BACKGROUND:Patients with phenotypically mild hypertrophic cardiomyopathy (HCM) do not require symptom management, but may be at an earlier stage in the disease course, with potential to benefit from disease-modifying therapies. However, little is known about the natural history and predictors of major adverse cardiovascular events (MACE). OBJECTIVES:Using the Sarcomeric Human Cardiomyopathy Registry, we identified predictors of incident MACE and characterized disease progression in phenotypically mild HCM. METHODS:Phenotypically mild HCM was defined as: having shorter disease duration (<10 years since diagnosis or age ≤30 years), no previous MACE, being NYHA functional class I, and having a left ventricular (LV) maximal wall thickness (MWT) <25 mm. These individuals were followed prospectively for the development of symptoms or MACE: atrial fibrillation (AF), malignant ventricular arrhythmia (MVA) (sudden cardiac death, resuscitated arrest, or appropriate defibrillator therapy), heart failure (HF) (cardiac transplantation, LV assist device implantation, LV ejection fraction <35%, or NYHA functional class III or IV symptoms), stroke, or all-cause mortality. Cox regression identified MACE predictors. Linear and latent class mixed models characterized LV remodeling trajectories and risk clusters. RESULTS:Of 2,500 participants with phenotypically mild HCM (mean age 43 years, 31% women) followed for a mean duration of 7 ± 6 years, 534 (21%) developed MACE, including 289 with AF, 69 with MVA, and 193 with HF. Individuals who progressed from NYHA functional class I to ≥ II symptoms during follow-up (n = 585, 23%) were 2.79 times (95% CI: 2.30-3.39 times) more likely to experience MACE. Age at baseline (HR: 1.24; 95% CI: 1.17-1.32 per 10-year increase), body mass index (HR: 1.10; 95% CI: 1.01-1.21 per 5-kg/m2 increase), left atrial (LA) diameter (HR: 1.16; 95% CI: 1.09-1.25 per 5-mm increase), LV MWT (HR: 1.27; 95% CI: 1.10-1.46 per 5-mm increase), and LV outflow tract (LVOT) gradient (HR: 1.08; 95% CI: 1.05-1.12 per 15-mm Hg increase) associated with higher MACE rates. LV late gadolinium enhancement presence was associated with 36% (95% CI: 5%-76%) higher hazard of MACE. Remodeling trajectories during follow-up predicted risk with each 0.5 mm/year steeper increase in LA diameter associating with doubled AF (HR: 2.24; 95% CI: 1.69-2.97) and HF rates (HR: 2.22; 95% CI: 1.62-3.04) and each 0.5 mm/year steeper LV MWT increase associating with doubled MVA rates (HR: 1.92; 95% CI: 1.38-2.69). Higher sustained values and/or steeper increases in LA diameter, LV MWT, or LVOT gradient associated with the highest MACE rates. CONCLUSIONS:Approximately 21% of patients with phenotypically mild HCM developed MACE over medium-term follow-up. Older age, symptoms development, and increasing LA diameter, LV hypertrophy, or LVOT gradient associated with MACE, particularly in instances of steeper rate of change. These findings can guide management strategies and inform future studies of disease-modifying therapies.

BACKGROUND AND AIMS:Familial ST-depression syndrome (FSTD) is a recently identified inherited cardiac disease associated with arrhythmias and systolic dysfunction. The underlying genetic aetiology has remained elusive. This study aimed at finding the causative variant. METHODS:A total of 67 FSTD patients (20 families) were studied. Linkage analysis and whole-genome sequencing (WGS) were initially performed. An identified non-coding variant was functionally characterized in AC16 human cardiomyocytes, muscle tissue, and human myocardium. In silico analyses, luciferase and dCas9-activator/repressor assays, protein-DNA experiments, chromosome conformation capture (4C), and RNA sequencing were also performed. RESULTS:The electrocardiographic (ECG) phenotype was inherited in an autosomal dominant manner in all families. Linkage analysis revealed a single peak on chromosome 20, and WGS identified a single, rare, non-coding variant located 18 kb downstream of KCNB1 on chromosome 20 in all affected individuals. Perfect co-segregation with the ECG phenotype was observed together with full penetrance in all families. The variant creates a MEF2-binding site and presence of the variant allele or MEF2 co-expression enhanced transcriptional activity. dCas9-activator/repressor assays showed that KCNB1 was the only gene consistently regulated by the locus and 4C experiments in AC16 cells and human muscle tissue confirmed the locus-KCNB1 promoter interaction. Expression analysis in human endocardial tissue did not document any change in gene expression likely explained by expressional heterogeneity. CONCLUSIONS:A gain-of-function enhancer variant creates a hyperactive regulatory locus that interacts with the KCNB1 promoter and causes FSTD. This is the first time that KCNB1 has been implicated in human cardiac electrophysiology and arrhythmogenesis.

Background Treatment with implantable cardioverter-defibrillators (ICDs) effectively prevents sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM). Identifying patients most likely to benefit from a primary prevention ICD remains challenging. We aimed to investigate the long-term incidence of ICD therapy in patients with HCM according to SCD-risk at baseline.Methods The study retrospectively included all patients with HCM treated with an ICD for primary or secondary prevention between 1995 and 2022 in Eastern Denmark. Medical records for each patient were evaluated. Patients were stratified into risk groups according to the European Society of Cardiology HCM Risk-SCD score.Results We included 208 patients (66% male) with HCM and an ICD for primary (78%) or secondary prevention (22%). During a median 10-year follow-up, 66 patients (32%) received appropriate ICD therapy (antitachycardia pacing and/or shock), while 20 (10%) received inappropriate therapy. Patients with an ICD implanted for secondary prevention were almost twice as likely to receive appropriate therapy compared with patients with an ICD implanted for primary prevention (47% vs 28%, p=0.02). The 5-year cumulative incidences of appropriate shock therapy were 17% in patients with a high HCM Risk-SCD score, 16% in patients with an intermediate-risk score and 6% in patients with a low-risk score. A high-risk score was associated with higher cumulative incidence of appropriate shock therapy (p=0.012).Conclusion One-third of patients with HCM treated with an ICD experienced appropriate ICD therapy. The HCM-Risk SCD score adequately distinguished between low-risk and high-risk patients among those who underwent ICD implantation. Further improvements of risk-tools are needed to identify a larger proportion of the two-thirds of patients who did not benefit from ICD implantation after 10 years of observation.

