Hemodynamic effects of epoprostenol in patients with systemic sclerosis and pulmonary hypertension

STUDY OBJECTIVES: To determine the cause of pulmonary hypertension (PH) in systemic sclerosis (SSc) patients since PH can occur because of pulmonary arteriopathy, pulmonary parenchymal destruction, and left ventricular cardiac dysfunction. DESIGN AND SETTING: Consecutive case series in a university hospital. PATIENTS: Nine SSc patients with PH (mean pulmonary artery pressure, 41 mm Hg), with (n = 6) or without (n = 3) concomitant interstitial lung disease (ILD). METHODS: Acute infusion of epoprostenol was begun at 2 ng/kg/min and was titrated upward at a rate of 2 ng/kg/min every 30 min until symptomatic complications developed or pulmonary artery vascular resistance (PVR) was reduced by 50%. RESULTS: Eight of nine patients demonstrated a reduction of > or = 20% in PVR, suggesting that vasoreactivity is common despite the presence of significant ILD. A single patient had no response to infusion with unchanged hemodynamics and oxygenation. One patient developed hypoxemia as cardiac output increased, suggesting a worsening of ventilation/perfusion matching or the presence of an anatomic shunt. Acute pulmonary edema developed in one patient at an infusion rate of 6 ng/kg/min. The results of cardiac catheterization suggested that pulmonary edema was caused by SSc heart disease. CONCLUSION: SSc patients with ILD have diverse and sometimes multiple causes of PH that can be determined by short-term epoprostenol infusion. Beneficial effects can be obtained from epoprostenol despite extensive ILD.     

Acute hemodynamic effects of ketanserin in pulmonary hypertension secondary to systemic sclerosis

A selective antagonist of S2-serotonergic receptors, ketanserin, was administered intravenously during right heart catheterization to 14 patients with pulmonary hypertension complicating systemic sclerosis. A significant reduction in pulmonary vascular resistance was noted which was accompanied by an increase in cardiac output. Paradoxical increase of pulmonary artery pressure occurred in 3 patients, whereas 2 patients with mild pulmonary hypertension normalized both pulmonary pressure and vascular resistance. Our data support the hypothesis that serotonin, released during in vivo platelet activation, influences pulmonary vascular tone in systemic sclerosis.     

Acute effects of sildenafil in patients with primary pulmonary hypertension receiving epoprostenol

Epoprostenol therapy has improved survival in primary pulmonary hypertension; however, only two thirds of patients are alive 3 years after starting treatment. Combined therapy with sildenafil, a phosphodiesterase 5 inhibitor, may provide additional benefit. The authors prospectively evaluated the acute hemodynamic and biochemical effects of sildenafil and inhaled nitric oxide, alone and in combination, in 8 patients with primary pulmonary hypertension receiving chronic epoprostenol. Average duration of epoprostenol therapy was 2.9 +/- 1.6 years (mean +/- SD) and mean dose was 25.7 +/- 10.8 ng/kg/min. A single 50 mg dose of sildenafil decreased mean pulmonary arterial pressure 10% (P<.05), increased cardiac output 8%, and decreased pulmonary vascular resistance 24% (P<.005). Although nitric oxide led to a similar decrease in mean pulmonary arterial pressure of 10% (P<.05), cardiac output was unchanged, resulting in a decrease in pulmonary vascular resistance of only 13%, which was not statistically different from baseline. These results suggest that sildenafil has greater acute hemodynamic effects than nitric oxide and that it can further reduce pulmonary vascular resistance in patients already demonstrating a benefit from chronic epoprostenol.     

Prevalence of pulmonary hypertension in systemic sclerosis

OBJECTIVE: To assess the prevalence of pulmonary arterial hypertension (PAH) in patients with the diagnosis of systemic sclerosis (SSc) followed at a tertiary university service. MATERIAL AND METHODS: Fifty-seven patients with SSc were studied by clinical assessment directed at the cardiopulmonary system, pulmonary function tests and Doppler echocardiography (ECHO). The following criteria were considered for the diagnosis of PAH: pulmonary artery systolic pressure (PASP) > or = 40 mmHg and/or the presence of other direct and indirect signs of PAH detected upon ECHO. RESULTS: Sixteen patients (28%) were diagnosed with PAH upon ECHO, 13 based on PASP > or = 40 mmHg and 3 based on direct and indirect signs of PAH; 8 patients had isolated PAH and 8 had PAH secondary to pulmonary fibrosis. Nine patients showed signs suggestive of cor pulmonale upon ECHO; among these patients, 6 had pressure recordings > or = 40 mmHg and 3 had a PSAP between 35 and 40 mmHg; one patient was asymptomatic and 8 showed signs suggestive of PAH upon clinical examination. Among the clinical and laboratory variables studied, a correlation was only observed between PAH and an elevated erythrocyte sedimentation rate (p = 0.004). CONCLUSIONS: The prevalence of PAH associated with SSc observed in this study was similar to those reported in the literature. However, the cut-off of PSAP measured by ECHO and used for the diagnosis of PAH associated with SSc needs to be revised.     

