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A complex strategy remains an optional treatment for patients with coronary bifurcation lesions without severe safety concerns. A complex strategy may be an optimal treatment for true bifurcation lesions with large side branches.

BackgroundPulmonary arterial hypertension (PAH) is a devastating disease and ultimately leads to right heart failure and premature death. A total of four classical targeted drugs, prostanoids, endothelin receptor antagonists (ERAs), phosphodiesterase 5 inhibitors (PDE-5Is), and soluble guanylate cyclase stimulator (sGCS), have been proved to improve exercise capacity and hemodynamics compared to placebo; however, direct head-to-head comparisons of these drugs are lacking. This network meta-analysis was conducted to comprehensively compare the efficacy of these targeted drugs for PAH.MethodsMedline, the Cochrane Library, and other Internet sources were searched for randomized clinical trials exploring the efficacy of targeted drugs for patients with PAH. The primary effective end point of this network meta-analysis was a 6-minute walk distance (6MWD).ResultsThirty-two eligible trials including 6,758 patients were identified. There was a statistically significant improvement in 6MWD, mean pulmonary arterial pressure, pulmonary vascular resistance, and clinical worsening events associated with each of the four targeted drugs compared with placebo. Combination therapy improved 6MWD by 20.94 m (95% confidence interval [CI]: 6.94, 34.94; P=0.003) vs prostanoids, and 16.94 m (95% CI: 4.41, 29.47; P=0.008) vs ERAs. PDE-5Is improved 6MWD by 17.28 m (95% CI: 1.91, 32.65; P=0.028) vs prostanoids, with a similar result with combination therapy. In addition, combination therapy reduced mean pulmonary artery pressure by 3.97 mmHg (95% CI: −6.06, −1.88; P<0.001) vs prostanoids, 8.24 mmHg (95% CI: −10.71, −5.76; P<0.001) vs ERAs, 3.38 mmHg (95% CI: −6.30, −0.47; P=0.023) vs PDE-5Is, and 3.94 mmHg (95% CI: −6.99, −0.88; P=0.012) vs sGCS. There were no significant differences in all-cause mortality and severe adverse events between prostanoids, ERAs, PDE-5Is, sGCS, combination therapy, and placebo.ConclusionAll targeted drugs for PAH are associated with improved clinical outcomes, especially combination therapy. However, all these drugs seem to show less favorable effects on survival in the short-term follow-up, suggesting further clinical trials are required.

Background. Studies indicate the dramatic reduction of shear stress (SS) within the rapamycin eluting stent (RES) segment of coronary arteries. It remains unclear about the role of rapamycin in endothelialization of stented arteries where SS becomes low. Since mTOR (mammalian target of rapamycin) pathway is involved in the antioxidative sestrins expression, we hypothesized that rapamycin attenuated low SS (LSS) induced endothelial dysfunction through mTOR and sestrin1 associated redox regulation. Methods and Results. To mimic the effect of LSS on the stented arteries, a parallel plate flow chamber was used to observe the interplay of LSS and rapamycin on endothelial cells (ECs). The results showed LSS significantly induced EC apoptosis which was mitigated by pretreatment of rapamycin. Rapamycin attenuated LSS induced reactive oxygen species (ROS) and reactive nitrogen species (RNS) production via prohibition of sestrin1 downregulation. Activities of mTORC1 and mTORC2 were detected contradictorily modulated by LSS. Inhibition of rictor expression by target small interfering RNA (siRNA) transfection prohibited sestrin1 downregulation induced by LSS, but inhibition of raptor did not. Conclusions. Rapamycin may prohibit sestrin1 downregulation through targeting mTORC2 in appeasing LSS induced EC oxidative apoptosis. Our results provide the in vitro evidence to explain the pathophysiology of RES stented arteries.

Fluid shear stress has been revealed to differentially regulate endothelial nitric oxide synthase (eNOS) distribution in vessels. eNOS, a key enzyme in controlling nitric oxide (NO) release, has a crucial role in mediating oxidative stress, and resveratrol (RSV)‑mediated eNOS also attenuates oxidative damage and suppresses endothelial dysfunction. To observe the protective effect of RSV on low shear stress (LSS)‑induced oxidative damage and the potential mechanisms involved, a parallel‑plate flow chamber, which imposed a low level of stress of 2 dynes/cm2 to cells, was employed. Reactive oxygen species (ROS), NO and apoptotic cells were examined in LSS‑treated endothelial cells (ECs) with or without RSV. Western blot analysis was used to examine LSS‑regulated eNOS‑Ser1177, Thr495 and Ser633, which were tightly associated with NO release. To further determine the underlying signaling pathways involved, extracellular signal‑regulated kinase (ERK), a possible upstream target of eNOS‑Thr495, was investigated, followed by examination of eNOS‑Thr495 in ERK‑inhibited cells. Additionally, eNOS mRNA expression levels were analyzed in cells challenged with LSS. The results revealed that RSV markedly decreased LSS‑induced oxidative damage in ECs. Furthermore, eNOS‑Ser1177 and Thr495 as well as phospho‑ERK were time‑dependently activated by LSS. The ERK inhibitor deactivated eNOS‑Thr495, which was accompanied by increased intracellular superoxide dismutase (SOD) levels. Of note, the activation effect of LSS on ERK/eNOS was markedly eliminated by RSV. In conclusion, RSV exerts antioxidant effects by suppressing LSS-activated ERK/eNOS and may provide a potential therapeutic target for atherosclerosis.