Background Hypertrophic cardiomyopathy is a complex disease with variable clinical presentation and familial impact. Age at diagnosis may influence phenotypic expression, but it is unclear if age also affects clinical outcomes, genetic findings, and yield of family screening. Methods This was a retrospective cohort study of families screened for hypertrophic cardiomyopathy in eastern Denmark (2006–2023). Probands were analyzed by age at diagnosis both continuously and in quartiles: 18 to 45, 46 to 56, 57 to 65, and >65 years. Results A total of 612 probands (62% men; median age, 56 years; median follow‐up, 9 years) and 919 relatives (45% men; median age, 42 years) were studied. A higher proband age at diagnosis was associated with more left ventricular outflow tract obstruction (odds ratio [OR], 1.19/10 years), hypertension (OR, 1.57/10 years) and atrial fibrillation (OR, 1.24/10 years), but less left ventricular hypertrophy (wall thickness ≥30 mm; OR, 0.52/10 years), and ventricular arrhythmias (OR 0.81/10 years). Older age at diagnosis was associated with higher all‐cause death, but similar cardiovascular death. Sarcomere variants were less common in the oldest versus youngest quartile of probands (13% versus 42%, P <0.001). The yield of family screening at baseline was higher in probands diagnosed at a younger age (OR, 1.34/10‐year decrease). Long‐term hypertrophic cardiomyopathy incidence in relatives was not associated with proband age at diagnosis, and overall yield of family screening was comparable across all proband ages at diagnosis. Conclusions The proband’s age at hypertrophic cardiomyopathy diagnosis was associated with clinical and genetic findings, but the cardiovascular death and the yield of family screening were similar across all ages at diagnosis, supporting the presently recommended follow‐up and family screening irrespective of the proband’s age at diagnosis.

INTRODUCTION/AIMS:Primary hypokalemic periodic paralysis (HypoPP) can present with periodic paralysis and/or permanent muscle weakness. Permanent weakness is accompanied by fat replacement of the muscle. It is unknown whether the permanent muscle weakness is solely due to fat replacement or if other factors affect the ability of the remaining muscle fibers to contract. We aimed to investigate muscle fat replacement and contractility in persons with HypoPP-causing variants in CACNA1S and to compare the results to healthy controls. METHODS:In this cross-sectional study, we used T1-weighted and 2-point Dixon magnetic resonance imaging (MRI) to assess fat replacement of the muscle and stationary dynamometry to assess muscle strength. Contractility was determined by maximal muscle contraction divided by the contractile cross-sectional muscle area. RESULTS:We included 45 persons with HypoPP-causing variants in CACNA1S and data from 37 healthy controls. We found that fat fraction was increased in ankle dorsiflexors and knee extensors and flexors, and further found that muscle strength was decreased in knee extensors and flexors in persons with HypoPP-causing variants in CACNA1S compared to healthy controls. Additionally, we found decreased contractility of thigh muscles in persons with HypoPP-causing variants in CACNA1S compared to healthy controls. DISCUSSION:The decreased contractility could relate to skeletal muscle voltage-gated calcium channel dysfunction, subclinical attacks of paralysis, and/or changed muscle architecture, but this needs further investigation.

BACKGROUND:In hypertrophic cardiomyopathy (HCM), the mechanisms through which pathogenic sarcomere variants (G+) lead to left ventricular hypertrophy (LVH) are not understood. METHODS:VANISH (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) was a multicenter, double-blind, placebo-controlled, randomized trial testing valsartan's ability to attenuate phenotypic progression in early sarcomeric (G+LVH+) and subclinical HCM (G+LVH‒). The outcome was a composite z-score reflecting change in cardiac remodeling from baseline to year 2 (end of study). Baseline and year 2 blood samples were used to quantify 276 proteins using a proximity extension assay (Olink, Sweden). We explored relative differences in protein abundance between early and subclinical HCM at baseline. In addition, we compared proteomic changes between baseline and year 2 in subclinical HCM participants who experienced phenotypic conversion to early HCM (convertors) versus nonconvertors; early HCM participants receiving valsartan versus placebo; and in association with changes in the phenotypic progression z-score. Comparisons were made using the t-test, Mann-Whitney U test, linear mixed models, and generalized linear models, correcting for multiple testing using a 5% false discovery rate. RESULTS:Circulating proteins were analyzed in 192 participants (32 subclinical and 160 early HCM [81 allocated to valsartan]). NT-proBNP (N-terminal pro-B-type natriuretic peptide) differentiated early from subclinical HCM and tracked with phenotypic progression in early HCM (1-unit worsening in z-score associated with a 27% increase in NT-proBNP [95% CI, 17-37%]). Some extracellular matrix remodeling proteins showed a higher abundance (eg, tissue-type plasminogen activator) in early compared with subclinical HCM or tracked with disease progression (decorin) in early HCM. Some growth factors had a higher relative abundance in early HCM (eg, fibroblast growth factor-21). While no individual protein was able to distinguish phenotypic convertors from nonconvertors, multiprotein panels including lipocalin 2, lectin-like oxidized low-density lipoprotein receptor 1, and either NT-proBNP or interleukin-17 receptor A, could distinguish these groups. CONCLUSIONS:NT-proBNP was the most informative protein, showing a higher abundance in early compared with subclinical HCM and tracking with the phenotypic progression z-score in early-stage HCM. Studying pathways involving growth factors and extracellular matrix remodeling may yield additional insights into the mechanisms behind disease progression in sarcomevere variant carriers and early HCM. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01912534.

