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Pulmonary artery denervation improves hemodynamics and cardiac function in pulmonary hypertension secondary to heart failure.

ABSTRACT: This study aimed to determine the benefits and correlated mechanisms of pulmonary artery denervation (PADN) for heart failure (HF) pulmonary hypertension (PH). PH secondary to HF is associated with poor clinical outcomes because there is no proper therapy for it. PADN showed improved outcomes for patients with HF-PH. However, the underlying mechanisms remain unknown. Supracoronary aortic banding (SAB) was used to create HF-PH models. Sprague-Dawley rats were randomly assigned to control, SAB, sham, SAB with PADN, and SAB without PADN groups. Surgical (longitudinally damaging vessel nerves) and chemical (10% phenol applied to the surface of nerves) PADN was performed for animals in the SAB with PADN group. Morphological, echocardiographic, hemodynamic, and protein expression changes were measured four weeks thereafter. Adrenergic receptor (AR) expressions of pulmonary arteries from four HF-PH patients and four patients without PH were measured. Ten HF-PH patients who underwent PADN were followed-up for six months. SAB-induced HF-PH was achieved by 50% of animals. Surgical and chemical PADN was associated with significant improvements in pulmonary artery muscularization, hemodynamics, and right ventricular functions. In pulmonary arterial specimens from HF-PH patients, ?2-AR and ?1A/B-AR, as well as eNOS, were downregulated and ?1D-AR was upregulated compared to those from patients without PH. PADN led to a mean increase of 84?m during the 6-min walk distance for HF-PH patients at six-month follow-up. HF-PH was characterized by downregulated ?2-AR, ?1A-AR, and ?1B-AR and by upregulated ?1D-AR. PADN is associated with significant improvements in hemodynamics and pulmonary artery remodeling.

SUBMITTER: Zhang H

PROVIDER: S-EPMC6614950 | biostudies-literature | 2019 Apr-Jun

REPOSITORIES: biostudies-literature

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Pulmonary artery denervation improves hemodynamics and cardiac function in pulmonary hypertension secondary to heart failure.

Zhang Hang H Yu Wande W Zhang Juan J Xie Dujiang D Gu Yue Y Ye Peng P Chen Shao-Liang SL

Pulmonary circulation 20181113 2

This study aimed to determine the benefits and correlated mechanisms of pulmonary artery denervation (PADN) for heart failure (HF) pulmonary hypertension (PH). PH secondary to HF is associated with poor clinical outcomes because there is no proper therapy for it. PADN showed improved outcomes for patients with HF-PH. However, the underlying mechanisms remain unknown. Supracoronary aortic banding (SAB) was used to create HF-PH models. Sprague-Dawley rats were randomly assigned to control, SAB, sh ...[more]

PMID: 30421645

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Project description:BackgroundMechanisms of positive effects of pulmonary artery (PA) denervation (PADN) remain poorly understood. The study aimed to evaluate pulmonary hemodynamic changes after PADN and their association with the extent of PA wall damage in an acute thromboxane A2 (TXA2)-induced pulmonary hypertension (PH) model in swine.MethodsIn this experimental sham-controlled study, 17 normotensive male white Landrace pigs (the mean weight 36.2 ± 4.5 kg) were included and randomly assigned to group I (n = 9)-PH modeling before and after PADN, group II (n = 4)-PADN only, or group III (n = 4)-PH modeling before and after a sham procedure. Radiofrequency (RF) PADN was performed in the PA trunk and at the proximal parts of the right and left PAs. PA wall lesions were characterized at the autopsy study using histological and the immunohistochemical examination.ResultsIn groups I and II, no statistically significant changes in the mean pulmonary arterial pressure nor systemic blood pressure were found after PADN (-0.8 ± 3.4 vs 4.3 ± 8.6 mmHg, P = 0.47; and 6.0 ± 15.9 vs -8.3 ± 7.5 mmHg, P = 0.1; correspondingly). There was a trend towards a lower diastolic pulmonary arterial pressure after PADN in group I when compared with group III during repeat PH induction (34.4 ± 2.9 vs 38.0 ± 0.8; P = 0.06). Despite the presence of severe PA wall damage at the RF application sites, S100 expression was preserved in the majority of PA specimens. The presence of high-grade PA lesions was associated with HR acceleration after PADN (ρ = 0.68, p = 0.03). No significant correlation was found between the grade of PA lesion severity and PA pressure after PADN with or without PH induction.ConclusionsExtended PADN does not affect PH induction using TXA2. Significant PA adventitia damage is associated with HR acceleration after PADN. Possible delayed effects of PADN on perivascular nerves and pulmonary hemodynamics require further research in chronic experiments.

Project description:Pulmonary hypertension due to left heart disease (PH-LHD) is the most frequent manifestation of PH but lacks any approved treatment. Activin receptor type IIA-Fc fusion protein (ActRIIA-Fc) was found previously to be efficacious in experimental and human pulmonary arterial hypertension (PAH). Here we tested the hypothesis that ActRIIA-Fc improves pulmonary vascular remodeling and alleviates PH in models of PH-LHD, specifically in subtypes of heart failure with reduced ejection fraction (PH-HFrEF) and preserved ejection fraction (PH-HFpEF). Treatment with murine ActRIIA-Fc reduced cardiac remodeling and improved cardiac function in two mouse models of left heart disease without PH, confirming that this inhibitor of activin-class ligand signaling can exert cardioprotective effects in heart failure. In a mouse model of PH-HFrEF with prolonged pressure overload caused by transverse aortic constriction, ActRIIA-Fc treatment significantly reduced pulmonary vascular remodeling, pulmonary fibrosis, and pulmonary hypertension while exerting beneficial structural, functional, and histological effects on both the left and right heart. Additionally, in an obese ZSF1-SU5416 rat model of PH-HFpEF with metabolic dysregulation, therapeutic treatment with ActRIIA-Fc normalized SMAD3 overactivation in pulmonary vascular and perivascular cells, reversed pathologic pulmonary vascular and cardiac remodeling, improved pulmonary and cardiac fibrosis, alleviated PH, and produced marked functional improvements in both cardiac ventricles. Studies in vitro revealed that treatment with ActRIIA-Fc prevents an abnormal, glucose-induced, activin-mediated, migratory phenotype in human pulmonary artery smooth muscle cells, providing a mechanism by which ActRIIA-Fc could exert therapeutic effects in experimental PH-HFpEF with metabolic dysregulation. Our results demonstrate that ActRIIA-Fc broadly corrects cardiopulmonary structure and function in experimental PH-LHD, including models of PH-HFrEF and PH-HFpEF, leading to alleviation of PH under diverse pathophysiological conditions. These findings highlight the important pathogenic contributions of activin-class ligands in multiple forms of experimental PH and support ongoing clinical evaluation of human ActRIIA-Fc (sotatercept) in patients with PH-HFpEF.

Project description:ObjectivePulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle.ConclusionsOur data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.

Dataset Information

Pulmonary artery denervation improves hemodynamics and cardiac function in pulmonary hypertension secondary to heart failure.

Publications

Pulmonary artery denervation improves hemodynamics and cardiac function in pulmonary hypertension secondary to heart failure.

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