Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide

STUDY OBJECTIVES: In patients with pulmonary hypertension (PH) secondary to congestive heart failure, inhaled nitric oxide (NO) increases pulmonary vascular smooth-muscle intracellular cyclic guanosine monophosphate (cGMP) concentration, thereby decreasing pulmonary vascular resistance (PVR) and increasing cardiac index (CI). However, these beneficial effects of inhaled NO are limited in magnitude and duration, at least in part due to cGMP hydrolysis by the type 5 isoform of phosphodiesterase (PDE5). The goal of this study was to determine the acute pulmonary and systemic hemodynamic effects of the selective PDE5 inhibitor, sildenafil, administered alone or in combination with inhaled NO in patients with congestive heart failure and PH. DESIGN: Single center, case series, pharmacohemodynamic study. SETTING: Cardiac catheterization laboratory of a tertiary care academic teaching hospital. PATIENTS: We studied 11 patients with left ventricular systolic dysfunction due to coronary artery disease or idiopathic dilated cardiomyopathy who had PH. INTERVENTIONS: We administered oral sildenafil (50 mg), inhaled NO (80 ppm), and the combination of sildenafil and inhaled NO during right-heart and micromanometer left-heart catheterization. MEASUREMENTS AND RESULTS: Sildenafil administered alone decreased mean pulmonary artery pressure by 12 +/- 5%, PVR by 12 +/- 5%, systemic vascular resistance (SVR) by 13 +/- 6%, and pulmonary capillary wedge pressure by 12 +/- 7%, and increased CI by 14 +/- 5% (all p < 0.05) [+/- SEM]. The combination of inhaled NO and sildenafil decreased PVR by 50 +/- 4%, decreased SVR by 24 +/- 3%, and increased CI by 30 +/- 4% (all p < 0.01). These effects were greater than those observed with either agent alone (p < 0.05). In addition, sildenafil prolonged the pulmonary vasodilator effect of inhaled NO. Administration of sildenafil alone or in combination with inhaled NO did not change systemic arterial pressure or indexes of myocardial systolic or diastolic function. CONCLUSIONS: PDE5 inhibition with sildenafil improves cardiac output by balanced pulmonary and systemic vasodilation, and augments and prolongs the hemodynamic effects of inhaled NO in patients with chronic congestive heart failure and PH.     

Differential effects of terlipressin on pulmonary and systemic hemodynamics in patients with cirrhosis and pulmonary hypertension: an echo study

Terlipressin has been associated with pulmonary arterial vasodilation in patients with pulmonary hypertension (PH). We investigated the effects of terlipressin on pulmonary vascular resistance (PVR) in patients with cirrhosis without and with PH. Pulmonary vascular resistance and cardiac output (CO) by Doppler ultrasound, mean arterial pressure (MAP), and systemic vascular resistance (SVR) were evaluated in patients with cirrhosis with PVR -120 dyne s cm?? (group 1, n = 20) and PVR >120 dyne s cm?? (group 2, n = 10) before and 30 minutes after terlipressin infusion (2 mg). After terlipressin, PVR increased significantly in group 1 (96.1 ± 20.2 vs 85.1 ± 18 dyne s cm??; P = .004) but decreased significantly in group 2 (170.4 ± 37.8 vs 157.8 ± 28.1 dyne s cm??; P= .04). Pulmonary vascular resistance changes in group 2 correlated significantly with baseline PVR (r = -0.632; P = .04). Terlipressin induced a significant increase in MAP and SVR and a significant decrease in CO in both groups. Terlipressin significantly reduces pulmonary pressures in patients with cirrhosis having PH together with systemic hemodynamic improvement.     

