Subclinical Hypertrophic Cardiomyopathy in Elite Athletes: Knowledge Gaps Persist.
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ABSTRACT:
SUBMITTER: Chan F
PROVIDER: S-EPMC8784716 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomeric proteins, the commonest being MYBPC3 encoding myosin-binding protein C. It is characterised by left ventricular hypertrophy but there is an important pre-hypertrophic phenotype with features including crypts, abnormal mitral leaflets and trabeculae. We investigated these during mouse cardiac development using high-resolution episcopic microscopy. In embryonic hearts from wildtype, homozygous (HO) and heterozygous (HET) Mybpc3-targeted knock-out (KO) mice we show that crypts (one or two) are a normal part of wildtype development but they almost all resolve by birth. By contrast, HO and HET embryos had increased crypt presence, abnormal mitral valve formation and alterations in the compaction process. In scarce normal human embryos, crypts were sometimes present. This study shows that features of the human pre-hypertrophic HCM phenotype occur in the mouse. In an animal model we demonstrate that there is an embryological HCM phenotype. Crypts are a normal part of cardiac development but, along with the mitral valve and trabeculae, their developmental trajectory is altered by the presence of HCM truncating Mybpc3 gene mutation.
| S-EPMC4914973 | biostudies-literature
Project description:BackgroundSarcomere protein mutations in hypertrophic cardiomyopathy induce subtle cardiac structural changes before the development of left ventricular hypertrophy (LVH). We have proposed that myocardial crypts are part of this phenotype and independently associated with the presence of sarcomere gene mutations. We tested this hypothesis in genetic hypertrophic cardiomyopathy pre-LVH (genotype positive, LVH negative [G+LVH-]).Methods and resultsA multicenter case-control study investigated crypts and 22 other cardiovascular magnetic resonance parameters in subclinical hypertrophic cardiomyopathy to determine their strength of association with sarcomere gene mutation carriage. The G+LVH- sample (n=73) was 29 ± 13 years old and 51% were men. Crypts were related to the presence of sarcomere mutations (for ≥1 crypt, β=2.5; 95% confidence interval [CI], 0.5-4.4; P=0.014 and for ≥2 crypts, β=3.0; 95% CI, 0.8-7.9; P=0.004). In combination with 3 other parameters: anterior mitral valve leaflet elongation (β=2.1; 95% CI, 1.7-3.1; P<0.001), abnormal LV apical trabeculae (β=1.6; 95% CI, 0.8-2.5; P<0.001), and smaller LV end-systolic volumes (β=1.4; 95% CI, 0.5-2.3; P=0.001), multiple crypts indicated the presence of sarcomere gene mutations with 80% accuracy and an area under the curve of 0.85 (95% CI, 0.8-0.9). In this G+LVH- population, cardiac myosin-binding protein C mutation carriers had twice the prevalence of crypts when compared with the other combined mutations (47 versus 23%; odds ratio, 2.9; 95% CI, 1.1-7.9; P=0.045).ConclusionsThe subclinical hypertrophic cardiomyopathy phenotype measured by cardiovascular magnetic resonance in a multicenter environment and consisting of crypts (particularly multiple), anterior mitral valve leaflet elongation, abnormal trabeculae, and smaller LV systolic cavity is indicative of the presence of sarcomere gene mutations and highlights the need for further study.
| S-EPMC4237712 | biostudies-literature
Project description: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.
| S-EPMC10483382 | biostudies-literature
Project description:BackgroundVentricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)-guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties.ObjectivesThe purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]-), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G-LVH+) and structural phenotype.MethodsThis was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH-, 104 LVH+ (51 G+/53 G-), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH- from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia.ResultsCompared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P < 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P < 0.05), and G+LVH+ had more fractionation than G-LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]).ConclusionsIn the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status.
