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.

Background: Pulmonary artery hypertension (PAH) is a fatal disease characterized by a complex pathogenesis. Exosomes containing microRNAs (miRs) have emerged as a novel biomarker. Transpulmonary exosomal miRs offer valuable insights into pulmonary circulation microenvironments. Hereby, we aimed to explore the potentials of transpulmonary exosomal miRs as differentiating factors between idiopathic PAH and congenital heart disease (CHD)–related PAH. Methods and Results: During right heart catheterization, we collected exosomes at pulmonary arteries in 25 patients diagnosed with idiopathic PAH and 20 patients with CHD‐related PAH. Next‐generation sequencing identified several candidate exosomal miRs. Using quantitative polymerase chain reaction, we validated the expressions of these miRs and revealed significantly elevated expressions of miR‐21, miR‐139‐5p, miR‐155‐5p, let‐7f‐5p, miR‐328‐3p, miR‐330‐3p, and miR‐103a‐3p in patients with CHD‐related PAH, in contrast to patients with idiopathic PAH. Among these miRs, miR‐21 exhibited the highest expression in patients with CHD‐related PAH. These findings were further corroborated in an external cohort comprising 10 patients with idiopathic PAH and 8 patients with CHD‐related PAH. Using an in vitro flow model simulating the shear stress experienced by pulmonary endothelial cells, we observed a significant upregulation of miR‐21. Suppressing miR‐21 rescued the shear stress–induced downregulation of the RAS/phosphatidylinositol 3‐kinase/protein kinase B pathway, leading to a mitigation of apoptosis. Conclusions: Our study identified a pronounced expression of transpulmonary exosomal miR‐21, particularly in patients with CHD‐related PAH, through next‐generation sequencing analysis. Further investigation is warranted to elucidate the regulatory mechanisms involving miR‐21 in the pathophysiology of PAH.

The incidence of atrial fibrillation (AF) increases with age and is particularly high in individuals with diabetes. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), such as dapagliflozin, show promise in treating heart failure (HF) and reducing the risk of AF. Sirtuin 1 (SIRT1), a key enzyme in metabolic regulation, may be influenced by SGLT2i and play a role in the development of AF. This study investigates the relationship between dapagliflozin therapy and atrial tachyarrhythmia in diabetic cardiomyopathy, with a focus on the role of SIRT1. A streptozotocin (STZ)-induced diabetes mellitus (DM) rat model was used to assess AF across four groups: sham, STZ, STZ with dapagliflozin, and STZ with dapagliflozin + sirtinol (a SIRT1 inhibitor). Additionally, HL-1 cardiomyocytes were cultured under high glucose (HG) conditions and treated with dapagliflozin, with or without sirtinol. In the rat model, dapagliflozin improved atrial fibrosis and reduced AF inducibility and duration—effects that were partially reversed by sirtinol. These findings suggest that dapagliflozin may alleviate cardiac fibrosis and atrial arrhythmia by modulating SIRT1. In HL-1 cells under HG conditions, dapagliflozin reduced apoptosis, restored autophagy and mitophagy, and improved calcium channel activity. However, sirtinol negated these protective effects. Dapagliflozin helped normalize autophagy, mitophagy, and calcium handling, while sirtinol diminished its protective effects, highlighting the key role of SIRT1 in regulating calcium handling under HG conditions. Overall, SIRT1 plays a protective role in diabetic cardiomyopathy by reducing apoptosis, regulating autophagy and mitophagy, and modulating calcium channel activity. Dapagliflozin reduces AF duration and inducibility in the STZ model, likely through SIRT1 upregulation and calcium channel modulation.

