sildenafil-citrate and Down-Syndrome

Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease (CHD), with most cases occurring in patients with congenital cardiac shunts. In patients with an uncorrected left-to-right shunt, increased pulmonary pressure leads to vascular remodelling and dysfunction, resulting in a progressive rise in pulmonary vascular resistance and increased pressures in the right heart. Eventually, reversal of the shunt may arise, with the development of Eisenmenger's syndrome, the most advanced form of PAH-CHD. The prevalence of PAH-CHD has fallen in developed countries over recent years and the number of patients surviving into adulthood has increased markedly. Today, the majority of PAH-CHD patients seen in clinical practice are adults, and many of these individuals have complex disease or received a late diagnosis of their defect. While there have been advances in the management and therapy in recent years, PAH-CHD is a heterogeneous condition and some subgroups, such as those with Down's syndrome, present particular challenges. This article gives an overview of the demographics, pathophysiology and treatment of PAH-CHD and focuses on individuals with Down's syndrome as an important and challenging patient group.

Topics: Antihypertensive Agents; Bosentan; Clinical Trials as Topic; Comorbidity; Down Syndrome; Eisenmenger Complex; Endothelium, Vascular; Epoprostenol; Health Behavior; Heart Defects, Congenital; Heart Transplantation; Humans; Hypertension, Pulmonary; Lung Transplantation; Oxygen Inhalation Therapy; Phosphodiesterase 5 Inhibitors; Piperazines; Practice Guidelines as Topic; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thrombosis

Despite the increased risk for pulmonary hypertension in children with Down syndrome, the response to treatment with targeted therapies for pulmonary hypertension in these patients is not well characterized. The Sildenafil in Treatment-naive children, Aged 1-17 years, with pulmonary arterial hypertension (STARTS-1) trial was a dose-ranging study of the short-term efficacy and safety of oral sildenafil in children with pulmonary arterial hypertension. We assessed the safety and efficacy of oral sildenafil in children with Down syndrome and pulmonary arterial hypertension.. This was a post-hoc analysis of children with Down syndrome and pulmonary arterial hypertension enrolled in the STARTS-1 trial. Mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance index (PVRI), and cardiac index (CI) were assessed at baseline and following 16 weeks of treatment with sildenafil.. Of 234 patients randomized and treated in the STARTS-1 trial, 48 (20.5%) had Down syndrome. Although sildenafil produced dose-related reductions in PVRI and mPAP, compared with placebo, in non-Down syndrome patients and children developmentally able to exercise, this was not satisfactorily marked in patients with Down syndrome. The dose-related reductions in PVRI, compared with placebo, occurred in all subgroups, with the exception of the Down syndrome subgroup. Sildenafil appeared to be well tolerated in the Down syndrome subpopulation and the most frequently reported AEs were similar to those reported for the entire STARTS-1 population.. Sildenafil treatment for 16 weeks had no effect on PVRI or mPAP in children with Down syndrome and pulmonary arterial hypertension. The results suggest that children with Down syndrome may be less responsive to sildenafil for pulmonary arterial hypertension, but the incomplete work-up for the etiology of pulmonary arterial hypertension may have introduced a potential bias.. Study received, September 8, 2005 (retrospectively registered); Study start, August 2003; ClinicalTrials.gov identifier, NCT00159913 .

Topics: Administration, Oral; Adolescent; Antihypertensive Agents; Arterial Pressure; Child; Child, Preschool; China; Down Syndrome; Female; Humans; Hypertension, Pulmonary; Infant; Male; Pulmonary Artery; Sildenafil Citrate; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Topics: Adenoidectomy; Anesthetics, Intravenous; Anticoagulants; Antihypertensive Agents; Bosentan; Child; Down Syndrome; Elective Surgical Procedures; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Intubation, Intratracheal; Piperazines; Piperidines; Propofol; Purines; Remifentanil; Severity of Illness Index; Sildenafil Citrate; Sleep Apnea, Obstructive; Sulfonamides; Sulfones; Tonsillectomy; Treatment Outcome; Vasodilator Agents; Warfarin

