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Cardiac Effects of Phosphodiesterase-5 Inhibitors: Efficacy and Safety.

ABSTRACT: The coexistence of cardiovascular disease and erectile dysfunction is widespread, possibly owing to underlying endothelial dysfunction in both diseases. Millions of patients with cardiovascular disease are prescribed phosphodiesterase-5 (PDE5) inhibitors for the management of erectile dysfunction. Although the role of PDE5 inhibitors in erectile dysfunction therapy is well established, their effects on the cardiovascular system are unclear. Preclinical studies investigating the effect of PDE5 inhibitors on ischemia-reperfusion injury, pressure overload-induced hypertrophy, and chemotoxicity suggested a possible clinical role for each of these medications; however, attempts to translate these findings to the bedside have resulted in mixed outcomes. In this review, we explore the biologic preclinical effects of PDE5 inhibitors in mediating cardioprotection. We then examine clinical trials investigating PDE5 inhibition in patients with heart failure, coronary artery disease, and ventricular arrhythmias and discuss why the studies likely have yet to show positive results and efficacy with PDE5 inhibition despite no safety concerns.

SUBMITTER: Roy S

PROVIDER: S-EPMC9010479 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Cardiac Effects of Phosphodiesterase-5 Inhibitors: Efficacy and Safety.

Roy Sumon S Kloner Robert A RA Salloum Fadi N FN Jovin Ion S IS

Cardiovascular drugs and therapy 20211015 4

The coexistence of cardiovascular disease and erectile dysfunction is widespread, possibly owing to underlying endothelial dysfunction in both diseases. Millions of patients with cardiovascular disease are prescribed phosphodiesterase-5 (PDE5) inhibitors for the management of erectile dysfunction. Although the role of PDE5 inhibitors in erectile dysfunction therapy is well established, their effects on the cardiovascular system are unclear. Preclinical studies investigating the effect of PDE5 in ...[more]

PMID: 34652581

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Project description:BackgroundChagasic cardiomyopathy (CCM) caused by Trypanosoma cruzi (Tc) infection is prevalent in Latin America and recognized as an emerging infectious heart disease in the US. The NO-cGMP-PKG1α pathway maintains cardiac homeostasis and inotropy and may be disturbed due to phosphodiesterase (PDE5) mediated cGMP catabolism in CCM.Methods and resultsC57BL/6 mice were infected with Tc, and at the end of acute parasitemia (i.e. 45 days post-infection), treated with sildenafil (SIL, 1 mg/kg) twice per week for 3 weeks. Mice were monitored at 150 days post-infection corresponding to chronic disease phase. The cGMP/PKG activity was decreased by 2-fold and PDE5 expression was increased by 1.4-fold and 100% at RNA and protein levels, respectively, in chagasic myocardium. Transthoracic echocardiography showed the left ventricular (LV) systolic function, i.e., stroke volume, cardiac output, and ejection fraction, were significantly decreased in chagasic mice. Sildenafil treatment resulted in normal levels of PDE5 and cGMP/PKG activity and preserved the LV function in chagasic mice. The cardioprotective effects of SIL were provided through inhibition of cardiac collagenosis and chronic inflammation that otherwise were pronounced in CCM. Further, mtDNA-encoded gene expression and ADP-coupled mitochondrial respiration were decreased and mitochondrial oxidative stress and cellular oxidative damage (lipid hydroperoxides and protein carbonyls) were increased in chagasic myocardium. SIL treatment restored the mtDNA-encoded gene expression and complex I (but not complex II) dependent ADP-coupled respiration, and established the oxidant/antioxidant balance in chagasic myocardium. In vitro studies in cardiomyocytes verified that SIL conserved the redox metabolic state and cellular health via maintaining the antioxidant status that otherwise was compromised in response to Tc infection.ConclusionSIL therapy was useful in controlling the LV dysfunction and chronic pathology in CCM.

