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Background Pulmonary arterial hypertension (PAH) represents a rare complication of both portal hypertension (Po-PAH) and HIV infection (HIV-PAH). Due to overlapping risk factors, in the latter patients there may frequently be a hepatic involvement that can cause portal hypertension, resulting in an overlap PAH form associated with both portal hypertension and HIV (HIV/Po-PAH). Methods A retrospective analysis was conducted on 204 patients with Po-PAH (128), HIV-PAH (41) and HIV/Po-PAH (35) referred to our centre from 1993 to 2021, with the aim of describing the clinical, functional and haemodynamic characteristics and identifying the prognostic determinants. At baseline, in patients with Po-PAH and HIV/Po-PAH, the severity of liver disease was estimated using the Child-Turcotte-Pugh (CTP) score, MELD score (Model for End-stage Liver Disease); instead, in patients with HIV-PAH and HIV/Po-PAH it was defined whether they received HAART (Highly Active Anti-Retroviral Therapy) and the CD4+ lymphocytes number. Data are expressed as median (interquartile range) and compared with Dunn's test. Prognostic determinants were identified by univariate and multivariate Cox-regression analysis. Survival was assessed using Kaplan Meier method. Patients were treated according to ESC/ERS guidelines. Results HIV-infected patients [40 (37-43) years] and HIV/Po-PAH [44 (39-48) years] are younger than Po-PAH patients [53 (44-60) years]; the exercise capacity assessed by the 6-minute walking test of patients with HIV/Po-PAH [516 (432-571) m] was superior to both patients with Po-PAH [426 (366-504) m] and HIV-PAH [448 (370-510) m], presumably justified by the demographic and haemodynamic differences between these groups. In fact, patients with concomitant portal hypertension (Po-PAH and HIV/Po-PAH) have a better haemodynamic profile than patients with HIV-PAH, specifically, lower pulmonary vascular resistance [6.2 (4.9-8.8) and 7.0 (5.5-11.2) WU vs 8.9 (7.5-12.2) WU] and higher cardiac index [3.1 (2.6-3.8) and 3.0 (2.7-3.7) l/min/m2 vs 2.6 (2.2-2.9) l/min/m2] and mixed venous oxygen saturation [70 (65-75) and 67 (62-71) % vs 61 (55-66)%] values. Despite these differences, the survival of the three groups of patients was not statistically different (5-year survival of patients with Po-PAH was 41%;of patients with HIV/Po-PAH was 46%; and of patients with HIV-PAH was 51%; log-rank test p-value= 0.059) and the prognostic factors that emerge at the multivariate analysis are only parameters associated with the underlying disease. In particular, the parameters independently associated with prognosis are, in patients with Po-PAH, only the CTP score [HR 1.665 (CI 1.153-2.403), p= 0.007]; in patients with HIV-PAH only the treatment with HAART [HR 0.283 (CI 0.119-0.675), p= 0.004]; in patients with HIV/Po-PAH both MELD-Na+ [HR 1.224 (CI 1.064-1.408), p= 0.005] and trans-hepatic venous gradient [HR 1.125 (CI 1.026-1.235), p= 0.013]. Conclusions in patients with Po-PAH, HIV-PAH, and HIV/Po-PAH adequately treated with PAH medications, the prognosis seems to be related to the underlying disease. This may explain why their survival is not statistically different despite significant demographic, exercise and hemodynamic differences.

Background patients with pulmonary arterial hypertension (PAH) associated with corrected congenital heart disease (CHD) have a worse prognosis than other 3 groups of patients with PAH associated with CHD (Eisenmenger, small defect, prevalent systemic-to-pulmonary shunt). For this reason, in CHD the indication and timing of defect repair should be evaluated carefully. Current recommendations rely essentially on pulmonary vascular resistance (PVR) when deciding about defect closure, but this may be insufficient as PAH may develop even in cases of normal pre-operative PVR. In particular, patients with PVR below 3 WU are usually deemed operable and patients between 3 and 5 WU (gray zone) are deemed operable in case of significant persistence of left-to-right shunt. Detecting preoperative characteristics of patients who developed PAH after pre-tricuspid shunt repair can be helpful when deciding about CHD correction. Methods we enrolled adult patients referred to our centre for the suspicious of PAH after pre-tricuspid shunt correction from 2006 to 2021. We evaluated clinical, echocardiographic and hemodynamic parameters before and after defect repair (a post-correction hemodynamic evaluation was performed only in case of non-invasive signs of PAH) and PAH after defect closure was defined by the concomitant occurrence of a mean pulmonary artery pressure (mPAP) >25 mmHg and PVR >3 WU. Continuous variables were summarized using mean and standard deviation and Student's t-test was used for comparisons. Results sixty patients were included in the final analysis. After shunt repair, 10 patients (16.6%) were diagnosed with PAH during the long-term follow-up, with no differences given by the type of defect or type of correction. As expected, these patients already had an abnormal baseline hemodynamic profile: 7 had a clear PAH diagnosis before the correction [mPAP >25 mmHg with PVR between 3 and 5 WU and with a pulmonary/systemic cardiac output ratio of at least 1.5] while 3 had pulmonary hypertension related to high pulmonary blood flow (mPAP >25 mmHg and PVR Conclusions currently there are no established evidence-based algorithms to predict the development of PAH after defect correction. Our study shows that this condition may persist or develop even when PVR values are lower than 5 WU despite a significant left-to-right shunt before defect closure. Patients with grey zone PVR values require a global clinical, instrumental and hemodynamic assessment that takes into account more than bare calculated PVR that, especially in patients with a high pulmonary blood flow, can be less reliable.

