Abstract
The presence of systemic left-to-right shunt and increased pulmonary blood flow can result in right heart failure and pulmonary arteriopathy. Correction of left-to-right shunt has been shown to improve cardiac function and physical performance. However, the cardiopulmonary remodeling processes following cessation of left-to-right shunt have yet to be reported. In this experimental study, excessive pulmonary flow was restored through ligation of the aortocaval fistula in rats with flow-induced pulmonary hypertension. The cardiopulmonary morphometric functions were assessed, and phenotypic switching of pulmonary vascular smooth muscle cells (VSMC) was determined. Ligation of aortocaval fistula significantly attenuated pulmonary blood flow and right ventricular mass, and potentiated the isometric contraction of pulmonary artery. Inflammatory cytokines IL-1β and IL-6 were reduced in the lung after ligation. Reduction of pulmonary blood flow restored the expressions of smooth muscle myosin heavy chain and α-smooth muscle actin in pulmonary artery, indicating the switching of VSMCs to the contractile phenotype. Our study demonstrated that normalization of pulmonary blood flow in flow-induced pulmonary hypertension reverses the remodeling in the right ventricle and pulmonary artery. The remodeling process of flow-induced pulmonary hypertension is functionally and morphometrically reversible by inducing transdifferentiation of pulmonary VSMC to contractile phenotypes and modulation of tissue inflammatory cytokines.
Highlights
Pulmonary arteriopathy is a unique vascular abnormality, which may develop in patients with pulmonary hypertension secondary to increased pulmonary blood flow, and can be observed in conditions such as left-to-right shunt congenital heart defects and systemic arteriovenous shunt[1,2]
Consistent with the clinical presentation in patients with flow-induced pulmonary hypertension who eventually received atrial septal defect (ASD) occlusion, the experimental findings of our animal study support the clinical evidence that changes in the reduction of pulmonary blood flow following application of ASD occluder improved the cardiopulmonary physiology and functional performance of these patients
In the pulmonary artery exposed to increased blood flow following the creation of aortocaval fistula in rats, the contractions to suboptimal KCl and cumulative phenylephrine stimulation were significantly increased in the pulmonary artery, and the EC50 of phenylephrine was reduced, suggesting that flow-induced pulmonary hypertension results in a serial morphological and molecular changes in the vascular medial layer
Summary
Pulmonary arteriopathy is a unique vascular abnormality, which may develop in patients with pulmonary hypertension secondary to increased pulmonary blood flow, and can be observed in conditions such as left-to-right shunt congenital heart defects and systemic arteriovenous shunt[1,2]. The characteristic vascular changes of pulmonary arteriopathy include intimal hyperplasia/fibrosis, medial hypertrophy, extensive extracellular matrix modulation and in more severe cases, the formation of plexiform lesions[1,3]. These changes lead to decreased compliance of pulmonary vasculature and changes in vasoreactivity[4,5]. Congenital heart diseases, intimal fibrosis and medial proliferation were found to regress over time (years) following a banding procedure of the pulmonary artery in patients with pulmonary hypertension secondary to left-to-right shunt, indicating that increased pulmonary blood flow is one of the fundamental pathophysiologies of flow-induced pulmonary hypertension[10]. The aim of this study was to characterize the morphometric function, vasoreactivity, and vascular smooth muscle phenotypic modulation of the pulmonary artery and right heart following cessation of excessive pulmonary blood flow in a rat model of prolonged systemic left-to-right shunt
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