Drug trials in neonates and children with pulmonary hypertensive vascular disease pose unique but not insurmountable challenges. Childhood is defined by growth and development. Both may influence disease and outcomes of drug trials. The developing pulmonary vascular bed and airways may be subjected to maldevelopment, maladaptation, growth arrest, or dysregulation that influence the disease phenotype. Drug therapy is influenced by developmental changes in renal and hepatic blood flow, as well as in metabolic systems such as cytochrome P450. Drugs may affect children differently from adults, with different clearance, therapeutic levels and toxicities. Toxicity may not be manifested until the child reaches physical, endocrine and neurodevelopmental maturity. Adverse effects may be revealed in the next generation, should the development of ova or spermatozoa be affected. Consideration of safe, age-appropriate tablets and liquid formulations is an obvious but often neglected prerequisite to any pediatric drug trial. In designing a clinical trial, precise phenotyping and genotyping of disease is required to ensure appropriate and accurate inclusion and exclusion criteria. We need to explore physiologically based pharmacokinetic modeling and simulations together with statistical techniques to reduce sample size requirements. Clinical endpoints such as exercise capacity, using traditional classifications and testing cannot be applied routinely to children. Many lack the necessary neurodevelopmental skills and equipment may not be appropriate for use in children. Selection of endpoints appropriate to encompass the developmental spectrum from neonate to adolescent is particularly challenging. One possible solution is the development of composite outcome scores that include age and a developmentally specific functional classification, growth and development scores, exercise data, biomarkers and hemodynamics with repeated evaluation throughout the period of growth and development. In addition, although potentially costly, we recommend long-term continuation of blinded dose ranging after completion of the short-term, double-blind, placebo-controlled trial for side-effect surveillance, which should include neurodevelopmental and peripubertal monitoring. The search for robust evidence to guide safe therapy of children and neonates with pulmonary hypertensive vascular disease is a crucial and necessary goal.
Aims Heart failure with preserved ejection fraction (HFpEF) and pathological cardiac aging share a complex pathophysiology, including extracellular matrix remodelling (EMR). Protease-activated receptor 2 (PAR2) deficiency is associated with EMR. The roles of PAR1 and PAR2 have not been studied in HFpEF, age-dependent cardiac fibrosis, or diastolic dysfunction (DD). Methods and results Evaluation of endomyocardial biopsies from patients with HFpEF (n = 14) revealed that a reduced cardiac PAR2 expression was associated with aggravated DD and increased myocardial fibrosis (r = −0.7336, P = 0.0028). In line, 1-year-old PAR2-knockout (PAR2ko) mice suffered from DD with preserved systolic function, associated with an increased age-dependent α-smooth muscle actin expression, collagen deposition (1.7-fold increase, P = 0.0003), lysyl oxidase activity, collagen cross-linking (2.2-fold increase, P = 0.0008), endothelial activation, and inflammation. In the absence of PAR2, the receptor-regulating protein caveolin-1 was down-regulated, contributing to an augmented profibrotic PAR1 and transforming growth factor beta (TGF-β)-dependent signalling. This enhanced TGF-β/PAR1 signalling caused N-proteinase (ADAMTS3) and C-proteinase (BMP1)-related increased collagen I production from cardiac fibroblasts (CFs). PAR2 overexpression in PAR2ko CFs reversed these effects. The treatment with the PAR1 antagonist, vorapaxar, reduced cardiac fibrosis by 44% (P = 0.03) and reduced inflammation in a metabolic disease model (apolipoprotein E-ko mice). Patients with HFpEF with upstream PAR inhibition via FXa inhibitors (n = 40) also exhibited reduced circulating markers of fibrosis and DD compared with patients treated with vitamin K antagonists (n = 20). Conclusions Protease-activated receptor 2 is an important regulator of profibrotic PAR1 and TGF-β signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-β-axis might be a promising therapeutic approach to reduce HFpEF.
