Du-Jiang Xie

Percutaneous pulmonary artery denervation completely abolishes experimental pulmonary arterial hypertension in vivo.

AIMS The study sought to assess the effect of percutaneous pulmonary artery denervation (PADN) on balloon-occlusion-induced acute pulmonary arterial hypertension (PAH) in vivo. The PADN is a minimally invasive and endovascular catheter-based interventional therapy using radiofrequency ablation to abolish the pulmonary arterial baroreceptors to pressure response. METHODS AND RESULTS To examine the efficacy of balloon-occlusion-induced PAH, twenty Mongolian dogs were randomly assigned to one of two groups: group 1 (left distal pulmonary basal trunk occlusion) and group 2 (left pulmonary interlobar artery occlusion). Afterwards, PADN treatment at the main pulmonary artery bifurcation level with left pulmonary interlobar artery occlusion in all 20 dogs was conducted. Haemodynamic parameters were measured at baseline and during balloon occlusion as well as the PADN treatment at different time points: one, two, three, five, and ten minutes. Before the PADN treatment, most haemodynamic parameters of the pulmonary artery remained unchanged in group 1 with distal pulmonary basal trunk occlusion. However, in group 2 with the occlusion of the left pulmonary interlobar artery, mean pulmonary arterial pressure, mean right ventricular pressure, and pulmonary vessel resistance gradually increased, and mean absolute difference reached peak at five minutes (Δ16.6 mmHg, Δ14.1 mmHg and Δ1,144 dye/s/cm5, respectively; each p<0.01). These haemodynamic parameters at five minutes induced by left pulmonary interlobar artery occlusion were completely abolished with the PADN treatment compared to baseline (Δ0.3 mmHg, Δ0.2 mmHg, and Δ34 dye/s/cm5, respectively). CONCLUSIONS Balloon occlusion of the left pulmonary interlobar artery led to a significant increase of haemodynamic parameters of the pulmonary artery. The pressure responses were completely abolished by the PADN treatment at the main bifurcation area of the left pulmonary artery.

Hemodynamic, Functional, and Clinical Responses to Pulmonary Artery Denervation in Patients With Pulmonary Arterial Hypertension of Different Causes Phase II Results From the Pulmonary Artery Denervation-1 Study

Background—The mechanisms underlying pulmonary arterial hypertension (PAH) are multifactorial. The efficacy of pulmonary artery denervation (PADN) for idiopathic PAH treatment has been evaluated. This study aimed to analyze the hemodynamic, functional, and clinical responses to PADN in patients with PAH of different causes. Methods and Results—Between April 2012 and April 2014, 66 consecutive patients with a resting mean pulmonary arterial pressure ≥25 mm Hg treated with PADN were prospectively followed up. Target drugs were discontinued after the PADN procedure. Hemodynamic response and 6-minute walk distance were repeatedly measured within the 1 year post PADN follow-up. The clinical end point was the occurrence of PAH-related events at the 1-year follow-up. There were no PADN-related complications. Hemodynamic success (defined as the reduction in mean pulmonary arterial pressure by a minimal 10% post PADN) was achieved in 94% of all patients, with a mean absolute reduction in systolic pulmonary arterial pressure and mean pulmonary arterial pressure within 24 hours of −10 mm Hg and −7 mm Hg, respectively. The average increment in 6-minute walk distance after PADN was 94 m. Worse PAH-related events occurred in 10 patients (15%), mostly driven by the worsening of PAH (12%). There were 8 (12%) all-cause deaths, with 6 (9%) PAH-related deaths. Conclusions—PADN was safe and feasible for the treatment of PAH. The PADN procedure was associated with significant improvements in hemodynamic function, exercise capacity, and cardiac function and with less frequent PAH-related events and death at 1 year after PADN treatment. Further randomized studies are required to confirm the efficacy of PADN for PAH. Clinical Trial Registration—URL: http://www.chictr.trc.com.cn. Unique identifier: chiCTR-ONC-12002085.

Pulmonary Artery Denervation Attenuates Pulmonary Arterial Remodeling in Dogs With Pulmonary Arterial Hypertension Induced by Dehydrogenized Monocrotaline.

