Continuous intravenous epoprostenol therapy for pulmonary hypertension in Gaucher's disease.

Gaucher's disease is a rare disorder characterized by a deficiency of lysosomal beta-glucosidase. Pulmonary hypertension, the etiology of which is unclear, has been reported to occur in association with Gaucher's disease. We report the use of continuous intravenous epoprostenol (prostacyclin), which has been used to treat other forms of pulmonary hypertension, in a patient with pulmonary hypertension associated with Gaucher's disease. Although its mechanism of action remains unknown, epoprostenol may be an effective form of therapy for chronic pulmonary hypertension due to a variety of conditions, one of which is Gaucher's disease.

Recreational use of aminorex and pulmonary hypertension.

Pulmonary hypertension has been associated with ingestion of the appetite suppressant aminorex. A similar compound, 4-methyl-aminorex (street names, "U-4-E-uh" [pronounced euphoria] or "ice"), is a "designer" drug with central stimulant activity. This drug was discovered on the property of three individuals with diagnoses of pulmonary hypertension. The association between "recreational" aminorex manufacture and ingestion and the development of pulmonary hypertension is described.

Epoprostenol for treatment of pulmonary hypertension in patients with systemic lupus erythematosus.

OBJECTIVE: Pulmonary hypertension with pathological changes similar to those observed in primary pulmonary hypertension occurs in patients with systemic lupus erythematosus (SLE). The efficacy of chronic epoprostenol therapy in SLE has not been well described. The objective of this paper is to describe our experience with long-term epoprostenol therapy in patients with pulmonary hypertension associated with SLE. DESIGN: Case series of six patients with SLE and associated pulmonary hypertension receiving chronic treatment with epoprostenol. RESULTS: All 6 patients had severe pulmonary hypertension. Mean pulmonary artery pressure (mPAP) was 57 +/- 9 mm Hg (mean +/- SD), and pulmonary vascular resistance was 14 +/- 7 units before beginning therapy with epoprostenol. In 4 patients who underwent repeat hemodynamic evaluation (9 to 16 months after starting epoprostenol), mean pulmonary artery pressure decreased by 38 +/- 21% and pulmonary vascular resistance by 58 +/- 12%. Clinically, all patients improved from New York Heart Association class III or IV to class I or II. Doses of epoprostenol ranged from 4 to 46 ng/kg/min, and the longest duration of therapy has been 2.5 years. Side effects from epoprostenol have not differed from those seen in patients with primary pulmonary hypertension, and except for one patient, there has been no exacerbation of SLE. CONCLUSION: Epoprostenol was effective for the treatment of pulmonary hypertension in this small group of patients with SLE. Further evaluation of epoprostenol therapy for patients with SLE and other diseases associated with pulmonary hypertension is warranted.

Anastomotic pulmonary hypertension after lung transplantation for primary pulmonary hypertension: report of surgical correction.

This report describes a patient who developed pulmonary hypertension 6 years after lung transplantation for primary pulmonary hypertension (PPH). Evaluation with right heart catheterization followed by pulmonary angiography, however, demonstrated that the pulmonary hypertension was secondary to an anastomotic narrowing of the pulmonary artery, rather than a recurrence of her PPH. Vascular complications of lung transplantation should be considered in patients who experience exertional dyspnea after lung transplantation. The suggestion of pulmonary hypertension on echocardiography should prompt further evaluation, including meticulous hemodynamic measurements.

Primary pulmonary hypertension is not associated with scleroderma-like changes in nailfold capillaries.

STUDY OBJECTIVES: To determine whether primary pulmonary hypertension (PPH) is associated with scleroderma-like changes in nailfold capillaries. DESIGN: Blinded, prospective, case-control study. SETTING: University medical centers in Baltimore, MD. PATIENTS: Thirty-seven patients with PPH, 15 patients with scleroderma, and 13 healthy control subjects. MEASUREMENTS: Subjects underwent nailfold capillary videomicroscopy of the fourth digits of both hands. Capillary images were evaluated by two blinded, trained graders according to standardized criteria for the presence of scleroderma nailfold changes. RESULTS: The prevalence of scleroderma-associated nailfold changes in patients with PPH (1 of 37 patients) was dramatically lower than that in patients with scleroderma (9 of 15 patients; p < 0.0001). The distribution of nailfold grades for the PPH patients was indistinguishable from that of the healthy control subjects. CONCLUSION: PPH is not associated with scleroderma-like vasculopathy of nailfold capillaries.

