Progression of pulmonary hypertension is associated with increased proliferation and migration of pulmonary vascular smooth muscle cells. PDGF is a potent mitogen and involved in this process. We now report that the PDGF receptor antagonist ST1571 (imatinib) reversed advanced pulmonary vascular disease in 2 animal models of pulmonary hypertension. In rats with monocrotaline-induced pulmonary hypertension, therapy with daily administration of ST1571 was started 28 days after induction of the disease. A 2-week treatment resulted in 100% survival, compared with only 50% in sham-treated rats. The changes in RV pressure, measured continuously by telemetry, and right heart hypertrophy were reversed to near-normal levels. ST1571 prevented phosphorylation of the PDGF receptor and suppressed activation of downstream signaling pathways. Similar results were obtained in chronically hypoxic mice, which were treated with ST1571 after full establishment of pulmonary hypertension. Moreover, expression of the PDGF receptor was found to be significantly increased in lung tissue from pulmonary arterial hypertension patients compared with healthy donor lung tissue. We conclude that ST1571 reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension regardless of the initiating stimulus. This regimen offers a unique novel approach for antiremodeling therapy in progressed pulmonary hypertension.
To determine the impact on survival and clinical correlates of pulmonary hypertension (PH) occurring in patients with idiopathic pulmonary fibrosis (IPF). Retrospective study. Tertiary care, referral medical center. Among 487 consecutive patients with IPF, we identified 136 patients who underwent transthoracic echocardiography within 3 months of their initial evaluation at our institution. Patients with left ventricular dysfunction, valvular heart disease, incomplete follow-up, and those in whom pulmonary artery pressures could not be assessed were excluded; the remaining 88 patients were included in this study. Correlations were performed between echocardiographic measures of PH and clinical variables including survival. The mean (± SD) estimated systolic pulmonary artery pressure (SPAP) for the 88 patients was 48 ± 16 mm Hg (range, 28 to 116 mm Hg). Among pulmonary function parameters, SPAP correlated best with diffusing capacity of the lung for carbon monoxide (Dlco), to which it was inversely related. For survival analysis, patients were stratified into three groups: ≤ 35 mm Hg (14 patients), 36 to 50 mm Hg (47 patients), and > 50 mm Hg (27 patients). Using the Kaplan-Meier method, the median survival rates for these three groups were 4.8 years, 4.1 years, and 0.7 years, respectively. Those patients with SPAP > 50 mm Hg had significantly worse survival compared to other subgroups (p = 0.009). In patients with IPF, PH correlates inversely with Dlco and has a significant adverse impact on survival, particularly when SPAP is > 50 mm Hg.
We performed an open-label multicenter study to evaluate the safety and efficacy of the dual endothelin receptor antagonist bosentan in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Nineteen patients with inoperable CTEPH were enrolled. The primary end point was a change in pulmonary vascular resistance (PVR). Secondary end points included 6-min walk test, peak oxygen uptake ( o ), New York Heart Association functional class, serum levels of N-terminal-pro brain natriuretic peptide (NT-pro-BNP), and various other hemodynamic parameters. After 3 months of treatment with bosentan, PVR decreased from 914 ± 329 to 611 ± 220 dyne·s·cm (p < 0.001). Functional class and peak o remained unchanged, but 6-min walk distance increased from 340 ± 102 to 413 ± 130 m (p = 0.009), and serum NT-pro BNP levels improved from 2,895 ± 2,620 to 2,179 ± 2,301 (p = 0.027). One patient died, presumably from influenza A infection, and another patient experienced progressive fluid retention despite reduction of PVR. Other than that, treatment was well tolerated by all patients. This open-label pilot trial suggests that bosentan may offer a therapeutic option for patients with inoperable CTEPH. Randomized controlled trials are warranted to confirm these findings.
