Respiratory tract infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first occurred in Wuhan, China, in December 2019 and was declared as a pandemic by WHO. The interaction between the 2019 coronavirus disease (COVID-19) and pulmonary hypertension (PH) in children is not widely known. Phosphodiesterase-5 inhibitors (PDEI), one class of drugs used to treat PH, including sildenafil, can suppress angiotensin type I (AT-1) receptor expression. Furthermore, it reduces proinflammatory cytokines and infiltrates the alveolar, inhibits endothelial and smooth muscle transition, mesenchymal cells in the pulmonary artery, and prevents clotting and thrombosis complications. Sildenafil has shown positive effects by diverting the blood flow to the lungs in such a way that ventilation is adequate and can also be anti-inflammatory.

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.

OBJECTIVE: To retrospectively evaluate the incidence rate (IR) of elevated echocardiographic estimated systolic pulmonary artery pressure (sPAP), suspected for pulmonary hypertension (PH), in systemic sclerosis (SSc) patients after the introduction of a combination therapy with bosentan and sildenafil for treatment or prevention of digital ulcers.
METHODS: Patients attending the Scleroderma Unit of the Universital Hospital of Careggi from July 2010 to July 2023 were enrolled. Patients older than 18 years old with a history of digital ulcers, treated with bosentan and sildenafil in combination for at least 12 months, were included. Patients with a diagnosis of PH preceding the introduction of the therapy were excluded. Demographical data, disease duration, laboratoristic, and instrumental data (pulmonary function tests, echocardiographic estimation of sPAP, and ultrasonographic value of renal resistive index) were collected. The IR of echocardiographic signs suspected of pulmonary hypertension and their 95% confidence interval were calculated in events/1000 patients-years.
RESULTS: Thirty-five patients were enrolled; the mean disease duration was 12.82 years (SD 5.92). The mean duration of the combination treatment was 81.03 (SD 43.1.3) months, and the total at-risk time was 2674 months. Two patients (5.7%) presented echocardiographic signs of PH (sPAP 50 mmHg and 40 mmHg); the IR was calculated to be 9/1000 patients-years (95% CI 7.95-10.12). In one of the two patients, right heart catheterism (RHC) excluded PAH, while the other patient refused to undergo RHC, and PAH could not be confirmed/excluded. The stability of PFTs and echocardiographic sPAP was observed during the observation time.
CONCLUSIONS: The results of this retrospective study suggest that combination therapy with endothelin receptor antagonists and phosphodiesterase-5 (PDE5) inhibitors could help in preventing PAH in SSc; prospective case-control studies on a larger population are needed to improve knowledge in this field.

