Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension.

Etiology is a third major cause--in addition to type of organ-involved (soft-tissue/heart) and tracer type--of scintigraphic variability in cardiac amyloidosis. This is a highly relevant consideration for future studies. We conclude that 99mTc-DPD scintigraphy is a useful step in the workup of the differential diagnosis of TTR versus AL etiology in patients with documented cardiac amyloidosis.

AimsThere is no cure for pulmonary arterial hypertension, but current approved treatment options include prostanoids, endothelin-receptor antagonists, and phosphodiesterase type-5 inhibitors. The effect on survival of these compounds has not been appropriately assessed in individual trials because of small sample size and short duration. We performed a meta-analysis of all randomized controlled trials with drugs published in this condition.Methods and resultsTrials were searched in the Medline database from January 1990 to October 2008. The primary analysis included only studies with a placebo comparator arm, the sensitivity analysis also included studies comparing two active treatment arms. The main outcome measure was all-cause mortality. Twenty-one trials were included in the primary analysis (3140 patients) and two additional studies (59 patients) were included in the sensitivity analysis. Average duration of the trials was 14.3 weeks. All-cause mortality rate in the control group was 3.8%. Active treatments were associated with a reduction in mortality of 43% (RR 0.57; 95% CI 0.35–0.92; P = 0.023); the sensitivity analysis confirmed a reduction in mortality of 38% (RR 0.62; 95% CI 0.39–1.00; P = 0.048).ConclusionThe results of this meta-analysis suggest an improvement of survival in the patients treated with the targeted therapies approved for pulmonary arterial hypertension.

Endothelin-1 (ET-1), a peptide produced primarily by vascular endothelial cells, was discovered in 1980 and it was characterized as a powerful vasoconstrictor and mitogen for smooth muscle. ET-1 binds to two types of receptors, ETA and ETB: ETA-receptors are found in smooth muscle cells, whereas ETB-receptors are localized on both endothelial cells and in smooth muscle cells. Activation of ETA- and ETB-receptors on smooth muscle cells mediates the vasoconstrictive and mitogenic effects of ET-1. Stimulation of endothelial ETB-receptors promotes ET-1 clearance and activation of NO and prostacyclin release. Pulmonary arterial hypertension (PAH) is a severe condition characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. An activation of the ET-1 system has been demonstrated in both plasma and lung tissues of PAH patients as well as in animal models of PAH. The most efficient way to antagonize the ET-1 system is the use of ET-1 receptor antagonists that can block either ETA- or ETA- and ETB-receptors. These drugs are effective in animal models of PAH and have been tested in multiple clinical trials in patients with PAH. Bosentan, an orally active, dual ET-1 receptor antagonist has been shown to improve symptoms, exercise capacity, hemodynamics, echocardiographic parameters and the outcome of patients with severe PAH, and it has been approved for clinical use in many countries. The selective ETA-receptor antagonist sitaxentan has improved exercise capacity and hemodynamics of PAH patients in two preliminary studies. The main side effect of ET-1 antagonists is the increase of liver enzymes likely due to an accumulation of bile salts cytotoxic to hepatocytes. Additional trials with these drugs are currently ongoing. In conclusion, the hypothesis that the ET-1 system over-activation can be successfully antagonised in patients with PAH has been clearly demonstrated.