Search

A striking feature of the human pulmonary circulation is that mean (mPAP) and systolic (sPAP) pulmonary artery pressures (PAPs) are strongly related and, thus, are essentially redundant. According to the empirical formula documented under normotensive and hypertensive conditions (mPAP = 0.61 sPAP + 2 mmHg), sPAP matches ~160%mPAP on average. This attests to the high pulsatility of PAP, as also witnessed by the near equality of PA pulse pressure and mPAP. Our prospective study tested if pressure redundancy and high pulsatility also apply in a piglet model of chronic thromboembolic pulmonary hypertension (CTEPH). At baseline (Week‐0, W0), Sham (n = 8) and CTEPH (n = 27) had similar mPAP and stroke volume. At W6, mPAP increased in CTEPH only, with a two‐ to three‐fold increase in PA stiffness and total pulmonary resistance. Seven CTEPH piglets were also studied at W16 at baseline, after volume loading, and after acute pulmonary embolism associated with dobutamine infusion. There was a strong linear relationship between sPAP and mPAP (1) at W0 and W6 (n = 70 data points, r² = 0.95); (2) in the subgroup studied at W16 (n = 21, r² = 0.97); and (3) when all data were pooled (n = 91, r² = 0.97, sPAP range 9–112 mmHg). The PA pulsatility was lower than that expected based on observations in humans: sPAP matched ~120%mPAP only and PA pulse pressure was markedly lower than mPAP. In conclusion, the redundancy between mPAP and sPAP seems a characteristic of the pulmonary circulation independent of the species. However, it is suggested that the sPAP thresholds used to define PH in animals are species‐ and/or model‐dependent and thus must be validated. [ABSTRACT FROM AUTHOR]

Background: The golden ratio (phi, Φ = 1.618) is a proportion that has been found in many phenomena in nature, including the cardiovascular field. We tested the hypothesis that the systolic over mean pulmonary artery pressure ratio (sPAP/mPAP) and the mean over diastolic pressure ratio (mPAP/dPAP) may match Φ in patients with pulmonary arterial hypertension (PAH) and in control patients.Methods: In the first, theoretical part of the study, we discuss why our hypothesis is consistent with three known hemodynamic features of the pulmonary circulation: (1) the 0.61 slope of the mPAP vs sPAP relationship, (2) pulmonary artery pulse pressure and mPAP have an almost 1:1 ratio, and (3) the proportional relationship among sPAP, mPAP, and dPAP. In the second part of the study, fluid-filled pressures were analyzed in 981 incident, untreated PAH and high-fidelity pressures were also analyzed in 44 historical control patients (mPAP range, 9-113 mm Hg).Results: In PAH (non-normal distribution), median values of sPAP/mPAP and mPAP/dPAP were 1.591 (98%Φ) and 1.559 (96%Φ), respectively. In control patients (normal distribution), mean sPAP/mPAP and mPAP/dPAP were 1.572 (97%Φ) and 1.470 (91%Φ), respectively. In both PAH and control patients, this was consistent with the Φ hypothesis, assuming < 1 mm Hg error in estimation of sPAP, mPAP, and dPAP on average.Conclusions: In PAH and in control patients, the fluctuations in sPAP and dPAP around mPAP exhibited a constant scaling factor matched to Φ. This remarkable property allows linkage of various empirical observations on pulmonary hemodynamics that were hitherto apparently unrelated. These findings warrant further confirmation in other types of pulmonary hypertension and warrant explanation. [ABSTRACT FROM AUTHOR]

Background: Our aim was to develop a model of acute right heart failure (ARHF) in the setting of pulmonary hypertension and to characterize acute right ventricular lesions that develop early after hemodynamic restoration.Methods and Results: We used a described piglet model of chronic pulmonary hypertension (cPH) induced by pulmonary artery occlusions. We induced ARHF in animals with cPH (ARHF-cPH group, n = 9) by volume loading and iterative acute pulmonary embolism until hemodynamic compromise followed by dobutamine infusion for hemodynamic restoration before sacrifice for right ventricular tissue evaluation. The median duration of ARHF before sacrifice was 162 (135-189) minutes. Although ventriculoarterial coupling (measured with multibeat pressure-volume loops) and stroke volume decreased after iterative pulmonary embolism and improved with dobutamine, relative pulmonary to systemic pressure increased by 2-fold and remained similarly increased with dobutamine. Circulating high-sensitivity troponin I increased after hemodynamic restoration. We found an increase in right ventricular subendocardial and subepicardial focal ischemic lesions and in expression of autophagy-related protein LC3-II (Western blot) in the ARHF-cPH group compared with the cPH (n = 5) and control (n = 5) groups.Conclusions: We developed and phenotyped a novel large animal model of ARHF on cPH in which right ventricular ischemic lesions were observed early after hemodynamic restoration. [ABSTRACT FROM AUTHOR]

