Authors’ reply

We would like to thank Riccardo Scagliola for his interesting comment to our article on a new, challenging phenotype of pulmonary arterial hypertension (PAH), published in the December issue of Polish Archives of Internal Medicine (Pol Arch Intern Med).1 Although recent advances in treatment contributed to improving prognosis of patients with PAH, this population has in fact changed substantially during the last decades, which has been recently described as a novel phenotype of PAH, atypical PAH, or PAH with comorbidities. More prevalent features of heart failure with preserved ejection fraction (HFpEF) in newly diagnosed patients with pulmonary hypertension (PH) made differential diagnosis more challenging and raised questions regarding a possible overlap between these 2 disease entities (PAH and HFpEF with PH).

As recently shown, the observed shift in the epidemiology of PAH and the higher number of cardiovascular comorbidities in patients with PAH can be associated with an increasing age of diagnosed patients. What is more, some of the main cardiovascular risk factors, including alterations in glucose and lipoprotein metabolism, can serve as prognostic factors and affect patients’ survival.2-4 As reported in the analysis of recent randomized, placebo-controlled trials by Rose et al,5 elderly patients were characterized by less severe hemodynamic impairment including lower baseline mean pulmonary arterial pressure and pulmonary vascular disease, despite worse functional impairment and a less favorable response to PAH-specific treatment, than their younger counterparts. This may be partially attributed to the presence of PH with more abundant risk factors for left ventricular diastolic dysfunction, yet still fulfilling the hemodynamic criteria of a precapillary disease. Furthermore, the authors found that older individuals with PAH compared with younger patients were less often diagnosed with idiopathic PAH and more often with PAH associated with connective tissue disease. This accounted for nearly 50% of cases diagnosed in the oldest age group, which may suggest an important role of altered immunity in the ethiology of PAH in the elderly.

The definitive distinction between PAH and a postcapillary disease may be challenging, especially considering numerous technical requirements and expertise needed to obtain reliable hemodynamic parameters. In the case of multifactorial diseases, single cutoff values may be insufficient to unequivocally separate disease entities. Additional provocative procedures, including volume loading or exercise challenge, have not been sufficiently validated and thus are not endorsed by the current guidelines. Of note, HFpEF may also affect pulmonary circulation, leading to secondary vascular remodeling, which further reinforces the hypothesis on a spectrum of diseases between HFpEF with PH and PAH.

A growing number of patients with a new phenotype of PH requires comprehensive diagnostic evaluation and close follow-up after initiation of treatment in the expert centers. As recently shown by McLaughlin et al,1 patients with PAH and a high number of risk factors for HFpEF are characterized by less favorable responsiveness to treatment. This involves drug-associated adverse events and clinical failure occurring in this patient group more frequently than in subjects without comorbidities. Future studies are therefore needed to establish the most appropriate treatment strategies, since this challenging population was often underrepresented or excluded in recent large clinical trial protocols. Analyzing the relationship between age and right heart function during diagnosis and after initiation of treatment may help to further optimize treatment methods in this novel population.

In conclusion, the disparity between an increasing number of patients with a new, challenging PAH phenotype and lack of comprehensive clinical data need to be addressed in future research to establish safe and effective diagnostic workup and therapeutic strategy for this population.