Natural histories of atrial septal defect with pulmonary hypertension, and ventricular septal defect with pulmonary hypertension

A study of the natural history of 51 adult patients with atrial septal defect with pulmonary hypertension (ASD + PH) was performed. ASD + PH of less than 14 Um2 of pulmonary artery resistance (PVR) was considered an indication for surgery. The prognosis of surgically treated patients was favorable, but that of medically treated patients was poor. For patients with ventricular septal defect with pulmonary hypertension (VSD + PH), surgery was considered for pulmonary-systemic vascular resistance ratio (Rp/Rs) less than 0.5, and for patients under than 10 years and, ideally, under 2 years of age.     

Pulmonary thromboembolism superimposed on a congenital ventricular septal defect in a 50-year-old man inhaled nitric oxide and sildenafil to the rescue

We report the combined use of inhaled nitric oxide (iNO) and sildenafil to selectively lower pulmonary vascular resistance (PVR) and reverse right-to-left shunt flow across a congenital ventricular septal defect (VSD) in a 50-year-old man. The patient developed right-to-left shunt flow with profound hypoxia because of an acute pulmonary embolism superimposed on underlying pulmonary hypertension. The dramatic improvement in oxygenation and PVR with sildenafil plus iNO has been sustained with sildenafil monotherapy. To our knowledge, use of this combination therapy in patients with decompensated pulmonary arterial hypertension (PAH) and a predisposition to right-to-left shunting has not been previously reported.     

Pulmonary hemodynamic responses to brain natriuretic peptide and sildenafil in patients with pulmonary arterial hypertension

STUDY OBJECTIVES: Brain natriuretic peptide (BNP) blunts hypoxic pulmonary hypertension in animal models, but its acute hemodynamic effects in patients with pulmonary arterial hypertension (PAH) are not known. The aim of this study was to determine if human B-type natriuretic peptide is a safe and efficacious pulmonary vasodilator in patients with PAH and if the pulmonary hemodynamic effects are potentiated by phosphodiesterase inhibition. DESIGN: Open-label study. SETTING: Medical ICUs of three tertiary care hospitals in New England. PATIENTS: Thirteen consecutive adult patients undergoing right-heart catheterization and a pulmonary vasodilator trial for the initial evaluation of PAH. INTERVENTIONS: Patients were administered inhaled nitric oxide (iNO), i.v. epoprostenol, and a 3-h infusion of BNP alone and 1 h after an oral dose of the phosphodiesterase-5 inhibitor sildenafil. RESULTS: iNO and sildenafil alone decreased mean pulmonary artery pressure (mPAP) without a significant fall in pulmonary vascular resistance (PVR). Epoprostenol decreased both mPAP and PVR. BNP alone had no significant effect on pulmonary hemodynamics, but the combination of sildenafil plus BNP decreased mPAP and PVR for up to 6 h after stopping BNP. The decrease in mPAP with sildenafil plus BNP (+/- SE) was greater than after 1 h of sildenafil alone (44.6 +/- 3.8 to 40.6 +/- 3.9 mm Hg, p = 0.027). An acute vasodilator response, defined as a decrease in mPAP > 10 mm Hg and end mPAP < 40 mm Hg, was seen in 0 of 8 patients with iNO, 1 of 13 patients with epoprostenol, 0 of 13 patients with BNP, and 4 of 12 patients with sildenafil plus BNP. BNP decreased mean systemic arterial pressure (5.6 +/- 2.8 mm Hg) but had no effect on cardiac output or systemic vascular resistance. CONCLUSIONS: A 3-h BNP infusion does not significantly improve pulmonary hemodynamics in most patients with PAH but is well tolerated and augments the acute pulmonary vasodilator effect of sildenafil.     

Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension

OBJECTIVES: To evaluate the effect of long-term oral therapy with sildenafil in patients with pulmonary arterial hypertension receiving long-term IV epoprostenol. DESIGN: Open, uncontrolled trial. SETTING: University hospital. PATIENTS: Two patients with primary pulmonary hypertension and one patient with pulmonary arterial hypertension after surgical closure of an atrial septal defect. All patients were receiving continuous epoprostenol for 1.7 to 7.1 years; two patients also received inhaled iloprost for 1.8 years and 3.8 years, respectively. INTERVENTIONS: Addition of oral sildenafil, up to 200 mg/d, divided in four to six single doses, and hemodynamic measurements and the 6-min walking distance (6MWD) before and after 5 months of treatment with sildenafil. RESULTS: One patient was treated with sildenafil, 200 mg/d; two patients received 75 mg/d due to nausea and headache. Long-term treatment with sildenafil in the three patients reduced mean pulmonary artery pressure by 14%, 41%, and 22%, respectively; in two patients, pulmonary vascular resistance was decreased by 52% and 55%. The 6MWD increased by 34%, 6%, and 29%, respectively. No significant systemic hypotension or decrease of arterial oxygen saturation was seen. CONCLUSION: Sildenafil therapy may be of benefit in patients with pulmonary arterial hypertension receiving long-term infusion of epoprostenol.     

Sildenafil and an early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets

Devising therapies that might prevent the onset or progression of pulmonary hypertension in newborns has received little attention. Our major objective was to determine whether sildenafil, a selective phosphodiesterase inhibitor, prevents the development of an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs. Another objective was to determine whether sildenafil causes pulmonary vasodilation without systemic vasodilation in piglets with chronic pulmonary hypertension. Piglets were raised in room air (control, n = 5) or 10-11% O(2) (hypoxic, n = 17) for 3 days. Some piglets (n = 4) received oral sildenafil, 12 mg/kg/day, throughout exposure to hypoxia. All piglets were anesthetized and catheterized, and pulmonary arterial pressure (Ppa), pulmonary wedge pressure (Pw), aortic pressure (Ao), and cardiac output (CO) were measured. Then for some piglets raised in hypoxia for 3 days, a single oral sildenafil dose (3 mg/kg, n = 6) or placebo (n = 5) was given, and hemodynamic measurements were repeated. For piglets raised in hypoxia for 3 days, mean Ppa and calculated PVR were elevated above respective values in control piglets. Mean Ppa and PVR did not differ between piglets that received sildenafil throughout exposure to hypoxia and those that did not. For piglets with chronic hypoxia-induced pulmonary hypertension that received a single oral dose of sildenafil, mean Ppa and PVR decreased, while mean Pw, CO, mean Ao, and systemic vascular resistance remained the same. All hemodynamic measurements were unchanged after placebo. Oral sildenafil did not influence the early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. However, a single oral dose of sildenafil caused pulmonary vasodilation, without systemic vasodilation, in piglets with chronic hypoxia-induced pulmonary hypertension, which may have therapeutic implications.     

Hemodynamic and hormonal effects of beraprost sodium, an orally active prostacyclin analogue, in patients with secondary precapillary pulmonary hypertension.

Earlier studies have shown that administration of beraprost sodium (BPS), an orally active prostacyclin analogue, improves hemodynamics in patients with primary pulmonary hypertension (PH), but it is not known whether BPS has beneficial effects in secondary precapillary PH. The present study investigated the hemodynamic and hormonal parameters of 18 patients with secondary precapillary PH (8 patients with chronic thromboembolic PH, 7 with collagen vascular disease, and 3 with residual PH after surgery for atrial septal defect). Hemodynamics were repeatedly measured by right heart catheterization. Treatment with BPS improved New York Heart Association (NYHA) functional class in 10 of the 18 patients and significantly decreased pulmonary vascular resistance by 17% (12.9+/-1.1 to 10.7+/-1.2 Wood units, p<0.01). Circulating brain natriuretic peptide and uric acid significantly decreased from 246+/-61 to 215+/-65 pg/ml and from 6.5+/-0.6 to 5.3+/-0.3 mg/dl, respectively. In summary, BPS therapy improved NYHA functional class, hemodynamics, and hormonal parameters in patients with secondary precapillary PH. Thus, oral administration of BPS may be a new therapeutic strategy for the treatment of secondary precapillary PH.     

Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension

STUDY OBJECTIVES: Different vasodilators and different routes of application are used for the treatment of primary pulmonary hypertension (PPH). Recently, sildenafil, a phosphodiesterase-V inhibitor, has been shown to have beneficial hemodynamic effects in PPH. However, the hemodynamic effects of sildenafil have not been characterized and compared to other vasodilators such as inhaled nitric oxide (iNO) or iloprost in PPH in the same group of patients. STUDY DESIGN: We investigated prospectively 10 consecutive patients with PPH using iNO, iloprost aerosol, and oral sildenafil to test acute hemodynamic response during right-heart catheterization. RESULTS: iNO, iloprost aerosol, and sildenafil caused a significant fall of mean pulmonary artery pressure and pulmonary vascular resistance (PVR) [p < 0.05]. Correspondingly, cardiac output and mixed venous saturation increased slightly in all groups. Systemic arterial pressure and vascular resistance were mainly unaltered. Using a PVR reduction of > or =20% to define a significant response, 7 of 10 patients were responders to iloprost aerosol, whereas 4 of 10 patients responded to iNO and oral sildenafil. Improvement of oxygenation as indicated by an increase of arterial oxygen tension was observed with iloprost aerosol (p < 0.01). CONCLUSION: All of the three substances, iNO, iloprost aerosol, and oral sildenafil, significantly improved pulmonary hemodynamics in patients with PPH. The most prominent hemodynamic effects and improvement of oxygenation were observed with iloprost aerosol.     

Continuous epoprostenol therapy and septal defect closure in a patient with severe pulmonary hypertension

A 31‐year‐old woman with exertional dyspnea diagnosed as having atrial septal defect (ASD) with severe pulmonary hypertension (PH). Intravenous epoprostenol therapy was started to improve PH. Although pulmonary arterial pressure decreased, her symptoms remained in class III of WHO functional class, probably because of exacerbation of the left‐to‐right shunt caused by the reduction of pulmonary vascular resistance (PVR). Transcatheter atrial septal closure was therefore performed. Soon after the procedure, additional reduction in pulmonary arterial pressure was achieved. Her symptoms improved and oxygen inhalation was discontinued. One year after the procedure, although intravenous epoprostenol was still required, her symptoms had improved to class I of WHO functional class without exacerbation of PH. Transcatheter atrial septal closure after lowering PVR by intravenous epoprostenol would be a novel therapy for patients with ASD accompanied by PH. © 2009 Wiley‐Liss, Inc.     

Type 5 phosphodiesterase inhibitors in the treatment of erectile dysfunction and cardiovascular disease

Since the discovery of sildenafil in 1989 as a highly selective inhibitor of the phosphodiesterase type-5 (PDE-5) receptor, 2 additional PDE-5 inhibitors, tadalafil and vardenafil, have emerged as safe and effective treatments of erectile dysfunction (ED). Enzymes in the PDE family catalyze the hydrolysis of the intracellular signaling molecules cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which is the second messenger of nitric oxide (NO) and a principal mediator of smooth muscle relaxation and vasodilation. Sildenafil was initially introduced for clinical use as the result of extensive research on chemical agents targeting PDE-5 that might potentially be useful in the treatment of coronary heart disease. Erection is largely a hemodynamic event, which is regulated by vascular tone and blood flow balance in the penis. Endothelial dysfunction, an early component of atherosclerosis, may inhibit a vascular event such as erection and is rarely confined to the arteries supplying blood to the penis, but more likely occurs throughout the vascular bed. In addition to the effects of the NO-cGMP signaling pathway on cavernosal smooth muscle, clinical findings have suggested that vascular tone in the pulmonary, coronary, and other vascular tissues expressed by PDE-5 is also influenced by this signal transduction mechanism. This has led to the emergence of novel therapeutic indications for sildenafil over a range of cardiovascular conditions that are either well-established risk factors or comorbidities with ED. Recently, the U.S. Food and Drug Administration approved sildenafil as an orally active therapy for the treatment of primary pulmonary hypertension. The drug will be marketed under the trade name of Revatio, not Viagra, the name used for the ED indication. The approved dose for primary pulmonary hypertension is 20 mg 3 times daily.     

