Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder characterized by cardiomyocyte hypertrophy and cardiac fibrosis. Pathological cardiac remodeling in the myocardium of HCM patients may progress to heart failure. An in-depth elucidation of the lineage-specific changes in pathological cardiac remodeling of HCM is pivotal for the development of therapies to mitigate the progression. Here, we performed single-nucleus RNA-seq of the cardiac tissues from HCM patients or healthy donors and conducted spatial transcriptomic assays on tissue sections from patients. Unbiased clustering of 55,122 nuclei from HCM and healthy conditions revealed 9 cell lineages and 28 clusters. Lineage-specific changes in gene expression, subpopulation composition, and intercellular communication in HCM were discovered through comparative analyses. According to the results of pseudotime ordering, differential expression analysis, and differential regulatory network analysis, potential key genes during the transition towards a failing state of cardiomyocytes such as FGF12, IL31RA, and CREB5 were identified. Transcriptomic dynamics underlying cardiac fibroblast activation were also uncovered, and potential key genes involved in cardiac fibrosis were obtained such as AEBP1, RUNX1, MEOX1, LEF1, and NRXN3. Using the spatial transcriptomic data, spatial activity patterns of the candidate genes, pathways, and subpopulations were confirmed on patient tissue sections. Moreover, we showed experimental evidence that in vitro knockdown of AEBP1 could promote the activation of human cardiac fibroblasts, and overexpression of AEBP1 could attenuate the TGFβ-induced activation. Our study provided a comprehensive analysis of the lineage-specific regulatory changes in HCM, which laid the foundation for targeted drug development in HCM.

This study aims to report our preliminary experience and anatomic findings in the surgical treatment and postoperative management of hypertrophic obstructive cardiomyopathy. This study included 277 patients with hypertrophic obstructive cardiomyopathy (168 [60.65%] were male), with a median age of 47 years (interquartile range, 35-54 years), who underwent surgical myectomy performed by 1 surgeon in Fuwai Hospital between May 2010 and April 2015. The median follow-up was 14 months (interquartile range, 7-24 months). A total of 127 patients (45.85%) underwent concomitant procedures, and 2 patients (0.72%) died in the early perioperative days. The left ventricular outflow gradient decreased from 78 mm Hg (interquartile range, 61-100 mm Hg) to 11 mm Hg (interquartile range, 8-15 mm Hg) when discharged (P < .001). Of the 228 patients with well-documented anatomic description, more than 80% had various intraventricular anomalies. The cumulative survival was 99.28% (95% confidence interval, 97.15-99.82) at 1 year and 96.98% (95% confidence interval, 92.56-98.79) at 5 years. Of the surviving 272 patients, 268 (98.53%) were categorized with functional class I and II of the New York Heart Association classification at the latest evaluation. Anomalous muscle bundles are common in hypertrophic obstructive cardiomyopathy, and they may lead to middle-apical obstruction. Surgical myectomy provides excellent clinical outcomes with low risk for sufficient relief of obstruction and radical correction of intraventricular anomalies in patients with hypertrophic obstructive cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) represents one of the most common heritable heart diseases. However, the signalling pathways and regulatory networks underlying the pathogenesis of HCM remain largely unknown. Here, we present a strand-specific RNA-seq dataset for both coding and lncRNA profiling in myocardial tissues from 28 HCM patients and 9 healthy donors. This dataset constitutes a valuable resource for the community to examine the dysregulated coding and lncRNA genes in HCM versus normal conditions.

Background: Filamin C (FLNC) mutation was reported as a cause of HCM, with a high probability of sudden cardiac death. However, the mutation profile of FLNC, and its relationship with phenotypic expression in HCM, remains to be elucidated.Methods: In this study, FLNC gene was sequenced in 540 HCM patients and 307 healthy controls.Results: We found that 39 (7.2%) patients carried FLNC mutations, with a similar frequency to that of controls (4.2%, p = 0.101). Pedigree analysis showed that mutations were not well segregated with HCM. The baseline characteristics between HCM patients, with and without mutations, were comparable. FLNC mutations did not increase the risk for either all‐cause mortality (HR 0.746, 95% CI 0.222–2.295, p = 0.575) or cardiac mortality (HR 0.615, 95% CI 0.153–1.947, p = 0.354) in HCM patients during a follow‐up of 4.7 ± 3.2 years. Moreover, there was no significant difference in survival free from sudden cardiac arrest (HR 0.721, 95% CI 0.128–3.667, p = 0.660) and heart failure (HR 0.757, 95% CI 0.318–1.642, p = 0.447).Conclusions: FLNC mutations were common in both HCM patients and healthy population. The pathogenicity of FLNC mutations detected in HCM patients and its association with the clinical outcomes should be cautiously interpreted.