The treatment with phosphodiesterase-5 (PDE-5) inhibitors was postulated in heart failure (HF). We conducted a systematic review and a meta-analysis on their beneficial and adverse effects in patients with HF.
A meta-analysis of randomized trials evaluating the chronic use of PDE-5 inhibitors in patients with HF was conducted. Endpoints included death, HF hospitalizations, functional capacity, pulmonary pressures, quality of life, and adverse effects. Random-effects models were used to pool outcomes. Categorical data were summarized with relative risks (RR) and 95% confidence intervals (95%CI), and continuous data with weighted mean differences and standardized mean differences.
Sixteen studies (1119 participants) were included. No effect was observed on mortality (RR: 1.16; 95%CI: 0.50-2.66; I2: 0.0%) or HF hospitalizations (RR: 0.75; 95%CI: 0.41-1.37; I2: 38.7%). Treatment significantly reduced pulmonary systolic pressure (-10.64 mmHg; 95%CI: -5.14 to -16.15 mmHg; I2: 96.0%), and increased peak oxygen consumption (2.06 ml/kg/min; 95%CI: 0.40-3.72; I2: 89.6%), although with high inconsistency. There were no significant effects on quality of life (-0.15; 95%CI: -0.48-0.18; I2: 0.0%). On the other hand, the risk of headaches was increased (RR: 1.63; 95%CI: 1.11-2.39; I2: 0.0%). Publication bias was identified for HF hospitalizations.
Current data suggest that PDE-5 inhibitors therapy does not improve prognosis or quality of life among HF patients. Hemodynamic and functional effects could be relevant, and more studies are necessary to define its role.
El tratamiento con inhibidores de la fosfodiesterasa 5 (iFDE-5) fue postulado en la insuficiencia cardiaca (IC). Se realizó una revisión sistemática y metaanálisis sobre sus efectos beneficiosos y adversos en pacientes con IC.
Metaanálisis de ensayos clínicos aleatorizados que evaluaron el uso crónico de iFDE-5 en pacientes con IC. Los criterios de valoración finales incluyeron la muerte, las hospitalizaciones por IC, la capacidad funcional, las presiones y las resistencias pulmonares, la calidad de vida y los efectos adversos. Se utilizaron modelos de efectos aleatorios para agrupar los resultados. Los datos categóricos fueron resumidos como riesgos relativos (RR) e intervalos de confianza del 95% (IC95%), y los datos continuos como diferencias de medias ponderadas y diferencias de medias estandarizadas.
Se incluyeron 16 estudios (1119 participantes). No se observaron efectos sobre la mortalidad (RR: 1,16; IC95%: 0.50-2.66; I2: 0.0%) ni sobre las hospitalizaciones por IC (RR: 0,75; IC95%: 0.41-1.37; I2: 38.7%). El tratamiento redujo significativamente la presión sistólica pulmonar (−10,64 mmHg; IC95%: −5.14 a −16.15 mmHg; I2: 96.0%) e incrementó el consumo máximo de oxígeno (2.06 ml/kg/min; IC95%: 0.40-3.72 ml/kg/min; I2: 89.6%), aunque con elevada inconsistencia. No se detectaron efectos significativos sobre la calidad de vida (−0.15; IC95%: −0.48-0.18; I2: 0.0%). Por otra parte, aumentó el riesgo de cefaleas (RR: 1.63; IC95%: 1.11-2.39; I2: 0.0%). Se identificó un sesgo de publicación para las hospitalizaciones por IC.
Los datos actuales sugieren que el tratamiento con iFDE-5 no mejora el pronóstico ni la calidad de vida de los pacientes con IC. Los efectos hemodinámicos y funcionales podrían ser relevantes, y son necesarios más estudios para definir su rol.

Postbariatric altered gastrointestinal (GI) anatomy/physiology may significantly harm oral drug absorption and overall bioavailability. In this work, sildenafil, the first phosphodiesterase-5 (PDE5) inhibitor, was investigated for impaired postbariatric solubility/dissolution and absorption; this research question is of particular relevance since erectile dysfunction (ED) is associated with higher body mass index (BMI). Sildenafil solubility was determined both in vitro and ex vivo, using pre- vs. postsurgery gastric contents aspirated from patients. Dissolution tests were done in conditions mimicking the stomach before surgery, after sleeve gastrectomy (post-SG, pH 5), and after one anastomosis gastric bypass (post-OAGB, pH 7). Finally, these data were included in physiologically based pharmacokinetic (PBPK) modelling (GastroPlus®) to simulate sildenafil PK before vs. after surgery. pH-dependent solubility was demonstrated with low solubility (0.3 mg/mL) at pH 7 vs. high solubility at pH 1-5, which was also confirmed ex vivo with much lower solubility values in postbariatric gastric samples. Hampered dissolution of all sildenafil doses was obtained under post-OAGB conditions compared with complete (100%) dissolution under both presurgery and post-SG conditions. PBPK simulations revealed delayed sildenafil absorption in postbariatric patients (increased tmax) and reduced Cmax, especially in post-OAGB patients, relative to a presurgery state. Hence, the effect of bariatric surgery on sildenafil PK is unpredictable and may depend on the specific bariatric procedure. This mechanistically based analysis suggests a potentially undesirable delayed onset of action of sildenafil following gastric bypass surgery.

