In the largest CMR-based study to date, significant phenotypic differences that characterize disease-gene subgroups are identified and resolved prior discrepancies through systematic review and meta-analysis.
Abstract
Background: Previous studies of genotype-phenotype correlations in hypertrophic cardiomyopathy (HCM) have presented inconsistent conclusions, potentially reflecting small studies and non-uniform phenotyping. Objectives: We aimed to identify genotype-phenotype correlations in sarcomeric variant-positive HCM cardiac magnetic resonance (CMR) imaging and adverse outcome data in the National Heart, Lung, and Blood Institute (NHLBI) HCM Registry. Methods: Of 2750 overall patients, 915 sarcomeric variant-positive ones were subgrouped by genotype. CMR measures of left ventricular (LV) hypertrophy, fibrosis and function, and adverse events, were compared. Findings were meta-analyzed with prior studies from systematic review. Results: Patients with pathogenic variants in thick-filament genes had greater hypertrophy than those in thin-filament genes - maximal LV wall thickness (maxLVWT) (21.7 {+/-} 5.0 vs. 20.0 {+/-} 4.4mm, P<0.01) and indexed LV mass (81.9 {+/-} 26.0 vs. 71.7 {+/-} 13.3g/m2, P<0.001). Of the former, MYBPC3 carriers had greater maxLVWT than MYH7 carriers (22.2 {+/-} 5.2 vs. 20.9 {+/-} 4.5mm, P<0.01) but lower LV ejection fraction (63.1 {+/-} 8.4 vs. 65.3 {+/-} 8.4%, P<0.001). Findings remained significant after covariate adjustment and meta-analysis. 23 (~1%) patients had >1 disease-linked variants with only 3 (~0.11%) carrying >1 pathogenic variants. MYBPC3 carriers had lower risk of a multiple event composite than MYH7 carriers. Conclusions: In the largest CMR-based study to date, we identified significant phenotypic differences that characterize disease-gene subgroups and resolved prior discrepancies through systematic review and meta-analysis. However, carriage of >1 sarcomeric variants did not contribute much to variation in phenotypic severity in the general HCM population due to its rarity.
BACKGROUND
Genotype-phenotype correlations in pediatric hypertrophic cardiomyopathy (HCM) are not well established. Determining whether specific genes or variants correlate with disease severity may impact clinical care.
OBJECTIVES
This study aims to identify associations between pathogenic genetic variants in pediatric HCM and echocardiographic maximal left ventricular wall thickness.
METHODS
Children with primary HCM from pediatric cardiomyopathy centers were recruited for research-based exome sequencing. Associations between genetic findings, imaging, and clinical outcomes were assessed. Genetic variants in established HCM genes were classified according to established guidelines. Left ventricular hypertrophy (LVH) at enrollment was classified as mild (z-score <12), moderate (z-score ≥12), or severe (z-score ≥17) based on LV septal or posterior wall thickness z-scores measured by a core echocardiography laboratory.
RESULTS
Severity of LVH was determined in 143 children with adequate echocardiograms. The median age at enrollment was 11.5 years (range: 3.8-14.4 years). Overall, 51% had a pathogenic variant, of which 93% were in sarcomeric genes. Children with severe LVH (n = 40, 28%) were diagnosed at younger ages than those with mild LVH (n = 78, 55%) at a median of 6.4 vs 12.9 years, P = 0.005. Those with severe LVH were more likely to have pathogenic variants; this association was driven by variants in MYBPC3 (OR: 4.1; 95% CI: 1.7-9.9). Missense variants in MYBPC3 predominated over stop, insertion-deletion, or splicing variants in severe cases.
CONCLUSIONS
In this population of children with primary HCM, severe LVH was associated with a younger age at enrollment and a higher likelihood of harboring a pathogenic variant in MYBPC3. (Genotype-Phenotype Associations in Pediatric Cardiomyopathy [PCM GENES]; NCT01873963).
