Women with HCM present at more advanced age, with more symptoms, worse cardiopulmonary exercise tolerance, and different haemodynamics than men. Sex is an important determinant in HCM management as women with HCM have worse survival. Women may require more aggressive diagnostic and therapeutic approaches.

Objective: To explore the transcriptomic differences between patients with hypertrophic cardiomyopathy (HCM) and controls. Patients and Methods: RNA was extracted from cardiac tissue flash frozen at therapeutic surgical septal myectomy for 106 patients with HCM and 39 healthy donor hearts. Expression profiling of 37,846 genes was performed using the Illumina Human HT-12v3 Expression BeadChip. All patients with HCM were genotyped for pathogenic variants causing HCM. Technical validation was performed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. This study was started on January 1, 1999, and final analysis was completed on April 20, 2020. Results: Overall, 22% of the transcriptome (8443 of 37,846 genes) was expressed differentially between HCM and control tissues. Analysis by genotype revealed that gene expression changes were similar among genotypic subgroups of HCM, with only 4% (1502 of 37,846) to 6% (2336 of 37,846) of the transcriptome exhibiting differential expression between genotypic subgroups. The qRT-PCR confirmed differential expression in 92% (11 of 12 genes) of tested transcripts. Notably, in the context of coronavirus disease 2019 (COVID-19), the transcript for angiotensin I converting enzyme 2 (ACE2), a negative regulator of the angiotensin system, was the single most up-regulated gene in HCM (fold-change, 3.53; q-value ¼1.30Â10 À23 ), which was confirmed by qRT-PCR in triplicate (fold change, 3.78; P¼5.22Â10 À4 ), and Western blot confirmed greater than 5-fold overexpression of ACE2 protein (fold change, 5.34; P¼1.66Â10 À6 ). Conclusion: More than 20% of the transcriptome is expressed differentially between HCM and control tissues. Importantly, ACE2 was the most up-regulated gene in HCM, indicating perhaps the heart's compensatory effort to mount an antihypertrophic, antifibrotic response. However, given that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 for viral entry,

Background Incomplete penetrance and variable expression of Hypertrophic Cardiomyopathy (HCM) is well appreciated. Common genetic polymorphisms variants that may affect HCM penetrance and expression have been predicted but are not well established. Methods and Results We performed a case-control genome wide association (GWA) study to identify common HCM-associated genetic polymorphisms and then asked whether such common variants were more represented in HCM or could explain the heterogeneity of HCM phenotypes. We identified an intronic FHOD3 variant (rs516514) associated with HCM (OR = 2.45 (95% CI 1.76–3.41), p=1.25 × 10−7) and validated this finding in an independent cohort. Next, we tested FHOD3-V1151I (rs2303510), a non-synonymous variant in partial linkage disequilibrium (LD) with rs516514, and we detected an even stronger association with HCM (p=1.76 × 10−9). While HCM patients were more likely to carry these FHOD3 alleles subjects homozygous for FHOD3-1151I had similar HCM phenotypes as carriers of the V1151 allele. FHOD3 expression is increased in the setting of HCM and both alleles of FHOD3-V1151I were detected in HCM myectomy tissue. Previously FHOD3 was found to be required for formation of the sarcomere and here we demonstrate that its fly homolog fhos is required for normal adult heart systolic contraction. Conclusions Here we demonstrate the association of a common non-synonymous FHOD3 genetic variant with HCM. This discovery further strengthens the potential role of gene mutations and polymorphisms that alter the amino acid sequence of sarcomere proteins and HCM.

Over one-third of adults evaluated in our referral HCM clinic demonstrated concomitant PH, and this was associated with increased mortality except in those with obstructive HCM who underwent SRT.

Background The Acute Decompensated Heart Failure National Registry (ADHERE) and Get with the Guidelines (GWTG) registries have developed simple heart failure (HF) in-hospital mortality risk scores. We hypothesized that HF scores predictive of in-hospital mortality would perform as well for early post-discharge mortality risk stratification. Methods and Results In this single center, community based, retrospective study of all consecutive primary HF hospitalizations (6203 hospitalizations in 3745 patients) from 2000 to 2013, the ADHERE and GWTG risk scores were calculated from admission data. There were 176 (3.0%) and 399 (6.7%), 869 (14.7%) and 1,272 (21.5%) deaths in-hospital and at 30, 90 and 180 days post-discharge respectively. The GWTG but not ADHERE risk score was well-calibrated for in-hospital mortality. Both the ADHERE (c-statistic 0.66 and 0.67, 0.64, 0.64) and GWTG (c-statistic 0.74 and 0.73, 0.71, 0.70) HF risk scores were similarly predictive of in-hospital and 30, 90 and 180-day post-discharge mortality. The ADHERE risk score identified 10% and the GWTG risk score identified 20% of hospitalizations where 180 day post-discharge mortality was 50%, a prognostic bench mark for hospice referral. In contrast, hospitalizations characterized as lowest risk by the ADHERE (57% of hospitalizations; 180 day mortality 16.2%) or GWTG score (20% of hospitalizations; 180 day mortality 8.0%) had substantially lower mortality (odds ratios high versus low risk of 5–8 (ADHERE) and 11–18 (GWTG) across time points, p<0.0001 for all). Conclusion The simple ADHERE and GWTG scores stratify hospitalized HF patients for both in-patient and early post-discharge mortality risk, allowing comprehensive risk assessment on admission.