OBJECTIVES This study aimed to investigate sympathetic nerve (SN) ultrastructural changes and hemodynamic and pulmonary artery (PA) pathological improvements by pulmonary arterial denervation (PADN) in animals with pulmonary arterial hypertension (PAH), as well as the underlying mechanisms. BACKGROUND SN overactivity plays a role in PAH. Previous studies have reported short-term improvements in pulmonary arterial pressure (PAP) and cardiac function by PADN, but PA remodeling and the associated mechanisms remain unclear. METHODS Forty dogs were randomly (ratio of 1:3) assigned to the control (intra-atrial injection of N-dimethylacetamide, 3 mg/kg) and test (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg) groups. After 8 weeks, the animals in the test group with a mean PAP >25 mm Hg (n = 20) were randomized (ratio of 1:1) into the sham and PADN groups. At 14 weeks, the hemodynamics, medial wall thickness and PA muscularization, and messenger ribonucleic acid expression of genes in lung tissues were measured. Another 35 PAH dogs were used to measure the SN conduction velocity, electron microscopic assessment, and nerve distribution. RESULTS PADN induced significant SN demyelination and axon loss and slowed SN conduction velocity over time, with resulting profound reductions in the mean PAP (23.5 ± 2.3 mm Hg vs. 33.7 ± 5.8 mm Hg), pulmonary vessel resistance (3.5 ± 2.3 Wood units vs. 7.7 ± 1.7 Wood units), medial wall thickness (22.3 ± 3.3% vs. 30.4 ± 4.1%), and full muscularization (40.3 ± 9.3% vs. 57.1 ± 5.7%) and increased nonmuscularization (29.8 ± 6.1% vs. 12.9 ± 4.9%) compared with the Sham group (all p < 0.001). PADN inhibited the messenger ribonucleic acid expression of genes correlated with inflammation, proliferation, and vasoconstriction. CONCLUSIONS PADN induces permanent SN injury and subsequent improvements in hemodynamics and PA remodeling in animals with PAH through mechanisms that may be experimentally and clinically beneficial.

Clinical Outcome of Double Kissing Crush Versus Provisional Stenting of Coronary Artery Bifurcation Lesions: The 5-Year Follow-Up Results From a Randomized and Multicenter DKCRUSH-II Study (Randomized Study on Double Kissing Crush Technique Versus Provisional Stenting Technique for Coronary Artery Bifurcation Lesions).

Background— Provisional stenting is effective for anatomic simple bifurcation lesions. Double kissing crush stenting reduces the 1-year rate of target lesion revascularization. This study aimed to investigate the 5-year clinical results of the DKCRUSH-II study (Randomized Study on Double Kissing Crush Technique Versus Provisional Stenting Technique for Coronary Artery Bifurcation Lesions). Methods and Results— A total of 370 patients with coronary bifurcation lesions who were randomly assigned to either the double kissing crush or provisional stenting group in the DKCRUSH-II study were followed for 5 years. The primary end point was the occurrence of a major adverse cardiac event at 5 years. Patients were classified by simple and complex bifurcation lesions according to the DEFINITION criteria (Definitions and Impact of Complex Bifurcation Lesions on Clinical Outcomes After Percutaneous Coronary Intervention Using Drug-Eluting Stents). At 5 years, the major adverse cardiac event rate (23.8%) in the provisional stenting group was insignificantly different to that of the double kissing group (15.7%; P=0.051). However, the difference in the target lesion revascularization rate between 2 groups was sustained through the 5-year follow-up (16.2% versus 8.6%; P=0.027). The definite and probable stent thrombosis rate was 2.7% in each group (P=1.0). Complex bifurcation was associated with a higher rate of target lesion revascularization (21.6%) at 5 years compared with 11.1% in patients with a simple bifurcation (P=0.037), with an extremely high rate in the provisional stenting group (36.8% versus 12.5%, P=0.005) mainly because of final kissing balloon inflation (19.4% versus 5.2%; P=0.036). Conclusions— The double kissing crush stenting technique for coronary bifurcation lesions is associated with a lower rate of target lesion revascularization. The optimal stenting approach based on the lesions’ complexity may improve the revascularization for patients with complex bifurcations. Clinical Trial Registration— URL: http://www.chictr.org. Unique identifier: ChiCTR-TRC-0000015.