Background: Angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) are emerging medical treatments for decompensated heart failure (HF) with reduced ejection fraction. In clinical practice, the combination of ARNI and SGLT2i cannot be administered owing to the poor hemodynamic status in patients with HF with reduced ejection fraction (HFrEF). This study aimed to compare different strategies of HF management for ARNI first or SGLT2i first in such a population. Methods: From January 2016 to December 2021, 165 patients were diagnosed with HFrEF and New York Heart Association functional class ≥II and already received optimal medical treatment. Ninety-five patients received the ARNI-first strategy, and 70 patients received the SGLT2i-first strategy according to the physician’s choice. Age, sex, hemodynamic condition, etiologies of HF, comorbidities, serum creatinine, N-terminal pro-B-type natriuretic peptide (NT-ProBNP), echocardiographic parameters, and clinical outcomes were compared between the ARNI and SGLT2i-first strategy groups. Results: In the SGLT2i-first group, the median interval between the addition of the second medication was longer (ARNI-first vs. SGLT2i-first; 74 [49–100] days vs. 112 [86–138] days; p = 0.044). Improvement in left ventricular ejection fraction (LVEF), change in left atrial dimension, and change in left ventricular end-diastolic and end-systolic volume (LVESV) did not differ between the two groups. The incidence of HF hospitalization, cardiovascular mortality, and all-cause mortality did not differ between the two groups. A non-significant trend of lower NT-proBNP levels (ARNI-first vs. SGLT2i-first; 1383 [319–2507] pg/mL vs. 570 [206–1314] pg/mL; p = 0.055) and significantly higher discontinuation rate of diuretic agents (ARNI-first vs. SGLT2i- first; 6.8% vs. 17.5%; p = 0.039) were noted in the SGLT2i-first group. When early combination (≤14D) compared to late combination (>14D), better positive remodeling of LVESV presented significantly in early combination subgroups. Conclusions: In patients with symptomatic HFrEF, SGLT2i-first strategy may provide a higher possibility of discontinuing diuretic agents than the ARNI-first strategy. Changes in LV performance, progression of renal function, and clinical outcomes did not differ between the two groups. Early combination (≤14D) provided better LV remodeling.

Mitral regurgitation (MR), the disruption of the mitral valve, contributes to heart failure (HF). Under conditions of volume overload, excess mineralocorticoids promote cardiac fibrosis. The mineralocorticoid receptor antagonist spironolactone is a potassium-sparing diuretic and a guideline-recommended therapy for HF, but whether it can ameliorate degenerative MR remains unknown. Herein, we investigate the efficacy of spironolactone in improving cardiac remodeling in MR-induced HF compared with that of a loop diuretic, furosemide. Using a novel and mini-invasive technique, we established a rat model of MR. We treated the rats with spironolactone or furosemide for twelve weeks. The levels of cardiac fibrosis, apoptosis, and stress-associated proteins were then measured. In parallel, we compared the cardiac remodeling of 165 patients with degenerative MR receiving either spironolactone or furosemide. Echocardiography was performed at baseline and at six months. In MR rats treated with spironolactone, left ventricular function—especially when strained—and the pressure volume relationship significantly improved compared to those of rats treated with furosemide. Spironolactone treatment demonstrated significant attenuation of cardiac fibrosis and apoptosis in left ventricular tissue compared to furosemide. Further, spironolactone suppressed the expression of apoptosis-, NADPH oxidase 4 (NOX4)- and inducible nitric oxide synthase (iNOS)-associated proteins. Similarly, compared with MR patients receiving furosemide those prescribed spironolactone demonstrated a trend toward reduction in MR severity and showed improvement in left ventricular function. Collectively, MR-induced cardiovascular dysfunction, including fibrosis and apoptosis, was effectively attenuated by spironolactone treatment. Our findings suggest a potential therapeutic option for degenerative MR-induced HF.

Background: Patients with chronic kidney disease (CKD) experience atrial fibrillation more frequently. The balance of medical management for stroke prevention and bleeding events presents a challenging issue in CKD population. Left atrial appendage occlusion (LAAO) may be an effective solution for stroke prevention in patients who experience frequent bleeding with oral anticoagulants. However, the specific impact of CKD on the procedural success, complications, and outcomes of LAAO implantations remains underexplored. Methods: We conducted a search of various databases for articles published before October 31, 2023. This search yielded 7 studies, comparing outcomes between CKD and non-CKD cohorts undergoing LAAO implantation. Our analysis focused on CHA2DS2-VASc scores, average eGFR, use of oral anticoagulants, procedural success rates, procedural complications, and associated outcomes. Results: The meta-analysis included data from 2576 patients, with 1131 identified as having CKD. The CKD group also had higher CHA2DS2-VASc scores (4.7 ± 1.4 vs 4.0 ± 1.5; P < .001) and HAS-BLED scores (3.8 ± 1.1 vs 3.1 ± 1.0; P < .001) than the non-CKD group. CKD patients showed a nonreduction in procedural success rates and a nonsignificant increase in total complications. The risks of stroke and transient ischemic attack, major bleeding, and cardiovascular mortality were not significantly different between the 2 groups. However, a significantly lower rate of total mortality was observed in the non-CKD group (odds ratio: 0.43; 95% confidence interval, 0.32–0.60). Conclusion: While CKD is associated with a nonsignificant decrease in procedural success and a nonsignificant increase in complication risks, the outcomes of LAAO implantation are comparably favorable between CKD and non-CKD groups. Despite similar procedural outcomes, the CKD group exhibited a higher rate of all-cause mortality.