Anco Boonstra

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−1min−1 starting dose, up to 14±2 ng·kg−1min−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.

Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy.

OBJECTIVES The purpose of this study was to examine the relationship between changes in pulmonary vascular resistance (PVR) and right ventricular ejection fraction (RVEF) and survival in patients with pulmonary arterial hypertension (PAH) under PAH-targeted therapies. BACKGROUND Despite the fact that medical therapies reduce PVR, the prognosis of patients with PAH is still poor. The primary cause of death is right ventricular (RV) failure. One possible explanation for this apparent paradox is the fact that a reduction in PVR is not automatically followed by an improvement in RV function. METHODS A cohort of 110 patients with incident PAH underwent baseline right heart catheterization, cardiac magnetic resonance imaging, and 6-min walk testing. These measurements were repeated in 76 patients after 12 months of therapy. RESULTS Two patients underwent lung transplantation, 13 patients died during the first year, and 17 patients died in the subsequent follow-up of 47 months. Baseline RVEF (hazard ratio [HR]: 0.938; p = 0.001) and PVR (HR: 1.001; p = 0.031) were predictors of mortality. During the first 12 months, changes in PVR were moderately correlated with changes in RVEF (R = 0.330; p = 0.005). Changes in RVEF (HR: 0.929; p = 0.014) were associated with survival, but changes in PVR (HR: 1.000; p = 0.820) were not. In 68% of patients, PVR decreased after medical therapy. Twenty-five percent of those patients with decreased PVR showed a deterioration of RV function and had a poor prognosis. CONCLUSIONS After PAH-targeted therapy, RV function can deteriorate despite a reduction in PVR. Loss of RV function is associated with a poor outcome, irrespective of any changes in PVR.

Interventricular Mechanical Asynchrony in Pulmonary Arterial Hypertension Left-to-Right Delay in Peak Shortening Is Related to Right Ventricular Overload and Left Ventricular Underfilling

OBJECTIVES The purpose of this study was to explore in pulmonary arterial hypertension (PAH) whether the cause of interventricular asynchrony lies in onset of shortening or duration of shortening. BACKGROUND In PAH, leftward ventricular septal bowing (LVSB) is probably caused by a left-to-right (L-R) delay in myocardial shortening. METHODS In 21 PAH patients (mean pulmonary arterial pressure 55 +/- 13 mm Hg and electrocardiogram-QRS width 100 +/- 16 ms), magnetic resonance imaging myocardial tagging (14 ms temporal resolution) was applied. For the left ventricular (LV) free wall, septum, and right ventricular (RV) free wall, the onset time (T(onset)) and peak time (T(peak)) of circumferential shortening were calculated. The RV wall tension was estimated by the Laplace law. RESULTS The T(onset) was 51 +/- 23 ms, 65 +/- 4 ms, and 52 +/- 22 ms for LV, septum, and RV, respectively. The T(peak) was 293 +/- 58 ms, 267 +/- 22 ms, and 387 +/- 50 ms for LV, septum, and RV, respectively. Maximum LVSB was at 395 +/- 45 ms, coinciding with septal overstretch and RV T(peak). The L-R delay in T(onset) was -1 +/- 16 ms (p = 0.84), and the L-R delay in T(peak) was 94 +/- 41 ms (p < 0.001). The L-R delay in T(peak) was not related to the QRS width but was associated with RV wall tension (p < 0.05). The L-R delay in T(peak) correlated with leftward septal curvature (p < 0.05) and correlated negatively with LV end-diastolic volume (p < 0.05) and stroke volume (p < 0.05). CONCLUSIONS In PAH, the L-R delay in myocardial peak shortening is caused by lengthening of the duration of RV shortening. This L-R delay is related to LVSB, decreased LV filling, and decreased stroke volume.

Pulmonary vascular resistance and compliance stay inversely related during treatment of pulmonary hypertension

AIMS Pulmonary arterial compliance (C) is increasingly being recognized as an important contributor to right ventricular afterload, but for monitoring of treatment of pulmonary hypertension (PH) most often still only pulmonary vascular resistance (R) is used. We aimed at testing the hypothesis that R and C are coupled during treatment of PH and that substantial changes in both R and C would result in more haemodynamic improvement than changes in R alone. METHODS AND RESULTS Data were analysed of two right-heart catheterizations of 52 patients with pulmonary arterial hypertension and 10 with chronic-thromboembolic PH. The product of R and C (= stroke volume over pulse pressure) did not change during therapy (P = 0.320), implying an inverse relationship. Changes in cardiac index correlated significantly (P < 0.001) with changes in R (R(2) = 0.37), better with changes in C (R(2) = 0.66), and best with changes in both (R(2) = 0.74). CONCLUSION During therapy for PH, R and C remain inversely related. Therefore, changes in both R and C better explain changes in cardiac index than either of them alone. Not only resistance but also compliance plays a prominent role in PH especially in an early stage of the disease.