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.

BACKGROUND AND AIMS:Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. METHODS:An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. RESULTS:A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80-30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06-5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27-3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35-9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08-.23). CONCLUSIONS:Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

Abstract Aim To investigate if asymptomatic relatives carrying genetic variants associated with familial dilated cardiomyopathy (DCM) show early signs of myocardial disease assessed by echocardiography. Methods and Results Asymptomatic relatives without a DCM-phenotype (n=176, 46% males, mean age 39 years ± 16) of 111 DCM index patients carrying likely pathogenic or pathogenetic variants in TTN, RBM20, and FLNC genes were recruited from two tertiary referral centers for inherited cardiac diseases. All participants underwent echocardiographic examinations focusing on left ventricular (LV) ejection fraction (LVEF), LV global longitudinal strain (LVGLS), and LV end-diastolic diameter (LVEDD), with operators blinded to genetic results. The participants were grouped into genotype positive ([G+], n=82) or genotype negative relatives ([G-], n=94) carrying or not carrying the disease-causing variant. The G+ group had significantly lower systolic LV parameters compared to G- individuals with a mean LVGLS of -18.7% ± 2.4 versus -20.1% ± 2.8, p: 0.0029; and a mean ejection fraction of 57.8% ± 3.7 versus 59.7% ± 2.4, p: <0.0001. The proportion of G+ individuals with an abnormal LVGLS (defined as less than -18%) was 46% compared to 18% in the G- group. 26 % of G+ individuals had an LVEF in the interval between 50 - 55% compared to of 5% G- individuals[MOU1] . Mean LVEDD did not differ significantly between G+ and G-groups (49.7 mm ± 4.9 versus 48.8 mm ± 4.7). However, LVEDD indexed to BSA were significantly increased in G+ individuals (26.7 mm/m2 ± 2.8 versus 25.4 mm/m2 ± 2.5, p-value 0.001). Conclusion Overall, the absolute mean values of LVGLS, LVEF, and LVEDD were within normal ranges in both G+ and G- groups of individuals. However, compared to non-carrier relatives, almost half of the asymptomatic G+ DCM relatives had signs of subclinical myocardial dysfunction with significantly lower values of LVGLS, LVEF, and larger left ventricular dimensions.

Background Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease, and clinical and genetic family screening is recommended by guidelines. Objectives This study sought to investigate the diagnostic yield of screening relatives of HCM patients and identify predictive factors for HCM development during long-term follow-up in relatives from gene-elusive families. Methods This was a retrospective cohort study of families screened at clinics for inherited cardiomyopathies in Eastern Denmark, from 2006 to 2023. Results We included 1,230 relatives (55% female; age: 42 ± 17 years) from 531 families. The combined clinical and genetic yield at baseline was 26% (n = 321). After 7 years (mean) of follow-up (6,762 person-years), 43 (4%) additional relatives developed HCM. The strongest predictors of developing HCM were carrying a likely pathogenic/pathogenic variant (HR: 4.58; 95% CI: 2.50-8.40; P < 0.001) and larger left ventricular maximum wall thickness (MWT) (HR: 2.21 per mm; 95% CI: 1.76-2.77 per mm; P < 0.001). In gene-elusive families, we found that an MWT of ≥10 mm represented the optimal classification threshold for developing HCM (area under the curve: 0.80), with only 2 (0.4%) relatives from gene-elusive families with an MWT of <10 mm developing HCM during follow-up. Conclusions In HCM, the diagnostic yield of a single screening visit was 1 in 4, and the additional yield during 7 years of follow-up was 4%. Gene carriers and relatives from gene-elusive families with a baseline MWT of ≥10 mm were at the highest risk of developing HCM during follow-up. These findings may inform future recommendations on the management of relatives of HCM patients.

BACKGROUND:Participation in regular exercise activities is recommended for patients with chronic heart failure. However, less is known about the effect of exercise in patients with genetic dilated cardiomyopathy (DCM). We sought to examine the effect of vigorousintensity training on physical capacity in patients with DCM caused by truncating titin variants (TTNtv). TRIAL DESIGN:Non-randomised clinical pre-post trial of exercise training. METHODS:Individuals with DCM-TTNtv were included from outpatient clinics for inherited cardiac diseases. The trial consisted of 8 weeks of usual care followed by 8 weeks of regular vigorous-intensity cycling exercise, enclosed by three test days. The primary outcome was change in peak oxygen uptake (VO2). Secondary outcomes included change in blood volume, total haemoglobin mass, measures of systolic function and cardiac output/stroke volume during exercise. RESULTS:Thirteen out of 14 included participants (43% women, age 48±11 years, body mass index: 30±6 kg/m2) completed the trial. In the exercise training period, peak VO2 increased by +1.9 mL/kg/min (95% CI +0.9 to +2.9, p=0.002). Compared with usual care, exercise training improved peak VO2 by +2.9 mL/kg/min (95% CI +1.2 to +4.5, p=0.002), corresponding to a 10% increase. Adaptations to exercise training included an increase in resting cardiac output (+0.8 L/min, p=0.042), total blood volume (+713 mL, p<0.001), total haemoglobin mass (+73 g, p<0.001), and improved left ventricular (LV) systolic function (LV ejection fraction: +3.2% (p=0.053) and global longitudinal strain: -2.0% (p=0.044)). No exercise-related adverse events or change in plasma biomarkers of cardiac or skeletal muscle damage were observed. CONCLUSIONS:Our study shows that vigorous intensity exercise training improved peak VO2 in patients with DCM-TTNtv. Exercise training was associated with improved LV systolic function and increased blood volume and oxygen carrying capacity. Future research should investigate the effect of long-term exercise in this group. TRIAL REGISTRATION NUMBER:NCT05180188.

