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Right ventricular (RV) function is a major determinant of the symptomatology and outcome in pulmonary hypertension. The normal RV is a thin-walled flow generator able to accommodate large changes in venous return but unable to maintain flow output in the presence of a brisk increase in pulmonary artery pressure. The RV chronically exposed to pulmonary hypertension undergoes hypertrophic changes and an increase in contractility, allowing for preserved flow output in response to peripheral demand. Failure of systolic function adaptation (homeometric adaptation, described by Anrep’s law of the heart) results in increased dimensions (heterometric adaptation; Starling’s law of the heart), with a negative effect on diastolic ventricular interactions, limitation of exercise capacity, and vascular congestion. Ventricular function is described by pressure-volume relationships. The gold standard of systolic function is maximum elastance (E max), or the maximal value of the ratio of pressure to volume. This value is not immediately sensitive to changes in loading conditions. The gold standard of afterload is arterial elastance (E a), defined by the ratio of pressure at E max to stroke volume. The optimal coupling of ventricular function to the arterial circulation occurs at an E max/E a ratio between 1.5 and 2. Patients with severe pulmonary hypertension present with an increased E max, a trend toward decreased E max/E a, and increased RV dimensions, along with progression of the pulmonary vascular disease, systemic factors, and left ventricular function. The molecular mechanisms of RV systolic failure are currently being investigated. It is important to refer biological findings to sound measurements of function. Surrogates for E max and E a are being developed through bedside imaging techniques.

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. 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. 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. 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.

Background Alterations in the renin–angiotensin system have been implicated in the pathophysiology of septic shock. In particular, angiotensin 1–7 (Ang-(1–7)), an anti-inflammatory heptapeptide, has been hypothesized to have beneficial effects. The aim of the present study was to test the effects of Ang-(1–7) infusion on the development and severity of septic shock. Methods This randomized, open-label, controlled study was performed in 14 anesthetized and mechanically ventilated sheep. Immediately after sepsis induction by bacterial peritonitis, animals received either Ang-(1–7) ( n  = 7) or placebo ( n  = 7) intravenously. Fluid resuscitation, antimicrobial therapy, and peritoneal lavage were initiated 4 h after sepsis induction. Norepinephrine administration was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg. Results There were no differences in baseline characteristics between groups. Septic shock was prevented in 6 of the 7 animals in the Ang-(1–7) group at the end of the 24-h period. Fluid balance and MAP were similar in the two groups; however, MAP was achieved with a mean norepinephrine dose of 0.4 μg/kg/min in the Ang-(1–7) group compared to 4.3 μg/kg/min in the control group. Heart rate and cardiac output index were lower in the Ang (1–7) than in the control group, as were plasma interleukin-6 levels, and creatinine levels. Platelet count and PaO 2 /FiO 2 ratio were higher in the Ang-(1–7) group. Mean arterial lactate at the end of the experiment was 1.6 mmol/L in the Ang-(1–7) group compared to 7.4 mmol/L in the control group. Conclusions In this experimental septic shock model, early Ang-(1–7) infusion prevented the development of septic shock, reduced norepinephrine requirements, limited interleukine-6 increase and prevented renal dysfunction.

Background Angiotensin II is one of the vasopressors available for use in septic shock. However, its effects on the septic myocardium remain unclear. The aim of the study was to compare the effects of angiotensin II and norepinephrine on cardiac function and myocardial oxygen consumption, inflammation and injury in experimental septic shock. Methods This randomized, open-label, controlled study was performed in 20 anesthetized and mechanically ventilated pigs. Septic shock was induced by fecal peritonitis in 16 animals, and four pigs served as shams. Resuscitation with fluids, antimicrobial therapy and abdominal drainage was initiated one hour after the onset of septic shock. Septic pigs were randomly allocated to receive one of the two drugs to maintain mean arterial pressure between 65 and 75 mmHg for 8 h. Results There were no differences in MAP, cardiac output, heart rate, fluid balance or tissue perfusion indices in the two treatment groups but myocardial oxygen consumption was greater in the norepinephrine-treated animals. Myocardial mRNA expression of interleukin-6, interleukin-6 receptor, interleukin-1 alpha, and interleukin-1 beta was higher in the norepinephrine than in the angiotensin II group. Conclusions In septic shock, angiotensin II administration is associated with a similar level of cardiovascular resuscitation and less myocardial oxygen consumption, and inflammation compared to norepinephrine.

