Rituximab treatment of pulmonary arterial hypertension associated with systemic lupus erythematosus: a case report.

Pulmonary hypertension is a common but underdiagnosed complication of systemic lupus erythematosus, which can be associated with significant morbidity and early mortality. Although often associated with anti-phospholipid antibodies, the etiology remains poorly understood. In case reports and small open trials, the anti-CD20, B-cell targeted therapeutic antibody, rituximab, has been reported to provide benefits for systemic lupus erythematosus patients with glomerulonephritis, anti-phospholipid antibody syndrome, vasculitis, arthritis, and refractory skin disease. However, the outcome of rituximab treatment of pulmonary arterial hypertension associated with systemic lupus erythematosus has not been described. We, therefore, present a case of a young systemic lupus erythematosus patient with early onset of pulmonary arterial hypertension during the disease course, refractory to multiple treatment modalities, who had significant improvement with rituximab therapy.

Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2.

The efficacy and safety of combining bosentan, an orally active dual endothelin receptor antagonist and epoprostenol, a continuously infused prostaglandin, in the treatment of pulmonary arterial hypertension (PAH) was investigated. In this double-blind, placebo-controlled prospective study, 33 patients with PAH started epoprostenol treatment (2 ng.kg(-1)min(-1) starting dose, up to 14+/-2 ng.kg(-1)min(-1) at week 16) and were randomised for 16 weeks in a 2:1 ratio to bosentan (62.5 mg b.i.d for 4 weeks then 125 mg b.i.d) or placebo. Haemodynamics, exercise capacity and functional class improved in both groups at week 16. In the combination treatment group, there was a trend for a greater (although nonsignificant) improvement in all measured haemodynamic parameters. There were four withdrawals in the bosentan/epoprostenol group (two deaths due to cardiopulmonary failure, one clinical worsening, and one adverse event) and one withdrawal in the placebo/epoprostenol group (adverse event). This study showed a trend but no statistical significance towards haemodynamics or clinical improvement due to the combination of bosentan and epoprostenol therapy in patients with pulmonary arterial hypertension. Several cases of early and late major complications were reported. Additional information is needed to evaluate the risk/benefit ratio of combined bosentan-epoprostenol therapy in pulmonary arterial hypertension.

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.

Single arterial occlusion to locate resistance in patients with pulmonary hypertension.

The purpose of this study was to determine the site of increased resistance using the arterial occlusion technique in patients with severe pulmonary hypertension. Pulmonary vascular resistance was partitioned in arterial and venous components based on double exponential fitting analysis of the pulmonary artery pressure decay curve: after balloon occlusion in 36 patients with pulmonary arterial hypertension (PAH); at baseline and during the inhalation of 20 parts per million of nitric oxide (NO); in four patients with chronic thromboembolic pulmonary hypertension; and in two patients with pulmonary veno-occlusive disease. In the patients with PAH, at baseline, mean pulmonary artery pressure was 56+/-2 mmHg (mean+/-SE), with an arterial component of resistance of 63+/-1%. Inhaled NO did not change the partition of resistance. The arterial component of resistance amounted on average to 42% and 77% in the patients with veno-occlusive disease and the patients with thromboembolic pulmonary hypertension, respectively. However, the partitioning of resistance did not discriminate between these three diagnostic categories. The occlusion technique may help to locate the predominant site of increased resistance in patients with severe pulmonary hypertension, but does not allow for a satisfactory differential diagnosis on an individual basis.

Outpatient inhaled nitric oxide in a patient with idiopathic pulmonary fibrosis: a bridge to lung transplantation.

Inhaled nitric oxide (INO) has been shown to improve oxygenation and decrease intrapulmonary shunt and pulmonary hypertension in various lung diseases. In this study we report a patient with end-stage idiopathic pulmonary fibrosis and pulmonary hypertension who received INO after coronary artery bypass surgery, with significant improvement in arterial oxygenation and pulmonary arterial pressure. Using a pulsing delivery system, the patient continued to receive outpatient INO for 30 months while waiting for lung transplantation. Exercise study and two-dimensional echocardiogram, after 3 months of inhaled NO, demonstrated continued benefits of INO for improvement of arterial oxygenation, pulmonary arterial pressure and exercise tolerance.

New and experimental therapies for pulmonary hypertension.

Advances in the understanding of the molecular and cellular pathogeneses of PPH have led clinicians beyond simple pulmonary vasodilation as the only treatment for PPH and to a realization that what were previously believed to be irreversible vascular lesions may, in fact, be reversible. The development of agents that target the known endothelial and nonendothelial defects in patients with PPH is well underway. Clinicians are witnessing an exciting new era for physicians and patients dealing with this disease.

