The pathophysiological approach: the best for phenotyping patients with pulmonary arterial hypertension

We’ve read with great interest the paper “Frequency, characteristics and risk assessment of pulmonary arterial hypertension with a left heart disease phenotype” (PAH-LHD), reporting the retrospective multicentric study conducted by Toma M. and colleagues with the aim of providing realworld evidence about the features and risk stratification of this subgroup of PAH patients. The 57 PAH patients with the LHD phenotype, as defined by clinical and emodynamic criteria proposed by the AMBITION trial, were older, had higher body mass index and had more cardiovascular comorbidities compared to the other 229 PAH participants. Moreover, although less commonly treated with dual oral therapy or prostanoid, they had milder pulmonary hemodynamic impairment, better echocardiographic parameters of right ventricular (RV) function but similar WHO-functional class, 6MWD and survival rates compared to the no-LHD group. In the present study, the application of the COMPERA 2.0 model in the risk stratification for PAH-LHD patients, representing the 20% of the overall population, was found to have a good discriminatory power at follow-up. This result was not unexpected since the refined four-stratum risk assessment model was firstly derived from a cohort of the European COMPERA registry, which included idiopathic PAH patients older (mean age of 65.7 ± 15.5 years) and with comorbidities (1.7 ± 1.2) compared to previous registries. The paper offers the reader interesting food for thoughts. 1. The need for more refined diagnosis among patients with pulmonary hypertension (PH) Fluid challenge as a provocative test able of unmasking occult pulmonary hypertension due to LDH (group 2) is underused in clinical practice and nowadays its clinical relevance is still underestimated. In patients with PH-LHD, a value of pulmonary artery wedge pressure (PAWP) below the 15 mmHg threshold may be recorded when the right heart catheterization (RHC) is performed in the resting state, during optimal therapy and volume depletion on diuretic intake. The rapid infusion of 7 ml/kg of saline in patients with high pre-test probability of group 2 PH may reveal an abnormal increase in PAWP (>18 mmHg), avoiding dangerous diagnostic misclassification. In this regard, D’Alto et al. showed that fluid loading may help clinicians reclassify 6 % of the patients otherwise thought to have PAH and 8% of patients with no PH at baseline as having post-capillary PH, thus influencing therapeutic choices. Nonetheless, as reported in the limitations, fluid challenge was not performed in any patient included in the study by Toma et al., thus reflecting a gap existing in real-world practice. 2. The high degree of disease heterogeneity among PAH patients requires new phenotyping approaches that take pathophysiology into account The demographic picture of patients suffering from PAH is changing over time: as resulted from international registries, the mean age at diagnosis has significantly increased, from 36 years reported for patients enrolled between 1981 and 1985 in the US National Institutes of Health NIH registry to 67 years in the recent Swedish registry, and the number of comorbidities has raised, affecting approximately three quarters of PAH patients. All these factors have contributed to increasing the diagnostic uncertainty of clinicians and making the need of phenotyping PAH patients increasingly pressingdates to 2020 when Badagliacca and colleagues, through the combination of mean pulmonary artery pressure, right ventricle (RV) dimension and oxygen pulse (VO2) assessed with cardiopulmonary test, identified four idiopathic PAH phenotypes significantly associated with clinical worsening. Cluster 1 was characterized by mild-PH, mild signs of RV remodeling with preserved RV function and thus by excellent long-term event-free survival. Conversely, clusters 2 and 3 had both severe PH and pronounced RV remodeling but different degree of exercise tolerance (high vs low VO2 pulse) and very different outcomes, due to the different adaptation pattern to the increased afterload (adaptive RV phenotype in cluster 2 vs maladaptive RV pattern in cluster 3). The last cohort (cluster 4), including older and more overweight patients, presented a emodynamic and echocardiographic profile similar to cluster 1 (low mPAP, low right atrial pressure, preserved cardiac index and mild RV dilatation) but poor exercise capacity, similar to cluster 3, because of deconditioning. Interestingly, cluster 4 patients partially overlap with the 57 patients included in the PAH-LHD group by Toma et al., as reflected in demographic, echocardiographic and hemodynamic similarities (mean age 63.2 ± 11.3 vs 65 ± 13 years; mPAP 34.8 ± 6.3 vs 39 ± 11 mmHg; PVR 5.4 ± 2 WU vs 5.93 ± 4.39 UW; TAPSE 20.5 ± 3.2 vs 20 ± 5 mm, respectively). To further support the novel pathophysiological approach proposed by Badagliacca et al., Ghio S. and colleagues demonstrated that a comprehensive echocardiographic evaluation of right heart function, including the assessment of RV strain, right atrial reservoir strain and degree of tricuspid regurgitation, is superior to risk stratification model based only on hemodynamic parameters in predicting prognosis of prevalent PAH patients. In conclusion, in an era characterized by complex patients increasingly difficult to manage, clinicians must try to reduce diagnostic misclassification errors as much as possible. In the field of PAH, a complete RHC including provocative test such as fluid challenge is pivotal to unmask occult PH-LHD (group 2) and thus avoid prescribing potentially dangerous PAH therapies in patients with post-capillary PH. In our experience, a clustering pathophysiological approach including a comprehensive echocardiographic assessment of right heart, focusing on the evaluation of the RV remodeling pattern, has proven valid in refining the phenotyping PAH patients and improving treatment strategy decision-making, compared to other phenotypic classifications based on strict clinical, demographic and hemodynamic criteria.