Sildenafil Therapy Research Articles

Retrospective evaluation of pimobendan and sildenafil therapy for severe pulmonary hypertension due to lung disease and hypoxia in 28 dogs (2007-2013).

Pulmonary hypertension (PH) is the persistent abnormal increase in pulmonary artery (PA) pressure and in dogs is usually secondary to congenital disease causing pulmonary over circulation, chronic respiratory disease and elevated left atrial pressure. Sildenafil (SF) is a phosphodiesterase (PDE) V inhibitor that causes pulmonary artery (PA) vasodilation by increasing pulmonary vascular concentrations of cyclic guanosine monophosphate which subsequently increases the activity of endogenous nitric oxide. Pimobendan (PB) is a PDE III inhibitor with calcium sensitizing effects thereby exerting positive inotropy and vasodilation. The purpose of this retrospective study was to evaluate the long‐term survival of dogs with severe PH treated with SF and PB compared to SF alone. The use of PB in combination with SF did not result in a statistically significant increase in survival times in dogs with pulmonary hypertension secondary to chronic respiratory disease compared to SF alone.

Effect of calcium channel blockers evaluated by cardiopulmonary exercise testing in idiopathic pulmonary arterial hypertension responding to acute pulmonary vasoreactivity testing

BackgroundThe baseline exercise capacity evaluated by cardiopulmonary exercise testing (CPET) and the change after administration of calcium channel blockers (CCB) therapy in patients with vasodilator-responsive idiopathic pulmonary arterial hypertension (VR-IPAH)are unknown. Methods25 patients with newly diagnosed VR-IPAH from 1 January 2012 to 16 November 2015 were prospectively enrolled, and 28 age, sex and pulmonary vascular resistance matched newly diagnosed patients with vasodilator-nonresponsive idiopathic pulmonary arterial hypertension (VNR-IPAH) were enrolled. CPET was performed before and after 3.5 ± 0.8 months of CCB or sildenafil therapy. ResultsVentilatory efficiency at rest, anaerobic threshold (AT), and peak were significantly higher (lower in V˙E/V˙CO2@AT and higher in PETCO2@AT) in VR-IPAH group than that in VNR-IPAH group. Peak V˙O2 (13.9 ± 2.9 mL kg−1·min−1 vs 16.4 ± 4.1 mL kg−1·min−1, p = 0.001), peak O2 pulse (5.5 ± 0.8 mL min−1·beat−1 vs 6.9 ± 1.3 mL min−1·beat−1, p = 0.001), V˙E/V˙CO2@AT (34.2 ± 5.0 vs 31.6 ± 3.1, p = 0.02) and PETCO2@AT (33.1 ± 4.0 mmHg vs 35.3 ± 3.2 mmHg, p = 0.02) were significantly improved after high dose of CCB therapy, along with improvement of WHO functional class, 6-min walking distance, NT-proBNP and tricuspid regurgitation pressure gradient. ConclusionsVentilatory efficiency in patients with VR-IPAH is better than that in patients with VNR-IPAH. CCB can improve aerobic capacity and ventilatory efficiency during exercise in patients with VR-IPAH.Clinical trial registration number: ClinicalTrials.gov:NCT02061787.

ASPECTS OF MODERN COMBINATION SPECIFIC THERAPY OF PULMONARY ARTERIAL HYPERTENSION: THE PROS AND CONS

The treatment algorithm for pulmonary arterial hypertension (PAH) includes three main stages: general measures; induction drug therapy; combined drug therapy and intervention methods for patients who fail to respond adequately to induction therapy. The specific therapy includes endothelin receptor antagonists (ARE), prostanoids, phosphodiesterase type 5 inhibitor (PT5I) and soluble guanylate cyclase stimulators (rGCS). The combined specific therapy, which means the simultaneous use of more than one class of specific drugs, is an attractive approach, taking into account the malignancy and complexity of PAH pathogenesis, and the successful experience in using medication combinations in the treatment of systemic arterial hypertension and heart failure. The article shows that down to recent times the issues of necessity and timeliness of the combined PAH-specific therapy, and the choice of rational combinations, require further study. The COMPASS-2 randomized study did not prove that the adding bosentan to the stable sildenafil therapy is more effective than sildenafil monotherapy, and extends the time to the development of the first morbidity event/ mortality in PAH patients. The meta-analysis of H.l. Liu et al. showed that the monotherapy leads to a significant reduction in mortality in patients with PAH, improvement of functional and hemodynamic status compared with the placebo or standard therapy. The combined therapy is associated with a significant improvement in functional and hemodynamic status, but the mortality of patients did not decrease reliably compared with the monotherapy. The combined therapy is associated with a significant increase in cancellation frequency due to adverse effects as compared with the monotherapy. The concept of the advantage of rGC stimulants over PT5I was studied in an international multicentre open-label IIIb phase RESPITE (Riociguatum Сlinical Effects Studied in Patients With Insufficient Treatment Response to PDE5) study of the safety and efficacy of the transition from the PT5I therapy to riociguatum therapy in patients with PAH who did not achieve the treatment goals when using PT5I. The study included patients with functional capacity III (WHO), a distance of 165–440 m in the 6-min walk distance (6MWD), cardiac index <3.0 l/min/m 2 , pulmonary vascular resistance> 400 dyne*s *cm -5 , the average pressure in the pulmonary artery > 30 Hg mm despite receiving stable doses of sildenafil in the highest dose of 80 mg 3 times a day or tadalafil in the highest dose of 40 mg 1 once a day. A part of patients also received an endothelin receptor antagonist (ERA). The clinical endpoints included changes in 6MWD, hemodynamics from baseline to Week 24 of therapy, WHO FC, the NT-proBNP levels, the quality of life evaluation, and % patients developing clinical worsening from baseline to Week 12 and 24 of therapy. After cancellation of PDE5i, the patients received riociguat. The interim analysis of the study showed that 50% of patients had improved to WHO FC II from III, increased 6MWD from 353 ± 78 to 392 ± 112 m (n = 25); improved hemodynamic parameters and NT-proBNP levels by Week 24, which may indicate that patients with an insufficient response to PDE5i therapy may benefit from a transition to riociguat. This approach should be further investigated, as suggested by 2016 Russian Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension.