Background despite therapeutic improvement, pulmonary arterial hypertension (PAH) is still a chronic, incurable, high mortality disease. Several clinical, laboratory, hemodynamic and instrumental prognostic factors have been already established in PAH patients. However, no electrocardiographic prognostic factors have been identified so far in a systematic multivariate analysis together with clinical, exercise and haemodynamic parameters. Methods patients with idiopathic/heritable/drug-induced PAH (I/H/D-PAH) referred to a single centre were included from 1993 to 2021. All patients underwent baseline clinical, 12-lead ECG, hemodynamic with vasoreactivity test, 6 minutes walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), WHO functional class evaluation and risk stratification (according to a recently validated simplified version of 2015 ESC/ERS guidelines’ risk table). All cause mortality has been considered to identify the predictors of mortality using univariate and multivariate Cox regression analysis. Results 570 PAH patients were included: 448 idiopathic (79%), 105 heritable (18%) and 17 drug-induced (3.0%). 20 patients were on atrial flutter/fibrillation at baseline. Considering only electrocardiographic parameters the variables independently associated with prognosis are shown in the table below: Taking into account also the risk stratification the independent prognostic variables are: Considering also clinical, exercise and haemodynamic variables the independent prognostic variables are: Conclusions in patients with I/H/D-PAH heart rate is a prognostic factor independently from other electrocardiographic, clinical, exercise and haemodynamic parameters as reflects the attempt to preserve the cardiac output in patients with an increased right ventricular afterload causing a reduced stroke volume; both PR interval prolongation, marker of right atrial overload, and QTc prolongation, marker of right ventricle's electrical remodeling, are prognostic variables independently from baseline patient's risk level; right bundle branch block, expression of right ventricular electrical remodeling, has proved to be an independent predictor of mortality merely if we consider only the electrocardiographic parameters.

Background Pulmonary arterial hypertension (PAH) is a progressive disease characterized by small pulmonary arteries remodeling that leads to increased pulmonary vascular resistance, dyspnea, fatigue, right heart failure and ultimately death. Prostacyclin analogue drugs, such as epoprostenol or treprostinil, have a vasodilator, antiproliferative and immunomodulatory effect, representing established therapies for cases of severe PAH. Both these drugs improve exercise capacity, functional class and hemodynamic parameters, while epoprostenol also improves survival among patients with PAH. Despite these therapeutic benefits, these treatments need parenteral administration. Recently, the approval of selexipag, an oral selective prostacyclin receptor agonist, may represent a possible alternative option in some PAH patients. Methods patients with PAH treated as third line therapy with epoprostenol, treprostinil or selexipag, on top of inhibitor of type 5 phosphodiesterases and endothelin-1 receptor antagonists, referred to our center from February 1995 to December 2021 were retrospectively included. All patients noninvasive [6 minutes walking distance (6MWD)] and invasive [mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI), right atrial pressure (RAP) and mixed venous oxygen saturation (SvO2)] parameters were first collected at the baseline right heart catheterization (prior to the beginning of prostacyclin treatment) and then 3-4 months after the beginning of third line therapy. The absolute improvements in these parameters were compared with Dunn's test. Data are expressed as median (interquartile range). Results 153 PAH patients treated as third line therapy with epoprostenol, treprostenil and selexipag were included (44, 73, 36 patients respectively). At 3 to 4 months after the beginning of the third line therapy, improvements in the 6MWD were: 65 (25 - 132) m with epoprostenol, 16 (-8 - 63) m with treprostenil and 12 (-10 - 57) m with selexipag (p = 0.044). Absolute RAP reduction was -1 (-4–2.5) mmHg with epoprostenol, -1 (-3 - 2) mmHg with treprostenil and 0 (-4 - 2) mmHg with selexipag (p = 0.953). Absolute PAPm reduction was -5 (-9 - -1) mmHg with epoprostenol, -5 (-11 - -1) mmHg with treprostenil and -6.5 (-14 - 0) mmHg with selexipag (p = 0.670). Absolute CI improvement was 0.9 (0.4–1.1) l/min/m2 with epoprostenol, 0.5 (0.2–0.8) l/min/m2 with treprostenil and 0.3 (0.1 - 1) l/min/m2 with selexipag (p = 0.022). Absolute PVR improvement was -4.5 (-7.6 - -2) WU with epoprostenol, -3.2 (-4.9 - -1.7) WU with treprostenil and -2 (-4.4–0.9) WU with selexipag (p = 0.021). Absolute SvO2 increase was 4.8 (1.7–13.2) % with epoprostenol, 2.6 (-2.2–6.2) % with treprostenil and 2.3 (-2.4–7.5) % with selexipag (p = 0.036). For all three-way significant comparisons, the only pairwise comparisons with a p-value Conclusions in our study population, epoprostenol, treprostenil and selexipag improve both exercise capacity and haemodynamic parameters in PAH patients when used as third line therapy, with the highest efficacy in the first group and, possibly, the lowest efficacy in the latter. These results confirm the beneficial role of these drugs in PAH patients and may suggest a possible favorable role for selexipag in the management of PAH patients with a less severe disease reserving a more invasive treatment strategy with parenteral prostanoids in patients with a higher risk disease.