atrial-natriuretic-factor and Familial-Primary-Pulmonary-Hypertension

Topics: Animals; Atrial Natriuretic Factor; Cytokine Receptor gp130; Disease Models, Animal; Familial Primary Pulmonary Hypertension; Fibrosis; Heart Failure; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Inflammasomes; Macrophage Activation; Macrophages; Monocrotaline; NLR Family, Pyrin Domain-Containing 3 Protein; Pulmonary Arterial Hypertension; Rats; Ventricular Dysfunction, Right

Although right ventricular (RV) function is an important determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), there is no treatment targeting directly the RV. We evaluate the efficacy of sacubitril/valsartan (LCZ 696) as add-on therapy to bosentan in rats with severe pulmonary hypertension (PH).. Combination therapy of LCZ 696 and bosentan has additive vascular protective effects against the pulmonary vascular remodelling and PH in two preclinical models of severe PH. Compared with monotherapy, co-treatment of LCZ 696 (30 or 68 mg/kg/day for 2 weeks, per os) and bosentan (100 mg/kg/day for 2 weeks, per os) started 7 days after monocrotaline (MCT) injection substantially reduces pulmonary pressures, vascular remodelling, and RV hypertrophy and fibrosis in rats. Consistent with these observations, co-treatment of rats with established PH induced by sugen/hypoxia (SuHx) with LCZ 696 (30 mg/kg/day for 3 weeks, per os) and bosentan (100 mg/kg/day for 3 weeks, per os) started 5 weeks after Sugen injection partially attenuate total pulmonary vascular resistance and cardiovascular structures. We also obtained evidence showing that LCZ 696 has anti-proliferative effect on cultured human pulmonary artery smooth muscle cells derived from patients with idiopathic PAH, an effect that is more pronounced in presence of bosentan. Finally, we found that the plasma levels of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) are higher in rats co-treated with LCZ 696 (30 mg/kg/day) and bosentan (100 mg/kg/day) than in MCT and SuHx rats treated with vehicle.. Dual therapy with LCZ 696 plus bosentan proved significantly superior beneficial effect to LCZ 696 or bosentan alone on vascular remodelling and severity of experimental PH.

Topics: Aminobutyrates; Angiotensin II Type 1 Receptor Blockers; Animals; Atrial Natriuretic Factor; Biphenyl Compounds; Bosentan; Cell Proliferation; Cells, Cultured; Cyclic GMP; Disease Models, Animal; Disease Progression; Drug Combinations; Drug Therapy, Combination; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Humans; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neprilysin; Protease Inhibitors; Pulmonary Arterial Hypertension; Pulmonary Artery; Rats, Wistar; Valsartan; Vascular Remodeling

The clinical significance of acute vasoreactivity testing (AVT) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. We analyzed changes in hemodynamics and oxygenation dynamics indices after AVT in patients with CTEPH using patients with pulmonary arterial hypertension (PAH) as controls.. We analyzed retrospectively the results of AVT in 80 patients with PAH and 175 patients with CTEPH registered in the research database of Beijing Chao-Yang Hospital between October 2005 and August 2014. Demographic variables, cardiopulmonary indicators, and laboratory findings were compared in these two subgroups. A long-term follow-up was conducted in patients with CTEPH. Between-group comparisons were performed using the independent-sample t-test or the rank sum test, within-group comparisons were conducted using the paired t-test or the Wilcoxon signed-rank test, and count data were analyzed using the Chi-squared test. Survival was estimated using the Kaplan-Meier method and log-rank test.. The rates of positive response to AVT were similar in the CTEPH (25/175, 14.3%) and PAH (9/80, 11.3%) groups (P > 0.05). Factors significantly associated a positive response to AVT in the CTEPH group were level of N-terminal pro-brain natriuretic peptide (≤1131.000 ng/L), mean pulmonary arterial pressure (mPAP, ≤44.500 mmHg), pulmonary vascular resistance (PVR, ≤846.500 dyn·s-1·m-5), cardiac output (CO, ≥3.475 L/min), and mixed venous oxygen partial pressure (PvO2, ≥35.150 mmHg). Inhalation of iloprost resulted in similar changes in mean blood pressure, mPAP, PVR, systemic vascular resistance, CO, arterial oxygen saturation (SaO2), mixed venous oxygen saturation, partial pressure of oxygen in arterial blood (PaO2), PvO2, and intrapulmonary shunt (Qs/Qt) in the PAH and CTEPH groups (all P > 0.05). The survival time in patients with CTEPH with a negative response to AVT was somewhat shorter than that in AVT-responders although the difference was not statistically significant (χ2 =3.613, P = 0.057). The survival time of patients with CTEPH who received calcium channel blockers (CCBs) was longer than that in the group with only basic treatment and not shorter than that of patients who receiving targeted drugs or underwent pulmonary endarterectomy (PEA) although there was no significant difference between the four different treatment regimens (χ2 =3.069, P = 0.381).. The rates of positive response to AVT were similar in the CTEPH and PAH groups, and iloprost inhalation induced similar changes in hemodynamics and oxygenation dynamics indices. A positive response to AVT in the CTEPH group was significantly correlated with milder disease and better survival. Patients with CTEPH who cannot undergo PEA or receive targeted therapy but have a positive response to AVT might benefit from CCB treatment.

