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Academic stress is a critical aspect of adolescent experience around the world, but particularly in countries with dense populations that lead to highly competitive college admissions. With a population of over one billion people, the competition for higher education in India is significantly high. Although research has shown that academic pressures are associated with anxiety in adolescents, this work is primarily cross-sectional. The current study examined academic stress and anxiety symptoms over time and assessed physiological hyperarousal as a mediator and social acceptance as a moderator of this relation in a sample of adolescents from India (N = 282, 13-18 years, 84% female). Adolescents completed measures of academic stress, physiological hyperarousal, social acceptance and anxiety symptoms at two-time points, 5 months apart. Findings demonstrate direct effects of academic stress on changes in symptoms of generalised anxiety and panic, as well as indirect effects through physiological hyperarousal. Social acceptance did not moderate the relation, although it uniquely predicted changes in panic disorder symptoms over time. The findings of this study contribute to the scientific understanding of a potential mechanism through which academic stress leads to anxiety among adolescents in India.

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti–desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.

Background Limited studies exist that describe diagnosis, treatment, and management experiences of patients with hypertrophic cardiomyopathy (HCM). This study's purpose is to characterize patient experiences related to symptom onset, diagnosis, symptom management, support from healthcare professionals, and impacts on daily living. Methods Semi-structured interviews were conducted using open-ended questions and question probes were conducted with adults aged ≥18 years diagnosed with HCM ≥1 year prior. Interview recordings were transcribed verbatim and inductive and deductive thematic analyses were performed. Results A total of 32 interviews were conducted. The majority of participants were female (53.1%), aged ≥45 years (90.6%), white (96.9%), and non-Hispanic (96.9%). Participants with longer time to HCM diagnosis described having atypical HCM symptoms, denial of their own symptoms, and experiences of misdiagnoses. For HCM information and support, participants utilized personal healthcare professionals as well as non-medical resources. Participants described experiences of anxiety, denial, and upset feelings about their diagnosis, but also gratitude, acceptance, and increased mindfulness toward healthy habits. Individuals reported making changes in daily activities because of reduced physical capacity and making changes in lifestyle choices because of desire to be close to HCM specialists. Over time, participants also described becoming less fearful through utilization of available resources and treatment options. Conclusions The diverse but often challenging experiences of individuals with HCM suggest that increasing availability and utilization of HCM patient resources may be effective at reducing the unfavorable physical and psychological impacts of HCM. Common reports of misdiagnoses resulting in delayed HCM diagnosis also indicate a need for HCM-related educational opportunities for healthcare professionals.

Objectives This study sought to identify predictors of major clinically important atrial fibrillation endpoints in hypertrophic cardiomyopathy. Background Atrial fibrillation (AF) is a common morbidity associated with hypertrophic cardiomyopathy (HCM). The HCMR (Hypertrophic Cardiomyopathy Registry) trial is a prospective natural history study of 2,755 patients with HCM with comprehensive phenotyping. Methods All patients received yearly telephone follow-up. Major AF endpoints were defined as requiring electrical cardioversion, catheter ablation, hospitalization for >24 h, or clinical decisions to accept permanent AF. Penalized regression via elastic-net methodology identified the most important predictors of major AF endpoints from 46 variables. This was applied to 10 datasets, and the variables were ranked. Predictors that appeared in all 10 sets were then used in a Cox model for competing risks and analyzed as time to first event. Results Data from 2,631 (95.5%) patients were available for analysis after exclusions. A total of 127 major AF endpoints events occurred in 96 patients over 33.3 ± 12.4 months. In the final model, age, body mass index (BMI), left atrial (LA) volume index, LA contractile percent (active contraction), moderate or severe mitral regurgitation (MR), and history of arrhythmia the most important. BMI, LA volume index, and LA contractile percent were age-dependent. Obesity was a stronger risk factor in younger patients. Increased LA volume, reduced LA contractile percent, and moderate or severe MR put middle-aged and older adult patients at increased risk. Conclusions The major predictors of major AF endpoints in HCM include older age, high BMI, moderate or severe MR, history of arrhythmia, increased LA volume, and reduced LA contractile percent. Prospective testing of a risk score based on these parameters may be warranted.

