Pulmonary artery denervation improves pulmonary arterial hypertension induced right ventricular dysfunction by modulating the local renin-angiotensin-aldosterone system

BMC Cardiovascular Disorders, Oct 2016

Background Pulmonary arterial hypertension (PAH) is commonly accompanied with the activation of the renin-angiotensin-aldosterone system (RAAS). Renal sympathetic denervation (RSD) reduces PAH partly through the inhibition of RAAS. Analogically, we hypothesized that pulmonary artery denervation (PADN) could reverse PAH and PAH-induced right ventricular (RV) dysfunction by downregulating the local RAAS activity. Methods Twenty-five beagle dogs were randomized into two groups: control group (intra-atrial injection of N-dimethylacetamide, 3 mg/kg, n = 6) and test group (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg, n = 19). Eight weeks later, dogs in the test group with mean pulmonary arterial pressure (mPAP) ≥25 mmHg (n = 16) were reassigned into the sham (n = 8) and PADN groups (n = 8) by chance. After another 6 weeks, the hemodynamics, pulmonary tissue morphology and the local RAAS expression in lung and right heart tissue were measured. Results PADN reduced the mPAP (25.94 ± 3.67 mmHg vs 33.72 ± 5.76 mmHg, P < 0.05) and the percentage of medial wall thickness (%MWT) (31.0 ± 2.6 % vs 37.9 ± 2.8 %, P < 0.05) compared with the sham group. PADN attenuated RV dysfunction, marked with reduced atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and ratio of right ventricular to left ventricular plus septum weight [RV/(LV + S)]. Moreover, the local RAAS expression was activated in PAH dogs while inhibited after PADN. Conclusions PADN improves hemodynamics and relieves RV dysfunction in dogs with PAH, which can be associated with the downregulating RAAS activity in local tissue.

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Pulmonary artery denervation improves pulmonary arterial hypertension induced right ventricular dysfunction by modulating the local renin-angiotensin-aldosterone system

Liu et al. BMC Cardiovascular Disorders Pulmonary artery denervation improves pulmonary arterial hypertension induced right ventricular dysfunction by modulating the local renin-angiotensin-aldosterone system Chen Liu 1 Xiao-Min Jiang 2 Juan Zhang 2 Bing Li 1 Jing Li 1 Du-Jiang Xie 2 Zuo-Ying Hu 1 0 Changle Road , Nanjing 210006 , China 1 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University , 68 2 Division of Cardiology, Nanjing First Hospital , 68 Background: Pulmonary arterial hypertension (PAH) is commonly accompanied with the activation of the renin-angiotensin-aldosterone system (RAAS). Renal sympathetic denervation (RSD) reduces PAH partly through the inhibition of RAAS. Analogically, we hypothesized that pulmonary artery denervation (PADN) could reverse PAH and PAH-induced right ventricular (RV) dysfunction by downregulating the local RAAS activity. Methods: Twenty-five beagle dogs were randomized into two groups: control group (intra-atrial injection of N-dimethylacetamide, 3 mg/kg, n = 6) and test group (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg, n = 19). Eight weeks later, dogs in the test group with mean pulmonary arterial pressure (mPAP) ≥25 mmHg (n = 16) were reassigned into the sham (n = 8) and PADN groups (n = 8) by chance. After another 6 weeks, the hemodynamics, pulmonary tissue morphology and the local RAAS expression in lung and right heart tissue were measured. Results: PADN reduced the mPAP (25.94 ± 3.67 mmHg vs 33.72 ± 5.76 mmHg, P < 0.05) and the percentage of medial wall thickness (%MWT) (31.0 ± 2.6 % vs 37.9 ± 2.8 %, P < 0.05) compared with the sham group. PADN attenuated RV dysfunction, marked with reduced atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and ratio of right ventricular to left ventricular plus septum weight [RV/(LV + S)]. Moreover, the local RAAS expression was activated in PAH dogs while inhibited after PADN. Conclusions: PADN improves hemodynamics and relieves RV dysfunction in dogs with PAH, which can be associated with the downregulating RAAS activity in local tissue. Pulmonary artery denervation; Pulmonary arterial hypertension; Right ventricular dysfunction; Renin-angiotensin-aldosterone system - Background Pulmonary arterial hypertension (PAH) is a lethal disease with poor long-term prognosis and high mortality, which is defined by a mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest [1]. Recent clinical trials study groups have reported that the mortality rate of French Registry patients at 3–5 years is approximately 20–30 % and the mortality rate of REVEAL Registry patients at 1–3 years is in the range of 10–30 % [2]. The disease is characterized by excessive pulmonary vascular remodeling, contributing to increased pulmonary vascular resistance (PVR) and pulmonary pressure [3, 4]. Increased pulmonary vascular afterload can result in RV adaptation, ultimately leading to RV failure and even death. Besides pressure overload, other factors, such as oxidative stress, ischemia, inflammation, and neurohormonal activation, are also involved in RV remodeling [5]. Actually, the RV function is a major determinant of prognosis in PAH patients [6, 7]. Despite the complex and multifactorial pathogenesis of PAH, neurohormonal activation has been considered as an important factor in the pathophysiology of PAH. Two key players of the neurohormonal system are the sympathetic nervous system (SNS) and the RAAS. It is well established that sympathetic nerve (SN) activity is increased in patients with PAH [8, 9], indicating that hyperactivity of the SNS plays a central role in PAH. Additionally, the RAAS has been proved to be activated when PAH occurs both in animal models and clinically [10–12]. For instance, the increased expression of angiotensin converting enzyme (ACE) along with angiotensin II (Ang II) was observed in the development of pulmonary hypertension (PH) [10, 11]. Elevation of Ang II type 1 receptor (AT1 receptor) was also demonstrated in patients with idiopathic pulmonary arterial hypertension [12]. All the evidence above has illustrated that SNS and RAAS are closely involved in the development of PAH, and may have long-term effects on the progression of PAH. Pulmonary artery denervation (PADN) is one of the newest potential therapies of PAH. Performed at the bifurcation area of the main pulmonary artery (PA), the ostial right PA and the ostial left PA, by inducing local injury or destruction to the baroreceptor or sympathetic nervous fibers, PADN reduces the pulmonary arterial pressure [13]. It has been demonstrated that PADN conducted in the main pulmonary artery bifurcation area induces severe SN injury and abolishes PAH induced by balloon inflations in a dog model [14]. Reduction of PAH and improvement of right heart function have also been proved clinically in patients with PAH [13]. However, the associated mechanisms of PADN remain unclear. Previous studies have shown that renal s (...truncated)


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Chen Liu, Xiao-Min Jiang, Juan Zhang, Bing Li, Jing Li, Du-Jiang Xie, Zuo-Ying Hu. Pulmonary artery denervation improves pulmonary arterial hypertension induced right ventricular dysfunction by modulating the local renin-angiotensin-aldosterone system, BMC Cardiovascular Disorders, 2016, pp. 192, 16, DOI: 10.1186/s12872-016-0366-4