Topics: Administration, Inhalation; Adult; Aged; Arterial Pressure; Atrial Natriuretic Factor; Calcium Channel Blockers; Endarterectomy; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Protein Precursors; Retrospective Studies; Software; Vasodilator Agents

Childhood-onset pulmonary arterial hypertension (PAH) is considered complex and multifactorial, with relatively poor estimates of the natural history of the disease. Strategies allowing earlier detection, establishment of disease aetiology together with more accurate and sensitive biomarkers could enable better estimates of prognosis and individualise therapeutic strategies. Evidence is accumulating that genetic defects play an important role in the pathogenesis of idiopathic and hereditary forms of PAH. Altogether nine genes have been reported so far to be associated with childhood onset PAH suggesting that comprehensive multigene diagnostics can be useful in the assessment. Identification of disease-causing mutations allows estimates of prognosis and forms the most effective way for risk stratification in the family. In addition to genetic determinants the analysis of blood biomarkers are increasingly used in clinical practice to evaluate disease severity and treatment responses. As in genetic diagnostics, a multiplex approach can be helpful, as a single biomarker for PAH is unlikely to meet all requirements. This consensus statement reviews the current evidence for the use of genetic diagnostics and use of blood biomarkers in the assessment of paediatric patients with PAH.

Topics: Activin Receptors, Type II; Adolescent; Antigens, CD; Atrial Natriuretic Factor; Biomarkers; Bone Morphogenetic Protein Receptors; C-Reactive Protein; Caveolin 1; Child; Consensus; Disease Management; Endoglin; Endothelial Cells; Endothelins; Familial Primary Pulmonary Hypertension; Galectin 3; Genetic Testing; Growth Differentiation Factor 15; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Potassium Channels, Tandem Pore Domain; Prognosis; Protein Serine-Threonine Kinases; Receptor, Notch3; Receptors, Cell Surface; Receptors, Notch; Smad8 Protein; Troponin T; Uric Acid

BIBF1000 is a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) and is a powerful inhibitor of fibrogenesis. BIBF1000 is very similar to BIBF1120 (nintedanib), a drug recently approved for the treatment of idiopathic pulmonary fibrosis (IPF). A safety concern pertaining to VEGFR, FGFR, and PDGFR inhibition is the possible interference with right ventricular (RV) responses to an increased afterload, which could adversely affect clinical outcome in patients with IPF who developed pulmonary hypertension. We tested the effect of BIBF1000 on the adaptation of the RV in rats subjected to mechanical pressure overload. BIBF1000 was administered for 35 days in pulmonary artery-banded (PAB) rats. RV adaptation was assessed by echocardiography, pressure volume loop analysis, histology, and determination of atrial natriuretic peptide (ANP) expression. BIBF1000 treatment resulted in growth attenuation but had no effects on RV function after PAB, given absence of changes in cardiac index, end-systolic elastance, connective tissue disposition, and capillary density. We conclude that, in this experimental model of increased afterload, combined VEGFR, FGFR, and PDGFR inhibition does not hamper RV adaptation to pressure overload.

