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BACKGROUND: Upfront combination therapy with ambrisentan and tadalafil has been reported to improve the condition of patients with pulmonary arterial hypertension (PAH) more than with either drug alone. However, little is known about the long-term associated changes in hemodynamics and risk assessment scores. METHODS: This was a multicenter, retrospective analysis of clinical data in 106 patients with newly diagnosed PAH. Clinical evaluations, including demographics, medical history, World Health Organization (WHO) functional class (FC) and 6-minute walk distance (6MWD), right heart catheterization, and Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score 2.0, were assessed over 48 months of ambrisentan‒tadalafil therapy. RESULTS: At baseline, 9 patients (9%) showed a low (8) REVEAL risk score. At a median follow-up of 2 years, 45 patients (43%) showed a low, 47 patients (44%) showed an intermediate, and 14 patients (13%) showed a high REVEAL score, along with improvements in WHO FC, 6MWD and a decrease in mean pulmonary artery pressure and N-terminal pro brain natriuretic peptide (all p < 0.001). Pulmonary vascular resistance (PVR) decreased by 37% from 11.5 ± 6.5 to 7.2 ± 4.1 Wood units (p < 0.001). A total of 61 patients (57%) remained in intermediate-risk or high-risk categories. Low-risk patients had either a decrease in PVR of >50% or a stroke volume within the limits of normal. CONCLUSIONS: Initial combination therapy with ambrisentan and tadalafil in PAH improves the REVEAL risk score in proportion to decreased PVR and preserved stroke volume but still insufficiently so in approximately 50% of the patients.

Doppler echocardiography is extensively used in clinical practice for the screening and detection of pulmonary hypertension (PH). It allows for accurate estimates of pulmonary artery pressures, but with moderate precision, which explains why it is more appropriate for population studies than for definitive diagnosis of PH in individual patients. Moreover, echocardiography allows one to distinguish different patterns of right ventricular remodelling in various forms of PH and enables clinically satisfactory differentiation between pre- and post-capillary PH. This article will review the methods for evaluating PH by echocardiography, while also providing an insight into specific strengths and weaknesses.

Background Pulmonary hypertension (PH) is a well-known independent prognostic factor in chronic obstructive pulmonary disease (COPD) and a sufficient criterion for lung transplant candidacy. Limited data are currently available on the hemodynamic and clinical effect of phosphodiesterase 5 inhibitors in patients with severe PH associated with COPD. This study assessed the effect of sildenafil on pulmonary hemodynamics and gas exchange in severe PH associated with COPD. Methods After screening, this multicenter, randomized, placebo-controlled double-blind trial randomized patients to receive 20 mg sildenafil or placebo 3 times a day (ratio 2:1) for 16 weeks. The primary end point was the reduction in pulmonary vascular resistance. Secondary end points included BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, 6-minute walk test, and quality of life questionnaire. Changes in the partial pressure of arterial oxygen were evaluated as a safety parameter. Results The final population included 28 patients, 18 in the sildenafil group and 10 in the placebo group. At 16 week, patients treated with sildenafil had a decrease in pulmonary vascular resistance (mean difference with placebo –1.4 WU; 95% confidence interval, ≤ –0.05; p = 0.04). Sildenafil also improved the BODE index, diffusion capacity of the lung for carbon monoxide percentage, and quality of life. Change from baseline in the partial pressure of arterial oxygen was not significantly different between the sildenafil and placebo groups. Conclusions This pilot study found that treatment with sildenafil reduced pulmonary vascular resistance and improved the BODE index and quality of life, without a significant effect on gas exchange.