We sought to determine the predictors of short-term morbidity and mortality (3 h (p = 0.04) were independent predictors of short-term morbidity. There were 10 early deaths (7%). A history of pulmonary embolism (p = 0.04), right-axis deviation (p = 0.02), right ventricular (RV) hypertrophy (p = 0.04), RV index of myocardial performance ≥0.75 (p = 0.03), RVSP/systolic blood pressure ≥0.66 (p = 0.01), intraoperative use of vasopressors (p < 0.01), and anesthesia when nitrous oxide was not used (p < 0.01) were each associated with postoperative mortality. In patients with PH undergoing noncardiac surgery with general anesthesia, specific clinical, diagnostic, and intraoperative factors may predict worse outcomes.
Bosentan, an oral endothelin (ET)-A/ET-B receptor antagonist, is effective in the treatment of pulmonary arterial hypertension. To investigate the safety and efficacy of bosentan therapy in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Case series. Pulmonary Hypertension Unit of the Medical University of Vienna, Austria. Sixteen patients (9 women and 7 men; mean age ± SD, 70 ± 13 years). Off-label bosentan treatment over 6 months. Changes from baseline in liver enzymes, New York Heart Association (NYHA) functional class, 6-min walking distance (6-MWD), and serum amino-terminal pro-brain natriuretic peptide (proBNP). After 6 months, NYHA functional class improved by one class in 11 patients. Mean 6-MWDs increased from 299 ± 131 m at baseline to 391 ± 110 m at 6 months (p = 0.01). In parallel, proBNP decreased from 3,365 ± 2,923 to 1,755 ± 1,812 pg/mL (p = 0.01). Neither aspartate aminotransferase (25 ± 2 U/L vs 25 ± 2 U/L, p = 0.25) nor alanine aminotransferase (23 ± 12 U/L vs 24 ± 9 U/L, p = 0.57) changed significantly. Limitations of the study were uncontrolled design and small sample size. Our study suggests a beneficial effect of the oral dual ET receptor antagonist bosentan in patients with inoperable CTEPH, urging the need for a randomized, placebo-controlled trial.
Objectives: To measure survival, haemodynamic function and functional class in patients with systemic sclerosis associated pulmonary arterial hypertension (SSc-PAH) in two treatment eras. Methods: Six year longitudinal study of 92 consecutive patients with SSc-PAH diagnosed by cardiac catheterisation. Data were collected both prospectively and retrospectively. Patients were given basic treatment (diuretics, digoxin, oxygen and warfarin). Where clinically indicated, a prostanoid was used as advanced treatment (historical control group). From 2002, the range of treatments available expanded to include bosentan, which was generally the preferred treatment (current treatment era group). Survival was measured from the date of diagnosis of pulmonary hypertension by cardiac catheterisation. Six minute walking distance and haemodynamic function were measured at the time of diagnosis and at least one month after treatment was started. Results: The historical control group comprised 47 patients, all of whom received basic treatment; 27 of these were also treated with prostanoids. The current treatment era group comprised 45 patients, all of whom received bosentan as preferred treatment. Kaplan–Meier survival in the historical control group was 68% at one year and 47% at two years. Survival in the current treatment era group was 81% and 71% (p = 0.016) at one and two years, respectively. Pulmonary vascular resistance increased in the historical control group (by 147 dyn·s·cm−5), whereas in the current treatment era group, it remained stable over an average of nine months (decrease of 16 dyn·s·cm−5, p < 0.006). Conclusion: Survival of selected patients with SSc-PAH has improved in the current treatment era. In contrast to patients treated historically with basic drugs and prostanoids, patients treated in the current treatment era had improved survival associated with a lack of deterioration in cardiac haemodynamic function.