The role of preoperative sildenafil therapy in controlling of postoperative pulmonary hypertension in children with ventricular septal defects.

Introduction: Most of the ventricular septal defects (VSD) are complicated with pulmonary arterial hypertension (PAH) which is the major cause of pulmonary hypertensive crisis and right ventricular failure. Methods: We reviewed clinical outcomes of 63 infants who underwent cardiac surgery and were divided into three groups. Control group (n=20) did not received sildenafil while group A (n = 22) received drug (0.3 mg/kg) before and after surgery. Group B (n=21) received drug at the initiation of surgery. Demographic data, preoperative and postoperative variables were compared among the patients. Results: Patients in the group A had lower preoperative pulmonary arterial pressure (PAP) compared to other groups (P < 0.001). Also, patients in control group had longer cardiopulmonary bypass time (P < 0.05). Postoperative PAP in patients of group A and B decreased significantly compared to control group (P < 0.001). Also, pre- and postoperative PVR (pulmonary vascular resistance) showed a significant decrease in group A compared with control and group B (P < 0.001). The intubation time in patients of the control group was significantly more prolonged compared with patients of group A and B (P < 0.001). Moreover, the length of ICU stay was significantly longer in patients of control group compared with group A and B (P < 0.001). Conclusion: Preoperative sildenafil therapy seems to be effective and safe to prevent postoperative PAH and pulmonary hypertensive crisis in children with ventricular septal defects and has a positive impact on postoperative care.

Perioperative sildenafil therapy for children with ventricular septal defects and associated pulmonary hypertension undergoing corrective surgery: A randomised clinical trial.

Background and Aims:Sildenafil is known to reduce pulmonary artery pressure but its role in the perioperative period has not been well studied. We aimed to evaluate the efficacy of sildenafil in controlling post-operative pulmonary hypertension in children with pulmonary hypertension undergoing surgeries for correction of ventricular septal defect.Methods:The patients were divided randomly into two groups of thirty each. Group 1 (placebo) received pre-operative placebo and post-operative sildenafil (0.5mg/kg every 6 hrs) while Group 2 (sildenafil) received pre- and post-operative sildenafil (0.5mg/kg every 6 hrs)Results:In the Group 1, systolic pulmonary artery pressure reduced from 81.63 (±12.1) mmHg preoperatively to 79.26 (±11.29) mmHg pre-cardiopulmonary bypass (CPB) and 56.76 (±11) mmHg (with 10 minutes post-CPB), whereas in Group 2, it reduced from 83.3 (±12.1) before surgery to 68.9 (±11.3) mmHg pre-CPB and after CPB, to 42.2 (±7.6) mmHg (P = 0.001). The mean pulmonary artery pressure decreased from 60.63 (±10.5) mmHg to 42.13 (±8.3) mmHg in the Group 1 whereas it reduced from 54.36 (±10) mmHg to 31.36 (±6.5) mmHg in Group 2 (P = 0.001). The reductions in pulmonary artery/aortic ratio and Intensive Care Unit stay were statistically significant No adverse effects were recorded.Conclusion:The use of perioperative sildenafil has a statistically significant reduction in the mean pulmonary artery pressure without any adverse effects.