Aims Risk stratification algorithms for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) and regional differences in clinical practice have evolved over time. We sought to compare primary prevention implantable cardioverter defibrillator (ICD) implantation rates and associated clinical outcomes in US vs. non-US tertiary HCM centres within the international Sarcomeric Human Cardiomyopathy Registry. Methods and results We included patients with HCM enrolled from eight US sites (n = 2650) and five non-US (n = 2660) sites and used multivariable Cox-proportional hazards models to compare outcomes between sites. Primary prevention ICD implantation rates in US sites were two-fold higher than non-US sites (hazard ratio (HR) 2.27 [1.89–2.74]), including in individuals deemed at high 5-year SCD risk (≥6%) based on the HCM risk-SCD score (HR 3.27 [1.76–6.05]). US ICD recipients also had fewer traditional SCD risk factors. Among ICD recipients, rates of appropriate ICD therapy were significantly lower in US vs. non-US sites (HR 0.52 [0.28–0.97]). No significant difference was identified in the incidence of SCD/resuscitated cardiac arrest among non-recipients of ICDs in US vs. non-US sites (HR 1.21 [0.74–1.97]). Conclusion Primary prevention ICDs are implanted more frequently in patients with HCM in US vs. non-US sites across the spectrum of SCD risk. There was a lower rate of appropriate ICD therapy in US sites, consistent with a lower-risk population, and no significant difference in SCD in US vs. non-US patients who did not receive an ICD. Further studies are needed to understand what drives malignant arrhythmias, optimize ICD allocation, and examine the impact of different ICD utilization strategies on long-term outcomes in HCM.

Background Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder which frequently leads to symptoms such as dyspnea and exercise intolerance, often due to severe dynamic left ventricular outflow tract obstruction (LVOTO). Current guideline-recommended pharmacotherapies have variable therapeutic responses to relieve LVOTO. In recent phases 2 and 3, clinical trials for symptomatic obstructive HCM (oHCM), mavacamten, a small molecule inhibitor of β-cardiac myosin has been shown to improve symptoms, exercise capacity, health status, reduce LVOTO, along with having a beneficial impact on cardiac structure and function. Methods VALOR-HCM is designed as a multicenter (approximately 20 centers in United States) phase 3, double-blind, placebo-controlled, randomized study. The study population consists of approximately 100 patients (≥18 years old) with symptomatic oHCM who meet 2011 American College of Cardiology/American Heart Association and/or 2014 European Society of Cardiology HCM-guideline criteria and are eligible and willing to undergo septal reduction therapy (SRT). The study duration will be up to 138 weeks, including an initial 2-week screening period, followed by16 weeks of placebo-controlled treatment, 16 weeks of active blinded treatment, 96 weeks of long-term extension, and an 8-week posttreatment follow-up visit. The primary endpoint will be a composite of the decision to proceed with SRT prior to or at Week 16 or remain guideline eligible for SRT at Week 16. Secondary efficacy endpoints will include change (from baseline to Week 16 in the mavacamten group vs placebo) in postexercise LVOT gradient, New York Heart Association class, Kansas City Cardiomyopathy Questionnaire clinical summary score, NT-proBNP, and cardiac troponin. Exploratory endpoints aim to characterize the effect of mavacamten on multiple aspects of oHCM pathophysiology. Conclusions In severely symptomatic drug-refractory oHCM patients meeting guideline criteria of eligibility for SRT, VALOR-HCM will primarily study if a 16-week course of mavacamten reduces or obviates the need for SRT using clinically driven endpoints.

Septal reduction therapy (SRT) in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy (oHCM) is associated with variable morbidity and mortality. The VALOR-HCM trial examined the effect of mavacamten on the need for SRT through Week 32 in oHCM.A double-blind randomized placebo-controlled multicenter trial at 19 US sites included oHCM patients on maximal tolerated medical therapy referred for SRT, with left ventricular outflow tract (LVOT) gradient ≥50 mmHg at rest or provocation (enrollment 7/202010/2021). The group initially randomized to mavacamten continued the drug for 32 weeks and the placebo group crossed over to dose-blinded mavacamten from Week 16 to 32. Dose titrations were based on investigator-blinded echocardiographic assessment of LVOT gradient and LV ejection fraction. The principal endpoint was proportion of patients proceeding with SRT or remaining guideline eligible at 32 weeks in both treatment groups.From the 112 randomized oHCM patients, 108 (mean age 60.3 years, 50% men and 94% in New York Heart Association [NYHA] class III/IV) qualified for Week 32 evaluation (56 in original mavacamten and 52 in placebo crossover group). After 32 weeks, 6/56 (10.7%) patients in original mavacamten and 7/52 (13.5%) in placebo crossover group met SRT guideline criteria or elected to undergo SRT. After 32 weeks, a sustained reduction in resting LVOT gradient (-33.0 mmHg 95% confidence interval [CI] -41.1 to -24.9) and Valsalva LVOT gradient (-43.0 mmHg, 95% CI -52.1 to -33.9) was observed in the original mavacamten group. A similar reduction in resting (-33.7 mmHg, 95% CI -42.2 to -25.2) and Valsalva gradients (-52.9 mmHg, 95% CI -63.2 to -42.6) was quantified in the crossover group after 16 weeks of mavacamten. After 32 weeks, ≥1 NYHA class improvement was observed in 48/53 (90.6%) of original mavacamten and 35/50 (70%) after 16 weeks in the crossover group.In severely symptomatic oHCM patients, 32 weeks of mavacamten treatment showed sustained reduction in the proportion proceeding to SRT or remaining guideline eligible, with similar effects observed in patients crossed over from placebo after 16 weeks.URL: Clinicaltrials.gov Unique Identifier: NCT04349072.