静脉注射地尔硫(卓)治疗先天性心脏病合并重度肺动脉高压

目的观察静脉注射地尔硫治疗先天性心脏病合并重度肺动脉高压的疗效。方法通过漂浮导管动态监测12例先天性心脏病合并重度肺动脉高压术后患者应用地尔硫(3~5μg.kg-1.min-1)持续静脉点滴,并记录应用地尔硫前、应用地尔硫后6h、试停呼吸机前、拔除气管插管后1h、24h的平均肺动脉压、平均动脉压、心率、每搏输出量、肺循环阻力、体循环阻力等指标的变化。结果12例患者无死亡,应用地尔硫后平均肺动脉压、肺循环阻力及心率显著降低,每搏输出量及平均动脉压显著增加,体循环阻力无明显改变,未发生肺高压危象。平均呼吸机辅助时间(88.7±50.1)h。结论静脉注射地尔硫能有效控制肺血管痉挛,从而降低肺动脉压,可用于治疗先天性心脏病合并重度肺动脉高压。     

Pulmonary vascular effects of inhaled nitric oxide and oxygen tension in bronchopulmonary dysplasia

Pulmonary hypertension contributes significantly to morbidity and mortality in bronchopulmonary dysplasia (BPD), but little is known about the relative contribution of arterial tone, structural remodeling, and vessel density to pulmonary hypertension, especially in older patients. To determine the role of high pulmonary vascular tone in pulmonary hypertension, we studied the acute effects of oxygen tension, inhaled nitric oxide (iNO), and calcium channel blockers (CCB) in 10 patients with BPD who underwent cardiac catheterization for evaluation of pulmonary hypertension. During normoxic conditions, mean pulmonary arterial pressure (PAP) and pulmonary to systemic vascular resistance ratio (PVR/SVR) were 34 +/- 3 mm Hg and 0.42 +/- 0.07, respectively. In response to hypoxia, PAP and PVR/SVR increased by 50 +/- 8% and 82 +/- 14%, respectively (p < 0.01). Hyperoxia decreased PVR/SVR by 28 +/- 9% (p = 0.05). The addition of iNO treatment (20-40 ppm) to hyperoxia decreased PAP and PVR/SVR by 29 +/- 5% (p < 0.01) and 45 +/- 6% (p < 0.05) from baseline values, respectively, achieving near normal values. CCB did not alter PAP or PVR/SVR from baseline values. We conclude that hyperoxia plus iNO causes marked pulmonary vasodilatation in older patients with BPD, suggesting that heightened pulmonary vascular tone contributes to pulmonary vascular disease in BPD.     