Chronic thromboembolic pulmonary hypertension.

Remarkable advances have occurred over the past 2 decades in the diagnostic approach, surgical management, and postoperative care of patients afflicted with chronic thromboembolic pulmonary hypertension. Despite these advances, a great deal needs to be achieved if the morbidity and mortality of the disease process are to be reduced further. First, the preliminary insights that have been achieved into the natural history of the disease must be defined further. The level of pulmonary hypertension encountered in most patients with chronic thromboembolic pulmonary hypertension at the time of initial clinical recognition cannot be reached on an acute basis. Gradual hemodynamic progression, therefore, must occur over time. The basis for this progression, why it occurs in certain patients and not others, following an acute thromboembolic event and why it seems to occur over months in certain patients and over decades in others, remain entirely speculative. It is possible that the overall extent of central pulmonary vascular obstruction represents the primary pathophysiologic determinant of disease progression. Given the lack of correlation between the degree of central thromboembolic obstruction and hemodynamic impairment in certain patients, however, it is also possible that other factors, such as the circulating vasoconstrictors, the development of a hypertensive pulmonary arteriopathy, an individual genetic predisposition to pulmonary hypertension, or the compensatory adaptations of the right ventricle, contribute to the extent and rate of disease progression. By identifying and sequentially evaluating patients with persistent pulmonary vascular obstruction or pulmonary hypertension following an acute thromboembolic event, valuable insights into the natural history of thromboembolic pulmonary hypertension and other variants of pulmonary hypertension might be achieved. It is also important to recognize that the development of chronic thromboembolic pulmonary hypertension represents a failure in the long-term management or follow-up surveillance of those with documented acute thromboembolic disease. Recent insights into the recurrent nature of acute thromboembolic disease and its potential for only partial resolution in a number of afflicted individuals suggest that a repeat perfusion scan and, if abnormal, an echocardiogram be performed at the time of anticipated discontinuation of anticoagulation in patients with documented pulmonary embolic disease. Although the cost-effectiveness of this approach has been questioned in the past, recent data suggest that doing so would help identify that subset of patients with unresolved embolism, provide additional information regarding the optimal duration of anticoagulation, and provide a new baseline study for patients in whom anticoagulation is discontinued and who subsequently present with suspected embolic recurrence. Improved diagnostic techniques are also necessary if the mortal risk of thromboendarterectomy is to be reduced. Even in the setting of a broad experiential base, prognostic uncertainty exists in approximately 10% of patients before operative intervention. Because many of these patients will benefit from the procedure, and because many are ineligible for transplantation for reason of age or other restriction, it has been the authors' practice to offer surgery to these patients, although at an assumed higher risk. To not do so would be to deny a potentially lifesaving procedure to many who would benefit and who might be left without an effective therapeutic alternative. The ability to better define the group of patients who will not benefit from surgery, however, would spare those patients the morbid and mortal risks of the procedure and provide a basis for the investigation of other therapeutic alternatives such as pulmonary vasodilating agents. Finally, this patient population offers a unique opportunity to enhance understanding of the pathophysiologic mechanisms involved in acute lung injury. The population involved is uniform, the predisposing event is consistent, the time of onset is predictable, and, compared with other populations at risk for acute lung injury, the presence of confounding variables is negligible. It also provides a unique opportunity to evaluate pharmacologic interventions designed to prevent or diminish the occurrence of acute lung injury and postoperative management strategies designed to minimize its impact.

Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.

BACKGROUND: Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension. METHODS: In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat. FINDINGS: In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], p=0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups. INTERPRETATION: Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.

"High probability" perfusion lung scans in pulmonary venoocclusive disease.

"High-probability" ventilation/perfusion (V/Q) lung scans generally indicate proximal pulmonary arterial occlusion by thromboemboli or, rarely, other processes such as tumors, fibrosing mediastinitis, or vasculitis. In this report we describe three patients with high probability V/Q scans in whom pulmonary angiography failed to demonstrate arterial occlusion. All three patients were determined to have pulmonary venoocclusive disease (PVOD). In two patients, a tissue diagnosis of PVOD was made, in one case with explanted tissue taken after a successful heart-lung transplant and in the other case with tissue taken at autopsy. PVOD in the third patient was diagnosed with pulmonary venography. A potential explanation for the discrepancy between perfusion lung scan and pulmonary angiographic findings in PVOD is discussed.

Pulmonary vascular remodeling distal to pulmonary artery ligation is accompanied by upregulation of endothelin receptors and nitric oxide synthase.