Impaired endothelial homeostasis underlies the pathophysiology of pulmonary arterial hypertension (PAH). We speculated that PAH patients are deficient in circulating endothelial progenitor cells (EPCs), potentially contributing to endothelial dysfunction and disease progression.. We recruited 41 patients with Eisenmenger syndrome (13 with Down syndrome), 55 with idiopathic PAH, and 47 healthy control subjects. Flow cytometry and in vitro assays were used to quantify EPCs and to assess cell function. The number of circulating CD34+, CD34+/AC133+, CD34+/KDR+, and CD34+/AC133+/KDR+ progenitor cells was low in Eisenmenger patients compared with healthy control subjects, and those with Down syndrome displayed even fewer EPCs. Reductions in EPC numbers correlated with New York Heart Association functional class, 6-minute walk distance, and plasma brain-type natriuretic peptide levels. The capacity of cultured peripheral blood mononuclear cells to form colonies and incorporate into tube-like structures was impaired in Eisenmenger patients. Idiopathic PAH patients had reduced numbers of EPCs, and the number of circulating EPCs correlated with invasive hemodynamic parameters in this cohort. Levels of immune inflammatory markers, cGMP, stable nitric oxide oxidation products, and asymmetric dimethylarginine were abnormal in patients with PAH and related to numbers of EPCs. Within the idiopathic PAH population, treatment with the phosphodiesterase inhibitor sildenafil was associated with a dose-dependent rise in EPC numbers, resulting in levels consistently above those found with other therapies.. Circulating EPC numbers are reduced in 2 well-characterized forms of PAH, which also exhibit raised levels of inflammatory mediators. Sildenafil treatment may represent a pharmacological means of increasing circulating EPC numbers long-term.

Topics: AC133 Antigen; Aged; Antigens, CD; Antigens, CD34; Arginine; Cells, Cultured; Cyclic GMP; Down Syndrome; Eisenmenger Complex; Endothelium, Vascular; Exercise; Female; Flow Cytometry; Glycoproteins; Hematopoietic Stem Cells; Humans; Hypertension, Pulmonary; Inflammation Mediators; Male; Middle Aged; Natriuretic Peptide, Brain; Peptides; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Stem Cells; Sulfones; Vascular Endothelial Growth Factor Receptor-2; Vasodilator Agents

Topics: Anti-Anxiety Agents; Attention Deficit and Disruptive Behavior Disorders; Child; Comorbidity; Diagnosis, Differential; Dose-Response Relationship, Drug; Down Syndrome; Heart Defects, Congenital; Hospitalization; Humans; Hypertension, Pulmonary; Lorazepam; Male; Oxygen Inhalation Therapy; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

A five-month-old girl of Down syndrome underwent a corrective surgery for complete atrioventricular septal defect. Her postoperative course was complicated with pulmonary hypertensive (PH) crises despite nitroglycerin (NTG) infusion and inhaled nitric oxide (NO). Sildenafil citrate, a phosphodiesterase 5 inhibitor, was administered through a nasogastric tube at a starting dose of 0.3 mg/kg by stepwise increment to the maximum dose of 2 mg/kg 4 hourly. Sildenafil citrate dramatically lowered pulmonary arterial pressure and the patient was weaned from NTG and NO without PH crisis. There was no side effect after sildenafil citrate administration. Oral sildenafil citrate is a safe and potent adjunct to the existing therapies for postoperative PH in infants after open heart surgery.

Topics: Administration, Inhalation; Administration, Oral; Cardiac Surgical Procedures; Down Syndrome; Female; Heart Septal Defects; Humans; Hypertension, Pulmonary; Infant; Nitric Oxide; Piperazines; Postoperative Complications; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents