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.

1st Department of Cardiology AHEPA University Hospital Aristotle University of Thessaloniki Thessaloniki Greece

Amsterdam Cardiovascular Sciences Pulmonary Hypertension and Thrombosis Amsterdam The Netherlands

Berlin Institute of Health at Charité BIH Center for Regenerative Therapies University of Medicine Berlin Germany

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

BioTechMed Graz Graz Austria

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

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

Cardiology Division San Paolo University Hospital Milan Italy

Cardiovascular Research Foundation New York NY USA

Center for Basic and Clinical Immunology Research Federico 2 University Naples Italy

Center for Molecular Medicine Cologne Faculty of Medicine University of Cologne Cologne Germany

CIBERCV Madrid Spain

Comprehensive Heart Failure Center and Medical Clinic 1 University Clinic Würzburg Würzburg Germany

Content and Communication Branded Products Orion Pharma Espoo Finland

Department of Cardiology and Cologne Cardiovascular Research Center Heart Center at the University Hospital Cologne Cologne Germany

Department of Cardiology Hopital Universitaire de Bruxelles Erasme Brussels Belgium

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

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

Department of Cardiology University Hospital Mannheim Heidelberg University Mannheim Germany

Department of Cardiology University Medical Center Groningen University of Groningen Groningen The Netherlands

Department of Cardiovascular Diseases Mayo Clinic Rochester MN USA

Department of Cardiovascular Research European Center for Angioscience Heidelberg University Mannheim Germany

Department of Internal Medicine 5 University Hospital Schleswig Holstein and German Centre for Cardiovascular Research Partner site Hamburg Kiel Lübeck Kiel Germany

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

Department of Internal Medicine and Excellence Cluster Cardio Pulmonary Institute Justus Liebig University Giessen Germany

Department of Internal Medicine University of Genova Genoa Italy

Department of Management Information and Production Engineering University of Bergamo Dalmine Italy

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

Department of Translational Medical Sciences Interdepartmental Center for Clinical and Translational Research Federico 2 University Naples Italy

Deutsches Herzzentrum der Charité Klinik für Kardiologie Angiologie und Intensivmedizin Charité Universitätsmedizin Berlin Berlin Germany

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

Division of Cardiology Department of Advanced Biomedical Sciences Federico 2 University Naples Italy

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

Division of Cardiology Medical University of Graz Graz Austria

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

Division of Clinical Physiology Department of Cardiology Faculty of Medicine University of Debrecen Debrecen Hungary

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

German Center for Cardiovascular Research Berlin Germany

German Centre for Cardiovascular Research Heidelberg Mannheim Partner Site Heidelberg and Mannheim Germany

German Centre for Cardiovascular Research Partner Site Berlin Berlin Germany

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

Heart Research Institute Sydney Australia

Institute of Experimental Cardiology University Hospital Heidelberg University of Heidelberg and DZHK Partner Site Heidelberg Mannheim Heidelberg Germany

Institute of Molecular and Translational Therapeutic Strategies Hannover Medical School Hannover Germany

IRCCS San Raffaele Rome Italy

Max Rubner Center Department of Cardiology Charité Universitätsmedizin Berlin Berlin Germany

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

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

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

Pulmonary Hypertension Association Europe Vienna Austria

St Georges Hospital London UK

Translational Approaches in Heart Failure and Cardiometabolic Disease Max Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin Germany

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

University of Milan Milan Italy

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"Form follows function": the developmental morphology of the cardiac atria