The cardiovascular consequences of neutral endopeptidase (NEP) inhibition with the NEP inhibitor ecadotril were evaluated by determining acute and long-term effects of the compound on hemodynamic, hormonal, renal, and structural parameters in hypertensive transgenic rats harboring a mouse renin gene (TGR (m(Ren2)27) and in normotensive controls (Sprague-Dawley rats, SDR). Acute administration of ecadotril (10 and 30 mg/kg, orally) produced a dose-dependent decrease in systolic blood pressure with a maximal effect of -23 mm Hg between 2 and 4 h after oral administration. The NEP activity in plasma was significantly inhibited and the plasma levels of atrial (ANP) and brain (BNP) natriuretic peptides and their second messenger, cyclic GMP, were distinctly raised after oral administration. In addition, ecadotril (10 and 30 mg/kg, orally) produced a dose-dependent increase in the urinary excretion of sodium and cyclic GMP. These effects were more pronounced in TGR (mRen2)27 than in the normotensive SDR without an activated natriuretic peptide system. In the long-term study, the systolic pressure in control TG (m(Ren2)27) rats increased from 213 +/- 5 to 255 +/- 7 mm Hg, whereas, in animals treated with ecadotril (30 mg/kg, orally twice daily), the blood pressure increased only from 213 +/- 5 to 227 +/- 6 mm Hg during the observation period of 13 weeks. The increases in heart weight and in kidney weight were also delayed. At the end of the study, cyclic GMP was elevated and ANP tended to be higher, whereas plasma renin activity had decreased. These data indicate a beneficial pharmacological profile of neutral endopeptidase inhibition that could prove useful in the treatment of cardiovascular diseases like hypertension.
The cardiovascular consequences of endothelin (ET) blockade with the ETA-receptor antagonist FR 139317 were evaluated by determining the long-term effects of the drug on hemodynamic, hormonal, renal and structural parameters in stroke-prone spontaneously hypertensive rats (SHR-SP). Young SHR-SP on a high-sodium diet develop malignant hypertension accompanied by renovascular and cerebrovascular lesions. In control SHR-SP the systolic blood pressure increased from 196 +/- 3 to 260 +/- 4 mm Hg, whereas in animals treated with FR 139317 (20 mg/kg intraperitoneally, twice daily) it increased only from 196 +/- 4 to 212 +/- 3 mm Hg during a treatment period of 6 weeks. There was also an increase in heart weight. At the end of the experiment the plasma levels of atrial natriuretic peptide and brain natriuretic peptide were significantly lower in the group treated with FR 139317 than in the controls. The endothelin plasma levels were significantly higher and the plasma renin activity was lower in the group treated with the endothelin receptor antagonist. These data indicate that endothelin is involved in the maintenance of high blood pressure and cardiac hypertrophy in malignant hypertension, as exemplified by SHR-SP.
Background: Atrial myopathy and atrial fibrillation (AF) accompany thrombo-inflammation. This facilitates disease progression and promotes major adverse cardiovascular events (MACEs). Thrombin receptor (protease-activated receptor 1, PAR1) signalling is central in mediating thrombo-inflammation. We hypothesised that PAR1 signalling links coagulation and inflammation through cytotoxic CD8+ T lymphocytes in patients presenting with first-diagnosed AF (FDAF). Methods: A total of 210 patients were studied. We included data and blood samples from patients presenting with FDAF (n = 160), cardiac tissue from patients with paroxysmal AF (n = 32) and 20 controls. Results: During early AF, a pro-inflammatory and cytotoxic subset of T lymphocytes (CD8+) circulated more frequently when compared to patients with chronic cardiovascular disease but without AF, accompanied by elevated plasma levels of CD8+ effector molecules, which corresponded to biomarkers of adverse cardiac remodelling and atrial dysfunction. Activation of tissue factor (TF) and PAR1 was associated with pro-inflammatory and cytotoxic effector functions. PAR1-related CD8+ cell activation was more frequent in FDAF patients that experienced a MACE. Conclusions: In patients with FDAF, the TF-factor Xa-factor IIa-axis contributes to thrombo-inflammation via PAR1 in CD8+ T cells. Intervening in this cascade might be a promising synergistic approach to reducing disease progression and the vascular complications of AF.
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