, Cyclerion, Cytokinetics, and Amgen; and royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Michels’ institution has received a research grant from Bristol Myers Squibb. Dr Michels has received consultant/advisor fees from Cytokinetics and Bristol Myers Squibb/Myokardia; and Speakers Bureau fees from Bristol Myers Squibb and Pfizer. Dr Oreziak has received investigator fees from Bristol Myers Squibb/MyoKardia; consultant/advisor fees from Biotronik Polska, Abbott Polska; and traveling fees from Hammermed. Dr Owens has received consultant/advisor fees from Cytokinetics, Bristol Myers Squibb/MyoKardia, and Pfizer. Dr Tfelt-Hansen is a consultant for Leo Pharma, MicroPort, and Johnson and Johnson. Dr Watkins has received consultant/advisor fees from Cytokinetics, BioMarin, and BridgeBio. Dr Heitner, Dr Jacoby, Dr Kupfer, Dr Malik, Dr Meng, and Ms Wohltman are employees of Cytokinetics, Incorporated and hold stock in Cytokinetics, Incorporated. Dr Masri has received consultant/advisor fees from Tenaya, Attralus, Cytokinetics, Bristol Myers Squibb, Eidos, Pfizer, Lexicon, Alnylam, Haya, Intellia, and Ionis; and research grants from Ionis, Akcea, Pfizer, Cytokinetics, Ultromics, and the Wheeler Foundation. 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: Data assessing the long-term safety and efficacy of mavacamten treatment for symptomatic obstructive hypertrophic cardiomyopathy are needed., Objectives: The authors sought to evaluate interim results from the EXPLORER-Long Term Extension (LTE) cohort of MAVA-LTE (A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed EXPLORER-HCM; NCT03723655)., Methods: After mavacamten or placebo withdrawal at the end of the parent EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545), patients could enroll in MAVA-LTE. Patients received mavacamten 5 mg once daily; adjustments were made based on site-read echocardiograms., Results: Between April 9, 2019, and March 5, 2021, 231 of 244 eligible patients (94.7%) enrolled in MAVA-LTE (mean age: 60 years; 39% female). At data cutoff (August 31, 2021) 217 (93.9%) remained on treatment (median time in study: 62.3 weeks; range: 0.3-123.9 weeks). At 48 weeks, patients showed improvements in left ventricular outflow tract (LVOT) gradients (mean change ± SD from baseline: resting: -35.6 ± 32.6 mm Hg; Valsalva: -45.3 ± 35.9 mm Hg), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (median: -480 ng/L; Q1-Q3: -1,104 to -179 ng/L), and NYHA functional class (67.5% improved by ≥1 class). LVOT gradients and NT-proBNP reductions were sustained through 84 weeks in patients who reached this timepoint. Over 315 patient-years of exposure, 8 patients experienced an adverse event of cardiac failure, and 21 patients had an adverse event of atrial fibrillation, including 11 with no prior history of atrial fibrillation. Twelve patients (5.2%) developed transient reductions in site-read echocardiogram left ventricular ejection fraction of <50%, resulting in temporary treatment interruption; all recovered. Ten patients discontinued treatment due to treatment-emergent adverse events., Conclusions: Mavacamten treatment showed clinically important and durable improvements in LVOT gradients, NT-proBNP levels, and NYHA functional class, consistent with EXPLORER-HCM. Mavacamten treatment was well tolerated over a median 62-week follow-up., Competing Interests: Funding Support and Author Disclosures This study was funded by Bristol Myers Squibb, Princeton, New Jersey, USA. Bristol Myers Squibb’s policy on data sharing is available online at https://www.bms.com/researchers-and-partners/clinical-trials-and-research/disclosure-commitment.html. Dr Rader has received consulting fees from Medtronic, Bristol Myers Squibb, and ReCor Medical. Dr Oręziak has received personal fees from Bristol Myers Squibb. Dr Saberi has received personal fees from Bristol Myers Squibb. Dr Fermin has received consulting fees from Alnylam, Eidos Therapeutics, Bristol Myers Squibb, and Pfizer. Dr Wheeler has received personal fees and research support from Bristol Myers Squibb. Dr Garcia-Pavia has received consulting and speaking fees from Bristol Myers Squibb, Rocket Pharmaceuticals, and Cytokinetics and speaking fees from Bristol Myers Squibb and Cytokinetics. Dr Zwas has received personal fees from Bristol Myers Squibb. Dr Masri has received grants from Akcea, Pfizer, and Ultromics and consulting fees from Alnylam, Cytokinetics, Eidos Therapeutics, Ionis, and Pfizer. Dr Owens has received consulting fees from Bristol Myers Squibb, Cytokinetics, and Pfizer. Dr Hegde serves on the faculty of the Cardiovascular Imaging Core Laboratory at Brigham and Women’s Hospital, and her institution has received payments for her consulting work from Bristol Myers Squibb. Dr Seidler has received consulting fees or honoraria for lectures from Bristol Myers Squibb and Cytokinetics. Dr Balaratnam and Dr Sehnert are employees of Bristol Myers Squibb and own stock of Bristol Myers Squibb. Shawna Fox is an employee of IQVIA, a partner providing statistics services to Bristol Myers Squibb. Dr Olivotto has received grants from Amicus, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Genzyme, and Menarini International and consulting fees from Amicus, Cytokinetics, Genzyme, MS Pharma, Rocket Pharmaceuticals, and Tenaya Therapeutics. 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.)

