A roadmap for therapeutic discovery in pulmonary hypertension associated with left heart failure. A scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Working Group on Pulmonary Circulation & Right Ventricular Function

Author:

Ameri Pietro12,Mercurio Valentina3,Pollesello Piero4,Anker Markus S.5,Backs Johannes6,Bayes‐Genis Antoni7,Borlaug Barry A.89,Burkhoff Daniel9,Caravita Sergio1011,Chan Stephen Y.12,de Man Frances1314,Giannakoulas George15,González Aránzazu1617,Guazzi Marco1819,Hassoun Paul M.20,Hemnes Anna R.21,Maack Cristoph22,Madden Brendan23,Melenovsky Vojtech24,Müller Oliver J.25,Papp Zoltan26,Pullamsetti Soni Savai27,Rainer Peter P.282930,Redfield Margaret M.8,Rich Stuart31,Schiattarella Gabriele G.32333435,Skaara Hall36,Stellos Kostantinos37383940,Tedford Ryan J.41,Thum Thomas42,Vachiery Jean Luc43,van der Meer Peter44,Van Linthout Sophie4546,Pruszczyk Piotr47,Seferovic Petar48,Coats Andrew J.S.49,Metra Marco50,Rosano Giuseppe51,Rosenkranz Stephan5253,Tocchetti Carlo Gabriele354

Affiliation:

1. Department of Internal Medicine University of Genova Genoa Italy

2. Cardiac, Thoracic, and Vascular Department IRCCS Ospedale Policlinico San Martino Genoa Italy

3. Department of Translational Medical Sciences Interdepartmental Center for Clinical and Translational Research (CIRCET), and Interdepartmental Hypertension Research Center (CIRIAPA), Federico II University Naples Italy

4. Content and Communication, Branded Products Orion Pharma Espoo Finland

5. Deutsches Herzzentrum der Charité, Klinik für Kardiologie, Angiologie und Intensivmedizin (Campus CBF), German Centre for Cardiovascular Research (DZHK) partner site Berlin Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin Berlin Germany

6. Institute of Experimental Cardiology University Hospital Heidelberg, University of Heidelberg and DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim Heidelberg Germany

7. Heart Institute Hospital Universitari Germans Trias i Pujol, CIBERCV, Universitat Autònoma de Barcelona Barcelona Spain

8. Department of Cardiovascular Diseases Mayo Clinic Rochester MN USA

9. Cardiovascular Research Foundation New York NY USA

10. Department of Management, Information and Production Engineering University of Bergamo Dalmine (BG) Italy

11. Department of Cardiology Istituto Auxologico Italiano IRCCS Ospedale San Luca Milan Italy

12. Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine University of Pittsburgh School of Medicine and UPMC Pittsburgh PA USA

13. PHEniX laboratory, Department of Pulmonary Medicine Amsterdam UMC location Vrije Universiteit Amsterdam Amsterdam The Netherlands

14. Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Thrombosis Amsterdam The Netherlands

15. First Department of Cardiology AHEPA University Hospital, Aristotle University of Thessaloniki Thessaloniki Greece

16. Program of Cardiovascular Diseases CIMA Universidad de Navarra and IdiSNA Pamplona Spain

17. CIBERCV Madrid Spain

18. University of Milan Milan Italy

19. Cardiology Division San Paolo University Hospital Milan Italy

20. Division of Pulmonary and Critical Care Medicine, Department of Medicine Johns Hopkins University Baltimore MD USA

21. Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville TN USA

22. Comprehensive Heart Failure Center (CHFC) and Medical Clinic I University Clinic Würzburg Würzburg Germany

23. St.Georges Hospital London UK

24. Department of Cardiology Institute for Clinical and Experimental Medicine – IKEM Prague Czech Republic

25. Department of Internal Medicine V University Hospital Schleswig‐Holstein, and German Centre for Cardiovascular Research (DZHK), Partner site Hamburg/Kiel/Lübeck Kiel Germany

26. Division of Clinical Physiology, Department of Cardiology Faculty of Medicine, University of Debrecen Debrecen Hungary

27. Department of Internal Medicine and Excellence Cluster Cardio‐Pulmonary Institute (CPI) Justus‐Liebig University Giessen Germany

28. Division of Cardiology Medical University of Graz Graz Austria

29. BioTechMed Graz Graz Austria

30. Department of Medicine St. Johann in Tirol General Hospital St. Johann in Tirol Austria

31. Division of Cardiology Northwestern University Feinberg School of Medicine Chicago IL USA

32. Max‐Rubner Center (CMR), Department of Cardiology Charité‐Universitätsmedizin Berlin Berlin Germany

33. German Centre for Cardiovascular Research (DZHK), Partner Site Berlin Berlin Germany

34. Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Germany

35. Division of Cardiology, Department of Advanced Biomedical Sciences Federico II University Naples Italy

36. Pulmonary Hypertension Association Europe Vienna Austria

37. Department of Cardiovascular Research European Center for Angioscience (ECAS), Heidelberg University Mannheim Germany

38. German Centre for Cardiovascular Research (Deutsches Zentrum für Herz‐Kreislauf‐Forschung, DZHK), Heidelberg/Mannheim Partner Site Heidelberg and Mannheim Germany

39. Department of Cardiology University Hospital Mannheim, Heidelberg University Mannheim Germany

40. Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne UK

41. Division of Cardiology, Department of Medicine Medical University of South Carolina Charleston SC USA

42. Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany

43. Department of Cardiology Hopital Universitaire de Bruxelles Erasme Brussels Belgium

44. Department of Cardiology University Medical Center Groningen, University of Groningen Groningen The Netherlands

45. Berlin Institute of Health (BIH) at Charité, BIH Center for Regenerative Therapies University of Medicine Berlin Germany

46. German Center for Cardiovascular Research (DZHK, partner site Berlin) Berlin Germany

47. Department of Internal Medicine and Cardiology Medical University of Warsaw Warsaw Poland

48. University of Belgrade Faculty of Medicine Belgrade University Medical Center, Serbian Academy of Sciences and Arts Belgrade Serbia

49. Heart Research Institute Sydney Australia

50. Cardiology. ASST Spedali Civili and Department of Medical and Surgical Specialties Radiological Sciences and Public Health, University of Brescia Brescia Italy

51. IRCCS San Raffaele Rome Italy

52. Department of Cardiology and Cologne Cardiovascular Research Center (CCRC) Heart Center at the University Hospital Cologne Cologne Germany

53. Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine University of Cologne Cologne Germany

54. Center for Basic and Clinical Immunology Research (CISI) Federico II University Naples Italy

Abstract

Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH‐LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH‐LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH‐LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre‐clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early‐stage development of candidate therapies for PH‐LHF.

Funder

National Institutes of Health

U.S. Department of Defense

American Heart Association

ZonMw

Ministerstvo Zdravotnictví Ceské Republiky

German Centre for Cardiovascular Research

Ministero della Salute

Publisher

Wiley

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