Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure

Triposkiadis, Filippos; Xanthopoulos, Andrew; Skoularigis, John; Starling, Randall C.

doi:10.1007/s10741-022-10239-5

Cited by 26 publications

(17 citation statements)

References 96 publications

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“…In particular, when PDE-5i are given pre-LVAD implant [ 37 ], they may cause selective pulmonary vasodilation, resulting in an increase in RV output. The increased RV output cannot be accommodated by the dilated LV (exhaustion of the preload reserve), leading to the further deterioration of LV function and causing RV dysfunction due to ventricular interdependence (shift of the interventricular septum towards the RV) [ 50 ]. When treatment with PDE-5i is initiated post-LVAD implant [ 11 , 12 ], the increase in RV output induced by these agents may improve the filling of the supported LV and optimize cardiac output.…”

Section: Discussionmentioning

confidence: 99%

“…When treatment with PDE-5i is initiated post-LVAD implant [ 11 , 12 ], the increase in RV output induced by these agents may improve the filling of the supported LV and optimize cardiac output. The optimized hemodynamics resulting from the post-implant use of PDE-5i, along with the other pleiotropic effects of these agents, including their antiplatelet and antithrombotic effects, contribute to the reported reduction in the risk of ischemic strokes and all-cause mortality in LVAD patients [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

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Post-Implant Phosphodiesterase-5 Inhibitors in Patients with Left Ventricular Assist Device: A Systematic Review and Meta-Analysis

Xanthopoulos

Magouliotis

Tryposkiadis³

et al. 2022

JCM

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Background: Despite the improvement in left ventricular assist device (LVAD) technology and the advent of third-generation LVADs, hemocompatibility-related events remain a significant issue. Therefore, new pharmacological treatments are necessary to optimize patient management and to further reduce hemocompatibility-related events. The purpose of the present systematic review and meta-analysis was to summarize the existing data regarding the safety and efficacy of post-implant phosphodiesterase-5 inhibitors (PDE-5i) on hemocompatibility-related events. Methods: Among the 258 articles in Pubmed, Scopus, and CENTRAL that were retrieved (1990–2022), 15 studies were included in the qualitative synthesis, and 9 studies were included in the quantitative synthesis. The fixed-effects model was used because it is statistically sound for combining a very small number of studies. The primary endpoint of the study was all-cause mortality, whereas the secondary endpoints were ischemic stroke, pump thrombosis, and gastrointestinal bleeding. Results: Mortality was significantly lower in the PDE-5i group vs. the control group (OR: 0.92 [95% CI: 0.85, 0.98]; p = 0.02). The secondary endpoints ischemic stroke (OR: 0.87 [95% CI: 0.78, 0.98]; p = 0.02) and pump thrombosis (OR: 0.90 [95% CI: 0.82, 0.99]; p = 0.04) were also lower in the PDE-5i group. The incidence of gastrointestinal bleeding was significantly higher in patients with LVAD receiving PDE-5i (OR: 1.26 [95% CI: 1.11, 1.44]; p < 0.01). In the overall analysis, the heterogeneity of outcomes was low, except for pump thrombosis. Conclusions: The use of PDE-5i post-implant was associated with lower mortality and thrombotic events but with a higher risk of gastrointestinal bleeding.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Post-Implant Phosphodiesterase-5 Inhibitors in Patients with Left Ventricular Assist Device: A Systematic Review and Meta-Analysis

Xanthopoulos

Magouliotis

Tryposkiadis³

et al. 2022

JCM

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“…cGMP is degraded by the phosphodiesterase (PDE) enzymes, with PDE5 being majorly expressed in the pulmonary vasculature. PDE5 inhibitors, namely sildenafil and tadalafil , exert their therapeutic effect via stimulating pulmonary vasodilation [ 32 ]. Riociguat is a sGC stimulator that acts independently of NO.…”

Section: Current Fda Approved Therapies For Pulmonary Arterial Hypert...mentioning

confidence: 99%

New Drugs and Therapies in Pulmonary Arterial Hypertension

Shah

Beckmann

Vorla

2023

IJMS

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Pulmonary arterial hypertension is a chronic, progressive disorder of the pulmonary vasculature with associated pulmonary and cardiac remodeling. PAH was a uniformly fatal disease until the late 1970s, but with the advent of targeted therapies, the life expectancy of patients with PAH has now considerably improved. Despite these advances, PAH inevitably remains a progressive disease with significant morbidity and mortality. Thus, there is still an unmet need for the development of new drugs and other interventional therapies for the treatment of PAH. One shortcoming of currently approved vasodilator therapies is that they do not target or reverse the underlying pathogenesis of the disease process itself. A large body of evidence has evolved in the past two decades clarifying the role of genetics, dysregulation of growth factors, inflammatory pathways, mitochondrial dysfunction, DNA damage, sex hormones, neurohormonal pathways, and iron deficiency in the pathogenesis of PAH. This review focuses on newer targets and drugs that modify these pathways as well as novel interventional therapies in PAH.

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“…The heme-free form of sGC is the target of sGC activators ( Dasgupta et al, 2015 ). In the pulmonary circulation, NO acts as an endogenous pulmonary vasodilator and that synthesized by the action of eNOS on L-arginine in pulmonary vascular endothelial cells and then diffuses to adjacent vascular smooth muscle cells (VSMCs) to activate sGC ( Triposkiadis et al, 2022 ). In VSMCs, MLCP, RhoA, RGS-2, IRAG, and BKCa are phosphorylated by PKG to promote vasodilation ( Klinger and Kadowitz, 2017 ; Sadek et al, 2020 ).…”

Section: Soluble Guanylate Cyclase Agonistsmentioning

confidence: 99%

Decoding signaling mechanisms: unraveling the targets of guanylate cyclase agonists in cardiovascular and digestive diseases

Yin,

Zheng,

Song

et al. 2023

Front. Pharmacol.

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Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure

Cited by 26 publications

References 96 publications

Post-Implant Phosphodiesterase-5 Inhibitors in Patients with Left Ventricular Assist Device: A Systematic Review and Meta-Analysis

Post-Implant Phosphodiesterase-5 Inhibitors in Patients with Left Ventricular Assist Device: A Systematic Review and Meta-Analysis

New Drugs and Therapies in Pulmonary Arterial Hypertension

Decoding signaling mechanisms: unraveling the targets of guanylate cyclase agonists in cardiovascular and digestive diseases

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