Competing Interests: Disclosures Dr McNally is or was a consultant for Amgen, AstraZeneca, Avidity, Cytokinetics, Pfizer, PepGen, Stealth Biopharma, Tenaya, and Invitae. She is the founder of Ikaika Therapeutics, Inc. These relationships are unrelated to this article.

The COVID-19 pandemic has had a significant impact on human health management. A rapid diagnosis of SARS-CoV2 at the point-of-care (POC) is critical to prevent disease spread. As a POC device for remote settings, a LFIA should not require cold-chain maintenance and should be kept at normal temperatures. Antigen stability can be enhanced by addressing instability issues when dealing with fragile components, such as proteinaceous capture antigens. This study used immunologically guided protein engineering to enhance the capture nucleocapsid (NP) antigen stability of SARS-CoV2. A search of the IEDB database revealed that antibodies detecting epitopes are almost uniformly distributed over NP 1-419 . In contrast, N-terminal stretches of NP 1-419 are theoretically more unstable than C-terminal stretches. We identified NP 250-365 as a NP stretch with a low instability index and B-cell epitopes. Apart from NP 1-419 , two other variants (NP 121-419 and NP 250-365 ) were cloned, expressed, and purified. The degradation pattern of the proteins was observed on SDS-PAGE after three days of stability studies at -20 °C, 4 °C, and 37 °C. NP 1-419 was the most degraded while NP 250-365 exhibited the least degradation. Also, NP 1-419 , NP 250-365 , and NP 121-419 reacted with purified antibodies from COVID-19 patient serum. Our results suggest that NP 250-365 may be used as a stable capture antigen in LFIA devices to detect COVID-19.

Importance: Whether vigorous intensity exercise is associated with an increase in risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown., Objective: To determine whether engagement in vigorous exercise is associated with increased risk for ventricular arrhythmias and/or mortality in individuals with HCM. The a priori hypothesis was that participants engaging in vigorous activity were not more likely to have an arrhythmic event or die than those who reported nonvigorous activity., Design, Setting, and Participants: This was an investigator-initiated, prospective cohort study. Participants were enrolled from May 18, 2015, to April 25, 2019, with completion in February 28, 2022. Participants were categorized according to self-reported levels of physical activity: sedentary, moderate, or vigorous-intensity exercise. This was a multicenter, observational registry with recruitment at 42 high-volume HCM centers in the US and internationally; patients could also self-enroll through the central site. Individuals aged 8 to 60 years diagnosed with HCM or genotype positive without left ventricular hypertrophy (phenotype negative) without conditions precluding exercise were enrolled., Exposures: Amount and intensity of physical activity., Main Outcomes and Measures: The primary prespecified composite end point included death, resuscitated sudden cardiac arrest, arrhythmic syncope, and appropriate shock from an implantable cardioverter defibrillator. All outcome events were adjudicated by an events committee blinded to the patient's exercise category., Results: Among the 1660 total participants (mean [SD] age, 39 [15] years; 996 male [60%]), 252 (15%) were classified as sedentary, and 709 (43%) participated in moderate exercise. Among the 699 individuals (42%) who participated in vigorous-intensity exercise, 259 (37%) participated competitively. A total of 77 individuals (4.6%) reached the composite end point. These individuals included 44 (4.6%) of those classified as nonvigorous and 33 (4.7%) of those classified as vigorous, with corresponding rates of 15.3 and 15.9 per 1000 person-years, respectively. In multivariate Cox regression analysis of the primary composite end point, individuals engaging in vigorous exercise did not experience a higher rate of events compared with the nonvigorous group with an adjusted hazard ratio of 1.01. The upper 95% 1-sided confidence level was 1.48, which was below the prespecified boundary of 1.5 for noninferiority., Conclusions and Relevance: Results of this cohort study suggest that among individuals with HCM or those who are genotype positive/phenotype negative and are treated in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or those who were sedentary. These data may inform discussion between the patient and their expert clinician around exercise participation.

