宋云虎
中国医学科学院阜外医院
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.
Cell discovery 2023
BACKGROUND:To simplify surgical septal reduction therapy for hypertrophic obstructive cardiomyopathy (HOCM), we developed a novel transapical beating-heart septal myectomy (TA-BSM) procedure.OBJECTIVES:In this study, we sought to evaluate the clinical utility of TA-BSM in a first-in-human trial.METHODS:Patients with HOCM were enrolled if they presented with drug-refractory disabling symptoms. TA-BSM was performed via minithoracotomy with the use of our beating-heart myectomy device under echocardiographic guidance, without the use of cardiopulmonary bypass. Repeated resections were performed to tailor the extent of the septal myectomy for sufficient abolishment of left ventricular outflow tract (LVOT) obstruction and mitral regurgitation (MR). The primary outcome measure was procedural success, defined by resting/provoked LVOT gradient <30/50 mm Hg and residual MR grade ≤1+ (of 4+) at 3-month follow-up.RESULTS:A total of 47 patients aged 12 to 77 years were enrolled. Of the 46 patients who were followed for 3 months, 42 achieved procedural success. The maximal LVOT gradient decreased from 86 mm Hg (IQR: 67-114 mm Hg) at baseline to 19 mm Hg (IQR: 14-28 mm Hg) at 3 months. MR grade was ≤1+ in 3 patients at baseline and in 45 patients at 3 months. One patient died on postoperative day 10 owing to device-unrelated reasons. Other major adverse events included 1 delayed ventricular septal perforation and 1 intraoperative left ventricular apical tear.CONCLUSIONS:TA-BSM is a safe and efficient minimally invasive procedure for septal reduction of heterogeneous HOCM. Compared with conventional septal myectomy, TA-BSM provides real-time evaluation to guide resection while reducing surgical trauma. (Transapical Beating-Heart Septal Myectomy in Patients With Hypertrophic Obstructive Cardiomyopathy; NCT05332691).
Journal of the American College of Cardiology 2023
OBJECTIVES:The objectives of this study were to validate 3 existing heart transplant risk scores with a single-centre cohort in China and evaluate the efficacy of the 3 systems in predicting mortality.METHODS:We retrospectively studied 428 patients from a single centre who underwent heart transplants from January 2015 to December 2019. All patients were scored using the Index for Mortality Prediction After Cardiac Transplantation (IMPACT) and the United Network for Organ Sharing (UNOS) and risk stratification scores (RSSs). We assessed the efficacy of the risk scores by comparing the observed and the predicted 1-year mortality. Binary logistic regression was used to evaluate the predictive accuracy of the 3 risk scores. Model discrimination was assessed by measuring the area under the receiver operating curves. Kaplan-Meier survival analyses were performed after the patients were divided into different risk groups.RESULTS:Based on our cohort, the observed mortality was 6.54%, whereas the predicted mortality of the IMPACT and UNOS scores and the RSSs was 10.59%, 10.74% and 12.89%, respectively. Logistic regression analysis showed that the IMPACT [odds ratio (OR), 1.25; 95% confidence interval (CI), 1.15-1.36; P < 0.001], UNOS (OR, 1.68; 95% CI, 1.37-2.07; P < 0.001) and risk stratification (OR, 1.61; 95% CI, 1.30-2.00; P < 0.001) scores were predictive of 1-year mortality. The discriminative power was numerically higher for the IMPACT score [area under the curve (AUC) of 0.691)] than for the UNOS score (AUC 0.685) and the RSS (AUC 0.648).CONCLUSIONS:We validated the IMPACT and UNOS scores and the RSSs as predictors of 1-year mortality after a heart transplant, but all 3 risk scores had unsatisfactory discriminative powers that overestimated the observed mortality for the Chinese cohort.