Patients with idiopathic pulmonary arterial hypertension (IPAH) have improved survival after heart-lung transplantation (HLT) and double-lung transplantation (DLT). However, the optimal procedure for patients with IP AH undergoing transplantation remains unclear. We hypothesized that critically ill IP AH patients, defined by admission to the intensive care units (ICU), would demonstrate improved survival with HLT vs. DLT. All adult IP AH patients (>18 yr) in the Scientific Registry of Transplant Recipients (SRTR) database, who underwent either HLT or DLT between 1987 and 2012, were included. Baseline characteristics, survival, and adjusted survival were compared between the HLT and DLT groups. Similar analyses were performed for the subgroups as defined by the recipients' hospitalization status. A total of 928 IP AH patients (667 DLT, 261 HLT) were included in this analysis. The HLT recipients were younger, more likely to be admitted to the ICU, and have had their transplant in previous eras. Overall, the adjusted survivals after HLT or DLT were similar. For recipients who were hospitalized in the ICU, DLT was associated with worse outcomes (HR 1.827; 95% CI 1.018-3.279). In IP AH patients, the overall survival after HLT or DLT is comparable. HLT may provide improved outcomes in critically ill IP AH patients admitted to the ICU at time of transplantation. [ABSTRACT FROM AUTHOR]

Background Pulmonary microvascular disease (PMD) develops in both occluded and non-occluded territories in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and may cause persistent pulmonary hypertension after pulmonary endarterectomy. Endothelin-1 (ET-1) and interleukin-6 (IL-6) are potential PMD severity biomarkers, but it remains unknown whether they are related to occluded or non-occluded territories. We assessed PMD and ET-1/IL-6 gene expression profiles in occluded and non-occluded territories with and without chronic lung reperfusion in an animal CTEPH model. Methods Chronic PH was induced in 10 piglets by left pulmonary artery (PA) ligation followed by weekly embolization of right lower lobe arteries with enbucrilate tissue adhesive for 5 weeks. At Week 6, 5 of 10 animals underwent left PA reperfusion. At Week 12, animals with and without reperfusion were compared with sham animals ( n = 5). Hemodynamics, lung morphometry and ET-1/IL-6 gene expression profiles were assessed in the left lung (LL, occluded territories) and right upper lobe (RUL, non-occluded territories). Results At Week 12, mean PA pressure remained elevated without reperfusion (29.0 ± 2.8 vs 27.0 ± 1.1 mm Hg, p = 0.502), but decreased after reperfusion (30.0 ± 1.5 vs 20.5 ± 1.7 mm Hg, p = 0.013). Distal media thickness in the LL and RUL PAs and systemic vasculature to the LL were significantly lower in the reperfused and sham groups compared with the non-reperfused group. PMD progression was related to ET-1 and IL-6 gene expression in the RUL and to the ET-A/ET-B gene expression ratio in the LL. Conclusions PMD regressed in occluded and non-occluded territories after lung reperfusion. Changes in ET-1 and IL-6 gene expression were associated with PMD in non-occluded territories. [ABSTRACT FROM AUTHOR]

Aims To investigate the physiological correlates of indices of RV function in a model of chronic pressure overload. Methods and results Chronic pulmonary hypertension (PH) was induced in piglets by ligation of the left pulmonary artery (PA) followed by weekly embolization of right lower lobe arteries for 5 weeks (the PH group, n = 11). These animals were compared with sham-operated animals (controls, n = 6). At 6 weeks, a subgroup of five PH pigs underwent surgical reperfusion of the left lung and four others were followed until 12 weeks without treatment. Right ventricular function was assessed using echocardiography and conductance catheter measurements. At 6 weeks, mean PA pressure was higher in PH group compared with controls (35 ± 9 vs. 14 ± 2 mmHg, P < 0.01). Although RV elastance (Ees) increased at 6 weeks in the PH group (0.55 ± 0.09 vs. 0.38 ± 0.05mmHg/mL, P < 0.001), ventricular–arterial coupling measured by the ratio of Ees on PA elastance (Ea) was decreased (0.68 ± 0.17 vs. 1.18 ± 0.18, P < 0.001). There was a strong direct relationship between Ees/Ea and indices of RV function, while relationship between Ees and indices of RV function was moderate. Changes in indices of RV function with time and after left lung reperfusion were associated with changes in Ees/Ea. Conclusion Usual indices of RV function are associated with ventricular–arterial coupling rather than with ventricular contractility in a model of chronic pressure overload. [ABSTRACT FROM PUBLISHER]