Precapillary pulmonary hypertension: effect of Captopril

The immediate and sustained haemodynamic effects of Captopril (CPT), an oral inhibitor of angiotensin converting enzyme, were studied in six patients (pts) with severe pulmonary hypertension (PH) (pulmonary artery pressure: mean +/- SD value = 57 +/- 20 mmHg). Two pts had primary PH, 2 embolic PH and 2 Eisenmenger Physiology (EP). Administration of 100 mg of CPT in a single oral dose produced a significant decrease only in systemic arterial pressure (SAP) (p less than 0.025) and systemic vascular resistance (SVR) (p less than 0.05) in 5 of 6 pts. Heart rate (HR), cardiac index (CI), pulmonary vascular resistance (PVR), pulmonary arterial (PAP), pulmonary wedge (PWP) and right atrial pressure (RAP) did not change significantly. These results were confirmed in a repeat haemodynamic study after 4 months of long-term treatment with 50 or 100 mg of CPT 3 times daily. In 1 pt with EP and severe congestive heart failure (CHF) the same chronic treatment produced a marked decrease in HR (from 114 to 88 b/min), RAP (from 10 to 1 mmHg), PWP (from 15 to 6 mmHg), PVR (from 41 to 30 UR), SVR (from 58 to 43 UR). Systemic CI increased from 1.68 to 2.60 l/min/m2 and pulmonary CI from 1.64 to 2.5 l/min/m2; no changes were seen in PAP and SAP. These data suggest that CPT is not effective on pulmonary haemodynamics in pts with precapillary PH and normal CI whereas the drug seems to influence favourably the pulmonary circulation in pts with PH secondary to or associated with left ventricular failure. The necessity of evaluating not only PVR but PAP as well, in studying the effect of vasodilators especially in pts with precapillary PH and normal CI, is discussed. In fact a reduction of PAR without decrease of PAP, as frequently seen in previous reports, is probably due to a primary increase of CI induced by the drug.     

Treatment of ethanol-induced acute pulmonary hypertension and right ventricular dysfunction in pigs, by sildenafil analogue (UK343-664) or nitroglycerin

In patients at risk for sudden ethanol (ETOH) intravascular absorption, prompt treatment of pulmonary hypertension (PHTN) will minimise the risk of cardiovascular decompensation. We investigated the haemodynamic effects of intravenous ETOH and the pulmonary vasodilatory effects of a sildenafil analogue (UK343-664) and nitroglycerin (NTG) during ETOH-induced PHTN in pigs. We studied pulmonary and systemic haemodynamics, and right ventricular rate or time derivate of pressure rise during ventricular contraction ( =dP/dT), as an index of contractility, in 23 pigs. ETOH was infused at a rate of 50 mg/kg/min, titrated to achieve a twofold increase in mean pulmonary arterial pressure (MPAP), and then discontinued. The animals were randomised to receive an infusion of 2 ml/kg ( n = 7) normal saline, a 500-microg/kg bolus of UK343-664 ( n = 8), or NTG 1 microg/kg ( n = 8); each was given over 60 seconds. Following ETOH infusion, dP/dT decreased central venous pressure (CVP), and MPAP increased significantly, resulting in significantly increased pulmonary vascular resistance (PVR). Within 2 minutes after treatment with either drug, CVP, heart rate (HR), and the systemic vascular resistance-to-pulmonary vascular resistance (SVR/PVR) ratio returned to baseline. However, at that time, only in the UK343-664 group, MPAP and dP/dT partially recovered and were different from the respective values at PHTN stage. NTG and UK343-664 decreased PVR within 2 minutes, from 1241+/-579 and 1224+/-494 dyne . cm/sec 5 , which were threefold-to-fourfold increased baseline values, to 672+/-308 and 538+/-203 dyne . cm/sec 5 respectively. However, only in the UK343-664 group, changes from baseline PVR values after treatment were significant compared to the maximal change during target PHTN. Neither drug caused a significant change in SVR. In this model of ETOH-induced PHTN, both UK343-664 and NTG were effective pulmonary vasodilators with a high degree of selectivity. However, the changes from baseline values of PVR, and the partial recovery of systemic pressure and RV contractility compared to the maximal change during target PHTN, were significant only in the sildenafil analogue group.     

Efficacy and safety of sildenafil in the evaluation of pulmonary hypertension in severe heart failure

This study sought to evaluate the utility of sildenafil in assessing pulmonary artery reactivity in left-sided cardiac failure and secondary pulmonary hypertension (PH). Fourteen consecutive patients with heart failure were studied, with oral doses of either sildenafil 25 mg (n = 8) or 50 mg (n = 6) every 8 hours for 20% decreases in pulmonary artery pressures. There was also a 20% reduction of the pulmonary vascular resistance/systemic vascular resistance ratio, indicating relative pulmonary artery selectivity. Compared with sildenafil 25 mg, sildenafil 50 mg demonstrated greater reductions of pulmonary pressures. Oral sildenafil is safe and effective for the evaluation of PH reactivity in heart failure.     

