Céline Dewachter

Prolonged overcirculation-induced pulmonary arterial hypertension as a cause of right ventricular failure

AIMS Three-month chronic systemic-to-pulmonary shunting in growing piglets has been reported as an early pulmonary arterial hypertension (PAH) model with preserved right ventricular (RV) function. We sought to determine whether prolonged shunting might be associated with more severe PAH and RV failure. METHODS AND RESULTS Fourteen growing piglets were randomized to a sham operation or the anastomosis of the left innominate artery to the pulmonary arterial trunk. Six months later, the shunt was closed and the animals underwent haemodynamic evaluation followed by tissue sampling for pathobiological assessment. Prolonged shunting had resulted in increased mean pulmonary artery pressure (22 ± 2 versus 17 ± 1 mmHg) and pulmonary arteriolar medial thickness, while cardiac output was decreased. However, RV-arterial coupling was markedly deteriorated, with a ~50% decrease in the ratio of end-systolic to pulmonary arterial elastances (Ees/Ea). Lung tissue expressions of endothelin-1, angiopoietin-1, and bone morphogenetic protein receptor-2 were similarly altered compared with previously observed after 3-month shunting. At the RV tissue level, pro-apoptotic ratio of Bax-to-Bcl-2 expressions and caspase-3 activation were increased, along with an increase in cardiomyocyte size, while expressions in voltage-gated potassium channels (Kv1.5 and Kv2.1) and angiogenic factors (angiopoietin-2 and vascular endothelial growth factor) were decreased. Right ventricular expressions of pro-inflammatory cytokines [interleukin (IL)-1α, IL-1β, tumour necrosis factor-α (TNF-α)] and natriuretic peptide precursors (NPPA and NPPB) were increased. There was an inverse correlation between RV Ees/Ea and pro-apoptotic Bax/Bcl-2 ratios. CONCLUSIONS Prolonged left-to-right shunting in piglets does not further aggravate pulmonary vasculopathy, but is a cause of RV failure, which appears related to an activation of apoptosis and inflammation.

Early right ventriculo-arterial uncoupling in borderline pulmonary hypertension on experimental heart failure.

Pulmonary hypertension on heart failure (HF) limits exercise capacity and survival probably because of associated right ventricular (RV) failure. This study investigated the mechanisms of RV function adaptation to early pulmonary hypertension in experimental HF. Seven weeks of rapid ventricular pacing in six dogs induced a HF characterized by cardiomegaly and decreased left ventricular ejection fraction. Compared with eight control dogs, pulmonary hypertension was borderline, with a mean pulmonary artery pressure increased to only 23 ± 2 (means ± SE) mmHg. However, the pulmonary vascular impedance spectrum was globally shifted to higher pressures, with an increase in 0 Hz impedance (resistance) to 662 ± 69 vs. 455 ± 41 dynes·cm(-5)·m(2) in controls (P < 0.01) and in characteristic impedance to 183 ± 20 vs. 104 ± 7 dynes·cm(-5)·m(2) in controls (P < 0.01). There was no change in RV end-systolic elastance (Ees), but arterial elastance (Ea) was increased to 1.8 ± 0.3 vs. 0.9 ± 0.1 mmHg/ml in controls so that RV-arterial coupling defined by the Ees-to-Ea ratio (Ees/Ea) was decreased to 0.8 ± 0.1 vs. 1.5 ± 0.1 in controls (P < 0.01). Inhaled nitric oxide, 40 ppm or 5 μg·kg(-1)·min(-1) nitroprusside i.v., did not affect Ees/Ea. Fifty milligrams (i.v.) of milrinone increased Ees/Ea to 1.6 ± 0.2 by an isolated increase in Ees. We conclude that overpacing-induced HF is accompanied by a borderline pulmonary hypertension but profound RV-arterial uncoupling explained by the failure of RV systolic function to adapt combined effects of increased pulmonary arterial resistance and elastance.

New therapies for pulmonary arterial hypertension: an update on current bench to bedside translation

Importance of the field: Treatments of pulmonary arterial hypertension (PAH) that have so far proven efficacious are all based on the restoration of endothelium control of pulmonary vascular tone and structure, by administration of prostacyclins, endothelin receptor antagonists and phosphodiesterase-5 inhibitors. However, results remain unsatisfactory, with persistent high mortality, insufficient clinical improvement and no convincing report of any reversal of the disease process. Areas covered in this review: New antiproliferative approaches that aim to actively limit pulmonary vascular remodeling are being sought. Several such treatments have shown promise in experimental models and in preliminary clinical studies. Noteworthy among these are dichloroacetate, survivin antagonists, nuclear factor of activated T-cell inhibitors, PPAR-γ agonists, tyrosine kinase inhibitors, Rho-kinase inhibitors, statins, vasoactive intestinal peptide, soluble guanylate cyclase stimulators/activators, adrenomedullin, elastase inhibitors, serotonin reuptake inhibitors, anti-inflammatory agents, and bone marrow-derived progenitor cells. What the reader will gain: Update on various strategies targeting proliferative, inflammatory and regenerating processes currently under evaluation in patients with PAH. Take home message: In spite of favorable results in experimental models, none of these strategies has achieved the ultimate goal of curing PAH. Further developments will depend on progress made in our pathobiological understanding of the disease and carefully designed randomized, controlled trials.

Myocardial inflammation in experimental acute right ventricular failure: Effects of prostacyclin therapy.

BACKGROUND Acute transient pulmonary hypertension may induce a state of persistent right ventricular (RV) failure. We hypothesized that this could be related to an activation of inflammatory processes and reduced by prostacyclin therapy. METHODS Sixteen dogs were assigned to a 90-minute pulmonary artery banding (n = 8), or to a sham operation (n = 8). Hemodynamic variables were measured 30 minutes after banding release. This was repeated in 7 dogs with pulmonary artery banding-induced RV failure, followed by a 60-minute epoprostenol infusion. After euthanasia of the animals, myocardial tissue was sampled. RESULTS Persistent RV failure was associated with increased myocardial expression of interleukin (IL)-1β, IL-6, monocyte chemoattractant protein 1, pro-inflammatory IL-6/IL-10, and neutrophil and macrophage infiltration, whereas heme oxygenase 1 expression was decreased. These changes were observed in RV and to a lesser extent in the left ventricle (LV). In the RV only, expressions of prostacyclin synthase and anti-inflammatory IL-10 and IL-33 decreased and vascular cell adhesion molecule expression increased, whereas macrophage inflammatory protein-1α and intercellular adhesion molecule 1 expressions remained unchanged. After epoprostenol infusion, there was decreased expression of IL-1β, macrophage inflammatory protein-1α, and vascular cell adhesion molecule 1 and increased IL-10 expression in the RV and the LV, whereas monocyte chemoattractant protein-1 decreased in the RV only. Epoprostenol infusion resulted in decreased RV IL-6/IL-10 and pro-apoptotic Bax/Bcl-2, together with decreased RV neutrophil and RV and LV macrophage infiltration. The RV ratio of end systolic-to-pulmonary arterial elastances was inversely correlated to RV IL-6/IL-10, macrophage, and neutrophil infiltration, and to RV heme oxygenase-1 and IL-33 expression. CONCLUSIONS Acute afterload-induced persistent RV failure is associated with an activation of inflammatory processes, which are limited by epoprostenol.

Heme Oxygenase-1 and Inflammation in Experimental Right Ventricular Failure on Prolonged Overcirculation-Induced Pulmonary Hypertension

Heme oxygenase (HO)-1 is a stress response enzyme which presents with cardiovascular protective and anti-inflammatory properties. Six-month chronic overcirculation-induced pulmonary arterial hypertension (PAH) in piglets has been previously reported as a model of right ventricular (RV) failure related to the RV activation of apoptotic and inflammatory processes. We hypothesized that altered HO-1 signalling could be involved in both pulmonary vascular and RV changes. Fifteen growing piglets were assigned to a sham operation (n = 8) or to an anastomosis of the left innominate artery to the pulmonary arterial trunk (n = 7). Six months later, hemodynamics was evaluated after closure of the shunt. After euthanasia of the animals, pulmonary and myocardial tissue was sampled for pathobiological evaluation. Prolonged shunting was associated with a tendency to decreased pulmonary gene and protein expressions of HO-1, while pulmonary gene expressions of interleukin (IL)-33, IL-19, intercellular adhesion molecule (ICAM)-1 and -2 were increased. Pulmonary expressions of constitutive HO-2 and pro-inflammatory tumor necrosis factor (TNF)-α remained unchanged. Pulmonary vascular resistance (evaluated by pressure/flow plots) was inversely correlated to pulmonary HO-1 protein and IL-19 gene expressions, and correlated to pulmonary ICAM-1 gene expression. Pulmonary arteriolar medial thickness and PVR were inversely correlated to pulmonary IL-19 expression. RV expression of HO-1 was decreased, while RV gene expressions TNF-α and ICAM-2 were increased. There was a correlation between RV ratio of end-systolic to pulmonary arterial elastances and RV HO-1 expression. These results suggest that downregulation of HO-1 is associated to PAH and RV failure.

Sildenafil added to sitaxsentan in overcirculation-induced pulmonary arterial hypertension.

Experimental left-to-right shunt-induced pulmonary arterial hypertension (PAH) can be partially prevented by the endothelin-A receptor blocker sitaxsentan or by the phosphodiesterase-5 inhibitor sildenafil. We hypothesized that the combined administration of these drugs would completely prevent shunt-induced PAH, arguing in favor of a major role of endothelial dysfunction in the initiation of the disease. Twenty-four 3-wk-old piglets were randomized to a sham operation or to placebo, sitaxsentan therapy, or sitaxsentan combined with sildenafil after the anastomosis of the left subclavian artery to the pulmonary arterial trunk. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry and quantitative real-time PCR for endothelin-1, angiopoietin-1, and bone morphogenetic protein receptor (BMPR) signaling molecules. Three months of left-to-right shunting induced an increase in pulmonary vascular resistance (PVR) and medial thickness, an overexpression of endothelin-1, and angiopoietin-1 and decreased expressions of BMPR-2 and BMPR-1A. Sitaxsentan partially prevented a shunt-induced increase in PVR, medial thickness, and associated biological disturbances. Sildenafil combined with sitaxsentan normalized PVR, medial thickness, and the expression of endothelin-1. However, the expression of angiopoietin-1 remained increased, and the expressions of BMPR-1A and BMPR-2 were incompletely returned to normal. The coupling of right ventricular end-systolic to arterial elastances was maintained in all circumstances. Sitaxsentan combined with sildenafil prevents shunt-induced PAH more effectively than sitaxsentan alone, suggesting a major role for the targeted signaling pathways in the initiation of the disease. Sitaxsentan alone or combined with sildenafil did not affect right ventricular function.

Myocardial Structural and Biological Anomalies Induced by High Fat Diet in Psammomys obesus Gerbils.

Background Psammomys obesus gerbils are particularly prone to develop diabetes and obesity after brief period of abundant food intake. A hypercaloric high fat diet has been shown to affect cardiac function. Here, we sought to determine whether a short period of high fat feeding might alter myocardial structure and expression of calcium handling proteins in this particular strain of gerbils. Methods Twenty Psammomys obesus gerbils were randomly assigned to receive a normal plant diet (controls) or a high fat diet. At baseline and 16-week later, body weight, plasma biochemical parameters (including lipid and carbohydrate levels) were evaluated. Myocardial samples were collected for pathobiological evaluation. Results Sixteen-week high fat dieting resulted in body weight gain and hyperlipidemia, while levels of carbohydrates remained unchanged. At myocardial level, high fat diet induced structural disorganization, including cardiomyocyte hypertrophy, lipid accumulation, interstitial and perivascular fibrosis and increased number of infiltrating neutrophils. Myocardial expressions of pro-apoptotic Bax-to-Bcl-2 ratio, pro-inflammatory cytokines [interleukin (IL)-1β and tumor necrosis factor (TNF)-α], intercellular (ICAM1) and vascular adhesion molecules (VCAM1) increased, while gene encoding cardiac muscle protein, the alpha myosin heavy polypeptide (MYH6), was downregulated. Myocardial expressions of sarco(endo)plasmic calcium-ATPase (SERCA2) and voltage-dependent calcium channel (Cacna1c) decreased, while protein kinase A (PKA) and calcium-calmodulin-dependent protein kinase (CaMK2D) expressions increased. Myocardial expressions of ryanodine receptor, phospholamban and sodium/calcium exchanger (Slc8a1) did not change. Conclusions We conclude that a relative short period of high fat diet in Psammomys obesus results in severe alterations of cardiac structure, activation of inflammatory and apoptotic processes, and altered expression of calcium-cycling determinants.

Prevention of pulmonary hypoplasia and pulmonary vascular remodeling by antenatal simvastatin treatment in nitrofen-induced congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) has a high mortality rate mainly due to lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). Simvastatin has been shown to prevent the development of pulmonary hypertension (PH) in experimental models of PH. We, therefore, hypothesized that antenatal simvastatin would attenuate PPHN in nitrofen-induced CDH in rats. The efficacy of antenatal simvastatin was compared with antenatal sildenafil, which has already been shown to improve pathological features of PPHN in nitrofen-induced CDH. On embryonic day (E) 9.5, nitrofen or vehicle was administered to pregnant Sprague-Dawley rats. On E11, nitrofen-treated rats were randomly assigned to antenatal simvastatin (20 mg·kg(-1)·day(-1) orally), antenatal sildenafil (100 mg·kg(-1)·day(-1) orally), or placebo administration from E11 to E21. On E21, fetuses were delivered by cesarean section, killed, and checked for left-sided CDH. Lung tissue was then harvested for further pathobiological evaluation. In nitrofen-induced CDH, simvastatin failed to reduce the incidence of nitrofen-induced CDH in the offspring and to increase the body weight, but improved the lung-to-body weight ratio and lung parenchyma structure. Antenatal simvastatin restored the pulmonary vessel density and external diameter, and reduced the pulmonary arteriolar remodeling compared with nitrofen-induced CDH. This was associated with decreased lung expression of endothelin precursor, endothelin type A and B receptors, endothelial and inducible nitric oxide synthase, together with restored lung activation of apoptotic processes mainly in the epithelium. Antenatal simvastatin presented similar effects as antenatal therapy with sildenafil on nitrofen-induced CDH. Antenatal simvastatin improves pathological features of lung hypoplasia and PPHN in experimental nitrofen-induced CDH.

Haemodynamics to predict outcome in pulmonary hypertension due to left heart disease: a meta-analysis

Pulmonary hypertension (PH) is a common complication of left heart disease (LHD), as the result of a “passive” increase of left atrial pressure (LAP), leading to isolated post-capillary PH [1–3]. Several haemodynamic parameters have been proposed to identify a more severe phenotype of PH-LHD, for which the increase in pulmonary artery pressure cannot be accounted for by the increase in LAP, and described as combined post-capillary PH with a pre-capillary component, or CpcPH [1–3]. The latter haemodynamic phenotype may potentially expose patients to a higher risk of right ventricular failure and a poorer outcome [4, 5]. However, since the last World Symposium in 2013, how to define the pre-capillary component in PH-LHD has been a matter of debate, as pathophysiological arguments have been suggested to potentially contrast with clinical and prognostic evidences [1]. PVR, DPG, PAC are all associated with survival in pulmonary hypertension due to left heart disease http://ow.ly/R8sF30ieHSQ

Clinical phenotypes and outcomes of pulmonary hypertension due to left heart disease: Role of the pre-capillary component

Background In pulmonary hypertension (PH), both wedge pressure elevation (PAWP) and a precapillary component may affect right ventricular (RV) afterload. These changes may contribute to RV failure and prognosis. We aimed at describing the different haemodynamic phenotypes of patients with PH due to left heart disease (LHD) and at characterizing the impact of pulmonary haemodynamics on RV function and outcome PH-LHD. Methods Patients with PH-LHD were compared with treatment-naïve idiopathic/heritable pulmonary arterial hypertension (PAH, n = 35). PH-LHD patients were subdivided in Isolated post-capillary PH (IpcPH: diastolic pressure gradient, DPG<7 mmHg and pulmonary vascular resistance, PVR≤3 WU, n = 37), Combined post- and pre-capillary PH (CpcPH: DPG≥7 mmHg and PVR>3 WU, n = 27), and “intermediate” PH-LHD (either DPG <7 mmHg or PVR ≤3 WU, n = 29). Results Despite similar PAWP and cardiac index, haemodynamic severity and prevalence of RV dysfunction increased from IpcPH, to “intermediate” and CpcPH. PVR and DPG (but not compliance, Ca) were linearly correlated with RV dysfunction. CpcPH had worse prognosis (p<0.05) than IpcPH and PAH, but similar to “intermediate” patients. Only NTproBNP and Ca independently predicted survival in PH-LHD. Conclusions In PH-LHD, haemodynamic characterization according to DPG and PVR provides important information on disease severity, predisposition to RV failure and prognosis. Patients presenting the CpcPH phenotype appear to have haemodynamic profile closer to PAH but with worse prognosis. In PH-LHD, Ca and NTproBNP were independent predictors of survival.