CLINICAL CASE: OPPORTUNITY OF THERAPY OPTIMIZATION DUE TO TRANSITIONING FROM SILDENAFIL TO RIOCIGUAT IN PATIENT WITH IDIOPATHIC PULMONARY HYPERTENSION

SUMMERY The patient with diagnosis of idiopathic pulmonary hypertension, functional class III (WHO) was treated by anticoagulants, diuretics. After 6 months of treatment with phosphodiesterase type 5-inhibitor sildenafil, there was observed the negative dynamic with systolic pulmonary arterial pressure, intolerance to exercises. The treatment goals were not achieved with sildenafil therapy. The transitioning from sildenafil to riociguat therapy was done. By 6 months of the riociguat therapy there was achieved the significant improvement of the functional and hemodynamic status. Ам^^ to the stratification risk scale the treatment goals were reached. Keywords: idiopathic pulmonary hypertension, phosphodiester-ase type 5 inhibitor, sildenafil, soluble guanylate cyclase stimulators, riociguat, risk assessment.

Sildenafil therapy for fetal cardiovascular dysfunction during hypoxic development: studies in the chick embryo.

Common complications of pregnancy, such as chronic fetal hypoxia, trigger a fetal origin of cardiovascular dysfunction and programme cardiovascular disease in later life. Sildenafil treatment protects placental perfusion and fetal growth, but whether the effects of sildenafil transcend the placenta to affect the fetus is unknown. Using the chick embryo model, here we show that sildenafil treatment directly protects the fetal cardiovascular system in hypoxic development, and that the mechanisms of sildenafil protection include reduced oxidative stress and increased nitric oxide bioavailability; Sildenafil does not protect against fetal growth restriction in the chick embryo, supporting the idea that the protective effect of sildenafil on fetal growth reported in mammalian studies, including humans, is secondary to improved placental perfusion. Therefore, sildenafil may be a good candidate for human translational antioxidant therapy to protect the chronically hypoxic fetus in adverse pregnancy. There is a need for developing clinically translatable therapy for preventing fetal origins of cardiovascular disease in pregnancy complicated by chronic fetal hypoxia. Evidence shows that sildenafil protects placental perfusion and fetal growth. However, whether beneficial effects of sildenafil transcend onto the fetal heart and circulation in complicated development is unknown. We isolated the direct effects of sildenafil on the fetus using the chick embryo and hypothesised that sildenafil also protects fetal cardiovascular function in hypoxic development. Chick embryos (n=11 per group) were incubated in normoxia or hypoxia (14% O2 ) from day 1 and treated with sildenafil (4mgkg-1 day-1 ) from day 13 of the 21-day incubation. Hypoxic incubation increased oxidative stress (4-hydroxynonenal, 141.1±17.6% of normoxic control), reduced superoxide dismutase (60.7±6.3%), increased phosphodiesterase type 5 expression (167±13.7%) and decreased nitric oxide bioavailability (54.7±6.1%) in the fetal heart, and promoted peripheral endothelial dysfunction (70.9±5.6% AUC of normoxic control; all P<0.05). Sildenafil treatment after onset of chronic hypoxia prevented the increase in phosphodiesterase expression (72.5±22.4%), protected against oxidative stress (94.7±6.2%) and normalised nitric oxide bioavailability (115.6±22.3%) in the fetal heart, and restored endothelial function in the peripheral circulation (89.8±2.9%). Sildenafil protects the fetal heart and circulation directly in hypoxic development via mechanisms including decreased oxidative stress and enhanced nitric oxide bioavailability. Sildenafil may be a good translational candidate for human antioxidant therapy to prevent fetal origins of cardiovascular dysfunction in adverse pregnancy.

Genetic Modifiers Identify a High Risk Group for Stroke in Three Independent Cohorts of Sickle Cell Anemia Patients