ImportanceValsartan has shown promise in attenuating cardiac remodeling in patients with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Genetic testing can identify individuals at risk of HCM in a subclinical stage who could benefit from therapies that prevent disease progression.ObjectiveTo explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM.Design, Setting, and ParticipantsThe multicenter, double-blind, placebo-controlled Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) randomized clinical trial was conducted from April 2014 to July 2019 at 17 sites in 4 countries (Brazil, Canada, Denmark, and the US), with 2 years of follow-up. The prespecified exploratory VANISH cohort studied here included sarcomere variant carriers with subclinical HCM and early phenotypic manifestations (reduced E′ velocity, electrocardiographic abnormalities, or an increased left ventricular [LV] wall thickness [LVWT] to cavity diameter ratio) but no LV hypertrophy (LVH). Data were analyzed between March and December 2022.InterventionsTreatment with placebo or valsartan (80 mg/d for children weighing <35 kg, 160 mg/d for children weighing ≥35 kg, or 320 mg/d for adults aged ≥18 years).Main Outcomes and MeasuresThe primary outcome was a composite z score incorporating changes in 9 parameters of cardiac remodeling (LV cavity volume, LVWT, and LV mass; left atrial [LA] volume; E′ velocity and S′ velocity; and serum troponin and N-terminal prohormone of brain natriuretic peptide levels).ResultsThis study included 34 participants, with a mean (SD) age of 16 (5) years (all were White). A total of 18 participants (8 female [44%] and 10 male [56%]) were randomized to valsartan and 16 (9 female [56%] and 7 male [44%]) were randomized to placebo. No statistically significant effects of valsartan on cardiac remodeling were detected (mean change in composite z score compared with placebo: −0.01 [95% CI, −0.29 to 0.26]; P = .92). Overall, 2-year phenotypic progression was modest, with only a mild increase in LA volume detected (increased by 3.5 mL/m2 [95% CI, 1.4-6.0 mL/m2]; P = .002). Nine participants (26%) had increased LVWT, including 6 (18%) who developed clinically overt HCM. Baseline LA volume index (LAVI; 35 vs 28 mL/m2; P = .01) and average interventricular septum thickness (8.5 vs 7.0 mm; P = .009) were higher in participants who developed HCM.Conclusions and RelevanceIn this exploratory cohort, valsartan was not proven to slow progression of subclinical HCM. Minimal changes in markers of cardiac remodeling were observed, although nearly one-fifth of patients developed clinically overt HCM. Transition to disease was associated with greater baseline interventricular septum thickness and LAVI. These findings highlight the importance of following sarcomere variant carriers longitudinally and the critical need to improve understanding of factors that drive disease penetrance and progression.Trial RegistrationClinicalTrials.gov Identifier: NCT01912534

Background: Approximately 40% of cases of dilated (DCM) and arrhythmogenic cardiomyopathy (AC) are caused by rare genetic variants of large-effect. Sex-based differences in the penetrance of genetic DCM and AC have been described, however, findings have been inconsistent. Age at the time of diagnosis can be used as an indicator of age-related penetrance. In this study we aimed to describe differences in age at diagnosis in subgroups of patients with DCM and AC; the latter defined as ventricular arrhythmias preceding or superseding systolic LV dysfunction. Methods: Patients with DCM and AC were identified using data from 3 centers participating in the international SHaRe registry. Age at diagnosis and other baseline characteristics were compared across genetic subtypes; including patients with pathogenic and likely pathogenic (LP/P) variants (G+), variants of unknown significance (VUS), without identifiable genetic cause (G-) and subgroups with LP/P variants in 3 genes most frequent in this cohort ( TTN , LMNA , and DSP ). Results: Of 3662 patients with DCM and AC, 1341 were females (37%) and 3551 probands (97%). There were no significant differences in LVEF (38±14 vs. 41±14, p=0.07) or NYHA III-IV symptoms (14% vs. 11%, p=0.2). Genetic testing was performed more frequently in females (27% vs. 22%; p<0.01) but the frequency of LP/P variants did not differ significantly by sex (female 49% vs. male 38%, p=0.07). In the entire cohort, the age of diagnosis did not vary between females and males; however, females with LP/P variants in TTN were 9 years older (p<0.01) whereas females with LP/P variants in DSP were 10 years younger (p=0.037) at diagnosis than males (figure). Conclusion: Sex-based differences in age related penetrance of DCM and AC may differ across disease genes. Increased vigilance is warranted for early presentation of AC. Future research should examine the factors that underlie this heterogeneity and determine associated differences in clinical outcomes.

Purpose To identify the cause of discrepancy between the INHERIT trial and VANISH trial in regards to disease modification of angiotensin receptor II blockers in hypertrophic cardiomyopathy (HCM).Methods We replicated the data analysis used in VANISH, converting individual change in each component of the composite endpoint into a z-score and applying this z-score to the INHERIT results.Results No significant improvement was identified in the composite z-score between the 2 groups at 12-month follow-up ( P = .4). With the exception of tissue Doppler systolic (s') velocity, we found no significant benefit or harm from losartan compared to placebo for any of the individual components of the composite score at 12-month follow-up. Results were similar in analyses without imputed data or when restricted to patients with sarcomeric HCM.Conclusion Despite applying the potentially more sensitive composite z-score endpoint as in the VANISH trial, no statistically significant benefits from the use of losartan compared to placebo could be detected at 12-month follow-up in patients with overt HCM participating in the INHERIT trial. (Am Heart J 2023;266:198-200.)

