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
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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.
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