Two common genetic modifiers, α-thalassemia and the BCL11A rs1427407 T allele, are observed in approximately one-third of patients with sickle cell anemia (SCA) and are associated with reduced hemolysis and higher hemoglobin F (HbF) levels, respectively.We investigated the laboratory and clinical effects of α-thalassemia and the BCL11A rs1427407 T allele in the University of Ibadan cohort of SCA patients and replicated our findings in two independent SCA cohorts, University of Illinois at Chicago (UIC) and Walk-Treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy (Walk-PHaSST). Alpha-thalassemia status was determined by PCR in all 3 cohorts while the BCL11A rs1427407 genotype was determined by PCR in the Ibadan and UIC cohorts and imputed in the Walk-PHaSST cohort. Comparisons according to genotype were performed using the linear trend test for continuous variables and Cochran’s test of linear trend for categorical variables.Alpha-thalassemia was observed in 43% of 257 SCA patients from Ibadan and was associated with higher body mass index and lower white blood cell count (Table 1). The BCL11A rs1427407 T allele was observed in 46% of SCA patients from Ibadan and was associated with higher hemoglobin concentration. HbF levels by HPLC were available in 25 patients (12 with the BCL11A rs1427407 T allele) enrolled in a study of low-dose hydroxyurea; these levels were higher in patients with at least one rs1427407 T allele at baseline and progressively during therapy with hydroxyurea 10 mg/kg/day (repeated measures P=0.01).We defined a high risk genetic group as the absence of α-thalassemia in combination with absence of the BCL11A rs1427407 T allele. This high risk group was observed in 31% of SCA patients from the Ibadan cohort and was associated with a higher reticulocyte percentage (15.0% vs. 7.8%, P=0.08) and a higher prevalence for a history of stroke (6% vs. 1%, P=0.02). The association with stroke history persisted on logistic regression analysis after adjusting for age, gender, and hydroxyurea therapy (OR 9.4, 95%CI: 1.2-72.8; P=0.03). We then replicated the association of this high risk group with markers of hemolysis and with history of stroke in the UIC and Walk-PHaSST SCA cohorts. In the UIC cohort, the high risk group was observed in 34% (92/271) and was also associated with higher reticulocyte counts (13.5% vs. 11.9%, P=0.10) and higher prevalence for stroke history (33% vs. 22%; age, gender, HU-adjusted OR 1.7, 95%CI: 1.0-3.0; P=0.066). In the Walk-PHaSST cohort, this high risk profile was observed in 38% (149/394) and was associated with a higher reticulocyte percentage (9.7% vs. 8.4%, P=0.0005), lower hemoglobin concentration (8.4 vs. 8.8 g/dL; P=0.017), and higher prevalence for stroke history (15% vs. 6%; age, gender, HU-adjusted OR 2.6, 95%CI: 1.3-5.3; P=0.007).In conclusion, a high risk group of SCA patients, defined by the lack of the protective α-thalassemia and the BCL11A rs1427407 variants, is associated with a higher degree of hemolysis and a higher prevalence of stroke history on cross sectional analysis in three independent cohorts. This high-risk profile may help identify patients to prioritize for hydroxyurea therapy and for closer monitoring strategies for stroke. [Display omitted] DisclosuresHsu:Sancilio: Research Funding; Astra Zeneca: Consultancy, Research Funding; Purdue Pharma: Research Funding; Gerson Lehman Group: Consultancy; Eli Lilly: Research Funding; Centers for Medicare and Medicaid Innovation: Research Funding; Hilton Publishing: Consultancy, Research Funding; Mast Therapeutics: Research Funding; EMMI Solutions: Consultancy; Pfizer: Consultancy, Research Funding.

GWAS Meta-Analysis of Glomerular Filtration Rate in Three Cohorts of Sickle Cell Disease Patients and In Vivo Functional Analysis Reveals Potential Nephropathy Candidate Genes

▪BACKGROUND: Sickle cell disease nephropathy (SCDN) is a common complication of sickle cell disease (SCD) associated with risk for early mortality (Platt et al., 1994; Elmariah et al, 2014). To identify potential genetic risk factors for SCDN, we performed genome-wide association studies (GWAS) for glomerular filtration rate (GFR) in three well-characterized SCD cohorts and performed in vivo functional analysis of one of the candidate genes in zebrafish.METHODS: Three previously described SCD cohorts were utilized in this analysis: Outcome Modifying Genes in Sickle Cell Disease (OMG-SCD) (Elmariah et al, 2014), Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) (Machado et al, 2011) and Pulmonary Hypertension and the Hypoxic Response in Sickle Cell Disease (PUSH) (Minniti et al, 2009). Patients less than 16 years old were excluded from PUSH. GFR was estimated using the ’Modification of Diet in Renal Disease’ (MDRD) study definition (Levey et al, 1999) and, in the OMG-SCD and Walk-PHaSST cohorts, dichotomized at the clinically relevant threshold of 90 ml/min/1.73m2. 1064 patients with complete data were included in the analysis (Table 1). Genotyping was performed using the Illumina Human610-Quad BeadChip (Illumina, San Diego, CA). Linear regression was utilized to test for association between each SNP and GFR, controlling for genome-wide principle components using PLINK (Purcell et al, 2008). Logistic regression was utilized for the analysis of GFR<90. A total of 479,389 SNPs in common across all three cohorts were tested in a meta-analysis using METAL (Willer et al, 2010). False discovery rate (FDR) p-values were generated using PROC MULTTEST in SAS (SAS Systems, Cary, NC). To target and functionally evaluate xylt1 in vivo, a morpholino (MO) was injected into zebrafish embryos at the 1-4 cell stage. A wild-type (WT) XYLT1 ORF clone (GenBank: BC156039) was transferred to the pCS2+ vector, and used as template to transcribe capped mRNA. XYLT1 mRNA was co-injected with xylt1-MO to rescue the phenotype and demonstrate assay specificity. Proteinuria was assessed in zebrafish models by quantification of GFP leakage as described (Zhou and Hildebrandt, 2012). Larva were scored at 5 days-post-fertilization (dpf) for cardiac or yolk-sac edema.RESULTS: For the meta-analysis of continuous GFR, the SNP with the most evidence for association was rs7553158 in the TNNI3K-FPGT locus (p= 7.1E-7). For the meta-analysis of GFR<90, the most significant association within a gene was rs7201659 in XYLT1 (p=1.7E-5). None of these findings met FDR significance. Nonetheless, knockdown of xylt1 in zebrafish embryos resulted in pericardial edema, a phenotype associated previously with glomerular filtration defects, which was confirmed by the detection of GFP leakage of an albumin equivalent protein in the surrounding media. Importantly, complementation of xylt1 morphants with WT human XYLT1 mRNA rescued significantly these filtration defects in developing embryos.DISCUSSION:The absence of mechanistic knowledge about SCDN has led to limited therapeutic options for patients. The present study seeks to identify genetic risk factors for SCDN and represents the largest GWAS of GFR in SCD patients to date. The GWAS was likely still underpowered, however, as none of the findings met FDR significance. Nonetheless, the most significant genes identified are excellent biologic candidates for kidney function. Fucose-1-Phosphate Guanylyltransferase (FPGT) converts GTP and β-l-fucose-1-phosphate to GDP-l-fucose, a process essential in the kidney to reutilize L-fucose from the turnover of glycolipids. It is also highly expressed in the porcine and human kidney (Pastuszak et al, 1998; GTEx, Broad Institute). Xylosyltransferase 1 (XYLT1, also known as XT-1) encodes the enzyme responsible for biosynthesis of heparin sulfate proteoglycans, which affect permeability of the glomerular basement membrane. Furthermore, the c.343G>T polymorphism in XYLT1 has been implicated in diabetic nephropathy (Schön et al, 2006). Here, we have identified putative novel nephropathy loci associated with kidney decline in the largest combined cohort of SCD patients to date. These results further our understanding of the underlying pathology of SCDN and have uncovered genetic markers that could be used for identification of at-risk SCD patients prior to the onset of kidney dysfunction. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Elevated serum HMGB1 in pulmonary arterial hypertension secondary to congenital heart disease