Increased levels of prostaglandin D(2) suggest macrophage activation in patients with primary pulmonary hypertension.

STUDY OBJECTIVE: TXA(2) (thromboxane A(2)) is a lipid mediator believed to be produced primarily by platelets in normal subjects, although macrophages are capable of synthesis. There is increased production of TXA(2) in patients with primary pulmonary hypertension (PPH), which may reflect augmented production by macrophages. The objective of this study was to determine if macrophages are activated in PPH and whether they contribute to the increased production of TXA(2). STUDY TYPE: Case control. SETTING: University hospital. METHODS: We measured the urinary metabolites of three mediators that predominantly derive from different cell types in vivo: (1) TX-M (platelets and macrophages), a TXA(2) metabolite; (2) prostaglandin D(2) (PGD(2)) metabolite (PGD-M); and (3) N-methylhistamine (mast cells), a histamine metabolite, in 12 patients with PPH and 11 normal subjects. RESULTS: The mean (+/- SEM) excretion of both TX-M and PGD-M at baseline was increased in PPH patients, compared to normal subjects (460 +/- 50 pg/mg creatinine vs 236 +/- 16 pg/mg creatinine [p = 0.0006], and 1,390 +/- 221 pg/mg creatinine vs 637 +/- 65 pg/mg creatinine [p = 0.005], respectively). N-methylhistamine excretion was not increased compared to normal subjects. There was a poor correlation between excretion of TX-M and PGD-M (r = 0.36) and between excretion of PGD-M and methylhistamine (r = 0.09) in individual patients. CONCLUSION: In patients with PPH, increased levels of PGD-M, without increased synthesis of N-methylhistamine, suggest that macrophages are activated. The lack of correlation between urinary metabolite levels of TXA(2) and PGD(2) implies that macrophages do not contribute substantially to elevated TXA(2) production in patients with PPH. They may, however, have a role in the pathogenesis and/or maintenance of PPH, which warrants further investigation.

The influence of continuous intravenous prostacyclin therapy for primary pulmonary hypertension on the timing and outcome of transplantation.

BACKGROUND: Primary pulmonary hypertension (PPH) is a progressive disease with a median survival of less than 3 years from diagnosis. Medical management has typically consisted of anticoagulation and oral calcium channel blocking agents, whereas lung transplantation (LT) has been reserved for patients who are unresponsive to medical therapy. Continuous intravenous prostacyclin was introduced for patients who did not respond to calcium channel blockers and who would have required LT. We reviewed our experience with prostacyclin in LT candidates to study its effects on the timing and outcome of LT. METHODS: We retrospectively reviewed the clinic and hospital records of patients with PPH who were both treated with prostacyclin and evaluated for LT. Additional information was obtained from the pulmonary vascular disease and lung transplantation databases. RESULTS: A total of 42 patients were identified who received prostacyclin for the treatment of PPH and were evaluated for LT. Thirty-seven patients were accepted as LT candidates, 22 at The University of Maryland Medical Center (UMMC), 15 at other LT programs. Overall, 70% (27/37) of LT candidates were removed from the LT waiting list or had listing for LT deferred because of clinical improvement. In patients listed for LT before initiation of prostacyclin therapy, 55% (12/22) were removed from the active waiting list for 27.2+/-17 months (range 8 to 60), and 92% (11/12) remain on the inactive status. In patients who received prostacyclin before listing for LT, listing for LT was deferred in 94% (14/15) for 17.4+/-9 months (range 6 to 33 months) because of clinical stability or improvement. In all, 93% of patients (39/42) experienced an improvement in 1 or more New York Heart Association functional class. The hemodynamic profiles of the eight patients removed from the active waiting list at UMMC demonstrated increases of 55%+/-18% in cardiac output, and decreases of 14.3%+/-4.9% in mean pulmonary artery pressure and 36%+/-8.3% in total pulmonary resistance (p < 0.05). The 1-year survival rate for LT after prostacyclin therapy was 88% (7/8) at UMMC and 60% (3/5) at the other centers. CONCLUSION: We conclude that prostacyclin therapy is an effective means of delaying, possibly indefinitely, the need for LT in patients with PPH and that excellent results can be obtained when LT is performed after prostacyclin therapy. Consideration should be given to initiating prostacyclin therapy in all patients whose conditions do not respond to conventional therapy before proceeding with transplantation.