BackgroundInherited cardiomyopathies can present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with putative pathogenic variants (PuPV) in cardiomyopathy-associated genes in the general population.ObjectiveWe aimed to determine the risk of mortality and cardiomyopathy-related outcomes associated with PuPV in cardiomyopathy-associated genes in UK Biobank.MethodsUsing whole exome sequencing data, variants in dilated, hypertrophic and arrhythmogenic cardiomyopathy-associated genes with at least limited evidence of disease causality according to ClinGen Expert Panel curations, were annotated using REVEL (≥0.65) and ANNOVAR (predicted loss of function) to identify PuPVs. Individuals with PuPV comprised the genotype-positive (G+) and those without PuPV the genotype-negative (G-) cohorts. Group comparisons were made using time-to-event analyses for the primary (all-cause mortality) and secondary outcomes (diagnosis of cardiomyopathy; composite outcome of diagnosis of cardiomyopathy, heart failure, arrhythmia, stroke, and death).ResultsAmong 200,619 participants, 22,401 (11.2%) were found to host ≥1 PuPV in cardiomyopathy-associated genes (G+). After adjusting for age and sex, G+ individuals had increased all-cause mortality [HR 1.07 (95%CI 1.02-1.13; p=0.011)] and increased rates of diagnosis of cardiomyopathy later in life [HR 2.37 (95%CI 1.98-2.85; pConclusionsAdults with PuPV in cardiomyopathy-associated genes have higher all-cause mortality and increased risk of developing cardiomyopathy-associated features and complications, compared to genotype-negative controls.Condensed AbstractLeveraging the UK Biobank prospective cohort, we analyzed whole exome sequencing data in dilated, hypertrophic and arrhythmogenic cardiomyopathy-associated genes using a population screening ‘genotype-first’ approach. Individuals with putative pathogenic variants in genes implicated in cardiomyopathies showed an increased risk of all-cause mortality, higher risk of developing clinical cardiomyopathy later in life, and higher risk of a composite outcome (cardiomyopathy, heart failure, arrhythmia, stroke, and death) compared to genotype-negative controls. These findings highlight the potential role of ‘genotype-first’ approach in elevating personalized medicine into population level precision health in the future.

ImportanceMavacamten, a cardiac myosin inhibitor, improved peak oxygen uptake (pVO2) in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) in the EXPLORER-HCM study. However, the full extent of mavacamten’s effects on exercise performance remains unclear.ObjectiveTo investigate the effect of mavacamten on exercise physiology using cardiopulmonary exercise testing (CPET).Design, Setting, and ParticipantsExploratory analyses of the data from the EXPLORER-HCM study, a randomized, double-blind, placebo-controlled, phase 3 trial that was conducted in 68 cardiovascular centers in 13 countries. In total, 251 patients with symptomatic obstructive HCM were enrolled.InterventionsPatients were randomly assigned in a 1:1 ratio to mavacamten or placebo.Main Outcomes and MeasuresThe following prespecified exploratory cardiovascular and performance parameters were assessed with a standardized treadmill or bicycle ergometer test protocol at baseline and week 30: carbon dioxide output (VCO2), minute ventilation (VE), peak VE/VCO2 ratio, ventilatory efficiency (VE/VCO2 slope), peak respiratory exchange ratio (RER), peak circulatory power, ventilatory power, ventilatory threshold, peak metabolic equivalents (METs), peak exercise time, partial pressure of end-tidal carbon dioxide (PETCO2), and VO2/workload slope.ResultsTwo hundred fifty-one patients were enrolled. The mean (SD) age was 58.5 (11.9) years and 59% of patients were male. There were significant improvements with mavacamten vs placebo in the following peak-exercise CPET parameters: peak VE/VCO2 ratio (least squares [LS] mean difference, −2.2; 95% CI, −3.05 to −1.26; P P P = .001), and peak PETCO2 (LS mean difference, 2.0 mm Hg; 95% CI, 1.12-2.79; P P = .02). There was a significant improvement in nonpeak-exercise CPET parameters, such as VE/VCO2 slope (LS mean difference, −2.6; 95% CI, −3.58 to −1.52; P P Conclusions and RelevanceMavacamten improved a range of CPET parameters beyond pVO2, indicating consistent and broad benefits on maximal exercise capacity. Although improvements in peak-exercise CPET parameters are clinically meaningful, the favorable effects of mavacamten on submaximal exertional tolerance provide further insights into the beneficial impact of mavacamten in patients with obstructive HCM.Trial RegistrationClinicalTrials.gov Identifier: NCT03470545

