Pulmonary artery hypertension (PAH) pathology involves extracellular matrix (ECM) remodeling in cardiac tissues, thus promoting cardiac fibrosis progression. miR-29a-3p reportedly inhibits lung progression and liver fibrosis by regulating ECM protein expression; however, its role in PAH-induced fibrosis remains unclear. In this study, we aimed to investigate the role of miR-29a-3p in cardiac fibrosis progression in PAH and its influence on ECM protein thrombospondin-2 (THBS2) expression. The diagnostic and prognostic values of miR-29a-3p and THBS2 in PAH were evaluated. The expressions and effects of miR-29a-3p and THBS2 were assessed in cell culture, monocrotaline-induced PAH mouse model, and patients with PAH. The levels of circulating miR-29a-3p and THBS2 in patients and mice with PAH decreased and increased, respectively. miR-29a-3p directly targets THBS2 and regulates THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis. The circulating levels of miR-29a-3p and THBS2 were correlated with PAH diagnostic parameters, suggesting their independent prognostic value. miR-29a-3p targeted THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis, indicating miR-29a-3p acts as a messenger with promising therapeutic effects.

Background: Long-term consumption of an excessive fat and sucrose diet (Western diet, WD) has been considered a risk factor for metabolic syndrome (MS) and cardiovascular disease. Caveolae and caveolin-1 (CAV-1) proteins are involved in lipid transport and metabolism. However, studies investigating CAV-1 expression, cardiac remodeling, and dysfunction caused by MS, are limited. This study aimed to investigate the correlation between the expression of CAV-1 and abnormal lipid accumulation in the endothelium and myocardium in WD-induced MS, and the occurrence of myocardial microvascular endothelial cell dysfunction, myocardial mitochondrial remodeling, and damage effects on cardiac remodeling and cardiac function. Methods: We employed a long-term (7 months) WD feeding mouse model to measure the effect of MS on caveolae/vesiculo-vacuolar organelle (VVO) formation, lipid deposition, and endothelial cell dysfunction in cardiac microvascular using a transmission electron microscopy (TEM) assay. CAV-1 and endothelial nitric oxide synthase (eNOS) expression and interaction were evaluated using real-time polymerase chain reaction, Western blot, and immunostaining. Cardiac mitochondrial shape transition and damage, mitochondria-associated endoplasmic reticulum membrane (MAM) disruption, cardiac function change, caspase-mediated apoptosis pathway activation, and cardiac remodeling were examined using TEM, echocardiography, immunohistochemistry, and Western blot assay. Results: Our study demonstrated that long-term WD feeding caused obesity and MS in mice. In mice, MS increased caveolae and VVO formation in the microvascular system and enhanced CAV-1 and lipid droplet binding affinity. In addition, MS caused a significant decrease in eNOS expression, vascular endothelial cadherin, and β-catenin interactions in cardiac microvascular endothelial cells, accompanied by impaired vascular integrity. MS-induced endothelial dysfunction caused massive lipid accumulation in the cardiomyocytes, leading to MAM disruption, mitochondrial shape transition, and damage. MS promoted brain natriuretic peptide expression and activated the caspase-dependent apoptosis pathway, leading to cardiac dysfunction in mice. Conclusion: MS resulted in cardiac dysfunction, remodeling by regulating caveolae and CAV-1 expression, and endothelial dysfunction. Lipid accumulation and lipotoxicity caused MAM disruption and mitochondrial remodeling in cardiomyocytes, leading to cardiomyocyte apoptosis and cardiac dysfunction and remodeling.

Right ventricular (RV) failure is a major cause of mortality in pulmonary arterial hypertension (PAH), but its mechanism remains largely unknown. MicroRNA-21 (miR-21) is involved in flow-mediated stress in the vasculature, but its effects on RV remodeling require investigations. Herein, we aim to study the mechanism of miR-21 in the early (compensated) and late (decompensated) phases of PAH-induced RV dysfunction. Using aorto-venous fistula (AVS) surgery, we established a rat model of PAH. To mimic the microenvironment of PAH, we treated cardiomyocytes with flow-mediated shear stress in 6 dyne for 3 and 8 h. To evaluate whether miR-21 could be a biomarker, we prospectively collected the sera of patients with congenital heart disease- (CHD) related PAH. Additionally, clinical, echocardiographic and right heart catheterization information was collected. The primary endpoint was hospitalization for decompensated heart failure (HF). It is of note that, despite an initial increase in miR-21 expression in hypertrophic RV post AVS, miR-21 expression decreased with RV dysfunction thereafter. Likewise, the activation of miR-21 in cardiomyocytes under shear stress at 3 h was downregulated at 6 h. The downregulated miR-21 at the late phase was associated with increased apoptosis in cardiomyocytes while miR-21 mimic rescued it. Among 76 CHD-induced PAH patients, 19 who were hospitalized for heart failure represented with a significantly lower expression of circulating miR-21. Collectively, our study revealed that the upregulation of miR-21 in the early phase (RV hypertrophy) and downregulation in the late phase (RV dysfunction) under PAH triggered a biphasic regulation of cardiac remodeling and cardiomyocyte apoptosis.

In Taiwan, the outcomes of acute limb ischemia have yet to be investigated in a standardized manner. In this study, we compared the safety, feasibility and outcomes of acute limb ischemia after surgical embolectomy or catheter-directed therapy in Taiwan. This study used data collected from the Taiwan’s National Health Insurance Database (NHID) and Cause of Death Data between the years 2000 and 2015. The rate ratio of all-cause in-hospital mortality and risk of amputation during the same period of hospital stay were estimated using Generalized linear models (GLM). There was no significant difference in mortality risk between CDT and surgical intervention (9.5% vs. 10.68%, adjusted rate ratio (95% CI): regression 1.0 [0.79–1.27], PS matching 0.92 [0.69–1.23]). The risk of amputation was also comparable between the two groups. (13.59% vs. 14.81%, adjusted rate ratio (95% CI): regression 0.84 [0.68–1.02], PS matching 0.92 [0.72–1.17]). Age (p < 0.001) and liver disease (p = 0.01) were associated with higher mortality risks. Heart failure (p = 0.03) and chronic or end-stage renal disease (p = 0.03) were associated with higher amputation risks. Prior antithrombotic agent use (p = 0.03) was associated with a reduced risk of amputation. Both surgical intervention and CDT are effective and feasible procedures for patients with ALI in Taiwan.

Background: Pulmonary arterial hypertension (PAH) is a life-threatening disease with different etiologies and outcomes. We aimed to explore differences in clinical features and outcomes of idiopathic PAH (iPAH) and connective tissue disease-related PAH (CTD-PAH) in Taiwanese patients and determine risk factors for mortality. Methods: We retrospectively reviewed the medical records of patients with right-sided heart catheterization-diagnosed PAH between January 2005 and December 2015. The iPAH (n = 31) and CTD-PAH (n = 14) patients were enrolled and followed until December 31, 2019. Between-group comparisons were conducted. Potential predictors of the mortality of PAH were determined using the Cox proportional hazard regression model. Results: CTD-PAH patients had higher levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and lower predicted diffusing capacity of carbon monoxide (DLCO) than iPAH patients. The mortality rates were similar between CTD-PAH and iPAH (21.4% vs. 22.6%, p = 0.99). A mean pulmonary arterial pressure (mPAP) > 46 mmHg was a predictor of PAH-induced mortality (adjusted hazard ratio 21.8, 95% confidence interval 2.32–204.8). Conclusions: A higher mPAP level, but not underlying CTDs, imposed a significantly increased risk of mortality to patients with PAH.