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Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, often caused by sarcomere gene mutations, though many sporadic cases remain genetically unexplained. Here we show that the somatic variant NAP1L1 p.D349E was involved in cardiac hypertrophy in sporadic HCM patients. Through next generation sequencing, we found that somatic variant NAP1L1 p.D349E was recurrent in the cardiomyocytes of gene-elusive sporadic HCM patients. Subsequent in vivo and in vitro functional analysis confirmed that NAP1L1 p.D349E contributes to HCM by triggering an innate immunity response. This mutation destabilizes nucleosome formation, causing DNA to leak into the cytoplasm. This leakage activates a key immune pathway, cGAS-STING, which leads to the release of inflammatory molecules and promotes heart muscle thickening. Our findings reveal a new mechanism driving HCM and suggest that somatic variants could be important in understanding and management of HCM. Many sporadic cases of hypertrophic cardiomyopathy have unknown genetic basis. Here, the authors identify a mutation in the gene NAP1L1 to be associated with cases of hypertrophic cardiomyopathy, linking it to cGAS-STING-IFN signaling.

Background Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, shows significant genetic and clinical heterogeneity, yet its molecular basis remains unclear. This study aims to uncover molecular insights behind HCM based on proteomic analysis. Methods We performed proteomic analysis on formalin-fixed paraffin-embedded septal tissue samples from 105 patients with obstructive HCM undergoing myectomy, including 35 with MYBPC3 and 35 with MYH7 mutations. The primary outcome was major adverse cardiovascular events (MACE), comprising all-cause mortality and other major cardiovascular events. Results We identified four molecular subtypes: 39 patients with subtype-I (S-I), 38 with S-II, 27 with S-III, and 1 with S-IV. During a median follow-up of 6.8 years, 28.6% of patients developed MACE. Among the subtypes, S-III exhibited the minimal fibrosis and the best clinical outcomes. S-II presented the most severe phenotype and poorest prognosis, characterized by activation of inflammatory and fibrotic pathways, along with downregulation of multiple metabolic processes. Compared to S-II, S-I displayed opposing pathway patterns and better outcomes, with a predominance of MYBPC3 mutation carriers. Beisides, we identified protein modules that were associated with genotypes and clinical features. MYH7-related modules were positively correlated with fibrosis and MACE, primarily enriched in inflammatory and fibrotic pathways. In contrast, MYBPC3-related modules were linked to better clinical outcomes, enriched in energy metabolism pathways. Conclusions This proteomic study revealed molecular mechanisms linking genotype, fibrosis and prognosis in HCM, and identified potential drivers of high-risk subtypes with severe phenotypes. These findings may guide future risk stratification and therapeutic target development. Graphical Abstract

The molecular mechanisms that drive the development of cardiac hypertrophy in hypertrophic cardiomyopathy (HCM) remain elusive. Accumulated evidence suggests that microRNAs are essential regulators of cardiac remodelling. We have been suggested that microRNAs could play a role in the process of HCM. To uncover which microRNAs were changed in their expression, microRNA microarrays were performed on heart tissue from HCM patients (n = 7) and from healthy donors (n = 5). Among the 13 microRNAs that were differentially expressed in HCM, miR‐451 was the most down‐regulated. Ectopic overexpression of miR‐451 in neonatal rat cardiomyocytes (NRCM) decreased the cell size, whereas knockdown of endogenous miR‐451 increased the cell surface area. Luciferase reporter assay analyses demonstrated that tuberous sclerosis complex 1 (TSC1) was a direct target of miR‐451. Overexpression of miR‐451 in both HeLa cells and NRCM suppressed the expression of TSC1. Furthermore, TSC1 was significantly up‐regulated in HCM myocardia, which correlated with the decreased levels of miR‐451. As TSC1 is a known positive regulator of autophagy, we examined the role of miR‐451 in the regulation of autophagy. Overexpression of miR‐451 in vitro inhibited the formation of the autophagosome. Conversely, miR‐451 knockdown accelerated autophagosome formation. Consistently, an increased number of autophagosomes was observed in HCM myocardia, accompanied by up‐regulated autophagy markers, and the lipidated form of LC3 and Beclin‐1. Taken together, our findings indicate that miR‐451 regulates cardiac hypertrophy and cardiac autophagy by targeting TSC1. The down‐regulation of miR‐451 may contribute to the development of HCM and may be a potential therapeutic target for this disease.

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.

Background The impact of septal myectomy on the progression of ascending aortic (AAo) dilation in patients with obstructive hypertrophic cardiomyopathy (HOCM) remains uncertain. This study aimed to investigate the relationship between septal myectomy and AAo dilation in HOCM patients. Methods A total of 69 patients with HOCM were enrolled. All the participants underwent sequential cardiac magnetic resonance scans at a mean interval of 5.13 ± 2.04 years, with each scan being more than 3 years apart. Results At baseline, 17 patients with HOCM (25%) exhibited AAo dilation (Indexed AAo dimension > 19 mm/m²). Age (OR 1.10, 95%CI: 1.01–1.019, P  = 0.026) and female (OR 4.80, 95%CI: 1.05–21.93, P  = 0.043) were independently associated with AAo dilation. In patients who underwent myectomy, the AAo dimension at follow-up was similar to that at baseline (32.47 ± 4.70 mm vs. 32.81 ± 5.06 mm, P  = 0.197). Furthermore, the rate of AAo dilation was lower in patients with myectomy compared to those without myectomy (-0.06 ± 0.38 mm/year vs. 0.18 ± 0.43 mm/year, P  = 0.016). Additionally, moderate or severe mitral regurgitation was significantly associated with AAo dilation rate (B = 0.273, P  = 0.032). Conclusions Myectomy in patients with HOCM was associated with the absence of progression of AAo dilatation.