Sildenafil improves hemodynamic parameters in COPD--an investigation of six patients

Pulmonary hypertension (PH) is an important predictor of mortality in chronic obstructive pulmonary disease (COPD). The phosphodiesterase 5 inhibitor sildenafil has been demonstrated to reduce pulmonary arterial pressure (PAP) in different diseases. We wanted to investigate the effect of sildenafil on hemodynamic parameters and the 6-min walk test (6 MWT) in six patients with severe COPD and echocardiographically estimated PH. A 6 MWT was performed and hemodynamic parameters were measured by right heart catheterization before and 1 and 12 h after injection of 50 mg sildenafil intravenously. A 3-months period of peroral sildenafil therapy 50 mg twice daily followed and finally hemodynamic parameters and a 6 MWT were repeated. Intravenously applied sildenafil could be demonstrated to reduce PAP and pulmonary vasculature resistance (PVR) significantly. And after 3 months of oral sildenafil, the mean PAP has decreased from 30.2±5.5 mmHg (range: 24–39 mmHg) to 24.6±4.2 mmHg (range: 20–30 mmHg) (p=0.01). The PVR has decreased from 401±108 dyn s cm⁻⁵ (range: 266–558 dyn s cm⁻⁵) to 264±52 dyn s cm⁻⁵ (range: 204–333 dyn s cm⁻⁵) (p<0.05). Physical conditions improved: the 6-min walk distance increased from 351±49 to 433±52 m. In conclusion, in six patients suffering from severe COPD we could demonstrate significantly improved hemodynamic parameters after 50 mg sildenafil intravenous application. And after 3 months of oral sildenafil, walking distance in the 6 MWT increased significantly as well as hemodynamic parameters in the five patients who had accepted a second right heart catheterization.     

Combination therapy with oral sildenafil and beraprost for pulmonary arterial hypertension associated with CREST syndrome

Pulmonary arterial hypertension (PAH) is commonly associated with CREST (Calcinosis, Raynaud phenomenon, Esophageal motility disorders, Sclerodactyly, and Telangiectasia) syndrome. Sildenafil, an oral phosphodiesterase type-5 inhibitor, may offer benefits in the pharmacological management of PAH. However, little is known about the long-term hemodynamic effects of sildenafil, and the potential role of sildenafil in long-term combination with beraprost, an oral prostacyclin analogue, remains unclear. We therefore examined the hemodynamic effect of oral sildenafil alone and when coadministered with beraprost in a patient with PAH associated with CREST syndrome. Traces of the acute hemodynamic effects of beraprost (20 microg) disappeared after 2 hours. In contrast, the acute hemodynamic effects of sildenafil (50 mg) produced a greater reduction in PAP (31%) and PVR (40%), and these effects also disappeared after 5 hours. After 1 month of combination therapy of sildenafil (25 mg) twice daily and beraprost (20 microg) 3 times daily, the fall in pulmonary artery pressure and pulmonary vascular resistance was sustained (31% in both). Furthermore, the patient had significantly improved her 3-minute walk test and NYHA function class without significant adverse effects at the reported doses. The findings indicate that oral sildenafil is a potent pulmonary vasodilator that appears to act synergistically with oral beraprost to cause sustained pulmonary vasodilatation in a patient with PAH associated with CREST syndrome.     

