The emerging role of sacubitril/valsartan in pulmonary hypertension with heart failure.

Pulmonary hypertension due to left heart disease (PH-LHD) represents approximately 65%-80% of all patients with PH. The progression, prognosis, and mortality of individuals with left heart failure (LHF) are significantly influenced by PH and right ventricular (RV) dysfunction. Consequently, cardiologists should devote ample attention to the interplay between HF and PH. Patients with PH and HF may not receive optimal benefits from the therapeutic effects of prostaglandins, endothelin receptor antagonists, or phosphodiesterase inhibitors, which are specific drugs for pulmonary arterial hypertension (PAH). Sacubitril/valsartan, the angiotensin receptor II blocker-neprilysin inhibitor (ARNI), was recommended as the first-line therapy for patients with heart failure with reduced ejection fraction (HFrEF) by the 2021 European Society of Cardiology Guidelines. Although ARNI is effective in treating left ventricular (LV) enlargement and lower ejection fraction, its efficacy in treating individuals with PH and HF remains underexplored. Considering its vasodilatory effect at the pre-capillary level and a natriuretic drainage role at the post-capillary level, ARNI is believed to have a broad range of potential applications in treating PH-LHD. This review discusses the fundamental pathophysiological connections between PH and HF, emphasizing the latest research and potential benefits of ARNI in PH with various types of LHF and RV dysfunction.

Secreted frizzled-related protein 3 alleviated cardiac remodeling induced by angiotensin II via inhibiting oxidative stress and apoptosis in mice.

Increased expression of secreted frizzled related protein 3 (SFRP3) is associated with adverse outcomes of heart failure. The purpose of this study was to investigate the effect of SFRP3 on cardiac remodeling and its mechanism. Cardiac remodeling was induced by angiotensin II (Ang II) infusion in the mice, and in the neonatal rat cardiomyocytes (NRCM) treated with Ang II. The expression decreased in the heart of mice, and NRCM and HL-1 cells with Ang II treatment. Ang II-induced hypertrophy and fibrosis of heart in mice were attenuated by upregulation of SFRP3, and were further deteriorated by downregulation of SFRP3. Ang II-induced hypertrophy of NRCM and HL-1 cells were improved by SFRP3 overexpression, and were further deteriorated by SFRP3 knockdown. The oxidative stress increased in the heart of Ang II-treated mice, and this enhancement was inhibited by overexpressing of SFPR3, and was worsened by downregulation of SFPR3. These outcomes suggested that upregulation of SFPR3 could improve cardiac remodeling via inhibition of oxidative stress.

A Signature for Smoking Status of Coronary Heart Disease Patients through Weighted Gene Coexpression Network Analysis.

BACKGROUND: Smoking is one of the risk factors of coronary heart disease (CHD), while its underlying mechanism is less well defined. PURPOSE: To identify and testify 6 key genes of CHD related to smoking through weighted gene coexpression network analysis (WGCNA), protein-protein interaction (PPI) network analysis, and pathway analysis. METHODS: CHD patients' samples were first downloaded from Gene Expression Omnibus (GEO). Then, genes of interest were obtained after analysis of variance (ANOVA). Thereafter, 23 coexpressed modules that were determined after genes with similar expression were incorporated via WGCNA. The biological functions of genes in the modules were researched by enrichment analysis. Pearson correlation analysis and PPI network analysis were used to screen core genes related to smoking in CHD. RESULTS: The violet module was the most significantly associated with smoking (r = -0.28, p = 0.006). Genes in this module mainly participated in biological functions related to the heart. Altogether, 6 smoking-related core genes were identified through bioinformatics analyses. Their expressions in animal models were detected through the animal experiment. CONCLUSION: This study identified 6 core genes to serve as underlying biomarkers for monitoring and predicting smoker's CHD risk.

Construction of a Support Vector Machine-Based Classifier for Pulmonary Arterial Hypertension Patients.

Pulmonary arterial hypertension (PAH) is a disease leading to right heart failure and death due to increased pulmonary arterial tension and vascular resistance. So far, PAH has not been fully understood, and current treatments are much limited. Gene expression profiles of healthy people and PAH patients in GSE33463 dataset were analyzed in this study. Then 110 differentially expressed genes (DEGs) were obtained. Afterward, the PPI network based on DEGs was constructed, followed by the analysis of functional modules, whose results showed that the genes in the major function modules significantly enriched in immune-related functions. Moreover, four optimal feature genes were screened from the DEGs by support vector machine-recursive feature elimination (SVM-RFE) algorithm (EPB42, IFIT2, FOSB, and SNF1LK). The receiver operating characteristic curve showed that the SVM classifier based on optimal feature genes could effectively distinguish healthy people from PAH patients. Last, the expression of optimal feature genes was analyzed in the GSE33463 dataset and clinical samples. It was found that EPB42 and IFIT2 were highly expressed in PAH patients, while FOSB and SNF1LK were lowly expressed. In conclusion, the four optimal feature genes screened here are potential biomarkers for PAH and are expected to be used in early diagnosis for PAH.