Background Myocardial bridging (MB) is common in patients with hypertrophic cardiomyopathy (HCM). There are sparse data on the impact of MB on myocardial fibrosis in HCM. This study was designed to evaluate the relationship between MB and myocardial fibrosis in patients with obstructive HCM. Methods In this cohort study, retrospective data were collected from a high-volume HCM center. Patients with obstructive HCM who underwent septal myectomy and preoperative cardiac magnetic resonance (CMR) were screened from 2011 to 2018. Results Finally, 492 patients were included in this study, with an average age of 45.7 years. Of these patients, 76 patients had MB. MB occurred mostly in the left anterior descending artery (73/76). The global extent of late gadolinium enhancement (LGE) was correlated with the degree of systolic compression ( r  = 0.33, p  = 0.003). Multivariable linear regression analysis revealed that the degree of systolic compression was an independent risk factor for LGE ( β  = 0.292, p  = 0.007). The LGE fraction of basal and mid anteroseptal segments in patients with severe MB (compression ratio ≥ 80%) was significantly greater than that in patients with mild to moderate MB (compression ratio < 80%). During a median follow-up of 28 (IQR: 15–52) months, 15 patients died. Kaplan–Meier analysis did not identify differences in all-cause death (log-rank p  = 0.63) or cardiovascular death (log-rank p  = 0.72) between patients undergoing MB-related surgery and those without MB. Conclusions MB with severe systolic compression was significantly associated with a high extent of fibrosis in patients with obstructive HCM. Concomitant myotomy or coronary artery bypass grafting might provide excellent survival similar to that of patients without MB. Identification of patients with severe MB and providing comprehensive management might help improve the prognosis of patients with HCM.

BackgroundAssessing the structure and function of left atrium (LA) is crucial in hypertrophic obstructive cardiomyopathy (HOCM) because LA remodeling correlates with atrial fibrillation. However, few studies have investigated the potential effect of myomectomy on LA phasic remodeling in HOCM after myectomy using cardiovascular magnetic resonance (CMR) feature tracking (FT). This study aims to evaluate the LA structural and functional remodeling with HOCM after myectomy by CMR-FT and to further investigate the determinants of LA reverse remodeling.MethodsIn this single-center study, we retrospectively studied 88 patients with HOCM who received CMR before and after myectomy between January 2011 and June 2021. Preoperative and postoperative LA parameters derived from CMR-FT were compared, including LA reservoir function (total ejection fraction [EF], total strain [εs], peak positive strain rate [SRs]), conduit function (passive EF, passive strain [εe], peak early negative strain rate [SRe]) and booster function (booster EF, active strain [εa], late peak negative strain rate [SRa]). Eighty-six healthy participants were collected for comparison. Univariate and multivariate linear regression identified variables associated with the rate of change of εa.ResultsCompared with preoperative parameters, LA reservoir function (total EF, εs, SRs), booster function (booster EF, εa, SRa), and SRe were significantly improved after myectomy (all P < 0.05), while no significant differences were observed in passive EF and εe. Postoperative patients with HOCM still had larger LA and worse LA function than healthy controls (all P < 0.05). After analyzing the rates of change in LA parameters, LA boost function, especially εa, showed the most dramatic improvement beyond the improvements in reservoir function, conduit function, and volume. In multivariable regression analysis, minimum LA volume index (adjusted β = − 0.39, P < 0.001) and Δleft ventricular outflow tract (LVOT) pressure gradient (adjusted β = − 0.29, P = 0.003) were significantly related to the rate of change of εa.ConclusionsPatients with HOCM after septal myectomy showed LA reverse remodeling with a reduction in LA size and restoration in LA reservoir and booster function but unchanged LA conduit function. Among volumetric and functional changes, booster function had the greatest improvement postoperatively. Besides, preoperative LAVmin index and ΔLVOT might be potential factors associated with the degree of improvement in εa.