AimsThis study investigated the potential value of serum high mobility group box-1 (HMGB1) level in the diagnosis, staging and treatment response of patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD). Methods and resultsThis was a single-center prospective study in 106 CHD patients. Serum HMGB1 levels were measured by enzymelinked immunosorbent assay. HMGB1 levels were significantly increased in patients with PAH compared to patients without PAH (P<0.01) and healthy controls (P<0.001). HMGB1 levels significantly correlated with pulmonary arterial pressure (P<0.001) and pulmonary vascular resistance (PVR) (P<0.001). In patients with severe PAH, HMGB1 levels were significantly higher in patients with Eisenmenger syndrome (ES) than in patients exhibiting low PVR (P<0.001). Severe PAH and ES was identified by serum HMGB1 with a cutoff value of 13.62ng/mL (P<0.001) with a specificity of 82.8% and a sensitivity of 90%, and a cutoff value of 21.62ng/mL (P=0.001) with a specificity of 85.2% and a sensitivity of 64.3%, respectively. HMGB1 levels were significantly decreased after sildenafil therapy for 6months (P<0.01). ConclusionsOur study suggests that serum HMGB1 level may be used as a biomarker to identify PAH in CHD patients, assess pulmonary vascular remodeling, and evaluate the treatment response to sildenafil.

Comparing the effects of treatment with sildenafil and cognitive-behavioral therapy on treatment of sexual dysfunction in women: a randomized controlled clinical trial.

BackgroundSexual dysfunction in women is prevalent and common in women after menopause. Many attempts to treat patients with sexual dysfunction by cognitive-behavioral therapy (CBT) methods. But to the best of our knowledge, there has been no study that compared these two methods.ObjectiveThe aim of this study was to assess and compare the effects of sildenafil and cognitive-behavioral therapy on treatment of sexual dysfunction in women.MethodsIn this randomized, controlled, clinical trial, 86 women with arousal and orgasm dysfunction were surveyed. The patients were divided into two groups, i.e., sildenafil and CBT groups. The patients in the sildenafil group were treated by 50 mg of oral sildenafil one hour before intercourse, and the other group had weekly sessions of CBT for eight weeks. Sexual dysfunctions were evaluated by the Female Sexual Function Index (FSFI), a sexual satisfaction questionnaire, and the Enrich marital satisfaction scale.ResultsThe mean age of the participants was 33.14 ± 7.34 years. The mean scores for female sexual function index, sexual satisfaction, and the Enrich marital satisfaction scale were increased in both groups during treatment (p < 0.001). It was found that cognitive-behavioral therapy compared to treatment with sildenafil increased all subscales, except arousal, orgasm, and lubrication.ConclusionCognitive-behavioral therapy is more effective than treatment with sildenafil for improving female sexual function.Clinical trial registrationThe trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the IRCT ID: IRCT2014070318338N1.FundingThe authors received no financial support for the research, authorship, and/or publication of this article.