The aim was to assess the early and mid-term clinical effects of transaortic extended septal myectomy (TAESM) on obstructive hypertrophic cardiomyopathy (HCM) in China. Ninety-three consecutive patients [57 men; mean age 45.8 ± 13.4 (11–74) years] with obstructive HCM underwent TAESM in Fuwai hospital. Their clinical data were analysed retrospectively. All the patients had drug-refractory symptoms and left ventricular outflow tract (LVOT) obstruction with a resting or physically provoked gradient of ≥50 mmHg. Preoperative transthoracic, intra-operative transoesophageal and postoperative transthoracic echocardiography was performed to assess LVOT gradients, septal thickness, LVOT diameter, mitral valve function, etc. Systolic anterior motion (SAM) of the anterior mitral valve leaflet had been detected in all preoperatively. All the surgical procedures of the 93 patients were technically successful. The average length of postoperative stay was 7.8 ± 3.7 days. The 30-day and in-hospital mortality was 0%. Initial postoperative transoesophageal echocardiography (TEE) demonstrated marked reduction in LVOT gradient (91.76 ± 25.08 to 14.34 ± 13.44 mmHg, P < 0.0005) and significant improvement in mitral regurgitation (MR; P < 0.0005). Concomitant surgical procedures were carried out in 37 (39.8%). Complete atrioventricular block occurred in 3, complete left bundle branch block in 44, intraventricular conduction delay in 18, complete right bundle branch block in 2, transient renal dysfunction in 2 and transient intra-aortic-balloon-pumping was needed in 2. No other complications were observed during hospital stay. During a follow-up of 10.72 ± 11.02 (1–24) months, there were no readmissions or deaths, and all patients subjectively reported an obvious decrease in limiting symptoms and a significant increase in physical ability. At the latest follow-up, the New York Heart Association functional class decreased from 3.09 ± 0.60 (2–4) preoperatively to 1.12 ± 0.32 (1–2) (P < 0.0005); the LVOT gradient remained low at 14.78 ± 14.01 mmHg; MR remained absent (51) or at mild-(41)-to-moderate-(1) levels and SAM resolved completely in 98.9% (92 of 93) patients. TAESM provides excellent relief from LVOT obstruction in HCM patients, with a conspicuous clinical and echocardiographic outcome at early and mid-term follow-up. For obstructive HCM and cardiac comorbidities, concomitant cardiac procedures with TAESM can be performed with low risk and satisfactory results.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and is characterized by primary left ventricular hypertrophy usually caused by mutations in sarcomere genes. The mechanism underlying cardiac remodeling in HCM remains incompletely understood. An investigation of HCM through integrative analysis at multi-omics levels will be helpful for treating HCM. DNA methylation and chromatin accessibility, as well as gene expression, were assessed by nucleosome occupancy and methylome sequencing (NOMe-seq) and RNA-seq, respectively, using the cardiac tissues of HCM patients. Compared with those of the controls, the transcriptome, DNA methylome, and chromatin accessibility of the HCM myocardium showed multifaceted differences. At the transcriptome level, HCM hearts returned to the fetal gene program through decreased sarcomeric and metabolic gene expression and increased extracellular matrix gene expression. In the DNA methylome, hypermethylated and hypomethylated differentially methylated regions were identified in HCM. At the chromatin accessibility level, HCM hearts showed changes in different genome elements. Several transcription factors, including SP1 and EGR1, exhibited a fetal-like pattern of binding motifs in nucleosome-depleted regions in HCM. In particular, the inhibition of SP1 or EGR1 in an HCM mouse model harboring sarcomere mutations markedly alleviated the HCM phenotype of the mutant mice and reversed fetal gene reprogramming. Overall, this study not only provides a high-precision multi-omics map of HCM heart tissue but also sheds light on the therapeutic strategy by intervening in the fetal gene reprogramming in HCM.