In early stage uncomplicated systemic hypertension (HT), increased pulmonary vascular resistance (PVR) has been reported at rest, but more rarely during exercise. Recently, limits of normal for stress echocardiography in the evaluation of the pulmonary circulation have been better defined. We therefore used this approach to assess the pulmonary circulation in early HT.One hundred thirteen patients with mild to moderate untreated, uncomplicated HT (blood pressure, 152 ± 19/89 ± 11 mm Hg, heart rate, 70 ± 13 beats per minute) and 345 age- and sex-matched healthy control subjects underwent resting Doppler echocardiography with estimation of mean pulmonary arterial pressure (mPAP), left atrial pressure (LAP), and cardiac output (CO). Measurements were repeated at exercise stress test in 25 patients from each group.At rest, hypertensive patients had normal right and left ventricular structure and function, higher systemic vascular resistance, mPAP (16 ± 5 vs 14 ± 5 mm Hg; P0.0001), and PVR (1.3 ± 1.1 vs 1.0 ± 1.2 Wood units; P = 0.006) than control participants, but similar LAP. During exercise, hypertensive patients showed a lower maximum workload and CO and higher peak mPAP than control subjects, but a similar increase in LAP. PVR determined according to multipoint mPAP-CO relationships was also higher in hypertensive patients than in control subjects (2.5 ± 1.1 vs 1.5 ± 0.7 mm Hg/L/min; P0.05), with no changes in pulmonary resistive vessel distensibility coefficient α (0.012 ± 0.007 vs 0.012 ± 0.010% change in diameter for each mm Hg increase in mPAP).Resting and exercise PVR are increased in uncomplicated HT, without this being related to increased pulmonary venous pressure or resistive vessel stiffness, suggesting an early increase in pulmonary vascular tone.

Background The differential diagnosis between pre- and postcapillary pulmonary hypertension (PH) is of major therapeutic relevance and thus requires optimal clinical probability assessment with echocardiography. Methods We prospectively analyzed 152 consecutive patients referred to a PH center over a 1-year period undergoing quasi-simultaneous (within 1 hour) echocardiography and right heart catheterization. Echocardiography was performed as usually recommended for the assessment of PH and left heart conditions. PH was defined as a mean pulmonary artery pressure ≥ 25 mm Hg. Postcapillary PH was diagnosed on the basis of a pulmonary capillary wedge pressure >15 mm Hg. Results Ten of 152 patients (7%) had no PH, 81 of 152 (53%) had precapillary PH, and 61 of 152 (40%) had postcapillary PH. The following five echocardiographic variables were found to predict precapillary PH: right heart chamber larger than the left ( P = .0018), left ventricular eccentricity index > 1.2 ( P = .0039), dilated inferior vena cava without inspiratory collapse ( P = .0076), E/e′ ratio ≤10 ( P = .00001), and the right ventricle forming the heart apex ( P = .0144). Beta coefficients from multiple logistic regression were significant for dilated inferior vena cava without inspiratory collapse ( P = .0464) and E/e′ ratio ≤ 10 ( P = .0002). The score based on β coefficients, ranging from 3 to 34 points, resulted in optimal discrimination at >5, with a positive predictive value of 67.9% and a negative predictive value of 77.5% for precapillary PH. Conclusion Echocardiography enables a clinically satisfactory differential diagnosis between pre- and postcapillary PH.

Ambrisentan, an oral endothelin-1-receptor antagonist (ERA) selective for the endothelin A, showed an improvement in WHO functional class, 6 minute walk distance, and time to clinical worsening relative to placebo in randomised, double-blind, placebo-controlled, multicenter, 12-week clinical trials (ARIES study 1 and 2, total n=394) [1]. At this time, the long-term effects of ambrisentan on haemodynamics have not been reported in a prospective study. The aim of this study was to evaluate prospectively the efficacy and safety of ambrisentan treatment in adult patients with pulmonary arterial hypertension by assessing its long term effects on clinical status, exercise capacity, and cardiopulmonary haemodynamics. This was a single-centre, open-label, single-arm, prospective study. All patients with PAH starting oral ambrisentan as first line therapy or combination therapy (based on recommendations of the current ESC/ERS guidelines on pulmonary hypertension) [2] were enrolled after obtaining the informed consent. Clinical status, resting transcutaneous oxygen saturation (SpO2), 6-minute walk distance, serology and right heart catheterization (RHC) were assessed at baseline (before starting ambrisentan therapy) and at 1 year follow-up. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [3]. Clinical status evaluation included medical history, assessment of WHO functional class, measurement of systemic arterial pressure, transcutaneous oxygen saturation (SpO2) and heart rate.