Medical and surgical treatment options for pulmonary hypertension.

Significant advances in the treatment of pulmonary hypertension have been achieved in the past decade. Approximately one quarter of patients with primary pulmonary hypertension (PPH) can be effectively managed with chronic calcium channel blocker therapy; for the remainder, transplantation or continuous intravenous epoprostenol are complex but effective approaches. Epoprostenol therapy was initially envisioned as a bridge to transplantation, but recent experience has established this approach as an alternative to transplantation in some patients, with comparable survival rates. Not all patients derive benefit from epoprostenol, however, and adverse effects are common. Accordingly, patients who fall into New York Heart Association Functional Classes III and IV and who are refractory to oral vasodilator therapy should be evaluated both for the initiation of epoprostenol therapy and concurrent listing for transplantation. By delaying or avoiding transplantation through the use of epoprostenol, these patients may also benefit from ongoing research that targets novel therapeutic approaches and less cumbersome delivery mechanisms. Thus, epoprostenol may serve as a bridge to transplantation for some patients and to newer therapeutic options for others.

Lung transplantation and systemic sclerosis.

We performed lung transplantation in nine patients with Scleroderma related lung disease. Patient characteristics included: 7 (78%) females, 6 (67%) with limited and 3 (33%) with diffuse Scleroderma. Pulmonary fibrosis was present in 7 (78%) and pulmonary hypertension in 4 (44%). All patients were carefully screened by the Johns Hopkins and University of Maryland Scleroderma Center and only referred for transplantation when concomitant renal insufficiency (creatinine clearance < or = 50 ml/min), aspiration, and skin brakdown were excluded. When compared to a similar group of transplant patients with nonscleroderma lung disease (primary pulmonary fibrosis), there was no significant difference in post-transplant survival at four years (76.2 +/- 0.15% vs. 69.2% +/- 0.12%), mean annual incidence rate for acute rejection (0.14 +/- 0.14 vs. 0.47 +/- 0.13) and infection (viral 0.17 +/- 0.17 vs. 0.29 +/- 0.11) (bacterial 0.17 +/- 0.17 vs. 1.4 +/- 0.4) (fungal 0.99 +/- 0.69 vs. 0.36 +/- 0.16) or serum creatinine (1.55 +/- 0.34 mg/dl vs. 1.15 +/- 0.09 mg/dl). We conclude that lung transplantation is viable option for carefully selected patients with scleroderma related lung disease.

Sitaxsentan: an endothelin-A receptor antagonist for the treatment of pulmonary arterial hypertension.

Endothelin (ET-1) is a potent vasoconstrictor and smooth muscle mitogen that mediates its effects through activation of ET-A and ET-B receptors. Pulmonary arterial hypertension (PAH) encompasses a heterogeneous group of disorders characterised by inappropriate overactivation of the ET system. There is clear evidence that strategies that block both ET receptors are associated with clinical improvement in PAH. However, there are theoretical physiological advantages to treatments that specifically inhibit only the ET-A receptor. Sitaxsentan is an orally active selective ET-A receptor antagonist that in recent clinical trials has demonstrated improvements in exercise capacity, functional class and haemodynamics in PAH patients with modified New York Heart Association class II, III and IV symptoms.

Primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a progressive disease characterised by raised pulmonary vascular resistance, which results in diminished right-heart function due to increased right ventricular afterload. PPH occurs most commonly in young and middle-aged women; mean survival from onset of symptoms is 2-3 years. The aetiology of PPH is unknown, although familial disease accounts for roughly 10% of cases, which suggests a genetic predisposition. Current theories on pathogenesis focus on abnormalities in interaction between endothelial and smooth-muscle cells. Endothelia-cell injury may result in an imbalance in endothelium-derived mediators, favouring vasoconstriction. Defects in ion-channel activity in smooth-muscle cells in the pulmonary artery may contribute to vasoconstriction and vascular proliferation. Diagnostic testing primarily excludes secondary causes. Catheterisation is necessary to assess haemodynamics and to evaluate vasoreactivity during acute drug challenge. Decrease in pulmonary vascular resistance in response to acute vasodilator challenge occurs in about 30% of patients, and predicts a good response to chronic therapy with oral calcium-channel blockers. For patients unresponsive during acute testing, continuous intravenous epoprostenol (prostacyclin, PGI2) improves haemodynamics and exercise tolerance, and prolongs survival in severe PPH (NYHA functional class III-IV). Thoracic transplantation is reserved for patients who fail medical therapy. We review the progress made in diagnosis and treatment of PPH over the past 20 years.