Summary paragraph Heart failure (HF), a syndrome of symptomatic fluid overload due to cardiac dysfunction, is the most rapidly growing cardiovascular disorder. Despite recent advances, mortality and morbidity remain high and treatment innovation is challenged by limited understanding of aetiology in relation to disease subtypes. Here we harness the de-confounding properties of genetic variation to map causal biology underlying the HF phenotypic spectrum, to inform the development of more effective treatments. We report a genetic association analysis in 1.9 million ancestrally diverse individuals, including 153,174 cases of HF; 44,012 of non-ischaemic HF; 5,406 cases of non-ischaemic HF with reduced ejection fraction (HFrEF); and 3,841 cases of non-ischaemic HF with preserved ejection fraction (HFpEF). We identify 66 genetic susceptibility loci across HF subtypes, 37 of which have not previously been reported. We map the aetiologic contribution of risk factor traits and diseases as well as newly identified effector genes for HF, demonstrating differential risk factor effects on disease subtypes. Our findings highlight the importance of extra-cardiac tissues in HF, particularly the kidney and the vasculature in HFpEF. Pathways of cellular senescence and proteostasis are notably uncovered, including IGFBP7 as an effector gene for HFpEF. Using population approaches causally anchored in human genetics, we provide fundamental new insights into the aetiology of heart failure subtypes that may inform new approaches to prevention and treatment.

BACKGROUND:Genetic variants in titin (TTN) are associated with dilated cardiomyopathy (DCM) and skeletal myopathy. However, the skeletal muscle phenotype in individuals carrying heterozygous truncating TTN variants (TTNtv), the leading cause of DCM, is understudied. OBJECTIVES:This study aimed to assess the skeletal muscle phenotype associated with TTNtv. METHODS:Participants with TTNtv were included in a cross-sectional study. Skeletal muscle fat fraction was evaluated by magnetic resonance imaging (compared with healthy controls and controls with non-TTNtv DCM). Muscle strength was evaluated by dynamometry and muscle biopsy specimens were analyzed. RESULTS:Twenty-five TTNtv participants (11 women, mean age 51 ± 15 years, left ventricular ejection fraction 45% ± 10%) were included (19 had DCM). Compared to healthy controls (n = 25), fat fraction was higher in calf (12.5% vs 9.9%, P = 0.013), thigh (12.2% vs 9.3%, P = 0.004), and paraspinal muscles (18.8% vs 13.9%, P = 0.008) of TTNtv participants. Linear mixed effects modelling found higher fat fractions in TTNtv participants compared to healthy controls (2.5%; 95% CI: 1.4-3.7; P < 0.001) and controls with non-TTNtv genetic DCM (n = 7) (1.5%; 95% CI: 0.2-2.8; P = 0.025). Muscle strength was within 1 SD of normal values. Biopsy specimens from 21 participants found myopathic features in 13 (62%), including central nuclei. Electron microscopy showed well-ordered Z-lines and T-tubuli but uneven and discontinuous M-lines and excessive glycogen depositions flanked by autophagosomes, lysosomes, and abnormal mitochondria with mitophagy. CONCLUSIONS:Mild skeletal muscle involvement was prevalent in patients with TTNtv. The phenotype was characterized by an increased muscle fat fraction and excessive accumulation of glycogen, possibly due to reduced autophagic flux. These findings indicate an impact of TTNtv beyond the heart.

We report a genome-wide association study of venous thromboembolism (VTE) incorporating 81,190 cases and 1,419,671 controls sampled from six cohorts. We identify 93 risk loci, of which 62 are previously unreported. Many of the identified risk loci are at genes encoding proteins with functions converging on the coagulation cascade or platelet function. A VTE polygenic risk score (PRS) enabled effective identification of both high- and low-risk individuals. Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A (c.*97 G > A) in F2 and p.R534Q in F5. We also document that F2 and F5 mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population. We further show that PRS improved individual risk prediction beyond that of genetic and clinical risk factors. We investigated the extent to which venous and arterial thrombosis share clinical risk factors using Mendelian randomization, finding that some risk factors for arterial thrombosis were directionally concordant with VTE risk (for example, body mass index and smoking) whereas others were discordant (for example, systolic blood pressure and triglyceride levels). Genome-wide association analyses identify 93 risk loci for venous thromboembolism (VTE). A polygenic score derived from these results identifies individuals at increased VTE risk equivalent to monogenic forms of the disease.

Abstract Background Treatment with implantable cardioverter-defibrillators (ICD) is effective for prevention of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM). Assessment of SCD risk and identification of patients most likely to benefit from primary prevention ICD is challenging. Purpose To investigate the long-term incidence of appropriate and inappropriate ICD therapy in patients with HCM. Methods This was a retrospective cohort study including all patients with HCM and ICDs implanted between 1995 to 2022 in our region (population 2.6 million). Both patients treated with primary and secondary prevention ICD were included. Data was retrieved from medical records. Patients with an ICD implanted for primary prevention were stratified into risk groups according to European Society of Cardiology HCM Risk-SCD score. Results We included 187 patients (65% male) with HCM and ICDs implanted for primary (80%) or secondary (20%) prevention. The median age at ICD implantation was 50 years (IQR: 40 to 61 years). During a mean follow-up of 9 years (IQR: 4 to 12 years), 53 patients (28%) experienced appropriate ICD therapy (antitachycardia pacing and/or shock), while 17 (9%) patients received inappropriate therapy. Patients with an ICD as secondary prevention were almost twice as likely to receive appropriate ICD therapy compared to patients with a primary prevention ICD (42% vs. 25%, p=0.04). The proportion of patients receiving appropriate shocks was 7 times higher in patients with an HCM Risk-SCD score ≥6% compared to patients with a risk score <4% (29% vs. 4%, p<0.001). There was no significant difference in the proportion of appropriate shocks between patients with a HCM Risk-SCD score ≥6% and patients with a risk score of 4%-6% (29% vs. 21%, p=0.49). (Figure 1). Conclusion One in four patients with HCM treated with an ICD experienced appropriate device intervention during 9 years of follow up. Patients with an HCM Risk-SCD score ≥6% had a 7-fold higher risk of appropriate ICD therapy compared to patients with an HCM Risk-SCD score <4%. There was no significant difference in the risk of appropriate shock therapy between patients with a risk score ≥6% and patients with a risk score of 4%-6%. The findings indicate the need for improved selection of patient with HCM for implantation of ICD’s.