Background: Tricuspid annular systolic excursion (TAPSE) or velocities (s′) and right ventricular (RV) end‐systolic dimensions are predictors of outcome in patients with pulmonary hypertension (PH). We explored the value of combining peak s′ and RV end‐systolic area index (RVESAi) as a surrogate of RV‐pulmonary artery (RV–PA) coupling in a large animal of precapillary PH as well as clinically. Method: The first experimental group included four control and four piglets with thromboembolic disease. RV–PA coupling was assessed by ventricular to arterial elastance ratio (Ees/Ea) at baseline, after esmolol and dobutamine administration. Echocardiographic metrics included s′, TAPSE, fractional area change (RVFAC), and RVESAi. The findings were validated in six piglets with severe PH. Clinical cohorts were stable outpatients (n = 141) and acutely decompensated pulmonary arterial hypertension (n = 48). Results: In the first experimental group, the best linear correlates of Ees/Ea were s′ (R2 =.51, p <.001) and RVESAi (R2 =.50, p <.001), while RVFAC (R2 =.17, p =.01) and TAPSE showed weaker association (R2 =.21, p =.39). The ratio s′/RVESAi showed nominally but not significantly (higher) association with Ees/Ea (R2 =.58, p <.01). The association between changes in s′/RVESAi and Ees/Ea was strong (R2 =.56, p <.001). In more severe PH, Ees/Ea and changes in Ees/Ea correlated significantly with s′/RVESAi and changes in s′/RVESAi (R2 =.69; p <.001 and R2 =.64, p <.001, respectively). In the two clinical cohorts, the s′/RVESAi did not emerge as a stronger predictor of outcome than RVESAi. Conclusion: RV s′/RVESAi index represents a reasonable bedside‐usable surrogate of RV–PA coupling and of its acute variations in PH. Its incremental prognostic value over end‐systolic dimension alone remains to be proven. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary arterial hypertension (IPAH) is a complex disease associated with vascular remodeling and a proliferative disorder in pulmonary artery smooth muscle cells (PASMCs) that has been variably described as having neoplastic features. To decode the phenotype of PASMCs in IPAH, PASMCs from explanted lungs of patients with IPAH (IPAH-PASMCs) and from controls (C-PASMCs) were cultured. The IPAH-PASMCs grew faster than the controls; however, both growth curves plateaued, suggesting contact inhibition in IPAH cells. No proliferation was seen without stimulation with exogenous growth factors, suggesting that IPAH cells are incapable of self-sufficient growth. IPAH-PASMCs were more resistant to apoptosis than C-PASMCs, consistent with the increase in the Bcl2/Bax ratio. As cell replication is governed by telomere length, these parameters were assessed jointly. Compared to C-PASMCs, IPAH-PASMCs had longer telomeres, but a limited replicative capacity. Additionally, it was noted that IPAH-PASMCs had a shift in energy production from mitochondrial oxidative phosphorylation to aerobic glycolysis. As DNA damage and genomic instability are strongly implicated in IPAH development a comparative genomic hybridization was performed on genomic DNA from PASMCs which showed multiple break-points unaffected by IPAH severity. Activation of DNA damage/repair factors (γH2AX, p53, and GADD45) in response to cisplatin was measured. All proteins showed lower phosphorylation in IPAH samples than in controls, suggesting that the cells were resistant to DNA damage. Despite the cancer-like processes that are associated with end-stage IPAH-PASMCs, we identified no evidence of self-sufficient proliferation in these cells—the defining feature of neoplasia. [ABSTRACT FROM AUTHOR]