Lung transplantation for pulmonary hypertension.

Although lung transplantation is a viable option for patients with end-stage pulmonary hypertension, it is associated with numerous problems including infection, rejection, and limited long-term survival. Because of these limitations, transplantation should only be considered for patients who are failing maximal medical therapy. Treatment options for patients with pulmonary hypertension that may serve to prolong or obviate the need for transplantation include anticoagulation with warfarin, diuretics, and vasodilators such as calcium channel blockers or continuous intravenous epoprostenol (prostacyclin). The response to medical therapy should be assessed at regular intervals by evaluating exercise tolerance and hemodynamic parameters. Because waiting periods for transplantation now exceed 1.5 to 2 years in the United States, and the response to medications is unpredictable, referral for transplantation should occur when patients become symptomatic. Those who are responding well to medical therapy should be removed from the active transplant waiting list, whereas those who fail therapy should go on to transplant. Utilizing medical therapy and transplantation as complementary treatments will achieve the best potential to improve quality of life and prolong survival.

Hypoxic pulmonary endothelial cells release a diffusible contractile factor distinct from endothelin.

Hypoxia (0% O2) evokes a late-phase, endothelium-dependent contractile response in porcine isolated pulmonary arteries that may be caused by a cyclooxygenase-independent, endothelium-derived contractile factor. The aim of this study was to further analyze the mechanism underlying this hypoxic response. Proximal porcine pulmonary arterial rings were suspended for isometric tension recording in organ chambers. Hypoxia (0% O2) caused a late-phase, endothelium-dependent contractile response that was not inhibited by the endothelin (ET)A-receptor antagonist BQ-123 (10(-6) M), by the ETB-receptor antagonist BQ-788 (10(-7) M), or by their combination. In contrast, ET-1 caused a concentration-dependent contraction of arterial rings that was inhibited by BQ-123 (10(-6) M) and a relaxation that was abolished by BQ-788 (10(-7) M) or by endothelial cell removal. Therefore, the endothelium-dependent contraction to hypoxia is not mediated by ET. Hypoxia caused only relaxation in endothelium-denuded rings. However, when a pulmonary valve leaflet, a rich source of pulmonary endothelial cells, was placed into the lumen of endothelium-denuded rings, hypoxia caused a late-phase contractile response that was similar to that observed in arterial rings with native endothelium. This hypoxic contraction persisted in the presence of indomethacin (10(-5) M) and N-nitro-L-arginine methyl ester (3 x 10(-5) M) to block cyclooxygenase and nitric oxide synthase, respectively. These results suggest that hypoxic contraction of pulmonary arteries is mediated by a diffusible, contractile factor released from hypoxic endothelial cells. This contractile mediator is distinct from ET.

Short-term outcome and predictors of adverse events following pulmonary thromboendarterectomy.

Pulmonary complications including hypoxemia, right heart failure, and prolonged ventilation may follow pulmonary thromboendarterectomy (PTE) performed via cardiopulmonary bypass (CPB) with deep hypothermic circulatory arrest. Seventeen adult patients have undergone PTE at the University of Maryland Medical System during the preceding 3 years. From these patients, clinical and hemodynamic parameters were tabulated pre-CPB, post-CPB, at admission to the intensive care unit (ICU), and prior to discontinuation of invasive monitoring in the ICU. Data on anthropometric variables, survival, and times of extracorporeal circulation, mechanical ventilation, and hospital stay were also collected. The mean values for pulmonary arterial systolic and diastolic pressures and pulmonary vascular resistance (PVR) decreased significantly from pre-CPB values after PTE (all p < 0.05). Mild mixed acidosis present at ICU admission resolved prior to discharge (p = 0.002). The length of mechanical ventilation time was positively correlated with the absolute post-CPB PVR and negatively correlated with the relative change in central venous pressure (CVP) from pre-CPB to post-CPB values (r = 0.75, p = 0.037). Of the pre-CPB anthropometric variables, only body mass index was significantly higher in nonsurvivors (p = 0.037). Pulmonary artery pressures and vascular resistance fall significantly after PTE. A lower post-CPB PVR and a relatively decreased (i.e., from pre-CPB values) CVP predict reduced length of postoperative ventilation but not of the hospital stay. Mortality appears increased in patients with a large body habitus.