A comparison of nesiritide vs. epoprostenol in a patient with precapillary pulmonary hypertension due to scleroderma complicated by postcapillary pulmonary hypertension

To the best of our knowledge, acute decompensated left-sided heart failure with preserved left ventricular ejection fraction in a patient with scleroderma has not been previously reported. We describe a patient with severe pulmonary hypertension due to limited scleroderma in whom nesiritide led to marked reductions in pulmonary arterial and capillary wedge pressure as well as resolution of symptoms and pulmonary edema. Subsequent epoprostenol use was associated with an increase in pulmonary capillary wedge pressure and a recurrence of pulmonary edema. Thus, nesiritide may be the preferred agent in scleroderma patients with severe pulmonary hypertension and preserved left ventricular systolic function since epoprostenol may lead to adverse hemodynamic effects.     

Low-dose epoprostenol improved pulmonary hypertension in a patient with systemic lupus erythematosus

A 43-year-old Japanese woman was referred to our hospital in 1997 because of Raynaud’s phenomenon. Systemic lupus erythematosus was diagnosed on the basis of the presence of antinuclear antibody (1:1,280), anti-DNA antibody (1:640), anti-Sm antibody, antiphospholipid antibody, lymphopenia, and proteinuria. She developed pulmonary fibrosis in 1999 and pulmonary hypertension in 2001. In October 2002, a 24-hr continuous infusion of epoprostenol was started. Dyspnea, Raynaud’s phenomenon, and pulmonary hypertension improved with low-dose epoprostenol (3.0 to 4.0 ng kg⁻¹ min⁻¹). The patient could not tolerate larger doses of epoprostenol so 4.0 ng kg⁻¹ min⁻¹ was selected as the maintenance dose. The clinical course was uneventful at this dosage. It appears that pulmonary hypertension can be controlled with low-dose epoprostenol such as 3.0 to 4.0 ng kg⁻¹ min⁻¹ in some rheumatic patients.     

Treatment of pulmonary arterial hypertension associated to systemic sclerosis

PURPOSE: Pulmonary arterial hypertension (PAH) is one of the main causes of death in patients with systemic sclerosis (SSc), particularly in its limited forms. CURRENT KNOWLEDGE AND KEY POINTS: Survival with conventional treatment associated with Epoprostenol is two times less in SSc patients than in idiopathic PAH. WHO recommendations (annually heart echoscreening) must be applied in all patients with SSc. Conventional therapy associates anticoagulation, to avoid excessive exertion, pregnancy, warm baths, no pressurised flights. Calcium-channel blockers give long term survival in patients with positive acute vasodilatator test with nitric oxide (NO) but these patients are very rare in SSc. Diuretics are very useful in treating right heart insufficiency. Randomized control trials in PAH have demonstrated the short term efficacy of i.v. epoprostenol, nebulized iloprost, oral beraprost and oral bosentan, a dual endothelin-1 receptor antagonist. Results in SSc are very limited except for i.v. epoprostenol. Long-term efficacy in terms of survival has been demonstrated in non randomized studies for i.v. epoprostenol and oral bosentan in patients with idiopathic and familial PAH. Atrial septostomy and lung transplantation could be an alternative to treatment, even in SSc patients, in case of refractory evolution. FUTURE PROSPECTS AND PROJECTS: Randomized control trials with sildenafil and selective endothelin-1 receptor antagonists are ongoing.     

Oral sildenafil improves primary pulmonary hypertension refractory to epoprostenol.