Dysregulated Renin–Angiotensin–Aldosterone System Contributes to Pulmonary Arterial Hypertension

RATIONALE Patients with idiopathic pulmonary arterial hypertension (iPAH) often have a low cardiac output. To compensate, neurohormonal systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system are up-regulated, but this may have long-term negative effects on the progression of iPAH. OBJECTIVES Assess systemic and pulmonary RAAS activity in patients with iPAH and determine the efficacy of chronic RAAS inhibition in experimental PAH. METHODS We collected 79 blood samples from 58 patients with iPAH in the VU University Medical Center Amsterdam (between 2004 and 2010) to determine systemic RAAS activity. MEASUREMENTS AND MAIN RESULTS We observed increased levels of renin, angiotensin (Ang)I, and AngII, which were associated with disease progression (P < 0.05) and mortality (P < 0.05). To determine pulmonary RAAS activity, lung specimens were obtained from patients with iPAH (during lung transplantation, n = 13) and control subjects (during lobectomy or pneumonectomy for cancer, n = 14). Local RAAS activity in pulmonary arteries of patients with iPAH was increased, demonstrated by elevated angiotensin-converting enzyme activity in pulmonary endothelial cells and increased AngII type 1 (AT(1)) receptor expression and signaling. In addition, local RAAS up-regulation was associated with increased pulmonary artery smooth muscle cell proliferation via enhanced AT(1) receptor signaling in patients with iPAH compared with control subjects. Finally, to determine the therapeutic potential of RAAS activity, we assessed the chronic effects of an AT(1) receptor antagonist (losartan) in the monocrotaline PAH rat model (60 mg/kg). Losartan delayed disease progression, decreased right ventricular afterload and pulmonary vascular remodeling, and restored right ventricular-arterial coupling in rats with PAH. CONCLUSIONS Systemic and pulmonary RAAS activities are increased in patients with iPAH and are associated with increased pulmonary vascular remodeling. Chronic inhibition of RAAS by losartan is beneficial in experimental PAH.

Effects of exercise training in patients with idiopathic pulmonary arterial hypertension

We determined the physiological effects of exercise training on exercise capacity and quadriceps muscle function in patients with idiopathic pulmonary arterial hypertension (iPAH). In total, 19 clinically stable iPAH patients (New York Heart Association II-III) underwent a supervised exercise training programme for the duration of 12 weeks. Maximal capacity, endurance capacity and quadriceps function were assessed at baseline and after 12 weeks. In 12 patients, serial quadriceps muscle biopsies were obtained. 6-min walk distance and peak exercise capacity did not change after training. However, endurance capacity improved significantly after training, demonstrated by a shift of the anaerobic threshold to a higher workload (from 32±5 to 46±6 W; p = 0.003) together with an increase in exercise endurance time (p<0.001). Moreover, exercise training increased quadriceps strength by 13% (p = 0.005) and quadriceps endurance by 34% (p = 0.001). Training enhanced aerobic capacity of the quadriceps, by increasing capillarisation (1.36±0.10 to 1.78±0.13 capillaries per muscle fibre; p<0.001) and oxidative enzyme activity, especially of the type-I (slow) muscle fibres. No changes were found in cross-sectional area and fibre type distribution. Exercise training in iPAH improves exercise endurance and quadriceps muscle function, which is also reflected by structural changes of the quadriceps.