Angiotensin-(3-7) alleviates isoprenaline-induced cardiac remodeling via attenuating cAMP-PKA and PI3K/Akt signaling pathways.

The renin-angiotensin system is involved in the regulation of various heart diseases. The present study aimed to determine the effects of angiotensin (Ang)-(3-7) on cardiac remodeling and its downstream signaling pathways in neonatal rat cardiomyocytes (NRCMs) and neonatal rat cardiac fibroblasts (NRCFs). The administration of Ang-(3-7) alleviated isoprenaline (ISO)-induced cardiac hypertrophy and fibrosis of mice. ISO treatment increased the levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (ß-MHC) in NRCMs, and reduced the levels of collagen I, collagen III, fibronectin, and alpha-smooth muscle actin (α-SMA) in NRCFs. These changes were inhibited by Ang-(3-7) administration. The levels of protein kinase A (PKA), phosphorylated phosphatidylinositol-3-kinase (p-PI3K), and phosphorylated protein kinase B (p-Akt) were increased in NRCMs and NRCFs treated with ISO. The increase of PKA, but not p-PI3K or p-Akt was attenuated by Ang-(3-7) treatment in NRCMs. The increases of p-PI3K and p-Akt, but not PKA were reversed by Ang-(3-7) treatment in NRCFs. Treatment with cAMP or PKA overexpression reversed the attenuating effects of Ang-(3-7) on ISO-induced hypertrophy of NRCMs. The administration of PI3K inhibitor or Akt inhibitor alleviated ISO-induced fibrosis of NRCFs. These results indicated that Ang-(3-7) could alleviate cardiac remodeling. The administration of Ang-(3-7) attenuated hypertrophy of NRCMs via inhibiting the cAMP/PKA signaling pathway, and alleviated fibrosis of NRCFs via inhibiting PI3K/Akt signaling pathway.

Extracellular Mitochondrial Components and Effects on Cardiovascular Disease.

Besides being powerhouses of the cell, mitochondria released into extracellular space act as intercellular signaling. Mitochondria and their components mediate cell-to-cell communication in free form or embedded in a carrier. The pathogenesis of cardiovascular disease is complex, which shows close relationship with inflammation and metabolic abnormalities. Since mitochondria sustain optimal function of the heart, extracellular mitochondria are emerging as a key regulator in the development of cardiovascular disease. In this review, we provide recent findings in the presence and forms of mitochondria transfer between cells, as well as the effects of these mitochondria on vascular inflammation and ischemic myocardium. Mitochondrial transplantation is a novel treatment paradigm for patients suffering from acute cardiovascular accident and challenges the traditional methods of mitochondria isolation.

Multicentre, randomized comparison of two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: the DEFINITION II trial.

AIM: The present study aimed to assess the benefits of two-stent techniques for patients with DEFINITION criteria-defined complex coronary bifurcation lesions. METHODS AND RESULTS: In total, 653 patients with complex bifurcation lesions at 49 international centres were randomly assigned to undergo the systematic two-stent technique (two-stent group) or provisional stenting (provisional group). The primary endpoint was the composite of target lesion failure (TLF) at the 1-year follow-up, including cardiac death, target vessel myocardial infarction (TVMI), and clinically driven target lesion revascularization (TLR). The safety endpoint was definite or probable stent thrombosis. At the 1-year follow-up, TLF occurred in 37 (11.4%) and 20 (6.1%) patients in the provisional and two-stent groups, respectively [77.8%: double-kissing crush; hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.30-0.90; P = 0.019], largely driven by increased TVMI (7.1%, HR 0.43, 95% CI 0.20-0.90; P = 0.025) and clinically driven TLR (5.5%, HR 0.43, 95% CI 0.19-1.00; P = 0.049) in the provisional group. At the 1 year after indexed procedures, the incidence of cardiac death was 2.5% in the provisional group, non-significant to 2.1% in the two-stent group (HR 0.86, 95% CI 0.31-2.37; P = 0.772). CONCLUSION: For DEFINITION criteria-defined complex coronary bifurcation lesions, the systematic two-stent approach was associated with a significant improvement in clinical outcomes compared with the provisional stenting approach. Further study is urgently warranted to identify the mechanisms contributing to the increased rate of TVMI after provisional stenting. STUDY REGISTRATION: http://www.clinicaltrials.com; Identifier: NCT02284750.