Interactive cardiovascular and thoracic surgery 2022
BACKGROUND:This study aimed to investigate the impact of septal myectomy on left atrial function, left ventricle remodeling, and fibrosis in patients with obstructive hypertrophic cardiomyopathy.METHOD:From May 2012 to September 2016, preoperative cardiac magnetic resonance imaging of 507 adult patients who underwent septal myectomy at Fuwai Hospital was retrospectively collected. Until October 2019, 57 patients were followed up with postoperative cardiac magnetic resonance imaging at 11.9 months (interquartile range, 6.4-25.3). Preoperative and postoperative left atrium and left ventricle changes, as well as late gadolinium enhancement as a surrogate of myocardial fibrosis, were analyzed.RESULTS:Patients with hypertrophic cardiomyopathy requiring myectomy showed increased left atrium volume, stroke volume, left ventricular ejection fraction, and left ventricle mass, as well as decreased left ventricle end-systolic volume. Echocardiography demonstrated that myectomy decreased the left ventricle outflow tract gradient, left atrium diameter, left ventricular ejection fraction, and posterior wall thickness. Postoperative cardiac magnetic resonance imaging showed that the minimal left atrium volume (P < .001), stroke volume (P = .009), left ventricle ejection fraction (P < .001), and left ventricle mass (166.9 [interquartile range, 135.8] vs 149.3 [interquartile range, 100.5] g, P < .001) decreased, whereas the left ventricle end-systolic volume (P = .001) and left atrium ejection fraction (37.9% ± 14.6% vs 47.8% ± 14%, P < .001) increased. However, left ventricle myocardial fibrosis, as detected by late gadolinium enhancement, still progressed after myectomy in patients with obstructive hypertrophic cardiomyopathy (15.2% ± 9.6% vs 18.6% [interquartile range, 21.6], P = .009).CONCLUSIONS:Septal myectomy alleviated left ventricle hypertrophy and reversed left atrium and left ventricle remodeling in patients with obstructive hypertrophic cardiomyopathy. Late gadolinium enhancement in the left ventricle increased despite myectomy in patients with obstructive hypertrophic cardiomyopathy.
The Journal of thoracic and cardiovascular surgery 2022
Background:This study aimed to explore the effect of sex on left atrial (LA) remodeling and its relationship with myocardial fibrosis in patients with hypertrophic obstructive cardiomyopathy (HOCM).Methods and results:A total of 85 patients with HOCM were enrolled. Myocardial fibrosis was quantified by the collagen volume fraction (CVF) in myocardial samples. The early atrial peak of emptying rate (PER-E) was assessed by LA volume/time (V/t) curves derived from cardiac magnetic resonance (CMR) imaging analysis. The PER-E index was PER-E normalized by left ventricular (LV) filling volume. Patients with HOCM showed a lower PER-E index than healthy controls (P = 0.027). Compared with men, the PER-E (P < 0.001) and the PER-E indexes (P = 0.012) in women were lower. In CVF-stratified subgroups, a sex difference in the PER-E index was eliminated (P > 0.05). The CVF was correlated with the PER-E and PER-E indexes in both sexes (all P-values were <0.05). In multivariate regression analysis, sex (P = 0.007) and CVF (P < 0.001) were independently correlated with PER-E (all P-values were <0.05).Conclusion:Patients with HOCM presented LA reverse remodeling. Impaired LA function was more common in female patients with HOCM due to their susceptibility to myocardial fibrosis.
Frontiers in cardiovascular medicine 2022
Herein we present a case of hypereosinophilic syndrome (HES) with recurrent involvement of mitral valve. The patient developed mitral regurgitation secondary to HES. Surgical mitral valve replacement was performed successfully. The prosthetic valve dysfunction occurred 3 years later and echocardiography showed severe mitral valve stenosis. Extensive mural thrombi were discovered on both sides of the stenotic valve with eosinophilic infiltration. The patient underwent a repeated mechanical prosthesis replacement and recovered uneventfully.
Echocardiography (Mount Kisco, N.Y.) 2022
BACKGROUND:The definitive treatment for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA), which has good long-term outcomes. However, after surgery, a quarter of the patients still have residual pulmonary hypertension (RPH). In pulmonary hemodynamics, there are no unified criteria for RPH, even though the level may affect long-term survival.METHODS:Between March 1997 and December 2021, 253 CTEPH patients were treated at our center with PEA. Patients were evaluated retrospectively and classified into early (1997-2014) and late (2015-2021) groups. The clinical characteristics and perioperative outcomes of the two groups were compared, and risk factor analysis for RPH and long-term survival for all cases was performed.RESULTS:There was no statistically significant difference in demographics between the two groups. However, the Early Group had a significantly higher rate of perioperative death (9.8% vs. 1.2%, p = .001), RPH (48.8% vs. 14.0%, p < .001), and reperfusion pulmonary edema (18.3% vs. 2.9%, p < .001). The median follow-up time was 66.0 months, and overall survival rates at 5, 10, 15, and 18 years after PEA were 91.2%, 83.9%, 64.5%, and 46.0%, respectively. Age and postoperative systolic pulmonary artery pressure (sPAP) were independently related to long-term outcomes in the multivariate Cox analyses. Patients with postoperative sPAP less than 46 mm Hg had a higher chance of survival.CONCLUSIONS:PEA improved CTEPH hemodynamics immediately and had a positive effect on long-term survival. Patients with postoperative sPAP ≥ 46 mm Hg indicate clinically significant RPH and have a lower long-term survival rate.