Objective: To describe an early experience of treating 40 children with the dual endothelin receptor antagonist bosentan, which is known to be safe and effective in adults with pulmonary hypertension (PH). Design: In this retrospective, observational study the UK Service for Pulmonary Hypertension for children treated 40 children with bosentan, 20 with idiopathic pulmonary arterial hypertension (IPAH) (mean age 8.03 years, range 1.2–17) and 20 with PH associated with other conditions (congenital heart disease, parenchymal lung or connective tissue disease, or HIV). Their mean age was 8.3 years (range 0.6–16 years). Patients: 39 patients were in World Health Organization (WHO) class III and IV, and all had shown recent deterioration. In IPAH the mean pulmonary vascular resistance (PVR) was 21.7 units⋅m2 (range 5.6–42.8). In secondary PH the mean PVR was 18 units⋅m2 (range 4.9–49). No child had a positive response to vasodilator testing with nitric oxide. Interventions: Bosentan was given as first line treatment to 25. Nine were given intravenous epoprostenol. Children were treated for a mean of 12.7 months (range 2–24 months). Main outcome measures: Response to treatment was judged by WHO functional class, six minute walk test, weight, ECG and echocardiographic findings, and need to add additional treatment. Results: Bosentan was well tolerated. In the IPAH group 19 (95%) stabilised with bosentan treatment but 12 (60%) patients needed combined treatment with epoprostenol. In secondary PH, WHO class, six minute walk test, and weight gain improved significantly. Conclusion: Bosentan helped stabilise children with IPAH but intravenous epoprostenol was also needed by 60%. Children with secondary PH improved.
Primary pulmonary hypertension (PPH) is a pulmonary vasculopathy resulting in exercise intolerance, usually due to dyspnea. We hypothesized that ventilation is increased during exercise in PPH relative to normal because the ventilated lung is underperfused, cardiac output increase is restricted, and arterial hypoxemia may develop. Our aim was to determine the size of the reduction in end-tidal Pco (Petco ) as a reflection of the abnormality in ventilatory efficiency and ventilatory drive in PPH patients. We performed cardiopulmonary exercise testing (CPET) in 52 PPH patients. All had hemodynamic measurements to confirm the diagnosis of PPH. A subgroup of 29 patients who underwent right-heart catheterization within 50 days of CPET were studied to compare their CPET responses to resting hemodynamics. Nine healthy volunteers matched for age and gender served as CPET control subjects. In PPH patients, the percentage of predicted peak oxygen uptake ( o ) correlated significantly with mean pulmonary artery pressure (mPAP) [ = − 0.59, p = 0.0007, n = 29]. Petco values at rest, anaerobic threshold (AT), and peak o were proportionately reduced as percentage of predicted peak o decreased ( = 0.66 to 0.72, p < 0.0001, n = 52). Petco values at rest, AT, and peak o were also reduced as mPAP increased (r = − 0.51 to − 0.53, p < 0.005, n = 29). In contrast to normal subjects in whom Petco increased from rest to AT, Petco decreased in PPH patients, except for two patients with mild PPH in whom there was no change. Also, Petco increased rather than decreased further at the start of recovery, in contrast to normal. Although usually normal at rest, oxyhemoglobin saturation decreased during exercise in most PPH patients. In patients with PPH, Petco at rest and exercise is significantly reduced in proportion to physiologic disease severity. The range of values is unusually low. Furthermore, the directional changes of Petco during exercise and early recovery are in the opposite direction of normal.
Aims To determine the presence and extent of delayed contrast enhancement (DCE) in patients with pulmonary hypertension (PHT) using contrast enhanced-cardiovascular magnetic resonance imaging (ce-CMR). Methods and results Twenty-five patients with PHT underwent ce-CMR and right heart catheterization. Right ventricular (RV) and left ventricular (LV) volumes, ejection fraction, mass, and DCE mass were determined with ce-CMR. Mean pulmonary artery pressure (mean PAP) averaged 43 (12) mmHg and cardiac output 4.3 (1.2) L/min. DCE was demonstrated in 23 out of 25 patients. DCE was confined to the RV insertion points (RVIPs) in seven patients and extended into the interventricular septum (IVS) in the remaining 16 patients. In these 16 patients, septal contrast enhancement was associated with IVS bowing. The extent of contrast enhancement correlated positively with RV end-diastolic volume/body surface area, RV mass, mean PAP, and pulmonary vascular resistance and correlated inversely with RV ejection fraction. Conclusion DCE was present within the RVIPs and IVS of most patients with PHT studied. Extent of DCE correlated with RV function and pulmonary haemodynamics. DCE was associated with IVS bowing and may provide a novel marker for occult septal abnormalities directly relating to the haemodynamic stress experienced by these patients.