Topics: Adaptation, Physiological; Animals; Atrial Natriuretic Factor; Blotting, Western; Disease Models, Animal; Echocardiography; Familial Primary Pulmonary Hypertension; Heart Ventricles; Indoles; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Pressure; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Ventricular Function, Right

Pulmonary arterial hypertension (PAH) is a rare, deadly condition. Although risk stratification is extremely important for assessment of prognosis and to guide therapy, there is lack of evidence concerning the role of novel biomarkers. In a pivotal study, we sought to comparatively investigate the predictive power of several new biomarkers in PAH.. Patients with prevalent PAH were enrolled in the study protocol, which included clinical, functional and echocardiographic assessment. Blood samples were collected at baseline for determination of NT-proBNP, CT-proET-1, MR-proANP, MR-proADM, copeptin and troponin I. Patients were clinically followed-up up to 12 months for first occurrence of hospital admission due to PAH-related clinical worsening, heart/lung transplantation or all-cause mortality.. Among the 28 included patients the pre-specified end-point occurred in 8 (29% event rate). There were higher baseline levels of CT-proET-1, copeptin, MR-proANP, NT-proBNP and troponin I in patients who reached the composite end-point. They also had larger right atria. In multivariate Cox regression, CT-proET-1 was the only biomarker associated with increased hazard of reaching the primary composite end-point (hazard ratio per tertile increase = 10.1; 95% CI 2.0 to 50.6).. CT-proET-1 provided prognostic information independent of other biomarkers. Importantly, we have provided the first evidence that CT-proET-1 may be superior to commonly used biomarkers.

Topics: Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Cohort Studies; Echocardiography; Endothelin-1; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Glycopeptides; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Prospective Studies; Regression Analysis; Risk Factors; Troponin I

Lung diffusion for carbon monoxide (DLCO) has been shown to associate with the risk of pulmonary arterial hypertension development and, most likely, with right ventricular (RV) myocardial dysfunction in sarcoidosis patients. Besides its known role as a marker of left ventricular dysfunction, experimental evidence suggests a role of NT-proAtrial Natriuretic Peptide (NT-proANP) also in modulating pulmonary circulation. We therefore investigated possible relationships between NT-proANP, lung diffusion impairment and RV dysfunction.. Thirty-two pulmonary sarcoidosis outpatients and eighteen volunteers underwent full clinical assessment, including full lung function tests and Doppler echocardiography integrated with tissue Doppler imaging (TDI) study. Resting circulating NT-proBNP and NT-proANP plasma levels were also determined.. NT-proANP and RV-myocardial performance index (RV-MPI) were significantly higher in those patients with the greatest DLCO impairment, whereas no differences were found for NT-proBNP values. At multivariable analysis, only DLCO (β: -0.496; standard error: 3.38; p=0.000) and RV-MPI (β: 0.373; standard error: 6.56; p=0.031) remained significantly associated with NT-proANP levels.. Our finding may support a key role of NT-proANP in the complex mechanisms underlying modulation of lung function. An early increase in pulmonary vascular resistance may stimulate NT-proANP increase, thus explaining its association with signs of early RV myocardial dysfunction. This hypothesis warrants further confirmation.

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Echocardiography, Doppler; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Multivariate Analysis; Protein Precursors; Respiratory Function Tests; Sarcoidosis; Vascular Resistance; Ventricular Dysfunction, Right

The information needed to diagnose pulmonary arterial hypertension (PAH) in dogs based on N-terminal pro B-type natriuretic peptide (NT-proBNP) and atrial natriuretic peptide (ANP) levels is unclear. In this study, serial changes in plasma NT-proBNP and ANP concentrations were evaluated in association with the development of chronic embolic pulmonary hypertension (CEPH). Six Beagle dogs underwent percutaneous pulmonary artery catheterization. CEPH was induced by the repeated injection of 300 μm microspheres into the pulmonary artery via the catheter. Measured peak systolic pulmonary arterial pressure (PAPs) was elevated up to 80 mm Hg at 90 days by repeated injection of microspheres. Echocardiographic examination showed significant increase in the main pulmonary artery enlargement, right ventricular dilation, transtricuspid late diastolic flow, and ventricular late diastolic myocardial velocity. Plasma concentrations of NT-proBNP and ANP were significantly increased by microsphere-induced severe CEPH, but not by mild CEPH. Measured PAPs correlated weakly with plasma NT-proBNP and ANP concentrations (r=0.63 and 0.69, respectively) and with several echocardiographic variables. Our results indicated that plasma ANP and NT-proBNP responded to severe PAH, but that they were not sensitive for mild PAH.

Topics: Animals; Atrial Natriuretic Factor; Disease Models, Animal; Dog Diseases; Dogs; Familial Primary Pulmonary Hypertension; Female; Hypertension, Pulmonary; Male; Microspheres; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Artery; Pulmonary Embolism; Ultrasonography