| S-EPMC10945386 | biostudies-literature
Project description:Hypertrophic cardiomyopathy (HCM), hypertensive heart disease (HHD) and athletes' heart share an increased prevalence of atrial fibrillation. Atrial cardiomyopathy in these patients may have different characteristics and help to distinguish these conditions. In this single-center study, we prospectively collected and analyzed electrocardiographic (12-lead ECG, signal-averaged ECG (SAECG), 24 h Holter ECG) and echocardiographic data in patients with HCM and HHD and in endurance athletes. Patients with atrial fibrillation were excluded. We compared data of 27 patients with HCM (70% males, mean age 50 ± 14 years), 324 patients with HHD (52% males, mean age 75 ± 5.5 years), and 215 endurance athletes (72% males, mean age 42 ± 7.5 years). HCM patients had significantly longer filtered P-wave duration (153 ± 26 ms) and PR interval (191 ± 48 ms) compared to HHD patients (144 ± 16 ms, p = 0.012 and 178 ± 31, p = 0.034, respectively) and athletes (134 ± 14 ms, p = 0.001 and 165 ± 26 ms, both p < 0.001, respectively). HCM patients had a mean of 4.9 ± 16 premature atrial complexes per hour. Premature atrial complexes per hour were significantly more frequent in HHD patients (27 ± 86, p < 0.001), but not in athletes (2.7 ± 23, p = 0.639). Left atrial volume index (LAVI) was 43 ± 14 mL/m2 in HCM patients and significantly larger than age- and sex-corrected LAVI in HHD patients 30 ± 10 mL/m2; p < 0.001) and athletes (31 ± 9.5 mL/m2; p < 0.001). A borderline interventricular septum thickness ≥13 mm and ≤15 mm was found in 114 (35%) HHD patients, 12 (6%) athletes and 3 (11%) HCM patients. Structural and electrical atrial remodeling is more advanced in HCM patients compared to HHD patients and athletes.
| S-EPMC8910879 | biostudies-literature
Project description:BackgroundBiomedical knowledge is dispersed in scientific literature and is growing constantly. Curation is the extraction of knowledge from unstructured data into a computable form and could be done manually or automatically. Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, with genotype-phenotype associations still incompletely understood. We compared human- and machine-curated HCM molecular mechanisms' models and examined the performance of different machine approaches for that task.ResultsWe created six models representing HCM molecular mechanisms using different approaches and made them publicly available, analyzed them as networks, and tried to explain the models' differences by the analysis of factors that affect the quality of machine-curated models (query constraints and reading systems' performance). A result of this work is also the Interactive HCM map, the only publicly available knowledge resource dedicated to HCM. Sizes and topological parameters of the networks differed notably, and a low consensus was found in terms of centrality measures between networks. Consensus about the most important nodes was achieved only with respect to one element (calcium). Models with a reduced level of noise were generated and cooperatively working elements were detected. REACH and TRIPS reading systems showed much higher accuracy than Sparser, but at the cost of extraction performance. TRIPS proved to be the best single reading system for text segments about HCM, in terms of the compromise between accuracy and extraction performance.ConclusionsDifferent approaches in curation can produce models of the same disease with diverse characteristics, and they give rise to utterly different conclusions in subsequent analysis. The final purpose of the model should direct the choice of curation techniques. Manual curation represents the gold standard for information extraction in biomedical research and is most suitable when only high-quality elements for models are required. Automated curation provides more substance, but high level of noise is expected. Different curation strategies can reduce the level of human input needed. Biomedical knowledge would benefit overwhelmingly, especially as to its rapid growth, if computers were to be able to assist in analysis on a larger scale.
| S-EPMC8487578 | biostudies-literature
Project description:BackgroundEarly diastolic myocardial tissue Doppler velocities have reported to be reduced in mutation-positive patients with hypertrophic cardiomyopathy (HCM) in some studies even in the absence of left ventricular hypertrophy (LVH). Strain is a sensitive tool in detecting early systolic abnormalities in patients with HCM. Our goal is to examine novel echocardiographic characteristics of phenotype-negative carriers for a known sarcomeric gene mutation for HCM.MethodsWe evaluated 41 consecutive subjects with a known myosin-binding protein C3 (MYBPC3) mutation (c.3330+2T>G). Subjects who were mutation positive without LVH (G+/LVH-, n = 35) were compared with healthy controls (n = 30) regarding tissue Doppler and segmental longitudinal strain measures.ResultsThe G+/LVH- group was similar to the healthy controls with respect to chamber size, left ventricular mass index, and most diastolic filling parameters, including tissue Doppler-derived early diastolic annular velocities. Global longitudinal strain was similar for both groups (20.3 ± 2.1 vs 19.8 ± 1.8, P = .36), although regional segment analysis showed a notable reduction in the basal septum (16.8 ± 3.1 vs 19.0 ± 4.0%, P = .02) and increase in the basal posterior (22.5 ± 5.2 vs 17.9 ± 5.2, P = .001) as well as mid posterior (21.8 ± 4.7 vs 18.2 ± 3.0, P = .001) walls.ConclusionsIn our cohort of phenotype-negative carriers of a specific MYBPC3 mutation, there were minimal differences in conventional 2-dimensional, Doppler, and speckle-tracking-derived parameters of systolic and diastolic function compared with that of healthy subjects. The presence of regional alterations in strain indicative of the presence of underlying subclinical disease requires further validation.
