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Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.
Copyright ©ERS 2018.
INTRODUCTION - In animal models, pretreatment with low-energy shock waves and a pause decreased renal injury from shockwave lithotripsy (SWL). This is associated with an increase in perioperative renal resistive index (RI). A perioperative rise is not seen without the protective protocol, which suggests that renal vasoconstriction during SWL plays a role in protecting the kidney from injury. The purpose of our study was to investigate whether there is an increase in renal RI during SWL in humans.
MATERIALS AND METHODS - Subjects were prospectively recruited from two hospitals. All subjects received an initial 250 shocks at low setting, followed by a 2-minute pause. Treatment power was then increased. Measurements of the renal RI were taken before start of procedure, at 250, after 750, after 1500 shocks, and at the end of the procedure. A linear mixed-effects model was used to compare RIs at the different time points.
RESULTS - Fifteen patients were enrolled. Average treatment time was 46 ± 8 minutes. Average RI at pretreatment, after 250, after 750, after 1500 shocks, and post-treatment was 0.67 ± 0.06, 0.69 ± 0.08, 0.71 ± 0.07, 0.73 ± 0.07, and 0.74 ± 0.06, respectively. In adjusted analyses, RI was significantly increased after 750 shocks compared with pretreatment (p = 0.05).
CONCLUSION - Renal RI increases early during SWL in humans with the protective protocol. Monitoring for a rise in RI during SWL is feasible and may provide real-time feedback as to when the kidney is protected.
BACKGROUND - A "classic" response to acute vasodilator testing (drop of >10 mm Hg in mean pulmonary artery pressure [mPAP] to <40 mm Hg) confers an excellent prognosis in patients with idiopathic pulmonary arterial hypertension (IPAH) and identifies candidates for treatment with calcium channel blockers (CCB). Little is known about vasodilator responsiveness (VR) in other types of PAH, or about outcomes in patients with a significant but "non-classic" decrease in mPAP. We hypothesized that VR occurs in non-idiopathic PAH and non-classic VR portends a better prognosis than no VR in PAH.
METHODS - Acute VR testing with nitric oxide was performed on 155 consecutive patients referred for PH evaluation. Non-classic response was defined as decrease in mPAP >10 mm Hg to >40 mm Hg with preserved cardiac output. Demographics and functional status were assessed at baseline and the first clinic visit after VR testing, and survival was followed over time.
RESULTS - Twenty patients (13%) displayed classic VR. Among classic responders, 12 (60%) had IPAH and 8 (40%) had connective tissue disease-associated PAH (CTD-PAH); however, only responders with IPAH had improved survival compared with non-responders (p = 0.02). Thirteen patients (8%) had a non-classic VR. Non-classic response was not associated with improved survival compared with non-responders (p = 0.86). Acute change in mPAP or pulmonary vascular resistance in the entire cohort did not predict survival.
CONCLUSIONS - Classic acute VR occurs in CTD-PAH as well as IPAH; however, only IPAH patients have improved outcomes. A significant but non-classic VR is not associated with improved survival.
Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Pulmonary vascular capacitance (PVC) is reduced in pulmonary arterial hypertension (PAH). In normal lung, PVC is largely a function of vascular compliance. In PAH, increased pulmonary vascular resistance (PVR) arises from the arterioles. PVR and PVC share pressure and volume variables. The dependency between the two qualities of the vascular bed is unclear in a state of intense vasoconstriction.
METHODS - We compared PVC and PVR before and during nitric oxide (NO) inhalation during right-sided heart catheterization in eight NO-responsive patients with PAH. NO only directly affects tone in parenchymal vessels.
RESULTS - During NO inhalation, pulmonary arterial systolic pressure decreased, 80 ± 20 SD to 48 ± 20 mm Hg, and stroke volume increased, 62 ± 19 mL to 86 ± 24 mL (P < .01). PVR dropped from 10 ± 4.4 Wood units to 4.7 ± 2.2 Wood units (P < .012), and PVC increased from 1.4 ± 1.1 mL/mm Hg to 3.2 ± 1.8 mL/mm Hg (P < .018). The magnitude of PVR drop was 57% ± 6% and the decrease in 1/PVC was 54% ± 14% (P = not significant).
CONCLUSIONS - In vasoresponsive PAH, PVC is a function of the pressure response of the vasoconstricted arterioles to stroke volume. Immediately upon vasodilation, the capacitance increases markedly. The compliance vessels are, thus, the same as the resistance vessels. The immediate reduction in pulmonary arterial pressure during NO inhalation suggests that large vessel remodeling is not a major contributor to systolic pressure in these patients.