E. Pahl, Stephanie M. Ware, Ling Shi et al.· JACC. Heart failure· 1 citation
BACKGROUND
Dilated cardiomyopathy (DCM) exhibits substantial genotypic heterogeneity, paralleled by diverse cardiac magnetic resonance (CMR) phenotypes and clinical presentations. However, the specific genotype-phenotype associations underlying this heterogeneity remain incompletely clear.
METHODS
Ninety DCM patients were prospectively enrolled and stratified into three subtypes: high-risk arrhythmogenic variant carriers (HRAv, n = 30), TTN truncating variant carriers (TTNtv, n = 30), and genotype-negative patients (GN, n = 30). High-risk arrhythmogenic variants were identified as DSP, FLNC, LMNA, and PLN variants. Comprehensive CMR parameter comparisons and logistic regression analyses were performed to identify the associations between genotypes and CMR features.
RESULTS
Among 90 participants (mean age, 46 years; 54 men), no significant differences were observed in ventricular volumes, systolic functions or LV strain among subtypes. HRAv patients presented with a higher prevalence of LGE (83%) compared with TTNtv (13%) and GN (40%) (p < 0.001), with typical linear midwall, ring-like, and subepicardial patterns. Global native T1 mapping(1379 vs. 1329 vs. 1335 ms, p = 0.037), T2 mapping (46.3 vs. 44.1 vs. 42.8 ms, p < 0.001), and extracellular volume (ECV)(35.8 vs. 31.3 vs. 30.5%, p < 0.001) were significantly elevated in HRAv compared with TTNtv and GN. In Firth penalized logistic regression models, higher global T2 (odds ratio[OR] = 1.22, 95%CI: 1.06-1.43, p = 0.004), higher global ECV(OR = 1.45, 95%CI: 1.17-1.86, p < 0.001), and LGE presence(OR = 9.22, 95%CI: 3.26-29.81, p < 0.001) were independently associated with HRAv status when separately added to the baseline model.
CONCLUSION
Compared with TTNtv and genotype-negative DCM, HRAv is characterized by a distinct CMR tissue phenotype marked by more extensive myocardial injury and fibrosis, despite similar ventricular remodeling and systolic impairment. These findings suggest that CMR tissue characterization may help identify genotype-associated phenotypic differences in DCM.
Zhi-Gang Zhang, Yang-Jie Li, Yuan-Wei Xu et al.· International Journal of Car...· 0 citations
Most patients with MYH7-related HCM presented with a benign phenotype over the long term, and the risks of AF, SCD, and worsening HF throughout life justify regular monitoring, and the need to look for particular genetic profiles that may potentially help tailored management strategies.
Catarina Gregório, M. Vilela, Ana Beatriz Garcia et al.· Revista Portuguesa de Cardio...· 0 citations
Hypertrophic cardiomyopathy (HCM) is marked by asymmetric cardiac wall thickening, hypercontractility, diastolic dysfunction, and fibrosis. Pathogenic sarcomere gene variants cause HCM, but comparable abnormalities occur in patients with unexplained disease, albeit with fewer adverse events. To investigate stage- and genotype-specific disease mechanisms, we performed single-nucleus RNA sequencing of cardiac tissues from 47 patients with HCM, spanning obstructive HCM with preserved systolic function and end-stage HCM, and compared them with nonfailing donor and dilated cardiomyopathy hearts. We identified transcriptional programs associated with cardiomyocyte hypertrophy, fibrosis, and vascular remodeling. Pathogenic variant-positive early-stage HCM samples showed reduced cardiomyocyte abundance and expansion of a proarrhythmogenic cardiomyocyte state. We identified proline-rich 16 (PRR16) as a cardiomyocyte growth-associated gene in HCM and validated its increased expression by RNA in situ hybridization and in a human induced pluripotent stem cell-derived cardiomyocyte HCM model. In HCM samples, fibroblast compositional shifts were associated with profibrotic activation and adverse extracellular matrix remodeling, accompanied by reduced collagen IV (COL4A1/COL4A2) expression and ultrastructural basement membrane abnormalities. HCM samples also exhibited extensive vascular alterations, including shifts in endothelial cell subpopulations, reduced pericyte abundance suggestive of microvascular dysfunction, and increased lymphangiogenic vascular endothelial growth factor C signaling. Unsupervised and supervised machine learning approaches distinguished HCM from dilated cardiomyopathy and accurately predicted genotype status in early-stage HCM from cell type-resolved transcriptional profiles, revealing widespread genotype-driven remodeling. Together, our findings uncover multicellular, genotype-associated remodeling programs in HCM, providing insight into mechanisms underlying arrhythmia, fibrosis, microvascular dysfunction, and heart failure progression.