Background The optimal timing of left ventricular unloading in patients with cardiogenic shock receiving venoarterial extracorporeal membrane oxygenation therapy remains controversial. This systematic review evaluated the latest evidence on the impact of left ventricular unloading timing in patients with cardiogenic shock receiving venoarterial extracorporeal membrane oxygenation. Methods The PubMed, Embase and Cochrane Library databases were searched from inception to February 2025. The identified studies were screened based on predefined inclusion and exclusion criteria, and eligible studies were subjected to quality assessment and data extraction. Heterogeneity testing and meta-analysis were performed using Review Manager software version 5.4. Results Eight studies involving 2,117 patients (proactive unloading, 1,338; passive unloading, 779) were included in the meta-analysis, which revealed no statistically significant differences in extracorporeal membrane oxygenation weaning rates (relative risk = 1.06, 95% confidence interval: 0.87–1.28; P  = 0.59), in-hospital mortality (relative risk = 0.95, 95% confidence interval: 0.86–1.04; P  = 0.28), or 30-day all-cause mortality (relative risk = 0.75, 95% confidence interval: 0.52–1.10; P  = 0.14) between the proactive and passive unloading groups. However, the risks of sepsis (relative risk = 0.79, 95% confidence interval: 0.64–0.96; P  = 0.02) and abdominal complications (relative risk = 0.67, 95% confidence interval: 0.46–0.96; P  = 0.03) were lower following proactive unloading than following passive unloading. Conclusion Compared to passive left ventricular unloading, proactive left ventricular unloading did not confer significant benefits in terms of extracorporeal membrane oxygenation weaning success or short-term survival outcomes, but was associated with reduced risks of sepsis and abdominal complications. Registration The review protocol was registered in PROSPERO (ID: CRD42024499028).

Background Myocardial bridging (MB) is associated with various forms of arrhythmia. However, whether MB is a risk factor for atrial fibrillation (AF) in patients with hypertrophic obstructive cardiomyopathy (HOCM) remains unknown. This study aimed to identify the relationship between myocardial bridging of the left anterior descending coronary artery (MB-LAD) and AF in patients with HOCM. Methods We reviewed the medical records of 1925 patients diagnosed with HOCM at Fuwai Hospital from January 2012 to March 2019. Patients with coronary artery disease, a history of heart surgery, and those who had not been subjected to angiography were excluded. Finally, 105 patients with AF were included in this study. The control group was matched in a ratio of 3:1 based on age and gender. Results Forty-three patients were diagnosed with MB-LAD in this study. The presence of MB was significantly higher in patients with AF than in those without AF (19.0% vs. 7.3%; p  = 0.001), although MB compression and MB length did not differ between the two groups. In conditional multivariate logistic analysis, MB (odds ratio [OR] 2.33; 95% confidence interval [CI] 1.08–5.01; p  = 0.03), pulmonary arterial hypertension (OR 2.63; 95% CI 1.26–5.47; p  = 0.01), hyperlipidemia (OR 1.83; 95% CI 1.12–3.00; p  = 0.016), left atrial diameter (OR 1.09; 95% CI 1.05–1.13; p  < 0.001), and interventricular septal thickness (OR 1.06; 95% CI 1.003–1.12; p  = 0.037) were independent risk factors for AF in patients with HOCM. Conclusions The presence of MB is an independent risk factor for AF in patients with HOCM. The potential mechanistic link between MB and the development of AF warrants further investigation.

Aims Chronic low‐grade inflammation, often observed in hypertrophic cardiomyopathy (HCM), promotes adverse ventricular remodelling. This study aimed to investigate the relationship between inflammatory markers and myocardial fibrosis (MF) in patients with HCM. Methods and results This study included 102 patients with complete baseline data who underwent septal myectomy. Myocardial samples were stained with Masson's trichrome and analysed to determine myocardial collagen content and MF levels. Plasma levels of inflammatory markers were measured using standard laboratory procedures. Univariate and multivariate logistic regression analyses were performed to explore the relationship between the inflammatory markers and MF. Among the 102 participants included in the analysis, the mean age was 48.9 years, with 69 [67.6%] being men. The overall MF ranged from 2.5% to 40.7% (mean = 15.2 ± 8.1%, median = 13.0%, IQR = 9.9%–18.4%). Participants were divided into two groups based on a median MF of 13%. The high MF group had a larger left atrial diameter and left ventricular ejection fraction. Levels of interleukin (IL)‐2, tumour necrosis factor (TNF)‐α and interferon (IFN)‐α were significantly higher in patients with high MF compared to those with low MF (2.3 vs. 4.0 pg/mL, 3.1 vs. 3.9 pg/mL, 4.2 vs.4.7 pg/mL, respectively; all P < 0.05). In multivariate models adjusted for age, sex and other clinical features, IL‐2, IL‐5 and TNF‐α, were correlated with increased interstitial MF [odds ratio (OR): 1.54, 95% confidence interval (CI): 1.10–2.14; OR: 1.42, 95% CI: 1.02–1.98; OR: 1.33, 95% CI: 1.04–1.70]. After additional adjustment for imaging indicators, IL‐2 and TNF‐α remained significant (OR: 1.49, 95% CI: 1.06–2.09, P = 0.021; OR:1.35, 95% CI: 1.01–1.80, P = 0.044). The correlation analysis between inflammation and replacement fibrosis assessed by CMR in 97 patients revealed that 72 (74.2%) showed late gadolinium enhancement (LGE). No significant correlation was found between inflammatory markers and the presence or extent of LGE. Conclusions Higher levels of IL‐2 and TNF‐α were associated with increased histopathological interstitial MF in patients with HCM. Given the gradual progression of MF in HCM, initiating anti‐inflammatory treatment in the early stages may delay its progression.