Management of hypoxemic respiratory failure and pulmonary hypertension in preterm infants.

While diagnoses of hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) in preterm infants may be based on criteria similar to those in term infants, management approaches often differ. In preterm infants, HRF can be classified as 'early' or 'late' based on an arbitrary threshold of 28 postnatal days. Among preterm infants with late HRF, the pulmonary vascular abnormalities associated with bronchopulmonary dysplasia (BPD) represent a therapeutic challenge for clinicians. Surfactant, inhaled nitric oxide (iNO), sildenafil, prostacyclin and endothelin receptor blockers have been used to manage infants with both early and late HRF. However, evidence is lacking for most therapies currently in use. Chronic oral sildenafil therapy for BPD-associated PH has demonstrated some preliminary efficacy. A favorable response to iNO has been documented in some preterm infants with early PH following premature prolonged rupture of membranes and oligohydramnios. Management is complicated by a lack of clear demarcation between interventions designed to manage respiratory distress syndrome, prevent BPD and treat HRF. Heterogeneity in clinical phenotype, pathobiology and genomic underpinnings of BPD pose challenges for evidence-based management recommendations. Greater insight into the spectrum of disease phenotypes represented by BPD can optimize existing therapies and promote development of new treatments. In addition, better understanding of an individual's phenotype, genotype and biomarkers may suggest targeted personalized interventions. Initiatives such as the Prematurity and Respiratory Outcomes Program provide a framework to address these challenges using genetic, environmental, physiological and clinical data as well as large repositories of patient samples.

Ocular toxicity assessment of chronic sildenafil therapy for pulmonary arterial hypertension.

The aim of this study was to investigate possible functional and structural ocular changes caused by chronic sildenafil therapy to treat pulmonary arterial hypertension (PAH). Case-control study included patients with pulmonary arterial hypertension: chronically using sildenafil and without sildenafil treatment. A comprehensive ophthalmologic exam including ectoscopy, extrinsic ocular motility, logMAR visual acuity measurement, contrast sensitivity test, color test, anterior segment biomicroscopy, Schirmer test 1, intraocular pressure, fundus exam under pupil dilation, fundus pictures, time domain and spectral domain optical coherence tomography, ocular Doppler ultrasound were performed. Full-field electroretinography (ERG) was tested for each eye in a subgroup of sildenafil-treated patients. Twenty patients from each group were tested. Bilateral severe keratitis was found in seven (35%) patients under sildenafil therapy. Lacrimal film break-up time (BUT) was significantly reduced (p = 0.006 respectively) and Doppler ultrasound showed a reduced resistance index of the central retinal artery in the group of sildenafil users (p = 0.019). No diffuse retinal functional abnormalities were found in ERG in treated patients. Visual acuity, contrast sensitivity and color discrimination were normal in both groups. No abnormalities were found in both time-domain and spectral-domain OCT for retinal parameters. One-third of the treated PAH group showed severe bilateral keratitis. This finding could be related to connective tissue abnormalities usually present in patients with this condition that might be exacerbated with the sildenafil usage. The resistance index of the central retinal artery was diminished in the chronic users group and it could be associated to the vasodilation caused by the medication in the choroidal vessels. An ophthalmic assessment for these patients is recommended to diagnose and treat possible ocular surface and choroidal blood flow abnormalities caused by sildenafil.

Right- versus left-sided congenital diaphragmatic hernia: a comparative outcomes analysis

PurposeRight-sided congenital diaphragmatic hernia (R-CDH) occurs in up to 25% of all CDH cases, but has been less widely studied compared to left-sided defects. We sought to compare characteristics and outcomes of left- versus right-sided defects in a large cohort of CDH patients who underwent standardized treatment and follow-up at a single institution. MethodsWe retrospectively reviewed charts of all CDH patients in our pulmonary hypoplasia program from January 2002 through December 2014. Categorical variables were analyzed by Fisher's exact test and continuous variables by Mann–Whitney t-test (p≤0.05). ResultsA total of 330 CDH patients were treated more than the 12-year study period, with 274 (83%) left-sided and 56 (17%) right-sided cases identified. Specific pulmonary morbidities were associated with R-CDH, with increased duration of nitric oxide therapy, increased requirement for tracheostomy, increased requirement for supplemental oxygen at the time of NICU discharge, and increased chronic pulmonary hypertension with requirement for long-term Sildenafil therapy. ConclusionsIn this series, R-CDH was not associated with increased mortality, but was associated with increased requirement for pulmonary vasodilatory therapy and requirement for tracheostomy. The high incidence of pulmonary complications indicates increased severity of pulmonary hypoplasia in R-CDH, supporting a role for delivery in tertiary centers with expertise in CDH management.

