Special Report: Pulmonary hypertension and cor pulmonale
A new collaborative research centre funded by the German Research Foundation (DFG) works on pulmonary hypertension and cor pulmonale. Collaborative research centres (CRC) are among the most highly rated project funding instruments awarded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation). They are tightly woven, mostly local, networks of researchers all working on a specific common topic. The recently established CRC 1213 ‘Pulmonary Hypertension and Cor Pulmonale’ focuses on the molecular and physiological pathomechanisms of the two conditions.
Heart and lung diseases are the leading causes of death and represent the highest socioeconomic burden of all diseases worldwide. Pulmonary hypertension (PH) could well be called the epitome of cardiopulmonary disease as it affects not only the lung vasculature, but also the right side of the heart. It is a chronic progressive disease of multifactorial aetiology with poor prognosis, which affects up to 100 million people worldwide in its various subtypes ranging from ‘no known cause’ (idiopathic PH) to familial PH where a genetic background has been identified. PH can also develop on the grounds of other pulmonary disorders, e.g. due to alveolar hypoxia (COPD) or chronic thromboembolic events in the pulmonary circulation.
PH is characterised by pathological inward remodelling and loss of patency of the lung vasculature. Challenged with increased afterload, the right ventricle (RV) initially responds to PH with a beneficial ‘adaptive’ hypertrophy, which is, however, often rapidly followed by ‘maladaptive’ changes leading to right-side heart decompensation and failure, the ultimate cause of death in PH (cor pulmonale). Although there has been fundamental progress within the last 25 years in terms of therapy, even the latest breakthroughs cannot cure the disease, indicating that the basic mechanisms of disease development need to be researched more closely.
The CRC’s approach
This CRC devoted to PH research combines basic science approaches and bedside clinical research in a highly interactive network to elucidate the pathogenic sequelae underlying PH and cor pulmonale and to evaluate novel treatment concepts. We are pursuing an integrated concept to understand the common pathophysiological processes and molecular mechanisms that underlie structural pulmonary vascular abnormalities as well as right heart adaptation and maladaptation in PH. Prevention of the progression from right heart adaptation to maladaptation may open new ways to prevent death from PH.
Our aim is to reverse remodel events to regain physiological lung vascular structure and function, and to develop RV-focused treatment concepts currently not available. The CRC has a strong translational orientation: its projects span the entire research spectrum from genetic/epigenetic signatures, molecular pathway mapping, cell and developmental biology, preclinical disease models, and in vivo molecular imaging, to clinical trials and registries/patient cohorts as well as extensive collection and archiving of biomaterials.
The CRC1213 has 19 projects with 26 researchers as project leaders, divided into two project areas: Area A is devoted to analysing development of the pulmonary circulation, aberrant remodelling in PH and design of reverse remodelling treatment concepts, Area B covers adaptive and maladaptive right heart hypertrophy with the aim of developing treatment strategies for cor pulmonale. The projects within the research areas are supported by core facilities and central projects like a biobank of human right ventricular tissue and blood specimens and a phenotyping facility.
The following topics will be addressed:
- Morphogenetic pathways: there is evidence that right heart and lung vasculature develop in a synchronised fashion. Research in the CRC will address transcription and growth factors in both systems as well as resident stem/progenitor cell populations and their role in development of PH;
- Hypoxia and reactive oxygen species (ROS) signalling as trigger or catalyst: Especially in the lung hypoxia and signalling events obviously play a major role in physiological regulation as well as disease. This will be addressed down to the subcellular level, e.g. by studying ROS levels in different cell compartments. However, also in the right heart, there is evidence that a metabolic switch (mitochondrial dysfunction and increased formation of ROS?) may be involved in right heart hypertrophy;
- Aberrant vasomotor and growth factor signalling: finding the switch between ‘just vasoconstriction’ to ‘hyperproliferation’ in the pulmonary vasculature and adaptive/maladaptive regulation in the right heart; and
- Epigenetic changes and epigenetic memory: Chromatin remodelling will be studied both in human samples (biomaterial repository) as well as experimental hypertrophic RV tissue.
The CRC faculty of scientists from the fields of basic and clinical research is very well prepared to fulfill this mission as documented by several groundbreaking contributions to lung vascular and cardiac research within the last years. The projects are carried out at different institutes of Giessen University, but also involving selected partners at the Max-Planck-Institute for Heart and Lung Research Bad Nauheim and Marburg University.
All faculty members have published their previous work in top ranking peer-reviewed journals, and have experience in other large national and international research consortia and translation of several key findings into clinical use and exploitation. Although several measures such as graduate schools and workshops are already in place, further efforts within the CRC will be spent to support career development of young basic and clinician scientists, as well as gender equality and compatibility of family and career as part of the CRC concept.
SFB 1213 is funded by the German Research Foundation, not by the Horizon 2020 programme.
Professor Dr Norbert Weissmann
SFB 1213 Pulmonary Hypertension and Cor Pulmonale
Justus Liebig University Giessen
+49 641 99 42422
[email protected]
http://www.uni-giessen.de/sfb1213