Background: Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients., Objectives: This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM., Methods: Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout., Results: From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: -40 ± 27 mm Hg, and -43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (-36 ± 27 mm Hg and -53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (-6% ± 7.5% and -12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro-B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms., Conclusions: Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM., Competing Interests: Funding Support and Author Disclosures The REDWOOD-HCM study was funded by Cytokinetics, Incorporated. Dr Maron has received consultant/advisor fees from Imbria and Takeda; and has received steering committee fees for REDWOOD-HCM from Cytokinetics, Incorporated. 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 Wheeler Foundation. Dr Olivotto has received Speakers Bureau fees from Boston Scientific, Amicus, and Novartis; has received consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, and Tenaya; and has received research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, and Boston Scientific. Dr Saberi has received consultant/advisor fees from Bristol Myers Squibb; and has received research grants from Bristol Myers Squibb, Cytokinetics, Novartis, and Actelion Pharmaceuticals. Dr Wang has received Speakers Bureau fees from Bristol Myers Squibb; has received consultant/advisor fees from Bristol Myers Squibb and Cytokinetics; and has received research grants from Bristol Myers Squibb, Cytokinetics, and Abbott Vascular. Dr Garcia-Pavia has received Speakers Bureau fees from Pfizer and Alnylam; has received consultant/advisor fees from Pfizer, Alnylam, MyoKardia/Bristol Myers Squibb, Cytokinetics, Neuroimmune, BridgeBio, Attralus, and AstraZeneca; and has received research/educational grants to his institution from Pfizer, BridgeBio, and Alnylam. Dr Lakdawala has received consultant/advisor fees from Tenaya, Pfizer, Bristol Myers Squibb, Cytokinetics, and Sarepta; and has received a research grant from Pfizer. Dr Rader has received Speakers Bureau fees from Bristol Myers Squibb and Medtronic; and has received consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, ReCor, and Medtronic. Dr Turer has received consultant/advisor fees from Cytokinetics. Dr Coats has received consultant/advisor fees from Cytokinetics. Dr Fifer has received consultant/advisor fees from Cytokinetics; and has received research grants from Bristol Myers Squibb and Novartis. Dr Owens has received consultant/advisor fees from Cytokinetics, Bristol Myers Squibb/MyoKardia, and Pfizer. Dr Solomon has received consultant/advisor fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, 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, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI. Dr Watkins has received consultant/advisor fees from Cytokinetics, BioMarin, and BridgeBio. Dr Barriales-Villa has received consultant/advisor fees from MyoKardia/Bristol Myers Squibb. Dr Kramer has received consultant/advisor fees from Cytokinetics, and Bristol Myers Squibb; and has received research grants from Cytokinetics and Bristol Myers Squibb. Dr Wong has received Speakers Bureau fees from Projects in Knowledge, PCM Scientific; and has served as an unpaid consultant/advisor for Bristol Myers Squibb and Cytokinetics. Drs Heitner, Kupfer, Malik, Meng, and Wohltman are employees of Cytokinetics Incorporated; and holds stock in Cytokinetics Incorporated. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The human body harbors approximately 10 14 cells belonging to a diverse group of microorganisms. Bacteria outnumbers protozoa, fungi and viruses inhabiting our gastrointestinal tract (GIT), commonly referred to as the "human gut microbiome". Dysbiosis occurs when the balanced relationship between the host and the gut microbiota is disrupted, altering the usual microbial population there. This increases the susceptibility of the host to pathogens, and chances of its morbidity. It is due to the fact that the gut microbiome plays an important role in human health; it influences the progression of conditions varying from colorectal cancer to GIT disorders linked with the nervous system, autoimmunity, metabolism and inheritance. A rare disease is a lethal and persistent condition affecting 2-3 people per 5,000 populaces. This review article intends to discuss such rare neurological, autoimmune, cardio-metabolic and genetic disorders of man, focusing on the fundamental mechanism that links them with their gut microbiome. Ten rare diseases, including Pediatric Crohn's disease (PCD), Lichen planus (LP), Hypophosphatasia (HPP), Discitis, Cogan's syndrome, Chancroid disease, Sennetsu fever, Acute cholecystitis (AC), Grave's disease (GD) and Tropical sprue (TS) stands to highlight as key examples, along with personalized therapeutics meant for them. This medicinal approach addresses the individual's genetic and genomic pathography, and tackles the illness with specific and effective treatments., Competing Interests: The authors have no conflicts of interest to disclose., (2022, International Research and Cooperation Association for Bio & Socio - Sciences Advancement.)