Mutations affecting transforming growth factor-beta (TGF-β) superfamily receptors, activin receptor-like kinase (ALK)-1, and endoglin (ENG) occur in patients with pulmonary arterial hypertension (PAH). To determine whether the TGF-β/ALK1/ENG pathway was involved in PAH, we investigated pulmonary TGF-β, ALK1, ALK5, and ENG expressions in human lung tissue and cultured pulmonary-artery smooth-muscle-cells (PA-SMCs) and pulmonary endothelial cells (PECs) from 14 patients with idiopathic PAH (iPAH) and 15 controls. Seeing that ENG was highly expressed in PEC, we assessed the effects of TGF-β on Smad1/5/8 and Smad2/3 activation and on growth factor production by the cells. Finally, we studied the consequence of ENG deficiency on the chronic hypoxic-PH development by measuring right ventricular (RV) systolic pressure (RVSP), RV hypertrophy, and pulmonary arteriolar remodeling in ENG-deficient (Eng+/-) and wild-type (Eng+/+) mice. We also evaluated the pulmonary blood vessel density, macrophage infiltration, and cytokine expression in the lungs of the animals. Compared to controls, iPAH patients had higher serum and pulmonary TGF-β levels and increased ALK1 and ENG expressions in lung tissue, predominantly in PECs. Incubation of the cells with TGF-β led to Smad1/5/8 phosphorylation and to a production of FGF2, PDGFb and endothelin-inducing PA-SMC growth. Endoglin deficiency protected mice from hypoxic PH. As compared to wild-type, Eng+/- mice had a lower pulmonary vessel density, and no change in macrophage infiltration after exposure to chronic hypoxia despite the higher pulmonary expressions of interleukin-6 and monocyte chemoattractant protein-1. The TGF-β/ALK1/ENG signaling pathway plays a key role in iPAH and experimental hypoxic PH via a direct effect on PECs leading to production of growth factors and inflammatory cytokines involved in the pathogenesis of PAH.

Background In metabolic disorders, myocardial fatty infiltration is critically associated with lipotoxic cardiomyopathy. Methods Twenty Psammomys obesus gerbils were randomly assigned to normal plant or high fat diet. Sixteen weeks later, myocardium was sampled for pathobiological evaluation. Results A sixteen-week high fat diet resulted in myocardial structure disorganization, with collagen deposits, lipid accumulation, cardiomyocyte apoptosis and inflammatory cell infiltration. Myocardial expressions of glucose transporter GLUT1 and pyruvate dehydrogenase (PDH) inhibitor, PDH kinase (PDK)4 increased, while insulin-regulated GLUT4 expression remained unchanged. Myocardial expressions of molecules regulating fatty acid transport, CD36 and fatty acid binding protein (FABP)3, were increased, while expression of rate-controlling fatty acid β-oxidation, carnitine palmitoyl transferase (CPT)1B decreased. Myocardial expression of AMP-activated protein kinase (AMPK), decreased, while expression of peroxisome proliferator activated receptors (PPAR)-α and -γ did not change. Conclusion In high fat diet fed Psammomys obesus , an original experimental model of nutritionally induced metabolic syndrome mixing genetic predisposition and environment interactions, a short period of high fat feeding was sufficient to induce myocardial structural alterations, associated with altered myocardial metabolic gene expression in favor of lipid accumulation.