HomeCirculation: Heart FailureVol. 16, No. 4Transforming Growth Factor-β Analysis of the VANISH Trial Cohort Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBTransforming Growth Factor-β Analysis of the VANISH Trial Cohort Yuri Kim, Mitra Mastali, Jennifer E. Van Eyk, E. John Orav, Christoffer R. Vissing, Sharlene M. Day, Anna Axelsson Raja, Mark W. Russell, Kenneth Zahka, Harry M. Lever, Alexandre C. Pereira, Anne M. Murphy, Charles Canter, Richard G. Bach, Matthew T. Wheeler, Joseph W. Rossano, Anjali T. Owens, Henning Bundgaard, Lee Benson, Luisa Mestroni, Matthew R.G. Taylor, Amit R. Patel, Ivan Wilmot, Philip Thrush, Jonathan H. Soslow, Jason R. Becker, Christine E. Seidman and Carolyn Y. Ho Yuri KimYuri Kim Correspondence to: Yuri Kim, MD, PhD, Division of Cardiovascular Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. Email E-mail Address: [email protected] https://orcid.org/0000-0001-5978-5779 Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (Y.K., C.R.V., C.E.S., C.Y.H.). , Mitra MastaliMitra Mastali Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (M.M., J.E.V.E.). , Jennifer E. Van EykJennifer E. Van Eyk https://orcid.org/0000-0001-9050-148X Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (M.M., J.E.V.E.). , E. John OravE. John Orav Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA (E.J.O.). , Christoffer R. VissingChristoffer R. Vissing https://orcid.org/0000-0002-0834-206X Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (Y.K., C.R.V., C.E.S., C.Y.H.). Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Denmark (C.R.V., A.A.R., H.B.). , Sharlene M. DaySharlene M. Day https://orcid.org/0000-0001-9802-7188 Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (S.M.D., A.T.O.). , Anna Axelsson RajaAnna Axelsson Raja https://orcid.org/0000-0001-8665-3309 Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Denmark (C.R.V., A.A.R., H.B.). , Mark W. RussellMark W. Russell https://orcid.org/0000-0003-4855-9260 Division of Pediatric Cardiology, Department of Pediatrics, University of Michigan Medical Center, Ann Arbor (M.W.R.). , Kenneth ZahkaKenneth Zahka Department of Pediatric Cardiology, Cleveland Clinic Children's, Pediatric Institute, Cleveland Clinic Foundation, OH (K.Z., H.M.L.). , Harry M. LeverHarry M. Lever Department of Pediatric Cardiology, Cleveland Clinic Children's, Pediatric Institute, Cleveland Clinic Foundation, OH (K.Z., H.M.L.). , Alexandre C. PereiraAlexandre C. Pereira https://orcid.org/0000-0002-7782-5540 Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of Sao Paulo Medical School, Brazil (A.C.P.). , Anne M. MurphyAnne M. Murphy https://orcid.org/0000-0001-9254-3202 Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD (A.M.M.). , Charles CanterCharles Canter https://orcid.org/0000-0002-0007-7337 Department of Pediatrics (C.C.), Washington University School of Medicine, St. Louis, MO. , Richard G. BachRichard G. Bach Department of Medicine (R.G.B.), Washington University School of Medicine, St. Louis, MO. , Matthew T. WheelerMatthew T. Wheeler https://orcid.org/0000-0001-8721-3022 Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA (M.T.W.). , Joseph W. RossanoJoseph W. Rossano https://orcid.org/0000-0002-8284-0673 Division of Cardiology, Children's Hospital of Philadelphia, PA (J.W.R.). , Anjali T. OwensAnjali T. Owens https://orcid.org/0000-0002-9669-8495 Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (S.M.D., A.T.O.). , Henning BundgaardHenning Bundgaard https://orcid.org/0000-0002-0563-7049 Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Denmark (C.R.V., A.A.R., H.B.). Department of Clinical Medicine, University of Copenhagen, Denmark (H.B.). , Lee BensonLee Benson https://orcid.org/0000-0002-1407-1825 The Labatt Family Heart Centre, The Hospital for Sick Children, University of Toronto, ON, Canada (L.B.). , Luisa MestroniLuisa Mestroni https://orcid.org/0000-0003-1116-2286 Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora (L.M., M.R.G.T.). , Matthew R.G. TaylorMatthew R.G. Taylor https://orcid.org/0000-0001-9043-0810 Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora (L.M., M.R.G.T.). , Amit R. PatelAmit R. Patel https://orcid.org/0000-0001-7621-6463 Division of Cardiology, University of Virginia, Charlottesville (A.R.P.). , Ivan WilmotIvan Wilmot Heart Institute, Cincinnati Children's Hospital Medical Center, OH (I.W.). , Philip ThrushPhilip Thrush Division of Pediatric Cardiology, Ann & Robert H. Lurie Children's Hospital of Chicago, IL (P.T.). , Jonathan H. SoslowJonathan H. Soslow https://orcid.org/0000-0001-9194-5330 Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (J.H.S.). , Jason R. BeckerJason R. Becker https://orcid.org/0000-0002-2107-8179 Division of Cardiology, University of Pittsburgh School of Medicine, PA (J.R.B.). , Christine E. SeidmanChristine E. Seidman https://orcid.org/0000-0001-6380-1209 Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (Y.K., C.R.V., C.E.S., C.Y.H.). Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.). and Carolyn Y. HoCarolyn Y. Ho https://orcid.org/0000-0002-7334-7924 Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (Y.K., C.R.V., C.E.S., C.Y.H.). and on behalf of the VANISH Investigators Originally published31 Mar 2023https://doi.org/10.1161/CIRCHEARTFAILURE.122.010314Circulation: Heart Failure. 2023;16Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 31, 2023: Ahead of Print Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder characterized by unexplained left ventricular hypertrophy. Rare damaging genetic variants in sarcomere genes, including myosin binding protein C3 (MYBPC3) and myosin heavy chain 7 (MYH7) are responsible for ≈70% of familial disease.1 Patients with HCM are at increased risk of developing heart failure, arrhythmias, and sudden cardiac death.1Previous basic investigation demonstrated that TGF-β (transforming growth factor β) plays an essential role in activating profibrotic pathways involved in the early pathogenesis of HCM.2,3 Furthermore, in a mouse model of sarcomeric HCM, treatment with either a TGF-β neutralizing antibody or with the angiotensin II receptor blocker (ARB) losartan attenuated the development of left ventricular hypertrophy and fibrosis. However, treatment was only effective if administered early in life, prior to the emergence of clinically overt features of HCM.3 These studies were the foundation for the VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy).4 One hundred seventy-eight participants with early stage sarcomeric HCM were randomized to receive placebo (n=90) or valsartan (n=88) for 2 years. The primary outcome assessed a composite z score reflecting changes in cardiac structure and function from baseline to end of study. The score included left ventricular (LV) wall thickness, LV mass, LV volumes, left atrial volume, tissue Doppler diastolic and systolic velocities, and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein. VANISH demonstrated that ARB valsartan attenuated disease progression in this cohort. Participants receiving valsartan had an increase in composite z score, indicating relative improvement, whereas those receiving placebo had a decrease, indicating relative worsening (P=0.001; Figure [A]). However, the mechanism underlying this treatment benefit is unknown. While data in HCM are currently limited, a previous study in Marfan syndrome patients suggested that beneficial effects of ARB may be associated with a reduction in circulating TGF-β levels.5 Therefore, here, we investigated if circulating TGF-β levels changed in response to valsartan therapy in the VANISH trial cohort.Download figureDownload