There is increasing evidence that the pathogenesis and progression of many forms of pulmonary vasculopathy are related to abnormalities in endothelial mediators, including endothelin-1 (ET-1) and nitric oxide (NO). Using a rat model of chronic unilateral pulmonary artery ligation, we investigated the role of ET-1 and NO in postobstructive pulmonary vasculopathy (POPV). Eight months after a left thoracotomy with either left main pulmonary artery ligation (ligated group) or no ligation (sham group), rat lungs, including those contralateral to the ligation (hyperperfused group), were fixed and mounted for histologic sectioning. Morphometric measurements were carried out by computer-assisted image analysis and immunohistochemical staining was performed using specific antibodies against ET-1, ETA, and EBB receptors, and endothelial NO synthase (eNOS). Compared to sham lungs, the ligated lungs showed (1) an increase in muscular, adventitial, and intimal thickness of pulmonary artery; (2) increase in external diameter of the bronchial artery (39.8 +/- 2.2 microns vs. 16.8 +/- 0.9 microns in sham group; P < .005) and number of bronchial arteries per bronchiole (3.21 +/- mu 0.26 vs. 1.86 +/- mu 0.21 in sham group; P < .001); and (3) increase in the intensity of eNOS and ETA, B receptor immunoreactivity. No morphometric or immunohistochemical differences were observed between the hyperperfused and sham lungs. These findings suggest that increased synthesis of endothelial NO may serve as a compensatory mediator in ET-1-mediated vascular remodeling.

The use of cylexin (CY-1503) in prevention of reperfusion lung injury in patients undergoing pulmonary thromboendarterectomy.

Pulmonary thromboendartectomy (PTE) for chronic thromboembolic pulmonary hypertension may be complicated by reperfusion lung injury. This has previously been demonstrated to be neutrophil-mediated. We postulated that blocking selectin-mediated adhesion of neutrophils to the endothelium with Cylexin (CY-1503) would prevent reperfusion lung injury in this patient population. In this double-blind, randomized, placebo-controlled, parallel study, 26 patients received Cylexin the day of surgery and 25 received placebo. Significantly fewer patients in the treated group (31%) compared with the placebo group (60%) developed lung injury (p = 0.036). However, the average number of days of mechanical ventilation, days in the intensive care unit (ICU) and hospital, as well as mortality were not significantly different between the treatment groups. Those with reperfusion lung injury had significantly elevated percent neutrophils, total protein, and soluble P-selectin in bronchoalveolar lavage fluid compared with those without lung injury. We conclude that reperfusion lung injury after PTE is a high-permeability lung injury and its incidence can be reduced by the administration of Cylexin on the day of surgery.

Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension.

It is well known that endothelin (ET)-1 mediates vascular remodelling in various kinds of clinical and experimental pulmonary hypertension. The aim of this study was to investigate whether ET-1 is associated with the development of pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. Pulmonary hypertension was induced in 10 mongrel dogs by repeated embolization with ceramic beads. In five of the dogs, bosentan, a nonselective ET receptor antagonist, was administered throughout the study. Haemodynamic measurements and plasma ET-1 assays were performed every 2 months. Eight months after initial embolization, computer-assisted morphometry and immunohistochemistry were performed on the lung tissue including that from three control dogs. Pulmonary arterial pressure and pulmonary vascular resistance were increased in all embolized dogs, compared to baseline. In nontreated embolized dogs, plasma ET-1 concentration and pulmonary arterial wall thickness were increased compared to control animals, and ET-1 immunoreactivity was detected in thickened pulmonary arteries. In bosentan treated dogs, pulmonary arterial walls were not significantly thickened. Pulmonary vascular remodelling, associated with elevated plasma endothelin-1 levels and positive endothelin-1 immunoreactivity in lung tissue is attenuated by the endothelin receptor antagonist, bosentan. These findings suggest that endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension.

Identifying the cause of unilateral hypoperfusion in patients suspected to have chronic pulmonary thromboembolism: diagnostic accuracy of helical CT and conventional angiography.