Background: Coronary angiography to identify coronary artery disease has been foundational to distinguish the cause of dilated cardiomyopathy (DCM), including the assignment of idiopathic or ischemic cardiomyopathy. Late gadolinium enhancement (LGE) with cardiovascular magnetic resonance (CMR) has emerged as an approach to identify myocardial scar and identify etiology. Methods: The DCM Precision Medicine Study included patients with left ventricular dilation and dysfunction attributed to idiopathic DCM, after expert clinical review excluded ischemic or other cardiomyopathies. Ischemic cardiomyopathy was defined as coronary artery disease with >50% narrowing at angiography of ≥1 epicardial coronary artery. CMR was not required for study inclusion, but in a post hoc analysis of available CMR reports, patterns of LGE were classified as (1) no LGE, (2) ischemic-pattern LGE: subendocardial/transmural, (3) nonischemic LGE: midmyocardial/epicardial. Results: Of 1204 idiopathic DCM patients evaluated, 396 (32.9%) had a prior CMR study; of these, 327 (82.6% of 396) had LGE imaging (mean age 46 years; 53.2% male; 55.4% White); 178 of the 327 (54.4%) exhibited LGE, and 156 of the 178 had LGE consistent with idiopathic DCM. The remaining 22 had transmural or subendocardial LGE. Of these 22, coronary angiography was normal (13), showed luminal irregularities (3), a distant thrombus (1), coronary artery disease with Conclusions: Of 327 probands enrolled in the DCM Precision Medicine Study cohort who had LGE-CMR data available, an ischemic-pattern of LGE was identified in 22 (6.7%), all of whom had idiopathic DCM as adjudicated by expert clinical review. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037632.

Background Subcutaneous implantable cardioverter-defibrillators (S-ICDs) are attractive for preventing sudden cardiac death in hypertrophic cardiomyopathy (HCM) as they mitigate risks of transvenous leads in young patients. However, S-ICDs may be associated with increased inappropriate shock (IAS) in HCM patients. Objective The purpose of this study was to assess the incidence and predictors of appropriate shock and IAS in a contemporary HCM S-ICD cohort. Methods We collected electrocardiographic and clinical data from HCM patients who underwent S-ICD implantation at 4 centers. Etiologies of all S-ICD shocks were adjudicated. We used Firth penalized logistic regression to derive adjusted odds ratios (aORs) for predictors of IAS. Results Eighty-eight HCM patients received S-ICDs (81 for primary and 7 for secondary prevention) with a mean follow-up of 2.7 years. Five patients (5.7%) had 9 IAS episodes (3.8 IAS per 100 patient-years) most often because of sinus tachycardia and/or T-wave oversensing. Independent predictors of IAS were higher 12-lead electrocardiographic R-wave amplitude (aOR 2.55 per 1 mV; 95% confidence interval 1.15–6.38) and abnormal T-wave inversions (aOR 0.16; 95% confidence interval 0.02–0.97). There were 2 appropriate shocks in 7 secondary prevention patients and none in 81 primary prevention patients, despite 96% meeting Enhanced American College of Cardiology/American Heart Association criteria and the mean European HCM Risk-SCD score predicting 5.7% 5-year risk. No patients had sudden death or untreated sustained ventricular arrhythmias. Conclusion In this multicenter HCM S-ICD study, IAS were rare and appropriate shocks confined to secondary prevention patients. The R-wave amplitude increased IAS risk, whereas T-wave inversions were protective. HCM primary prevention implantable cardioverter-defibrillator guidelines overestimated the risk of appropriate shocks in our cohort.

Background Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering t...

Background: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features. Methods: UK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative. Results: Among 18 665 individuals included in the study, 1463 (7.8%) possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes. Conclusions: In the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.