Project description:Introduction: Fetal growth restriction (FGR) is associated with a higher risk of perinatal morbidity and mortality, as well as long-term health issues in newborns. Currently, there is no effective medicine for FGR. Phosphodiesterase-5 (PDE-5) inhibitors have been shown in pre-clinical studies to improve FGR. This study aimed to evaluate the latest evidence about the clinical outcomes and safety of PDE-5 inhibitors for the management of FGR. Methods: Eight databases (PubMed, Embase, Medline, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Database and WangFang Database) were searched for English and Chinese articles published from the database inception to December 2023. Randomized controlled trials (RCTs) reporting the use of PDE-5 inhibitors in FGR were included. The quality of the RCTs was assessed using the Cochrane Risk of Bias Tool. Odds ratio and mean difference (MD) (95% confidence intervals) were pooled for meta-analysis. Results: From 253 retrieved publications, 16 studies involving 1,492 pregnant women met the inclusion criteria. Only sildenafil (15 RCTs) and tadalafil (1 RCT) were studied for FGR. Compared with the control group (placebo, no treatment, or other medication therapies), sildenafil increased birth weight, pregnancy prolongation and umbilical artery pulsatility indices. However, it also increased the risk of pulmonary hypertension in newborns, as well as headache and flushing/rash in mothers. There were no significant differences in gestation age, perinatal mortality or major neonatal morbidity, stillbirth, neonate death, infants admitted to neonatal intensive care unit, intraventricular hemorrhage and necrotizing enterocolitis in infants, as well as pregnancy hypertension and gastrointestinal side effects in mothers between the treatment and the control groups. Discussion: Sildenafil was the most investigated PDE-5 inhibitors for FGR. Current evidence suggests that sildenafil can improve birth weight and duration of pregnancy but at the same time increase the risk of neonatal pulmonary hypertension. It remains uncertain whether the benefits of sildenafil in FGR outweigh the risks and further high-quality RCTs are warranted. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=325909.

Project description:BackgroundPulmonary arterial hypertension (PAH) is a fatal disease characterized by pulmonary vascular remodeling and increased pulmonary artery pressure, leading to impaired lung oxygenation, right heart failure, and even death. Although great advances have been made in PAH-targeted medications for pediatric patients, the efficacy and safety of these treatments are controversial.MethodsWe retrieved relevant articles from electronic databases including PubMed, EMBASE, Web of Science, and Cochrane Library until 12 April 2022. To compare the effectiveness and safety of endothelin receptor antagonists (ERAs), phosphodiesterase type 5 Inhibitors (PDE-5i), and prostaglandins (ProA) in the treatment of pediatric PAH, we investigated six hemodynamic parameters, four respiratory parameters, intensive care unit (ICU) stay duration, length of hospital stay, and two safety outcomes.ResultsA total of 27 randomized controlled trials (RCTs) were included in the meta-analysis with 1,574 pediatric participants. The duration of mechanical ventilation was shorter for patients using bosentan, sildenafil, and ProsA, compared with that for patients using the placebo. Bosentan helped to shorten more time for mechanical ventilation than ProsA did, while ProsA was more effective than sildenafil in this respect. As for the length of stay in the ICU, patients administered by ProsA or sildenafil needed shorter ICU stay, compared to those using the placebo, while ProsA was more effective for shortening ICU stay time. In light of safety outcomes, there was a statistically significant difference between the sildenafil and the placebo group. Sildenafil surpassed ProsA in reducing the incidence of pulmonary hypertension (PH) crisis.ConclusionsERAs were more effective than ProsA in shortening the duration of mechanical ventilation, while ProsA were better for shortening the duration of mechanical ventilation and ICU stay than PDE-5i. PDE-5i were found to generate more benefits in decreasing the occurrence of PH crisis, though further investigation is warranted.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=351505.

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Cardiac Effects of Phosphodiesterase-5 Inhibitors: Efficacy and Safety.

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Cardiac Effects of Phosphodiesterase-5 Inhibitors: Efficacy and Safety.

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