Pulmonary artery denervation for treatment of a patient with pulmonary hypertension secondary to left heart disease

Pulmonary hypertension (PH) predicts poor outcome in patients with left heart disease. A 62-year-old man was referred for heart failure associated with ischemic cardiomyopathy. He received a diagnosis of combined postcapillary and precapillary PH secondary to left heart disease on the basis of hemodynamic parameters. After the pulmonary artery denervation procedure was performed, hemodynamic parameters were markedly improved, which resulted in a significant increase in functional capacity.

Low shear stress induces vascular eNOS uncoupling via autophagy-mediated eNOS phosphorylation

Uncoupled endothelial nitric oxide synthase (eNOS) produces O2- instead of nitric oxide (NO). Earlier, we reported rapamycin, an autophagy inducer and inhibitor of cellular proliferation, attenuated low shear stress (SS) induced O2- production. Nevertheless, it is unclear whether autophagy plays a critical role in the regulation of eNOS uncoupling. Therefore, this study aimed to investigate the modulation of autophagy on eNOS uncoupling induced by low SS exposure. We found that low SS induced endothelial O2- burst, which was accompanied by reduced NO release. Furthermore, inhibition of eNOS by L-NAME conspicuously attenuated low SS-induced O2- releasing, indicating eNOS uncoupling. Autophagy markers such as LC3 II/I ratio, amount of Beclin1, as well as ULK1/Atg1 were increased during low SS exposure, whereas autophagic degradation of p62/SQSTM1 was markedly reduced, implying impaired autophagic flux. Interestingly, low SS-induced NO reduction could be reversed by rapamycin, WYE-354 or ATG5 overexpression vector via restoration of autophagic flux, but not by N-acetylcysteine or apocynin. eNOS uncoupling might be ascribed to autophagic flux blockade because phosphorylation of eNOS Thr495 by low SS or PMA stimulation was also regulated by autophagy. In contrast, eNOS acetylation was not found to be regulated by low SS and autophagy. Notably, although low SS had no influence on eNOS Ser1177 phosphorylation, whereas boosted eNOS Ser1177 phosphorylation by rapamycin were in favor of the eNOS recoupling through restoration of autophagic flux. Taken together, we reported a novel mechanism for regulation of eNOS uncoupling by low SS via autophagy-mediated eNOS phosphorylation, which is implicated in geometrical nature of atherogenesis.

Pericardial effusion is correlated with clinical outcome after pulmonary artery denervation for pulmonary arterial hypertension

OBJECTIVES Pericardial effusion (PE) is correlated with outcomes in patients with pulmonary arterial hypertension (PAH). Pulmonary artery denervation (PADN) was used for treatment of PAH. The present study aimed to analyze the prognostic value of PE for outcomes after PADN in patients with WHO Group I, Group II and Group IV PAH. RESULTS PE, frequently seen in patients with connective tissue disease, was featured by fast heart rate, decreased exercise capacity, more syncope, worsening pulmonary arterial hemodynamic and right atrium size. PADN procedure resulted in dramatic reduction of PE. After a median of 376 days follow-up, the rate of PAH-related event, all-cause death and rehospitalization increased over the PE amount and occurred in 29.8%, 19.7% and 25.2% of patients with PE, different to 3.4%, 3.4% and 6.8% of patients without PE (p = 0.034, p = 0.041 and p = 0.039, respectively). The reduction of PE during follow-up was similar among three groups. MATERIALS AND METHODS Between March 2012 and July 2014, a total of 66 consecutive patients (52 ± 16 years) who underwent PADN were stratified by no PE (n = 20), PE < 10 mm (n = 29) and PE ≥ 10 mm (n = 17) according to baseline echocardiograph. Dynamic change of PE and its correlation with PAH-related event after PADN were measured. CONCLUSIONS PE is associated with increased PAH-related event after PADN. PADN results in significant similar reduction of PE among patients with Group I, Group II and Group IV PAH.Objectives Pericardial effusion (PE) is correlated with outcomes in patients with pulmonary arterial hypertension (PAH). Pulmonary artery denervation (PADN) was used for treatment of PAH. The present study aimed to analyze the prognostic value of PE for outcomes after PADN in patients with WHO Group I, Group II and Group IV PAH. Results PE, frequently seen in patients with connective tissue disease, was featured by fast heart rate, decreased exercise capacity, more syncope, worsening pulmonary arterial hemodynamic and right atrium size. PADN procedure resulted in dramatic reduction of PE. After a median of 376 days follow-up, the rate of PAH-related event, all-cause death and rehospitalization increased over the PE amount and occurred in 29.8%, 19.7% and 25.2% of patients with PE, different to 3.4%, 3.4% and 6.8% of patients without PE (p = 0.034, p = 0.041 and p = 0.039, respectively). The reduction of PE during follow-up was similar among three groups. Materials and methods Between March 2012 and July 2014, a total of 66 consecutive patients (52 ± 16 years) who underwent PADN were stratified by no PE (n = 20), PE < 10 mm (n = 29) and PE ≥ 10 mm (n = 17) according to baseline echocardiograph. Dynamic change of PE and its correlation with PAH-related event after PADN were measured. Conclusions PE is associated with increased PAH-related event after PADN. PADN results in significant similar reduction of PE among patients with Group I, Group II and Group IV PAH.