Clinical cardiology 2022
Obstructive sleep apnea (OSA) is much common and associated with worse clinical outcomes in patients with hypertrophic cardiomyopathy (HCM), however, the diagnosis of OSA in HCM is still insufficient. We aim to investigate the clinical predictors of OSA in a large series of patients with HCM. A total of 589 patients with HCM who underwent sleep evaluations were retrospectively enrolled. Data from clinical characteristics and polysomnography studies were recorded. OSA was present in 346 patients (58.7%). Patients who had OSA were older, more likely to be male and had more clinical comorbidities such as hypertension, atrial fibrillation and cardiac remodeling. Multivariate logistic analyses showed that male, age, body mass index, hypertension and left ventricular outflow tract obstruction were significant factors associated with OSA. The area under the ROC curve (AUC) was 0.78 (95% CI 0.74-0.82; P < 0.001). These factors were also able to identify moderate to severe OSA with an AUC of 0.77 (95% CI 0.73-0.81; P < 0.001). These findings suggest that identifying HCM patients with high risk for OSA is feasible using characteristics from clinical practices and clinicians should have no hesitate to conduct sleep test in these patients.
Scientific reports 2021
BACKGROUND:Myocardial fibrosis (MF) is considered a result of microvascular dysfunction in patients with hypertrophic cardiomyopathy. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), capable of degrading collagen, directly participate in the development of MF. First we investigated the relationships among MF, microvascular rarefaction, and MMPs. Then we assessed the prognostic value of MF-related circulating biomarkers.METHODS:Fifty-five obstructive hypertrophic cardiomyopathy (HOCM) patients were enrolled after surgical myectomy. Myocardial samples were performed with Masson's trichrome staining and immunohistochemical procedures for collagen volume fraction and microvascular density, respectively. Enzyme-linked immunosorbent assays were used to assess myocardial and plasma of MMP-2, MMP-9, and TIMP-1 and plasma C-terminal propeptide of procollagen type Ⅰ (PICP) and C-terminal telopeptide of type Ⅰ collagen (ICTP) levels. The composite cardiovascular endpoint consisted of new-onset atrial fibrillation, heart failure requiring hospitalization, and all-cause death.RESULTS:In HOCM patients microvascular density was associated with the myocardial MMP-2/TIMP-1 ratio (r = -0.348, P = .009), whereas no correlation was found between collagen volume fraction and myocardial MMPs. During the 44-month follow-up 6 patients experienced a cardiovascular endpoint. The plasma PICP/ICTP ratio and MMP-2/TIMP-1 ratio were the 2 strongest prognostic makers. In multivariable analyses high PICP/ICTP and MMP-2/TIMP-1 ratios remained independent predictors of cardiovascular outcomes after adjusting for clinical confounders (hazard ratios, 12.683 [P = .021] and 17.037 [P = .027], respectively).CONCLUSIONS:In HOCM patients the myocardial MMP-2/TIMP-1 ratio was elevated because of microvascular rarefaction but may not be responsible for MF. High plasma PICP/ICTP and MMP-2/TIMP-1 ratios are independent predictors of adverse outcomes in HOCM patients.
The Annals of thoracic surgery 2021
BACKGROUND:Guidelines on the diagnosis and management of hypertrophic cardiomyopathy (HCM) recommend that septal myectomy be performed by experienced operators. However, the impact of operator volume on surgical treatment outcomes for isolated HCM has been poorly investigated.METHODS:From 2002 to 2014, 435 consecutive patients with isolated HCM undergoing myectomy at the Fuwai Hospital were retrospectively enrolled. All 29 surgeons were divided into beginner surgeons (operator volume ≤20) and experienced surgeons (operator volume >20) according to the guidelines for the diagnosis and treatment of HCM. Propensity score matching of patients in the two groups was performed.RESULTS:Baseline differences included advanced New York Heart Association classification and older age in the experienced surgeon group. After matching, in the beginner surgeon group (107 cases), residual obstruction (18.7% vs. 0.9%, P<0.001) was more common, and the postoperative left ventricular outflow tract pressure gradient (20.7±15.1 vs. 14.3±7.4 mmHg, P<0.001) was higher than that of the experienced surgeon group. In the experienced surgeon group (107 cases), the incidence of mitral valve replacement (1.9% vs. 11.2%, P<0.001) and permanent pacemaker implantation (1.9% vs. 3.7%, P<0.001) was significantly lower than that in the beginner surgeon group. However, there was no difference in procedural mortality (1.9% vs. 1.9%) between the two groups.CONCLUSIONS:Operator volume is an important factor in achieving better obstruction obliteration after septal myectomy in patients with isolated HCM.
Journal of thoracic disease 2021