Introduction: Management of acute myocardial infarction (MI) mandates careful optimization of volemia, which can be challenging due to the inherent risk of congestion. Increased myocardial compliance in response to stretching, known as stretch-induced compliance (SIC), has been recently characterized and partly ascribed to cGMP/cGMP-dependent protein kinase (PKG)-related pathways. We hypothesized that SIC would be impaired in MI but restored by activation of PKG, thereby enabling a better response to volume loading in MI. Methods: We conducted experiments in ex vivo rabbit right ventricular papillary muscles under ischemic and non-ischemic conditions as well as pressure-volume hemodynamic evaluations in experimental in vivo MI induced by left anterior descending artery ligation in rats. Results: Acutely stretching muscles ex vivo yielded increased compliance over the next 15 min, but not under ischemic conditions. PKG agonists, but not PKC agonists, were able to partially restore SIC in ischemic muscles. A similar effect was observed with phosphodiesterase-5 inhibitor (PDE5i) sildenafil, which was amplified by joint B-type natriuretic peptide or nitric oxide donor administration. In vivo translation revealed that volume loading after MI only increased cardiac output in rats infused with PDE5i. Contrarily to vehicle, sildenafil-treated rats showed a clear increase in myocardial compliance upon volume loading. Discussion: Our results suggest that ischemia impairs the adaptive myocardial response to acute stretching and that this may be partly prevented by pharmacological manipulation of the cGMP/PKG pathway, namely, with PDE5i. Further studies are warranted to further elucidate the potential of this intervention in the clinical setting of acute myocardial ischemia.

BACKGROUND: Achieving and maintaining a low-risk profile is associated with favorable outcome in pulmonary arterial hypertension (PAH). The effects of treatment on risk profile are variable among patients.
OBJECTIVE: To Identify variables that might predict the response to treatment with phosphodiesterase-5 inhibitors (PDE-5i) in PAH.
METHODS: We carried out a cohort analysis of the Spanish PAH registry in 830 patients diagnosed with PAH that started PDE5i treatment and had > 1 year follow-up. 644 patients started PDE-5i either in mono- or add-on therapy and 186 started combined treatment with PDE-5i and endothelin receptor antagonist (ERA). Responders were considered when at 1 year they: (1) were alive; (2) did not present clinical worsening; and (3) improved European Society of Cardiology/European Respiratory Society (ESC/ERS) risk score or remained in low-risk. Univariate and multivariate logistic regression models were used to analyze variables associated with a favorable response.
RESULTS: Two hundred and ten patients (33%) starting PDE-5i alone were classified as responders, irrespective of whether it was mono- or add-on therapy. In addition to known predictors of PAH outcome (low-risk at baseline, younger age), male sex and diagnosis of portopulmonary hypertension (PoPH) or HIV-PAH were independent predictors of favorable response to PDE-5i. Diffusing capacity for carbon monoxide (DLco) ≤ 40% of predicted was associated with an unfavorable response. When PDE-5i were used in upfront combination, 58% of patients were responders. In this group, diagnosis of idiopathic PAH (IPAH) was an independent predictor of favorable response, whereas connective tissue disease-PAH was associated with an unfavorable response.
CONCLUSIONS: Male sex and diagnosis of PoPH or HIV-PAH are predictors of favorable effect of PDE-5i on risk profile when used as mono- or add-on therapy. Patients with IPAH respond more favorably to PDE-5i when used in upfront combination. These results identify patient profiles that may respond favorably to PDE-5i in monotherapy and those who might benefit from alternative treatment strategies.

UNASSIGNED: Multiple domains of quality of life (QoL) such as erectile function are not sufficiently investigated among left ventricular assist-device (LVAD) patients. We aimed to evaluate the prevalence of erectile dysfunction (ED) and its association with QoL and depression.
UNASSIGNED: This is a prospective, single-center, cross-sectional study. We included adult male LVAD patients who were clinically stable after at least 3 months post-implantation. Erectile function was assessed with the International Index of Erectile Function (IIEF-5) questionnaire with a score of ≤21 being confirmatory for ED. QoL and depression were estimated with the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Patient Health Questionnaire depression scale (PHQ-8), respectively.
UNASSIGNED: The study included 56 patients, of whom 45 (80 %) met criteria for ED, a prevalence much higher than previously reported in patients with established cardiovascular disease or conservatively treated heart failure. Patients with ED were older and had lower 6-minute walking distance. ED was not associated with comorbidities and heart failure medications but with less frequent use of diuretics and phosphodiesterase-5 inhibitors. There was a correlation between erectile function and depression as well as QoL.
UNASSIGNED: These findings underscore that ED deserves special attention and should be included in a multi-targeted approach to address suboptimal QoL outcomes after LVAD implantation.