Assessment and Prognostic Impact of Right Ventricular Function in Patients with Pulmonary Arterial Hypertension Undergoing Pulmonary Artery Denervation: Central Role of Global Right Ventricular Longitudinal Peak Systolic Strain

ABSTRACT Background: Echocardiographic right ventricular (RV) functional parameters and longitudinal peak systolic strain (LS) are important determinants of prognosis in patients with pulmonary arterial hypertension (PAH). Pulmonary artery denervation (PADN) has been shown to reduce pulmonary artery pressures (PAP) in PAH. Whether this results in improved RV function is unknown. We therefore sought to evaluate serial changes in RV function and clinical outcomes after PADN, and determine the role of baseline RV-LS as a prognostic tool. Methods: Between March 2014 and March 2016, 40 patients with PAH who underwent PADN were studied. RV function was evaluated at baseline, 1 week, 3 months, 6 months, and >1 year after PADN, and correlations between RV-LS, RV functional parameters, 6-minute walk distance (6MWD), and pulmonary vessel resistance (PVR) were examined. Receiver operating characteristic curve analysis was used to determine the optimal baseline RV-LS cutoff value to predict PADN responder status, and prognosis was assessed in these groups. Results: PADN resulted in sustained changes in PVR and RV-LS over time (mean follow-up of 763 ± 254 days). By multivariate analysis, baseline RV-LS was the only independent predictor of ∆mPAP (β = −0.736, p = 0.001) and ∆PVR (β = −0.076, p = 0.03), and significantly correlated with 6MWD (r = −0.586, p < 0.001) at the end of follow-up. Baseline RV-LS ≥ −11.3% had a sensitivity of 78.1% and a specificity of 75.0% for predicting non-responders to PADN. During follow-up there were 10 (25%) PAH-related events, including 4 (10%) cardiac deaths. PAH-related events after PADN were more frequent in patients with RV-LS ≥ −11.3% vs. < −11.3% (46.2% vs. 14.8%, p = 0.03). Conclusions: PADN results in sustained improvements in PVR and RV-LS. Baseline RV-LS is the strongest predictor of improved hemodynamic measures after PADN in patients with PAH, and is strongly associated with late 6MWD and prognosis. Specifically, baseline RV-LS ≥ −11.3% predicts non-responder status and PAH-related events after PADN, and thus may be useful to identify which PAH patients may benefit from the PADN procedure.

Response to Letter Regarding Article, “Hemodynamic, Functional, and Clinical Responses to Pulmonary Artery Denervation in Patients With Pulmonary Arterial Hypertension of Different Causes: Phase II Results From the Pulmonary Artery Denervation-1 Study”

We read with interest the letter by Hoeper and Galie,1 which raised several concerns about our article2 recently published in Circulation: Cardiovascular Interventions . As we described in Pulmonary Artery Denervation-1 (PADN-I) study,3 the withdrawal of target drugs for pulmonary arterial hypertension was based on the clinical and hemodynamic measurements when patients had taken these targeted therapies for several years. A reason seemed to be ethical. …