Thrombospondin 1 and Reelin act through Vldlr to regulate cardiac growth and repair.

Adult mammalian cardiomyocytes have minimal cell cycle capacity, which leads to poor regeneration after cardiac injury such as myocardial infarction. Many positive regulators of cardiomyocyte cell cycle and cardioprotective signals have been identified, but extracellular signals that suppress cardiomyocyte proliferation are poorly understood. We profiled receptors enriched in postnatal cardiomyocytes, and found that very-low-density-lipoprotein receptor (Vldlr) inhibits neonatal cardiomyocyte cell cycle. Paradoxically, Reelin, the well-known Vldlr ligand, expressed in cardiac Schwann cells and lymphatic endothelial cells, promotes neonatal cardiomyocyte proliferation. Thrombospondin1 (TSP-1), another ligand of Vldlr highly expressed in adult heart, was then found to inhibit cardiomyocyte proliferation through Vldlr, and may contribute to Vldlr's overall repression on proliferation. Mechanistically, Rac1 and subsequent Yap phosphorylation and nucleus translocation mediate the regulation of the cardiomyocyte cell cycle by TSP-1/Reelin-Vldlr signaling. Importantly, Reln mutant neonatal mice displayed impaired cardiomyocyte proliferation and cardiac regeneration after apical resection, while cardiac-specific Thbs1 deletion and cardiomyocyte-specific Vldlr deletion promote cardiomyocyte proliferation and are cardioprotective after myocardial infarction. Our results identified a novel role of Vldlr in consolidating extracellular signals to regulate cardiomyocyte cell cycle activity and survival, and the overall suppressive TSP-1-Vldlr signal may contribute to the poor cardiac repair capacity of adult mammals.

Algorithms of Electrocardiographic Changes for Quantitative and Localization Analysis of Thrombus Burden in Patients with Acute Pulmonary Thromboembolism.

Background: Various electrocardiographic (ECG) abnormalities are associated with the severity of pulmonary thromboembolism (PTE). The utility of evaluating the clot burden of PTE based on ECG findings alone has yet to be thoroughly investigated in Chinese patients. The aim of this study was therefore to use ECG signs to establish novel models for quantitative and localization analysis of clot burden in patients with acute PTE. Methods: Acute PTE patients from three centers were enrolled between 2015 and 2019 in a retrospective cohort study (NCT03802929). We analyzed the 12-lead ECGs at admission and studied computed tomography pulmonary angiography (CTPA) features to obtain the Qanadli score of clot burden and location of thrombus. Novel risk prediction models were developed and validated using derivation and external validation cohorts, respectively. Results: A total of 341 acute PTE patients were screened, of whom 246 (72.1%) were from Shanghai Tenth People's Hospital, 71 (20.8%) were from Shanghai Pulmonary Hospital and 24 (7.0%) were from Qidong People's Hospital. In the derivation cohort, predictors included in the final models were congestive heart failure, chronic obstructive pulmonary disease, hypertension, coronary heart disease, atrial fibrillation and ECG abnormalities. The CHARIS (COPD/CHF/CHD, HTN, Atrial arrhythmias/AF, RBBB/RAD, Inverted T wave and S1Q3T3/ Sinus tachycardia) I model was established for quantitatively assessing Qanadli score. It had moderate discrimination in both the derivation cohort (concordance index (c-index) of 0.720, 95% CI 0.655-0.780) and the validation cohort (c-index of 0.663, 95% CI 0.559-0.757). The CHARIS II model was used to predict the probability of trunk obstruction. It showed similar discrimination in the derivation cohort (c-index of 0.753, 95% CI 0.691-0.811) and in the validation cohort (c-index of 0.741, 95% CI 0.641-0.827). Calibration curves and Hosmer-Lemeshow test confirmed the accuracy of the risk prediction equations in the external validation dataset. Decision curve analysis showed the CHARIS I and CHARIS II algorithms had positive net benefits in both the derivation and validation cohorts. Conclusions: From quantitative and localization perspectives, the CHARIS algorithms can identify acute PTE patients with heavy thrombus burdens prior to imaging diagnosis. Clinical Trial Registration: NCT03802929, https://www.clinicaltrials.gov/study/NCT03802929.

Characterization of a novel mitophagy-related 5-genes signature for diagnosis of acute myocardial infarction.

Myocardial infarction (MI) and the ensuing heart failure (HF) remain the main cause of morbidity and mortality worldwide. One of the strategies to combat MI and HF lies in the ability to accurately predict the onset of these disorders. Alterations in mitochondrial homeostasis have been reported to be involved in the pathogenesis of various cardiovascular diseases (CVDs). In this regard, perturbations to mitochondrial dynamics leading to impaired clearance of dysfunctional mitochondria have been previously established to be a crucial trigger for MI/HF. In this study, we found that MI patients could be classified into three clusters based on the expression levels of mitophagy-related genes and consensus clustering. We identified a mitophagy-related diagnostic 5-genes signature for MI using support vector machines-Recursive Feature Elimination (SVM-RFE) and random forest, with the area under the ROC curve (AUC) value of the predictive model at 0.813. Additionally, the single-cell transcriptome and pseudo-time analyses showed that the mitoscore was significantly upregulated in macrophages, endothelial cells, pericytes, fibroblasts and monocytes in patients with ischemic cardiomyopathy, while sequestosome 1 (SQSTM1) exhibited remarkable increase in the infarcted (ICM) and non-infarcted (ICMN) myocardium samples dissected from the left ventricle compared with control samples. Lastly, through analysis of peripheral blood from MI patients, we found that the expression of SQSTM1 is positively correlated with troponin-T (P < 0.0001, R = 0.4195, R2 = 0.1759). Therefore, this study provides the rationale for a cell-specific mitophagy-related gene signature as an additional supporting diagnostic for CVDs.