PURPOSE: To determine the prevalence of unilateral hypoperfusion in patients suspected to have chronic thromboembolism (CTE), to identify the most common cause of hypoperfusion, and to compare the accuracy of helical computed tomographic (CT) angiography with that of conventional angiography in helping to determine the cause. MATERIALS AND METHODS: Radionuclide lung scan reports showed asymmetric hypoperfusion in 47 of 410 consecutive patients referred because of suspected CTE. Twenty-seven patients had unilateral or predominantly unilateral perfusion abnormalities. Each pulmonary angiogram and CT angiogram in these patients was interpreted independently by two readers blinded to clinical information and surgical outcome. Surgical confirmation of the diagnosis was available in 39 of the 47 patients with asymmetric hypoperfusion. RESULTS: Unilateral (n = 11) or predominantly unilateral hypoperfusion (n = 16) was found in 6.6% (27 of 410 patients) of patients referred, and CTE was the most common cause. The accuracies of CT angiogram readers (reader 1, 83%; reader 2, 89%) were greater than those of conventional angiogram readers (reader 1, 73%; reader 2, 65%) for distinguishing CTE from other causes. CONCLUSION: Unilateral hypoperfusion occurred in 6.6% of our study population, most frequently because of CTE. CT angiography is an excellent diagnostic alternative to conventional angiography for distinguishing patients with CTE from those with other causes.

Reoperative pulmonary thromboendarterectomy.

BACKGROUND: Recurrent symptomatic pulmonary hypertension is uncommon after primary pulmonary thromboendarterectomy (PTE). We reviewed our experience with patients undergoing repeat PTE to determine the risk factors for recurrent disease, and the selection criteria, relative risks, and functional outcomes of reoperative PTE. METHODS: Since 1990, 13 of 870 (1.5%) patients underwent reoperative PTE at our institution. These 7 men and 6 women (mean age 38.6 years) were contrasted with the most recent 225 patients (111 men, 114 women, mean age 52.7 years) who underwent primary PTE for whom complete hemodynamic data are available. The preoperative evaluation of all patients was similar. Pulmonary hemodynamic data and outcome measures were compared between groups. RESULTS: Of 13 reoperated patients: 69% (9/13) had their primary operation at another institution, 54% (7/13) initially underwent unilateral PTE, 38% (5/13) had identifiable coagulation disorders, 38% (5/13) had ineffective caval filtration, 31% (4/13) had suboptimal anticoagulation management, and 31% (4/13) had complete unilateral pulmonary artery obstruction. The mean interval to reoperation was 5.2 years (range 0.7 to 10.9 years). All control patients underwent bilateral PTE using hypothermic circulatory arrest. Operative mortality was 7.7% (1/13) with reoperation vs 8.4% (19/225) in controls. No difference (p = NS) was observed between groups in the preoperative pulmonary artery pressure (PAP) or pulmonary vascular resistance; however, the control group had a significantly (p < 0.05) greater reduction in the postoperative PAP (46/19, mean 28 mm Hg vs 59/23, mean 35 mm Hg) and PVR (271 +/- 172 vs 399 +/- 154 dynes/s/cm(-5)) compared with the redo group. No substantial difference in morbidity or functional outcomes was observed between groups. CONCLUSIONS: Reoperative PTE can be performed with a perioperative risk comparable with primary PTE, although the improvement in pulmonary hemodynamics is not as favorable. Bilateral primary operation, effective caval filtration, and vigilant anticoagulant management would prevent the need for most reoperative PTEs.

Atrial septostomy as a bridge to lung transplantation in patients with severe pulmonary hypertension.

Long waiting times for lung transplantation have limited the survival of patients with advanced pulmonary hypertension. Atrial septostomy has been used in this group of patients in an attempt to prolong survival. We evaluated the results of atrial septostomy in 12 patients using the static graded balloon dilation technique. Between December 1990 and May 1998, 10 women and 2 men (ages 13 to 56 years, mean 37 years) underwent atrial septostomy. Nine patients had primary and 3 patents had secondary pulmonary hypertension. Five patients deteriorated despite long-term intravenous prostacyclin infusions. The atrial septum was crossed with a Brockenbrough needle, followed by an 0.035-J exchange wire and progressively larger catheter balloons for atrial septal dilation, until systemic oxygen saturation decreased 5% to 10%. An atrial septal defect was successfully created in each patient. The mean right atrial pressure decreased from 23 to 18 mm Hg and the mean systemic oxygen saturation decreased from 93% to 85%. The mean cardiac index increased from 1.7 to 2.1 L/min/m2 and the mean systemic oxygen transport increased from 268 to 317 ml/min/m2. Complications occurred in 3 patients: transient hypotension during transesophageal echocardiography, a femoral pseudoaneurysm, and a femoral arteriovenous fistula. After septostomy, 6 patients had clinical improvement (resolution of ascites, edema, and no further episodes of syncope); 5 of these 6 patients underwent lung transplantation a mean of 6.1 months after septostomy. Six patients did not have clinical improvement after septostomy. Atrial septostomy improves the hemodynamic status and may be useful as a bridge to lung transplantation in selected patients with pulmonary hypertension.