Pilot assessment of the response of several pulmonary hemodynamic variables to sublingual sildenafil in candidates for heart transplantation

OBJECTIVE: To determine the acute vasodilator effect of sublingual sildenafil in heart transplant candidates with severe pulmonary hypertension due to severe left ventricular dysfunction (LVD). BACKGROUND: Pulmonary hypertension confers an increased risk of early graft failure. PATIENTS AND METHODS: Seven patients, (mean age of 53+/-8) with severe LVD (mean EF: 19+/-1.7%, functional class III-IV) due to coronary artery disease, dilated cardiomyopathy and valvulopathy were evaluated for heart transplant. All patients presented a mean transpulmonary gradient >12 mmHg and pulmonary vascular resistances >2.5 W.U., despite full treatment for advanced heart failure. The following hemodynamic data were obtained at basal state and then 15, 30 and 45 min after administration of 100 mg of sublingual sildenafil: right atrial, mean pulmonary artery pressure (mPAP), mean pulmonary capillary wedge pressures, mean transpulmonary gradient (mTPG), blood pressure, cardiac output, pulmonary vascular resistances (PVR) and systemic vascular resistances. Sublingual sildenafil was given without changing the previous treatment of heart failure. RESULTS: After 30 min of sublingual sildenafil, mPAP decreased from 37 (28-61) to 30 (16-42) mmHg and PVR decreased from 5.2 (1.9-13.8) to 2.5 (1.4-3.9) W.U. after 45 min. Mean TPG decreased from 19 (16-33) to 12 (8-14) mmHg at 45 min. Mean pulmonary capillary wedge pressure, cardiac output, systemic vascular resistances and mean blood pressure were unchanged. Sublingual sildenafil was well tolerated, with only transient facial flushing in 4 patients and mild headache in 2. CONCLUSIONS: Based on this initial study, sublingual sildenafil may be a useful alternative drug to perform acute vasodilator test in heart transplant candidates with significant pulmonary hypertension due to severe LVD. Nevertheless, further studies are warranted to confirm our results.     

Long-term outcome of patients operated for large ventricular septal defects with increased pulmonary vascular resistance

BACKGROUND: There is a paucity of data regarding the long-term outcome of patients operated for ventricular septal defect with severe pulmonary arterial hypertension and elevated pulmonary vascular resistance. METHODS AND RESULTS: We evaluated the long-term follow-up results of a selected cohort of patients with nonrestrictive ventricular septal defect and elevated pulmonary vascular resistance (>6 Wood units). Thirty-eight patients, median age 7.5 years (range 6 months-27 years), with nonrestrictive ventricular septal defect with severe pulmonary hypertension were operated between 1985 and 1996 at our institute. Preoperative pulmonary vascular resistance, ratio of pulmonary blood flow to systemic blood flow, and ratio of pulmonary vascular resistance to systemic vascular resistance were 7.63+/-1.8 Wood units, 1.9+/-0.48, and 0.41+/-0.12, respectively. The majority (68.4%) had perimembranous ventricular septal defect. Thirty patients (79%) had a good outcome and were asymptomatic at a mean follow-up of 8.7 years, with significant reduction in pulmonary artery pressures. Eight patients (21%) had a poor outcome, which included 5 immediate postoperative deaths, 1 late death and 2 surviving patients with persistent severe pulmonary arterial hypertension. There was no significant difference regarding hemodynamic parameters at baseline between those who had a good outcome and those who did not. Eleven patients with a preoperative pulmonary blood flow to systemic blood flow ratio of <2:1. who had a good outcome following surgery, underwent repeat catheterization at follow-up. There was a significant reduction in their mean pulmonary vascular resistance (8.03+/-1.4 v. 4.16+/-1.6 Wood units, p=0.001) and pulmonary vascular resistance to systemic vascular resistance ratio (0.41+/-0.12 v. 0.19+/-0.06, p=0.05). CONCLUSIONS: The late results of surgery on this selected group of patients with nonrestrictive ventricular septal defect with high pulmonary vascular resistance are encouraging. Operative correction of the ventricular septal defect should be actively considered in all children presenting with nonrestrictive ventricular septal defect with a significant left-to-right shunt, despite moderately elevated pulmonary vascular resistance. Even among older patients with ventricular septal defect and moderately elevated pulmonary vascular resistance, there is a specific group that does well after operation.