Adjuvant sildenafil therapy in poor responders undergoing in vitro fertilization: A prospective, randomized, double-blind, placebo-controlled trial

Abstract Objective: To evaluate the effect of adjuvant sildenafil on ovarian responsiveness in low responders undergoing IVF. Patient(s) and methods: Prospective randomized, double-blind, placebo controlled study was conducted at Obstetrics and Gynecology department, Tanta university hospital and Center of Assisted Reproduction, Om El-kora Hospital, Tanta, Egypt. Sixty patients were classified as low responders undergoing IVF. Supplementation with sildenafil (50 mg daily) or placebo to a gonadotropin releasing hormone antagonist protocol was provided. Result(s): There were no significant differences in total number of 75 IU FSH ampoules used (60.025 ± 5.52) versus (66.025 ± 4.51), the number of mature follicles recruited (3.35 ± 1.137) versus (2.95 ± .826), and the number of oocytes retrieved (3.95 ± 1.395) versus (3.65 ± 1.137) or cycle cancelation rates (26.7% in the treatment group versus 23.3% in placebo group). Conclusion: Adjuvant sildenafil does not enhance ovarian responsiveness in cases of previous low ovarian response to controlled ovarian hyperstimulation.

Matrix metalloproteinases are possible targets in monocrotaline-induced pulmonary hypertension: investigation of anti-remodeling effects of alagebrium and everolimus.

Objective:In our study, sildenafil alone and everolimus or alagebrium in combination with sildenafil were investigated in terms of their additional therapeutic and anti-remodeling activity in monocrotaline-induced pulmonary hypertension (PH) model in rats. In particular, the inter-relationships between PH and matrix metalloproteinases (MMPs) were investigated.Methods:The pulmonary artery responses of male Sprague Dawley rats were recorded using myography, and the quantities and activities of MMPs were analyzed in homogenates of the pulmonary arteries and lungs by enzyme-linked immunosorbent assays, activity assays, and gelatin zymography techniques.Results:Our results indicated that the therapeutic effects of sildenafil were accompanied by its suppressor effects on MMP activity. It was also shown that everolimus or alagebrium in combination with sildenafil showed additional regulatory effects on MMPs as well as functional responses on pulmonary artery pressure. Therefore, the enzymes in the MMP superfamily are likely to be target molecules for the treatment of PH.Conclusion:In conclusion, MMPs were involved in the pathogenesis of PH, and our results suggested that the addition of everolimus or alagebrium to sildenafil therapy may be beneficial in PH. Our results indicated that agents that limit pulmonary vascular hypertrophy and inflammation via their anti-remodeling effects significantly ameliorate mortality and morbidity in PH.

Positive effects of sildenafil therapy on outcomes of congenital heart surgery

Positive effects of sildenafil therapy on outcomes of congenital heart surgery

747: Does sildenafil therapy modulate vascular function in adult offspring who underwent fetal programming?

747: Does sildenafil therapy modulate vascular function in adult offspring who underwent fetal programming?

Kidney Disease among Patients with Sickle Cell Disease, Hemoglobin SS and SC

Sickle cell disease (SCD) is an inherited anemia that afflicts millions worldwide. Kidney disease is a major contributor to its morbidity and mortality. We examined contemporary and historical SCD populations to understand how renal disease behaved in hemoglobin SS (HbSS) compared with HbSC. Kidney function was examined in the multicentered Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) Trial (HbSS=463; HbSC=127; years 2007-2009) and historical comparator populations from the Cooperative Study of Sickle Cell Disease (CSSCD; HbSS=708) and the Multicenter Study of Hydroxyurea in Sickle Cell Disease (MSH; HbSS=299). In adults with SCD, eGFR was lower among older individuals: -1.78 ml/min per 1.73 m(2) per year of age (95% confidence interval [95% CI], -2.06 to -1.50; Walk-PHaSST Trial), -1.75 ml/min per 1.73 m(2) per year of age (95% CI, -2.05 to -1.44; MSH), and -1.69 ml/min per 1.73 m(2) per year of age (95% CI, -2.00 to -1.38; CSSCD) in HbSS compared with -1.09 ml/min per 1.73 m(2) per year of age (95% CI, -1.39 to -0.75) in HbSC (Walk-PHaSST Trial). Macroalbuminuria was seen in 20% of participants with SCD (HbSS or HbSC; P=0.45; Walk-PHaSST Trial), but microalbuminuria was more prevalent in HbSS (44% versus 23% in HbSC; P<0.002). In the Walk-PHaSST Trial, albuminuria was associated with hemolysis (higher lactate dehydrogenase, P<0.001; higher absolute reticulocyte count, P<0.02; and lower Hb, P=0.07) and elevated systolic BP (P<0.001) in HbSS. One half of all participants with HbSS (20 of 39) versus one fifth without (41 of 228) elevated tricuspid regurgitant jet velocity (≥3 m/s; adverse prognostic indicator in SCD) had macroalbuminuria (P<0.001). In the CSSCD, overt proteinuria, detected (less sensitively) by urine dipstick, associated with higher 3-year mortality (odds ratio, 2.48; 95% CI, 1.07 to 5.77). Serum bicarbonate was lower in HbSS (23.8 versus 24.8 mEq/dl in HbSC; P<0.05) and associated with reticulocytopenic anemia and decreased renal function. In SCD, albuminuria or proteinuria was highly prevalent, in HbSS more than in HbSC. Proteinuria associated with mortality in HbSS. Older individuals had a lower than expected eGFR, and this was more prominent in HbSS. Current management does not routinely address renal complications in SCD, which could plausibly reduce morbidity and mortality.

Thrombospondin-1 Gene Polymorphism Is Associated with Estimated Pulmonary Artery Pressure in Patients with Sickle Cell Anemia

Thrombospondin-1 (TSP1) is a multifunctional glycoprotein present in platelet α-granules that contains domains for adhesive proteins, enzymes, and cell receptors. It is released by activated platelets and is increased in the plasma of patients with sickle cell anemia (SCA). TSP1 is known to mediate adherence of sickle reticulocytes to endothelial cells. Furthermore, TSP1 also inhibits the NO signaling pathway through its binding to the CD47 cell receptor on endothelial cells and platelets. Thus, we hypothesized that genetic variants in TSP1 may contribute to the marked phenotypic variation seen in SCA.We tested whether genetic variants of the TSP1 gene are associated with biomarkers of SCA severity and specific complications in a cohort of 452 patients with homozygous HbSS disease from the multicenter walk-PHaSST (Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy) trial. Genetic data from 406 patients were included in the analysis. Patients ranged in age from 12 to 70 years, and 51% were females. 307 patients were enrolled at various sites in the United States, while 99 patients were enrolled at Hammersmith Hospital in the UK. A total of 10 SNPs were selected, including haplotype tagged SNPs, coding variants, and SNPs potentially regulating gene expression and alternative splicing. DNA isolated from peripheral blood was used for genotyping.We found that the TSP1 SNPs rs1478604 and rs1478605 were significantly positively correlated with tricuspid regurgitation velocity (TRV) >2.5 m/sec, an echocardiographic marker of pulmonary hypertension associated with increased mortality, under a recessive model (r=0.10, p=0.0288 and r=0.13, p=0.0047 respectively). TRV was also analyzed as a categorical variable using regression analysis, and subjects were grouped based on the following clinically relevant cut-off points, 2.5 m/sec, 2.7 m/sec, and 3 m/sec. Univariate regression analyses showed TRV>2.5 m/sec was independently associated with the recessive genotypes of rs1478604 and rs1478605 (p=0.069 and 0.017 respectively). As previously published, we confirmed the association of TRV with age, gender, NT-proBNP and creatinine, and we adjusted for these variables in multivariate regression analyses for the association of TRV and each SNP. The results showed that the two SNPs were significantly associated with TRV>2.5 m/sec (rs1478604, OR 2.54, 95% CI (1, 6.44), p<0.05 and rs1478605, OR 4.20, 95% CI (1.41, 12.49), p<0.01) even after controlling for these variables.The results suggest that genetic variations in the TSP1 gene are associated with variations in estimated pulmonary artery pressure in patients with SCA. Both rs1478604 and rs1478605 are localized to the 5' untranslated region. Bioinformatic analysis of these SNPs for putative transcription factor binding sites demonstrated that the two SNPs are associated with both gain and loss of transcription factor binding compared to the wild type. Therefore, both SNPs are potentially functional in TSP1 regulation. These data also suggest possible translational implications in light of earlier pre-clinical reports that showed that mice lacking TSP1 were protected from hypoxia-mediate pulmonary and right ventricular remodeling and showed less alterations in PA pressure.In populations without SCA, these alleles have been independently linked to risk of malaria, corneal immune function, and gastric cancer. TSP1 activity has also been linked to fibrotic renal disease in a rat model and to IRI-mediated AKI in a murine model. The mechanism implicated in some of these cases involves disordered TSP1 regulation of transforming growth factor beta (TGF-beta), whose superfamily of receptors is dysregulated in the pathogenesis of pulmonary hypertension and kidney disease.Our findings support a hypothetical model of TSP1 involvement in the pathophysiology of SCA. Efforts to seek validation of the genetic findings from this study in an independent SCA cohort are currently underway. DisclosuresIsenberg:RCTI, Inc.: Equity Ownership, Patents & Royalties: US Patent No. 8236313; Vasculox, Inc.: Equity Ownership, Patents & Royalties: US Patent No. 8236313.