Abstract Pulmonary vascular remodeling is key to the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). We recently reported that fibroblast growth factor (FGF)2 is markedly overproduced by pulmonary endothelial cells (P-ECs) in IPAH and contributes significantly to smooth muscle hyperplasia and disease progression. Excessive FGF2 expression in malignancy exerts pathologic effects on tumor cells by paracrine and autocrine mechanisms.We hypothesized that FGF2 overproduction contributes in an autocrine manner to the abnormal phenotype of P-ECs, characteristic of IPAH. In distal pulmonary arteries (PAs) of patients with IPAH, we found increased numbers of proliferating ECs and decreased numbers of apoptotic ECs, accompanied with stronger immunoreactivity for the antiapoptotic molecules, B-cell lymphoma (BCL)2, and BCL extra long (BCL-xL) compared with PAs from control patients. These in situ observations were replicated in vitro, with cultured P-ECs from patients IPAH exhibiting increased proliferation and diminished sensitivity to apoptotic induction with marked increases in the antiapoptotic factors BCL2 and BCL-xL and levels of phosphorylated extracellular signal-regulated (ERK)1/2 compared with control P-ECs. IPAH P-ECs also exhibited increased FGF2 expression and an accentuated proliferative and survival response to conditioned P-EC media or exogenous FGF2 treatment. Decreasing FGF2 signaling by RNA interference normalized sensitivity to apoptosis and proliferative potential in the IPAH P-ECs. Our findings suggest that excessive autocrine release of endothelial-derived FGF2 in IPAH contributes to the acquisition and maintenance of an abnormal EC phenotype, enhancing proliferation through constitutive activation of ERK1/2 and decreasing apoptosis by increasing BCL2 and BCL-xL.

Background Inducible nitric oxide synthase (iNOS) is a key driver of aberrant angiogenesis in inflammatory conditions and cancer, making it an attractive therapeutic target. Nevertheless, its function can be affected by the complex immune responses and tumor microenvironment (TME). Hence, combinatorial treatment approaches that simultaneously target iNOS and immune-modulatory signaling are strongly recommended for cancer therapy. Moreover, the current iNOS inhibitors are limited by poor pharmacokinetics and a lack of selectivity. Results To address these challenges, we developed a glutathione (GSH)-responsive iNOS-inhibiting polymeric prodrug (GRIP) decorated with betamethasone succinate (NP BeS ). These dual-function nanoparticles (NP BeS ) remain stable under physiological conditions but selectively release their payload in response to elevated GSH levels, a hallmark of the TME. Only upon activation by GSH, NP BeS inhibits iNOS, as evidenced by suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. NP BeS also normalized vascular endothelial growth factor (VEGF)-mediated tube formation in HUVECs and 3T3-L1 fibroblast cell migration, and angiogenesis in the CAM assay, demonstrating its anti-angiogenic activity. Importantly, GRIP did not impair acetylcholine (ACh)-induced vasodilation in rat aorta, even at elevated concentrations, indicating preservation of eNOS function. Conclusions This is the first report of a GSH-responsive polymeric prodrug system that leverages intracellular GSH for both controlled release of anionic therapeutic agents and in situ synthesis of an iNOS antagonist. Through these two complementary pathways, the system enables targeted, sustained anti-angiogenic effects and promotes vascular normalization. This dual-function platform holds strong potential for the treatment of cancer-associated angiogenesis. Graphical Abstract

The mechanisms of brain death (BD)-induced lung injury remain incompletely understood, as uncertainties persist about time-course and relative importance of mechanical and humoral perturbations. Brain death was induced by slow intracranial blood infusion in anesthetized pigs after randomization to placebo (n = 11) or to methylprednisolone (n = 8) to inhibit the expression of pro-inflammatory mediators. Pulmonary artery pressure (PAP), wedged PAP (PAWP), pulmonary vascular resistance (PVR) and effective pulmonary capillary pressure (PCP) were measured 1 and 5 hours after Cushing reflex. Lung tissue was sampled to determine gene expressions of cytokines and oxidative stress molecules, and pathologically score lung injury. Intracranial hypertension caused a transient increase in blood pressure followed, after brain death was diagnosed, by persistent increases in PAP, PCP and the venous component of PVR, while PAWP did not change. Arterial PO2/fraction of inspired O2 (PaO2/FiO2) decreased. Brain death was associated with an accumulation of neutrophils and an increased apoptotic rate in lung tissue together with increased pro-inflammatory interleukin (IL)-6/IL-10 ratio and increased heme oxygenase(HO)-1 and hypoxia inducible factor(HIF)-1 alpha expression. Blood expressions of IL-6 and IL-1β were also increased. Methylprednisolone pre-treatment was associated with a blunting of increased PCP and PVR venous component, which returned to baseline 5 hours after BD, and partially corrected lung tissue biological perturbations. PaO2/FiO2 was inversely correlated to PCP and lung injury score. Brain death-induced lung injury may be best explained by an initial excessive increase in pulmonary capillary pressure with increased pulmonary venous resistance, and was associated with lung activation of inflammatory apoptotic processes which were partially prevented by methylprednisolone.

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.