Abstract
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.
Highlights
Pulmonary arterial hypertension (PAH) is a rare but fatal condition [1,2]
In response to pulmonary arterial hypertension (PAH), the Right ventricular (RV) undergoes structural and functional remodeling, including RV hypertrophy, which is a key determinant of long-term PAH outcomes and is associated with an increased risk of heart failure as well as sudden death [12,15]
Hereby, starting from a clinical observation, we found that despite an increasing expression of circulating miR-21 in patients with PAH, there was a significant drop in circulating miR-21 expression along with RV dysfunction among patients who were hospitalized for decompensated heart failure (HF)
Summary
Pulmonary arterial hypertension (PAH) is a rare but fatal condition [1,2]. Chronic pressure overload leads to right ventricular (RV) hypertrophy, volume overload and failure [3]. The survival rate in patients with PAH is closely associated with RV dysfunction [3]. Different etiologies associated with pulmonary hypertension lead to various outcomes [4]. Apart from other groups, the pulmonary vasculature in patients with congenital heart disease- (CHD) related PAH is continually exposed to hemodynamic forces, including wall shear stresses [5]. The impact of flow-mediated stress on RV remodeling remains largely unknown. The major determinant of PAH-induced RV structural and functional maladaptation requires exploration
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