Abstract Background Right ventricular (RV) failure is the main prognostic factor in pulmonary hypertension, and ventricular capillary density (CD) has been reported to be a marker of RV maladaptive remodeling and failure. Our aim was to determine whether right intracoronary endothelial progenitor cell (EPC) infusion can improve RV function and CD in a piglet model of chronic thromboembolic pulmonary hypertension (CTEPH). Methods We compared 3 groups: sham (n = 5), CTEPH (n = 6), and CTEPH with EPC infusion (CTEPH+EPC; n = 5). After EPC isolation from CTEPH+EPC piglet peripheral blood samples at 3 weeks, the CTEPH and sham groups underwent right intracoronary infusion of saline, and the CTEPH+EPC group received EPCs at 6 weeks. RV function, pulmonary hemodynamics, and myocardial morphometry were investigated in the animals at 10 weeks. Results After EPC administration, the RV fractional area change increased from 32.75% (interquartile range [IQR], 29.5%-36.5%) to 39% (IQR, 37.25%-46.50%; P =.030). The CTEPH+EPC piglets had reduced cardiomyocyte surface areas (from 298.3 μm2 [IQR, 277.4-335.3 μm2] to 234.6 μm2 (IQR, 211.1-264.7 μm2; P =.017), and increased CD31 expression (from 3.12 [IQR, 1.27-5.09] to 7.14 [IQR, 5.56-8.41; P =.017). EPCs were found in the RV free wall at 4 and 24 hours after injection but not 4 weeks later. Conclusions Intracoronary infusion of EPC improved RV function and CD in a piglet model of CTEPH. This novel cell-based therapy might represent a promising RV-targeted treatment in patients with pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Background: Ventricular–arterial coupling is a measure of the relationship between ventricular contractility and afterload. We sought to determine the relationship between ventricular–arterial coupling and right ventricular (RV) remodeling in a novel porcine model of progressive pulmonary hypertension (PH). Methods: Chronic PH was induced in pigs by ligation of the left pulmonary artery (PA) followed by 5 weekly injections of cyanoacrylate to progressively obstruct the right lower lobe arteries (PH group, n = 10). At 6 weeks, 5 PH animals underwent reperfusion of the left lung through conduit anastomosis to decrease RV afterload, whereas 5 other animals received no treatment. Five sham-operated piglets were used as controls. RV function was assessed using echocardiography and conductance catheterization. RV gene expression of beta-myosin heavy chain (β-MHC) and B-type natriuretic peptide (BNP) were quantified by polymerase chain reaction. Results: At 6 weeks, compared with controls, the PH group had higher mean PA pressure (32 ± 6 vs 14 ± 2 mm Hg, p < 0.01). The increase in RV elastance was insufficient to compensate for the increase in pulmonary arterial elastance in the PH group and altered ventricular–arterial coupling occurred (0.65 ± 0.16 vs 1.28 ± 0.14, p < 0.01). The degree of ventricular–arterial uncoupling was related to RV enlargement and systolic dysfunction. Ventricular–arterial uncoupling and increased RV mass index were associated with up-regulation of β-MHC and BNP expression. Conclusions: Ventricular–arterial coupling is closely associated with ventricular remodeling and systolic function as well as contractile and BNP gene expression. Dynamic changes in myosin expression may determine RV work efficiency in PH. [ABSTRACT FROM AUTHOR]

BACKGROUND Balloon pulmonary angioplasty (BPA) is a technique proposed for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). In this study we aimed to determine whether initiation of the BPA program has modified the characteristics and outcome of patients undergoing pulmonary endarterectomy (PEA), and compared the characteristics of patients undergoing one or the other procedure. METHODS This prospective registry study included all patients with CTEPH who underwent PEA in the French National Reference Center before (2012 to 2013) and after (2015 to 2016) BPA program initiation (February 2014). Pre-operative clinical and hemodynamics profiles, peri-operative (Jamieson classification, surgery duration, need of assistance) characteristics of both groups, and all-cause mortality were compared using the t -test or chi-square test. Characteristics of patients subjected to surgery or BPA since February 2014 were also compared. RESULTS The total number of patients referred to the CTEPH team increased in the BPA era ( n = 291 vs n = 484). The pre-operative characteristics of patients from the pre-BPA era ( n = 240) were similar to those from the BPA era ( n = 246). Despite more Jamieson Type 3 cases (29%) in the second period, 30- and 90-day mortality remained stable (both p > 0.30). Patients subjected to BPA ( n = 177) were older than those subjected to PEA ( n = 364) (64 ± 14 vs 60 ± 14 years, respe`ctively), and had higher rates of splenectomy (10% vs 1%) or implantable port (9% vs 3%), lower total pulmonary resistance, better cardiac index, and better renal function (all p < 0.01). CONCLUSIONS This study shows the influence of the initiation of the BPA program on the profile of patients with CTEPH undergoing PEA. [ABSTRACT FROM AUTHOR]