PowerPointFigure. Description of the study cohort and changes in TGF-β levels with placebo and valsartan treatment. A, Baseline characteristics of the study cohort and results of the primary outcome of the VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy).4 Nine clinical components, including serum troponin T and NT-proBNP (N-terminal pro-B-type natriuretic protein) levels, left ventricular (LV) mass index, LV end diastolic volume index, LV end systolic volume index, maximal LV wall thickness, left atrial volume index, E′ velocity, and S′ velocity, were integrated to create the composite z score (primary efficacy outcome). The positive z-score value indicates relative improvement. *n=77 and 80 for placebo and valsartan groups, respectively. ^n=73 and 77 for placebo and valsartan groups, respectively. B, Differences in log values of circulating TGF-β (transforming growth factor β) measurements (pg/mL) from baseline to year 2. No significant difference was identified between the 2 treatment groups in the primary cohort with early hypertrophic cardiomyopathy in the VANISH trial. P values were calculated using unpaired t test. IQR indicates interquartile range.The study population included 178 participants with early stage HCM in the VANISH trial. All participants provided informed consent, and the study was approved by institutional review committees. Peripheral blood was collected prior to randomization (placebo n=90 or valsartan n=88) and at end of study at year 2. We measured circulating TGF-β levels (pg/mL) in free and total (free plus TGF-β bound to latent TGF-β binding proteins) forms using an enzyme-linked immunosorbent assay (Quanterix, Billerica, MA) and compared the change in levels from baseline to year 2. TGF-β values were not normally distributed, therefore, log transformed for analysis. P values were calculated using paired t test when comparing changes within each subject and unpaired t test when comparing differences between 2 groups. Participants, who did not have interpretable TGF-β measurements available from both time points were excluded (21 for total TGF-β and 28 for free TGF-β). The data and analytic methods will be made available to other researchers upon request.We compared the change in TGF-β levels in placebo- and valsartan-treated participants. Overall, total TGF-β levels increased significantly during follow-up in both placebo (mean from 8.27 to 8.52; P=0.003) and valsartan-treated groups (mean from 8.26 to 8.49; P=0.02). However, the degree of increase of total TGF-β levels was not significantly different between the treatment groups (P=0.85; Figure [B]). Changes in free TGF-β levels were also similar between the 2 treatment groups (P=0.63; Figure [B]).In this study, we analyzed changes in circulating TGF-β levels in the VANISH trial to determine if valsartan treatment was associated with a decrease in TGF-β levels as a potential mechanism underlying the improvement in cardiac remodeling seen in patients with early HCM. No significant difference was seen in the change in circulating TGF-β levels between placebo- and valsartan-treated participants.Limitations of the current study include the small number of participants, uncertain relationship between the circulating levels of TGF-β measured and myocardial levels of TGF-β, which may be more biologically relevant, and inability to differentiate between the TGF-β isoforms (TGF-β1, TGF-β2, and TGF-β3). Although a previous study using animal models suggested potential effects of ARBs in downregulating TGF-β signaling,3 findings from animal studies may not directly translate to human studies. In addition, the current study focused on only 1 aspect of a very complex TGF-β signaling pathway, which includes a wide array of upstream and downstream regulators and interacts with multiple other signaling pathways. For example, ARBs may affect clinical progression of HCM via signaling pathways other than the TGF-β pathway such as the renin-angiotensin system or the PI3K/AKT pathway.Recognizing these limitations, our results suggest that disease-modifying effects of ARBs identified in early stage HCM are not dependent on decreasing circulating TGF-β levels. Further studies are needed to better characterize how ARBs improve cardiac remodeling in early HCM, to elucidate the pathogenesis of HCM, and to refine development of additional disease-modifying therapies.Article InformationAcknowledgmentsThe authors thank the families and patients, who participated in this study and the Cedars-Sinai Medical Center Proteomics and Metabolomics Core, who performed the ELISA.Sources of FundingThe VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) was funded by the National Institutes of Health/National Heart, Lung, and Blood Institute (P50HL112349; Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01912534).AppendixVANISH Investigators: E. Kevin Hall, MD (Department of Pediatrics, Yale University School of Medicine, New Haven, CT); Lubna Choudhury, MD (Division of Cardiology, Feinberg School of Medicine, Bluhm Cardiovascular Institute, Northwestern University, Chicago, IL); Elfriede Pahl, MD (Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN); Kimberly Y. Lin, MD (Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA).Disclosures Study medication (blinded valsartan and matching placebo) was provided by Novartis. Novartis was not involved in the design or conduct of the study; data collection, data management, data analysis, or data interpretation; preparation, review, or approval of the manuscript; or decision to submit the article for publication.Footnotes*A list of VANISH Investigators is provided in the Appendix.This manuscript was sent to John C. Burnett, Jr, MD, Guest Editor, for review by expert referees, editorial decision, and final disposition.For Sources of Funding and Disclosures, see page 376.Correspondence to: Yuri Kim, MD, PhD, Division of Cardiovascular Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. Email ykim@genetics.med.harvard.eduReferences1. Ho CY, Day SM, Ashley EA, Michels M, Pereira AC, Jacoby D, Cirino AL, Fox JC, Lakdawala NK, Ware JS, et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy.Circulation. 2018; 138:1387–1398. doi: 10.1161/CIRCULATIONAHA.117.033200LinkGoogle Scholar2. Kim JB, Porreca GJ, Song L, Greenway SC, Gorham JM, Church GM, Seidman CE, Seidman JG. Polony multiplex analysis of gene expression (PMAGE) in mouse hypertrophic cardiomyopathy.Science. 2007; 316:1481–1484. doi: 10.1126/science.1137325CrossrefMedlineGoogle Scholar3. Teekakirikul P, Eminaga S, Toka O, Alcalai R, Wang L, Wakimoto H, Nayor M, Konno T, Gorham JM, Wolf CM, et al. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β.J Clin Invest. 2010; 120:3520–3529. doi: 10.1172/JCI42028CrossrefMedlineGoogle Scholar4. Ho CY, Day SM, Axelsson A, Russell MW, Zahka K, Lever HM, Pereira AC, Colan SD, Margossian R, Murphy AM, et al. Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.Nat Med. 2021; 27:1818–1824. doi: 10.1038/s41591-021-01505-4CrossrefMedlineGoogle Scholar5. Matt P, Schoenhoff F, Habashi J, Holm T, Van Erp C, Loch D, Carlson OD, Griswold BF, Fu Q, De Backer J, et al. Circulating TGFβ in Marfan's syndrome.Circulation. 2009; 120:526–532. doi: 10.1161/CIRCULATIONAHA.108.841981LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails April 2023Vol 16, Issue 4 Advertisement Article Information Metrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.122.010314PMID: 36999957 Originally publishedMarch 31, 2023 Keywordsangiotensin receptor blockershypertrophic cardiomyopathyTGF-βPDF download Advertisement Subjects Cardiomyopathy Hypertrophy Remodeling Translational Studies