BACKGROUND: Epoprostenol (prostaglandin I(2)) has become recognized as a therapeutic breakthrough that can improve hemodynamics and survival in patients with primary pulmonary hypertension (PPH). However, a significant number of patients have PPH that is refractory to epoprostenol, and lung transplantation has been the only remaining treatment option. METHODS AND RESULTS: The study subjects included 20 consecutive patients with PPH (mean pulmonary arterial pressure: 65+/-15 mmHg) who had received epoprostenol for more than 12 months. The patients were divided into 2 groups; responders and non-responders. In the non-responders, New York Heart Association (NYHA) functional class did not improve and mean right atrial pressure (mRA) increased to 8 mmHg or more, and additional sildenafil, a phosphodiesterase-5 inhibitor, was started. Six patients were included in the non-responders, whose mRA was 9+/-5 mmHg before and significantly increased to 13+/-3 mmHg after epoprostenol administration (p < 0.05). One patient died and the other 5 patients received oral sildenafil. The mRA of 12+/-4 mmHg (value before sildenafil) improved to 8+/-5 mmHg after sildenafil administration. Three patients were classified in the NYHA functional class 4 and improved to class 3, and 2 patients were in class 3 and remained in the same class after the addition of sildenafil. CONCLUSIONS: In patients with severe PPH refractory to epoprostenol treatment, additional oral sildenafil can improve pulmonary hemodynamics and symptoms. The combination therapy of epoprostenol and sildenafil is a new medical treatment to attempt before progressing to lung transplantation for patients with PPH refractory to epoprostenol.     

Significance of serum uric acid in pulmonary hypertension due to systemic sclerosis: a pilot study

Systemic sclerosis is a connective tissue disease, which may lead to elevated pulmonary arterial pressure due to pulmonary arterial hypertension and/or left ventricular diastolic dysfunction. Uric acid (UA) has been shown to be elevated in patients with pulmonary hypertension (PH) and heart failure. We aimed to investigate the potent relationship between serum UA and pulmonary pressure as well as functional capacity in patients with SSc. We studied 66 patients (mean age 57.7 ± 12.1 years, 63 women), presenting with SSc. Systolic pulmonary artery pressure assessed by echocardiography, lung function tests, six-minute walk test (6MWT) and serum UA levels were recorded in all patients. In 24 (36%) patients, the diagnosis of PH was established by echocardiography (systolic pulmonary artery pressure ≥40 mmHg). Patients with PH had higher UA serum levels compared to patients without PH (5.1 ± 2.1 mg/dl vs. 4.2 ± 0.9 mg/dl, p = 0.04). Among patients with PH, UA values were inversely correlated with the SMWT distance (r = −0.51, p = 0.01). Serum UA values increased in proportion to the functional capacity in PH patients with scleroderma. Further investigations in prospective studies will unfold in detail the pathophysiological significance of UA in SSc patients with PH and determine its role as a prognostic marker in the assessment and monitoring of the disease.     

Long-term effects of epoprostenol on the pulmonary vasculature in idiopathic pulmonary arterial hypertension

The current treatment of pulmonary arterial hypertension (PAH) uses vasodilator drugs. Although they improve symptoms associated with PAH, their chronic effects on the pulmonary vasculature and the right ventricle (RV) in humans remain unknown. We report the autopsy findings from a patient with idiopathic PAH treated with epoprostenol successfully for 18 years. The patient died of colon cancer. The pulmonary vasculature surprisingly showed extensive changes of a proliferative vasculopathy. Immunohistochemical studies confirmed ongoing cellular proliferation. Studies of the RV demonstrated concentric hypertrophy with seemingly preserved contractility. The myocardium shifted to glycolytic metabolism. Although the long-term use of epoprostenol contributed to the patient's increased survival, it did not prevent progression of the underlying vascular disease. Remarkably, the RV was able to sustain a normal cardiac output in the face of advanced vascular pathology. The mechanisms by which the RV adapts to chronic PAH need further study.     

Acute and chronic effects of nitrendipine in patients with precapillary pulmonary hypertension due to pulmonary fibrosis