BACKGROUND - Cell-free hemoglobin (CFH) is a potent nitric oxide scavenger associated with poor outcomes in several diseases. Pulmonary arterial hypertension (PAH) is characterized by reduced nitric oxide availability. We hypothesized that CFH would be elevated in PAH and would associate with hemodynamics and clinical outcomes.
METHODS - We measured CFH in 200 consecutively evaluated patients with PAH, 16 unaffected bone morphogenetic receptor protein type 2 (BMPR2) mutation carriers, 19 healthy subjects, and 29 patients with pulmonary venous hypertension (PVH). CFH values were tested for association with hemodynamics, time to hospitalization, and death.
RESULTS - CFH was elevated in patients with PAH and BMPR2 carriers compared with healthy subjects and patients with PVH (P ≤ .01 all comparisons). There were no differences in CFH across PAH subtypes. CFH modestly correlated with mean pulmonary artery pressure (ρ = 0.16, P = .03) and pulmonary vascular resistance (ρ = 0.21, P = .01) and inversely with cardiac index (ρ = -0.18, P = .02) in patients with PAH. CFH was not associated with hemodynamic response to nitric oxide or death. Patients with the highest CFH levels had increased risk of PAH-related hospitalization when adjusted for age, sex, and PAH cause (hazard ratio, 1.69; 95% CI ,1.08-2.66; P = .02).
CONCLUSIONS - CFH is elevated in patients with PAH and BMPR2 carriers compared with healthy subjects and patients with PVH. Elevated CFH levels are independently associated with an increased risk of hospitalization. Further study is required to understand the mechanism of CFH elevation and the potential pathologic contribution of CFH in PAH.
UNLABELLED - Dipeptidyl peptidase-4 inhibitors prevent the degradation of incretin hormones and reduce postprandial hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase-4 degrades other peptides with a penultimate proline or alanine, including bradykinin and substance P, which are also substrates of angiotensin-converting enzyme (ACE). During ACE inhibition, substance P is inactivated primarily by dipeptidyl peptidase-4, whereas bradykinin is first inactivated by aminopeptidase P. This study tested the hypothesis that dipeptidyl peptidase-4 inhibition potentiates vasodilator and fibrinolytic responses to substance P when ACE is inhibited. Twelve healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received sitagliptin 200 mg by mouth or placebo. Substance P and bradykinin were infused via brachial artery before and during intra-arterial enalaprilat. Sitagliptin and enalaprilat each reduced forearm vascular resistance and increased forearm blood flow without affecting mean arterial pressure, but there was no interactive effect of the inhibitors. Enalaprilat increased bradykinin-stimulated vasodilation and tissue plasminogen activator release; sitagliptin did not affect these responses to bradykinin. The vasodilator response to substance P was unaffected by sitagliptin and enalaprilat; however, substance P increased heart rate and vascular release of norepinephrine during combined ACE and dipeptidyl peptidase-4 inhibition. In women, sitagliptin diminished tissue plasminogen activator release in response to substance P both alone and during enalaprilat. Substance P increases sympathetic activity during combined ACE and dipeptidyl peptidase-4 inhibition.
CLINICAL TRIAL REGISTRATION - - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01413542.
BACKGROUND - Mechanical circulatory support is an accepted strategy to bridge patients to heart transplantation (HTx). Among mechanical circulatory support patients who go on to HTx, factors associated with improved graft survival have not been fully elucidated.
METHODS - Using the Scientific Registry for Transplant Recipients, we identified adults who were treated with a left ventricular assist device (LVAD) or total artificial heart (TAH) before HTx. Kaplan-Meier and multivariate Cox regression models were used to identify patient, donor, and device characteristics associated with graft survival.
RESULTS - Between January 1997 and February 2012, 2,785 adults underwent HTx. Before HTx, 2,674 patients were treated with a LVAD (HeartMate XVE, 724; HeartMate II, 1,882; HeartWare, 68), and 111 were treated with a TAH. Follow-up averaged 25 ± 24 months. Gender mismatch occurred in 23%. Graft survival did not differ between LVAD groups (all p > 0.168), but TAH was associated with reduced graft survival compared with LVADs (p < 0.001). After controlling for device type (LVAD vs TAH), lower recipient pulmonary vascular resistance, shorter ischemic time, younger donor age, donor-to-recipient gender match, and higher donor-to-recipient body mass index ratio were independent predictors of longer graft survival (all p < 0.05).
CONCLUSIONS - TAH was associated with reduced graft survival after transplant, and survival did not differ between the LVAD device groups. Additional variables that were independently associated with graft survival were donor age, recipient peripheral vascular resistance, ischemic time, gender match, and donor-to-recipient body mass index ratio. Recognition of these factors may inform decisions regarding device support and donor suitability.
Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.