Sildenafil treatment in COPD does not affect stroke volume or exercise capacity

In chronic obstructive pulmonary disease (COPD) patients, stroke volume response to exercise is impaired. The aim of the present study was to investigate whether 3 months of sildenafil treatment improves stroke volume and, if so, whether this improvement is related to the pulmonary artery pressure and translated into an improved exercise capacity. A total of 15 stable COPD patients (Global Initiative for Chronic Obstructive Lung Disease stage II–IV) underwent right heart catheterisation at rest and during exercise. Stroke volume was assessed by magnetic resonance imaging (MRI) at rest and during submaximal exercise in the supine position and compared with eight age-matched controls. Additionally, a cardiopulmonary exercise test and a 6-min walking distance test were performed. Exercise tests and MRI were repeated after 12 weeks of oral therapy with 50 mg sildenafil three times daily. Stroke volume in COPD patients was significantly lower than in healthy controls (62±12 versus 81±22 mL at rest and 70±15 versus 101±28 mL during exercise). Pulmonary hypertension (PH) was diagnosed in nine patients and was absent in six. Treatment with sildenafil had no effect on stroke volume or exercise capacity. Although the stroke volume was lower in COPD patients with associated PH in comparison with non-PH patients, there was no difference in treatment response between both groups. In the present group of 15 chronic obstructive pulmonary disease patients, a reduced stroke volume was found at rest and during exercise. Neither stroke volume nor exercise capacity were improved by 3 months of sildenafil therapy.

A comparison of noninvasive MRI-based methods of estimating pulmonary artery pressure in pulmonary hypertension.

To assess the accuracy of several noninvasive MRI‐based estimators of pulmonary artery pressure by comparing them with invasive pressure measurement.

Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy.

Systemic sclerosis-associated pulmonary arterial hypertension (SScPAH) has a worse prognosis and response to pulmonary arterial hypertension (PAH) therapy than idiopathic PAH (IPAH). These differences have not yet been explained. Knowledge concerning histological pulmonary vasculopathy in SScPAH is limited in contrast to IPAH. Therefore, we explored patterns of vasculopathy in SScPAH compared with IPAH. Parameters of vasculopathy were assessed from lung tissue of eight PAH patients with limited cutaneous systemic sclerosis and 11 IPAH patients. Lung tissue was obtained at autopsy (n = 15), explantation (n = 3) and biopsy (n = 1). Pulmonary arterial/arteriolar intimal fibrosis was identified in all SScPAH patients and in three IPAH patients (p = 0.003). Fibrosis of pulmonary veins/venules was found in all SScPAH patients and in three IPAH patients (p = 0.003). In four SScPAH patients, fibrosis of veins/venules was focal and associated with capillary congestion as in pulmonary veno-occlusive disease (PVOD). Of the IPAH patients, 10 had unequivocal evidence of plexogenic arteriopathy compared with none of the SScPAH patients (p = 0.001). SScPAH is characterised by small vessel intimal fibrosis, which is associated with a PVOD-like pattern in some cases. This might explain its different clinical behaviour from IPAH. Small vessel intimal fibrosis may provide clues to elucidation of differences in pathogenetic mechanisms between the groups.

Exercise testing to estimate survival in pulmonary hypertension.

BACKGROUND : The 6-min walk distance (6MWD) predicts survival in pulmonary hypertension (PH). The peak oxygen consumption (V O2peak) measured during a cardiopulmonary exercise test (CPET) also relates to survival in PH, and it is unknown how the prognostic information from measurements of ventilatory responses and gas exchange during CPET compares to the prognostic information obtained by the 6MWD alone. The aims of our study were to compare prognostic values of different exercise parameters in PH and to assess whether CPET adds prognostic value to the information from the 6MWD. METHODS : After baseline right-heart catheterization and exercise testing, survival was assessed in a cohort of 115 PH patients. RESULTS : During the 4 yr of follow-up, 18 patients died. At baseline, pulmonary arterial pressure was 49 +/- 17 mm Hg, the slope relating minute ventilation to carbon dioxide output (V E/V CO2slope) = 45 +/- 11, V O2peak = 15 +/- 6 mL.kg.min, increase in O2 pulse from rest to peak exercise (DeltaO2 pulse) = 5 +/- 2 mL.beat, and 6MWD = 445 +/- 128 m. For the prediction of mortality, the areas under the receiver operating curves were very similar for the different parameters and ranged from 0.69 to 0.74. Patients with a V E/V CO2slope < 48, V O2peak > 13.2 mL.kg.min, DeltaO2 pulse > 3.3 mL.beat, or a 6MWD > 399 m had a higher cumulative survival (P < 0.05). Multivariable Cox regression with a forward selection procedure showed that only DeltaO2 pulse improved the univariate 6MWD prediction model significantly (P < 0.05). CONCLUSION : CPET parameters predict survival in PH patients and add marginally to the prognostic value of the 6MWD.