Eleven patients with histologically confirmed fibrosis of the lung were investigated for the effects of the dihydropyridine calcium antagonist nitrendipine on pulmonary hemodynamics. After 5 mg of acute sublingual nitrendipine, mean pulmonary artery pressure was significantly lowered (p≤0.05) from 32 ± 3 to 29 ± 3 mmHg at rest, and significantly lowered (p≤0.05) during exercise from 55 ± 4 to 49 ± 4 mmHg. Short-term oxygen application at rest significantly reduced this parameter to 28 ± 3 mmHg(p≤0.01). Nitrendipine lowered total pulmonary vascular resistance during both rest (from 412 ± 50 to 351 ± 49 dyn?S?cm^-5; p≤0.05) and exercise (from 433 ± 61 to 383 ± 54 dyn?s?cm^-5; p≤0.05), although it did not affect pulmonary arteriolar resistance. Also, oxygen treatment at rest influenced only total pulmonary vascular resistance (reduction from 412 ± 50 to 373 ± 48 dyn?s?cm^-5; p≤0.01), but not pulmonary arteriolar resistance. Pressure-flow curves, which were derived from cardiac output at rest and during exercise and from the corresponding gradient between mean pulmonary artery pressure and pulmonary capillary wedge pressure, remained unchanged by acute medication. Since a change in arterial oxygen partial pressure was not noticed after nitrendipine, arteriovenous shunting or a worsening of ventilation perfusion relationships can be excluded. Long-term (3 weeks) treatment (double-blind parallel design) with 10 mg of nitrendipine (4 patients) once daily showed no advantage in comparison to placebo (6 patients). From these observations we conclude that the reduction of lower circulatory pressures after nitrendipine is not caused by pulmonary arteriolar vasodilation, but rather by indirect effects due to the reduction of total peripheral resistance and left ventricular filling pressure.     

Hypoxic pulmonary vasoconstriction in systemic sclerosis and primary pulmonary hypertension

Reduction of pulmonary vascular resistance by a high inspired oxygen concentration is a common, but not universal phenomenon in patients with pulmonary vascular disease of varying etiology that may determine their response to long-term domiciliary oxygen therapy. We therefore determined changes in PVR during oxygen therapy in two patient populations not previously studied: systemic sclerosis (n = 8, mean age +/- SEM, 44.5 +/- 5.4 years) and primary pulmonary hypertension (n = 7, mean age +/- SEM 38 +/- 7.8 years). All patients were hypoxemic (arterial oxygen tension, on air 9.5 +/- 1.2 kPa for SSc and 8.3 +/- 0.6 kPa for PPH, p greater than 0.05). Right atrial pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, systemic arterial pressure, PaO2 and cardiac output by thermodilution were measured at three, 20-min intervals while inspiring air and again after inspiring 60 percent oxygen for 30 min. The PVR fell significantly with oxygen in patients with SSc from 797.6 +/- 179.2 to 610 +/- 151.6 dynes/s/cm-5 (p less than 0.01), and this fall correlated with baseline PAP and PaO2 prior to oxygen therapy (r = 0.86, p less than 0.025; r = 0.77, p less than 0.05, respectively). In patients with PPH, there was no significant fall in PVR with oxygen (from 969 +/- 80.2 to 851.9 +/- 91.2 dynes/s/cm-5, p greater than 0.05) and no predictor of a vasodilator response in individual patients. In SSc, hypoxic pulmonary vasoconstriction contributes more consistently to elevated PVR than in patients with PPH.     

Evaluation and management of pulmonary hypertension in systemic sclerosis

This review summarizes the most recent studies on pulmonary hypertension related to systemic sclerosis, emphasizing new insights into pathophysiology, identification of new markers, and advances in the diagnosis and treatment of this complication that greatly worsens the prognosis of patients with systemic sclerosis.     

Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension.

Pathophysiological findings in chronic thromboembolic pulmonary hypertension (CTEPH) have suggested that a secondary small vessel arteriopathy may contribute to the haemodynamic impairment observed in these patients. It was hypothesised that this element of the elevated vascular resistance may be responsive to continuous intravenous epoprostenol therapy. Retrospectively, the clinical and haemodynamic responses to continuous intravenous epoprostenol were evaluated in nine CTEPH patients who subsequently underwent pulmonary thromboendarterectomy (PTE). Cardiopulmonary haemodynamics were determined prior to the initiation of epoprostenol, while on epoprostenol, prior to PTE, and after PTE. Six patients, treated for 2-26 months prior to PTE, experienced either clinical stability or improvement that was associated with a mean reduction in pulmonary vascular resistance (PVR) of 28% (median 33%, range 0-46%). Three patients, treated for 3-9 months, experienced clinical deterioration during epoprostenol administration, with a significant increase in PVR in two patients. Subsequent PTE resulted in a highly significant improvement of cardiac index, mean pulmonary artery pressure and total pulmonary resistance. To conclude, selected patients with chronic thromboembolic pulmonary hypertension may benefit clinically and haemodynamically from continuous intravenous epoprostenol treatment prior to pulmonary thromboendarterectomy. Factors predictive of a beneficial response, and whether this intervention influences either morbidity or mortality associated with pulmonary thromboendarterectomy, remain to be established.