Importance:Valsartan has shown promise in attenuating cardiac remodeling in patients with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Genetic testing can identify individuals at risk of HCM in a subclinical stage who could benefit from therapies that prevent disease progression. Objective:To explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM. Design, Setting, and Participants:The multicenter, double-blind, placebo-controlled Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) randomized clinical trial was conducted from April 2014 to July 2019 at 17 sites in 4 countries (Brazil, Canada, Denmark, and the US), with 2 years of follow-up. The prespecified exploratory VANISH cohort studied here included sarcomere variant carriers with subclinical HCM and early phenotypic manifestations (reduced E' velocity, electrocardiographic abnormalities, or an increased left ventricular [LV] wall thickness [LVWT] to cavity diameter ratio) but no LV hypertrophy (LVH). Data were analyzed between March and December 2022. Interventions:Treatment with placebo or valsartan (80 mg/d for children weighing <35 kg, 160 mg/d for children weighing ≥35 kg, or 320 mg/d for adults aged ≥18 years). Main Outcomes and Measures:The primary outcome was a composite z score incorporating changes in 9 parameters of cardiac remodeling (LV cavity volume, LVWT, and LV mass; left atrial [LA] volume; E' velocity and S' velocity; and serum troponin and N-terminal prohormone of brain natriuretic peptide levels). Results:This study included 34 participants, with a mean (SD) age of 16 (5) years (all were White). A total of 18 participants (8 female [44%] and 10 male [56%]) were randomized to valsartan and 16 (9 female [56%] and 7 male [44%]) were randomized to placebo. No statistically significant effects of valsartan on cardiac remodeling were detected (mean change in composite z score compared with placebo: -0.01 [95% CI, -0.29 to 0.26]; P = .92). Overall, 2-year phenotypic progression was modest, with only a mild increase in LA volume detected (increased by 3.5 mL/m2 [95% CI, 1.4-6.0 mL/m2]; P = .002). Nine participants (26%) had increased LVWT, including 6 (18%) who developed clinically overt HCM. Baseline LA volume index (LAVI; 35 vs 28 mL/m2; P = .01) and average interventricular septum thickness (8.5 vs 7.0 mm; P = .009) were higher in participants who developed HCM. Conclusions and Relevance:In this exploratory cohort, valsartan was not proven to slow progression of subclinical HCM. Minimal changes in markers of cardiac remodeling were observed, although nearly one-fifth of patients developed clinically overt HCM. Transition to disease was associated with greater baseline interventricular septum thickness and LAVI. These findings highlight the importance of following sarcomere variant carriers longitudinally and the critical need to improve understanding of factors that drive disease penetrance and progression. Trial Registration:ClinicalTrials.gov Identifier: NCT01912534.