Editor's Note: Commentary based on the article; Opitz CF, Hoeper MM, Gibbs JSR, et al. Pre-Capillary, Combined, and Post-Capillary Pulmonary Hypertension: A Pathophysiological Continuum. J Am Coll Cardiol 2016;68:368-78.

While therapy for patients with pulmonary arterial hypertension (PAH) has evolved into an integrated, and mostly evidence-based, treatment approach combining supportive, pharmacologic and surgical therapies, the optimal treatment of patients with left heart disease with preserved left ventricular systolic function and severe pulmonary hypertension (PH-HFpEF) remains unclear.¹

Since adequate randomized data are lacking, the authors of this Expert Analysis aimed to address the following questions by analyzing 786 patients with pulmonary hypertension from the COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) registry:²

1. Who are the patients with PH-HFpEF that have been treated with targeted therapy in PH expert centers?
   
   The treating physicians were highly selective when choosing 226 PH-HFpEF patients for PH-targeted therapy. Hemodynamic key parameters such as mean pulmonary artery pressure (46 ± 9 mm Hg) and cardiac index (2.2 ± 0.7 l/min/m²) were as severely compromised as in patients with idiopathic pulmonary arterial hypertension (IPAH), and the elevated transpulmonary gradient (26 ± 9 mm Hg) documents a relevant pre-capillary component in the presence of severe combined post- and pre-capillary PH (Cpc-PH).
   
   Despite these hemodynamic similarities, significant differences emerged; patients with PH-HFpEF were > 10 years older, had more co-morbidities and risk factors for left heart disease, and were functionally more severely compromised when compared to "typical" IPAH.
   
   Overall, the PH-HFpEF cohort described in our paper is the result of a restrictive selection process at PH expert centers, and probably does not reflect the usual heart failure patient with some degree of pulmonary artery pressure elevation.
   
   
2. Should patients with severe PH-HFpEF be treated with PH-targeted therapy?
   
   Our data rather emphasize the need for randomized controlled trials in this field; while there was some improvement in exercise capacity, functional class, and natriuretic peptide levels from baseline to 12 months in the PH-HFpEF patients, the effects were less pronounced when compared to typical IPAH. Furthermore, side effects were more frequent and the drugs used – mainly sildenafil – had to be withdrawn more often due to side effects or lack of efficacy. Both efficacy and tolerability declined gradually from typical IPAH towards atypical IPAH and PH-HFpEF.
   
   With respect to outcome, no differences in mortality were observed between the three groups during a five-year period. As a limitation, no adjustments were made for differences in baseline characteristics between groups.
   
   It should be emphasized, that optimized heart failure treatment remains the foundation of all therapeutic efforts in these patients, including effective volume control and decongestion. Whether this potential has fully been used cannot be verified in each of our patients due to the inherent limitations of registry data. However, data from pressure-sensor guided therapy in HFpEF patients point to this possibility.³
   
   For the time being, the decision to treat PH-HFpEF patients with PH-targeted drugs, a class III indication in the current guidelines, should be made with great caution on a case-by-case decision in cooperation with an experienced PH center.
   
   
3. Can it be helpful to distinguish between "typical" and "atypical" IPAH?
   
   Inspired by the AMBITION (Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension) investigators⁴ we explored the question whether in COMPERA all patients fulfilling the formal diagnostic criteria of IPAH are alike (e.g. typical IPAH), or is there a group of patients with "atypical" IPAH? Due to gaps in the accepted criteria establishing the diagnosis of IPAH, some patients fulfilling hemodynamic key parameters may enter this diagnostic category, despite a number of co-morbidities and risk factors for left heart disease. By using a threshold of ≥ 3 such co-morbidities, we identified a group of 139 patients with atypical IPAH, while 421 patients had typical IPAH. The comparison of both groups might illustrate potential limitations of the current PH classification and emphasizes the need for a comprehensive evaluation beyond hemodynamic cut-off values from single-point measurements.⁵ An example might be the acquisition and interpretation of the pulmonary artery wedge pressure and its role for separating pre- from post-capillary PH.
   
   Even without proposing a new PH classification, the recognition of a subgroup of atypical patients within the spectrum of IPAH might help us to better delineate those patients that will have the greatest benefit from PH-targeted therapy. On the contrary, these atypical patients might need further study and refined therapeutic approaches enabling us to adequately treat the full spectrum of patients from typical IPAH to atypical IPAH and combined post- and pre-capillary PH.

References

1. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67-119.
2. Opitz CF, Hoeper MM, Gibbs JSR, et al. Pre-Capillary, Combined, and Post-Capillary Pulmonary Hypertension. J Am Coll Cardiol 2016;68:368-78.
3. Abraham WT, Stevenson LW, Bourge RC, et al. Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from the CHAMPION randomised trial. Lancet 2016;387:453-61.
4. Galiè N, Barberà JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med 2015;373:834-44.
5. Rosenkranz S, Gibbs JSR, Wachter R, De Marco T, Vonk Noordegraaf A, Vachiery JL. Left ventricular heart failure and pulmonary hypertension. Eur Heart J 2015;37:942-54.

Keywords: Hypertension, Pulmonary, Heart Failure, Natriuretic Peptides, Phenylpropionates, Pulmonary Artery, Pulmonary Wedge Pressure, Pyridazines, Registries, Risk Factors, Systole, Ventricular Function, Left

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