E. Adami, Yuri Kim, Sean L. Zheng et al.· Science Translational Medici...· 1 citation
clinical monitoring. Patients with sarcomeric variants generally have worse prognosis than those without, including earlier disease onset and higher rates of sudden cardiac death, heart failure and arrhythmias. 3 Historically, HCM was regarded as a monogenic disorder caused by pathogenic variants in sarcomeric genes. While MYH7 and MYBPC3 continue to account for the majority of genetically confirmed cases, contemporary research has revealed a more complex and heterogeneous genetic architecture. Recent gene re-evaluations and variant reclassifications have highlighted the role of non-sarcomeric genes, including FHOD3 , ALPK3 , CSRP3 and TRIM63 , as contributors to HCM phenotypes. 3 Common genetic variants play a substantial role in HCM susceptibility and disease expression, with genome-wide association studies identifying 70 susceptibility loci associated with HCM risk. Polygenic risk scores derived from these common variants significantly modify disease penetrance, severity and outcomes, particularly in pathogenic variant carriers where penetrance differs. 3 These findings have important implications for clinical practice; they reinforce the concept of HCM as a spectrum of diseases rather than a single genetic entity, setting the stage for more individualised approaches to diagnosis, counselling and management.
Clara Saldarriaga· Cardiac failure review· 0 citations
Background: Contemporary data on the clinical detection rate and profile of phenotypical hypertrophic cardiomyopathy (HCM) in major Chinese healthcare settings are limited. This multicenter study aimed to determine the detection rate and echocardiographic features of the HCM phenotype in a large Chinese cohort. Methods: This cross-sectional study analyzed echocardiography databases from nine medical centers across China, including adult patients examined during 2023. HCM phenotype was defined as end-diastolic wall thickness ≥15 mm in the left ventricle. Patients with moderate to severe aortic stenosis were excluded. Subcategories included phenotypes of obstructive HCM and apical hypertrophy. Results: Among 655,383 examinations, 2610 patients met the criteria of the HCM phenotype, yielding a detection rate of 0.40% (≈1 in 250). The mean age was 60.2 years with male predominance (70.3%). Asymmetric septal hypertrophy was present in 53.3% of patients. The most commonly involved site with maximal wall thickness was the interventricular septum (57.6%), followed by the apex (20.9%) and the basal septum (17.7%). The overall intra-left ventricular obstruction rate was 16.2%; left ventricular outflow tract obstruction (LVOTO) accounted for 12.1%. LVOTO patients had greater septal thickness, smaller left ventricular diastolic dimensions, and more mitral regurgitation. Female sex was associated with a significantly higher LVOTO rate than males (18.2% vs. 9.6%, p < 0.001). Pure apical hypertrophy was identified in 4.5% of patients, with an increasing detection rate in older age groups. Conclusions: This large-scale, multicenter study confirms a high clinical detection rate for the HCM phenotype (≈1 in 250) in major Chinese centers. Substantial phenotypic heterogeneity across age and sex, coupled with the identification of key factors associated with LVOTO, highlights the need for sex- and age-specific diagnostic strategies and therapeutic planning in clinical practice.
Bei-Ning Wang, Bei Wang, Hui Sun et al.· Journal of Clinical Medicine· 0 citations
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