Treatment effects of systematic two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: rationale and design of a prospective, randomised and multicentre DEFINITION II trial.

INTRODUCTION: Provisional stenting (PS) for simple coronary bifurcation lesions is the mainstay of treatment. A systematic two-stent approach is widely used for complex bifurcation lesions (CBLs). However, a randomised comparison of PS and two-stent techniques for CBLs has never been studied. Accordingly, the present study is designed to elucidate the benefits of two-stent treatment over PS in patients with CBLs. METHODS AND ANALYSIS: This DEFINITION II study is a prospective, multinational, randomised, endpoint-driven trial to compare the benefits of the two-stent technique with PS for CBLs. A total of 660 patients with CBLs will be randomised in a 1:1 fashion to receive either PS or the two-stent technique. The primary endpoint is the rate of 12-month target lesion failure defined as the composite of cardiac death, target vessel myocardial infarction (MI) and clinically driven target lesion revascularisation. The major secondary endpoints include all causes of death, MI, target vessel revascularisation, in-stent restenosis, stroke and each individual component of the primary endpoints. The safety endpoint is the occurrence of definite or probable stent thrombosis. ETHICS AND DISSEMINATION: The study protocol and informed consent have been approved by the Institutional Review Board of Nanjing First Hospital, and accepted by each participating centre. Written informed consent was obtained from all enrolled patients. Findings of the study will be published in a peer-reviewed journal and disseminated at conferences. TRIAL REGISTRATION NUMBER: NCT02284750; Pre-results.

Angiographic prevalence of myocardial bridging in a defined very large number of Chinese patients with chest pain.

BACKGROUND: Muscle fibers overlying the intramyocardial segment of an epicardial coronary artery are termed myocardial bridging (MB). Variable prevalence of MB has been described at autopsy and angiographic series with small and large sample size studies. In addition, no similar study was reported in Chinese population. The aim of this study was to investigate the angiographic prevalence of MB in consecutive 37,106 Chinese patients with chest pain from our center. METHODS: We conducted an observational study to evaluate the consecutive cases with MB among patients undergone selective coronary angiography, and analyzed the angiograhic prevalence and clinical features of MB in this study of very large sample size. RESULTS: Among 37 105 patients with chest pain we found 1002 cases with 1011 MBs in a retrospective manner, and the overall prevalence was 2.70%. Although more than 99% (991/1002) of patients had single bridge, 8 cases were found to have more than two MBs (seven with two, and one with three). Altogether 54.39% of cases (545/1002) had MB without atherosclerotic lesions, and 96.24% (973/1011) of bridging located in the left anterior descending coronary artery (LAD), mainly in the middle of LAD (792/1011, 78.33%). According to Nobel classification, of the single bridge (n=991), <50% of obstruction was predominant (471/991, 47.52%). Totally 50%-69% accounted for 34.81% (345/991), >70% of obstruction was 17.65% (175/991). CONCLUSIONS: These data showed that the prevalence of angiographically detectable MB in Chinese patients with chest pain was similar to those of the previous studies, with 2.7% prevalence in this very large sample size.

[Electrophysiological characterization of long QT syndrome associated mutations V630A and N633S].

OBJECTIVE: To identify the electrophysiological properties of long-QT syndrome (LQTS) associated missense mutations in the outer mouth of the HERG potassium channel in vitro. METHODS: Mutations V630A and N633S were constructed by Megaprimer PCR method and cRNA were produced by T7 RNA polymerase. The electrophysiological properties of the mutation were investigated in the Xenopus oocyte heterologous expression system. RESULTS: Coexpression of mutant and wild-type HERG subunits caused a dominant-negative effect, and the currents were significantly decreased. Compared with wild-type HERG channels, V630A and N633S mutations were related to decreased time constants for inactivation for V630A/WT and N633S/WT at all potentials, reduced slope conductance and the voltage dependence of steady-state inactivation was shifted to negative potentials for V630A/WT and N633S/WT. CONCLUSION: Present study shows that LQTS associated missense mutations located in the outer mouth of HERG cause a dominant-negative effect and alterations in steady-state voltage dependence of channel gating of heteromultimeric channels suggesting a reduction in expressional current might be one of the pathophysiologic mechanisms of LQTS.