| S-EPMC3155874 | biostudies-literature
Project description:Today, elite athletes form an important social group, and the non-sport facets of their lives matter as much as their sports performances. However, there has been little empirical research on the lifestyles of elite athletes. Therefore, this study aimed to develop knowledge about the Iranian elite athletes' lifestyle. The study was conducted with a qualitative approach in two phases. Glaserian grounded theory was used in the first phase, and thematic analysis was used in the second phase. Participants of the first phase included 19 sports experts, such as sports sociologists, sports psychologists, and sports coaches, who were selected by purposive and snowball sampling methods for holding unstructured in-depth interviews. The data were simultaneously analyzed using a set of open, theoretical, selective coding and memos. The codes were grouped into three different categories with different natures. The emerged theory advanced our understanding of the lifestyle shaping structures of elite athletes, lifestyle indicators, and even professionalization of their lifestyles. According to the results, the Iranian elite athletes' lifestyles include indicators, such as professional mindset, competencies, life vision, financial literacy, responsibility, consumption, leisure, personal issues, and religious behavior. Subjects of the second phase were 44 Iranian athletes in the national levels who participated voluntarily in the study. The data were analyzed by thematic analysis method, and lifestyles typologies were identified. Based on results, five dominant lifestyles among the Iranian elite athletes were identified: consumerist, easy going, socially useful, profit-oriented, and professional. Finally, the features of each lifestyle were discussed.
| S-EPMC9512170 | biostudies-literature
Project description:Whole genome sequencing (WGS) has great potential to explore all possible DNA variants associated with physical performance, psychological traits and health conditions of athletes. Here we present, for the first time, annotation of genomic variants of elite athletes, based on the WGS of 20 Tatar male wrestlers. The maximum number of high-quality variants per sample was over 3.8 M for single nucleotide polymorphisms (SNPs) and about 0.64 M for indels. The maximum number of nonsense mutations was 148 single nucleotide variants (SNVs) per individual. Athletes' genomes on average contained 18.9 nonsense SNPs in a homozygous state per sample, while non-athletes' exomes (Tatar controls, n = 19) contained 18 nonsense SNPs. Finally, we applied genomic data for the association analysis and used reaction time (RT) as an example. Out of 1884 known genome-wide significant SNPs related to RT, we identified four SNPs (KIF27 rs10125715, APC rs518013, TMEM229A rs7783359, LRRN3 rs80054135) associated with RT in wrestlers. The cumulative number of favourable alleles (KIF27 A, APC A, TMEM229A T, LRRN3 T) was significantly correlated with RT both in wrestlers (P = 0.0003) and an independent cohort (n = 43) of physically active subjects (P = 0.029). Furthermore, we found that the frequencies of the APC A (53.3 vs 44.0%, P = 0.033) and LRRN3 T (7.5 vs 2.8%, P = 0.009) alleles were significantly higher in elite athletes (n = 107) involved in sports with RT as an essential component of performance (combat sports, table tennis and volleyball) compared to less successful (n = 176) athletes. The LRRN3 T allele was also over-represented in elite athletes (7.5%) in comparison with 189 controls (2.9%, P = 0.009). In conclusion, we present the first WGS study of athletes showing that WGS can be applied in sport and exercise science.
| S-EPMC7433326 | biostudies-literature
Project description:Takotsubo cardiomyopathy (TCM) is a condition characterized by transient left ventricular dysfunction and apical ballooning, best seen on an echocardiogram or left ventriculogram. It mimics acute myocardial infarction but without evidence of coronary artery disease on an angiogram. Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart muscle disease that is significant with hypertrophy of the left ventricle with various morphologies. We hereby report a case of TCM in a male patient with a known history of HCM. The patient's hemodynamic findings were challenging because the TCM produced an increased left ventricular outflow tract (LVOT) gradient that was previously not seen on his prior echocardiogram or cardiac catheterizations. Assessment and continuous monitoring are warranted in such a rare case. Supportive care afterward with beta blockers, along with echocardiogram surveillance, are the mainstay of management of such a patient.
| S-EPMC6333265 | biostudies-other