UNASSIGNED: Three selective and most used inhibitors of PDE-5-sildenafil, vardenafil and tadalafil- have been successfully used for the treatment of erectile dysfunction. Erectile dysfunction and cardiovascular diseases might be considered as two dissimilar clinical signs of the identical systemic disease. PDE-5 inhibitors can through different models and mechanisms induce vasodilation, decrease apoptosis and cell proliferation, and they are widely present in various tissues that make them promising targets in a range of cardiovascular diseases.
UNASSIGNED: PubMed was explored to identify papers published from 1990-2019, presenting data for the most used PDE-5 inhibitors (sildenafil, tadalafil or vardenafil) in treatment of cardiovascular diseases.
UNASSIGNED: This article analyses the therapeutic potentials of PDE-5 inhibitors in cardiovascular diseases and discusses mechanisms, possible risks and limitations. Comparable to earlier studies, newer studies suggest cardioprotective effects of PDE-5 inhibitors, which include different models and mechanisms and do not indicate an increased rate of significant cardiovascular adverse reactions. Dissimilarity in the pharmacokinetics and pharmacodynamics of PDE-5 inhibitors are significant to their risk- benefit profile and clinical use. Some of the studies suggesting infarct size reduction after PDE-5 inhibition described the especially close dose-effect relation, other studies dosage adaptation in drug- drug interactions.
UNASSIGNED: PDE-5 inhibitors indicate the encouraging useful effects by ischemia/reperfusion injury, myocar-dial infarction, cardiac hypertrophy, cardiomyopathy and systolic and diastolic congestive heart failure. Therefore, this and similar reviews can help for additional clinical targeting in the therapy of cardiovascular diseases.

UNASSIGNED: Phosphodiesterase-5 inhibitors exert positive vascular and metabolic effects in type 2 diabetes (T2D), but the effect on insulin resistance in T2D is unclear.
UNASSIGNED: This randomised, double blind, placebo-controlled, two-period crossover trial was conducted at Sahlgrenska University Hospital (Gothenburg, Sweden). Men without apparent erectile dysfunction (age 40-70 years) and women (age 55-70 years, post-menopause) diagnosed with T2D between 3 months and 10 years, haemoglobin A1c (HbA1c) < 60 mmol/mol and a body mass index (BMI) 27-40 kg/m2 were enrolled. Participants were randomly assigned to one period of oral tadalafil 20 mg once a day and one period of placebo for 6 weeks, separated by an 8-week wash-out period. Placebo and tadalafil tablets were made visually indistinguishable and delivered randomized in two separate boxes for each participant. Both treatment periods ended with a glucose clamp, and measurements of body composition and metabolic markers in blood, subcutaneous and muscular interstitial fluid. The primary aim was to assess difference in whole-body insulin resistance after 6-weeks of treatment, determined after completion of the two study arms, and secondary aims were to study effects of tadalafil on pathophysiology of T2D as well as tolerability of high-dose tadalafil in T2D. Primary analysis was performed in participants with full analysis set (FAS) and safety analysis in all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT02601989), and EudraCT (2015-000573).
UNASSIGNED: Between January 22nd, 2016, and January 31st, 2019, 23 participants with T2D were enrolled, of whom 18 were included in the full analysis set. The effect of tadalafil on insulin resistance was neutral compared with placebo. However, tadalafil decreased glycaemia measured as HbA1c (mean difference -2.50 mmol/mol, 95% confidence interval (CI), -4.20; -0.78, p = 0.005), and, further, we observed amelioration of endothelial function and markers of liver steatosis and glycolysis, whereas no statistically significant differences of other clinical phenotyping were shown. Muscle pain, dyspepsia, and headache were more frequent in participants on high-dose tadalafil compared with placebo (p < 0.05) but no difference between treatments appeared for serious adverse events.
UNASSIGNED: High-dose tadalafil does not decrease whole-body insulin resistance, but increases microcirculation, induces positive effects in the liver and in intermediate metabolites, in parallel with an improved metabolic control measured as HbA1c. High-dose tadalafil is moderately well tolerated, warranting larger trials to define the optimal treatment regimen in T2D.
UNASSIGNED: The Swedish Research Council, Swedish Diabetes Foundation, Novo Nordisk Foundation, the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement, Sahlgrenska University Hospital funds, Gothenburg Society of Medicine, Eli Lilly & Company, USA, and Eli Lilly & Company, Sweden AB.