Recent Grant Awards
Targeting metabolism to reverse RV dysfunction in PAH.
Principle Investigator: Dr. Yuchi Han at the University of Pennsylvania.
Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature leading to increased pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP). The ability of the right ventricle (RV) to adapt to the increased PVR and sustain stroke volume and cardiac output determines the severity of clinical symptoms and is the most important determinant of survival in patients with PAH. It is increasingly recognized that early pulmonary vascular (PV) remodeling is met with an initial adaptive RV hypertrophy, but with progressive PV and RV remodeling, regional myocardial ischemia develops that leads to increased production of reactive oxygen species and mitochondrial dysfunction. In addition, other patient-specific genetic differences may exist in the RV that control cardiomyocyte function; these molecular differences may dictate individualized manifestations of RV failure and response to PAH therapy. We propose that the maladaptive molecular signaling pathways and metabolic response of the RV to alterations in load and pulmonary vascular function is the central determinant of RV-PV axis coupling and adaptation. This proposal will identify: (A) Key molecular and metabolic regulatory pathways that may be targeted for the preservation or recovery of RV function in patients with PAH; and (B) Specific imaging, plasma, and metabolic markers to better guide prognosis and therapy of the RV dysfunction in PAH. Specifically, we will compare novel metabolic, structural, and functional RV parameters in patients who have relatively preserved RV function on PAH therapy to patients who have poor RV function despite therapy and symptomatic improvement. In the latter patients, we will conduct a pilot placebo controlled randomized trial to compare clinical outcome with ranolazine therapy and again study the metabolic, structural, and functional RV parameter changes. We will conduct our investigations using echocardiography, cardiovascular magnetic resonance imaging, and positron emission tomography imaging techniques in addition to metabolic profiling, molecular studies on microRNA, and induced pluripotent stem cells in individual patients.
Instantaneous and non-invasive measurement of pulmonary artery pressure by acoustic analysis (advanced signal processing) of the second heart sound.
Principal Investigator: Dr. Ian Adatia from the University of Alberta and Mazankowski Heart Institute.
Our proposal combines the efforts of a physician, a biomedical engineer and computer scientist to test the following hypothesis: The intensity of the pulmonary component (P2) of the second heart sound (S2) and the width of the splitting interval between the aortic (A2) and pulmonary (P2) components of the second heart sound (S2) can quantify the pulmonary artery pressure in adults and children.
Aim 1: To acquire simultaneous, synchronized acoustic recordings of the heart sounds, direct catheter measurements of pulmonary artery pressure, and high frame rate ultrasound images from the aortic and pulmonary valve in both children and adults.
Aim 2: To develop and validate algorithms to measure pulmonary artery pressure from acoustic recordings of the second heart sound in children and adults.
Background: PH may affect 25 million or more people worldwide.1 However until recently, PH was regarded as a rare orphan disease. It was neglected because it is difficult to diagnose and effective treatments were unavailable. However, recent advances in vascular biology have been translated into new therapies, which improve symptoms and outcome.2 The widespread availability of orally administered agents has made treatment a reality even in underprivileged parts of the world.3 The new therapies have renewed interest in studying PH. They have led to the recognition that PH complicates the course and affects outcomes adversely in congenital heart disease, rheumatic heart disease, high altitude, schistosomiasis, hemolytic anemia, infection with human immunodeficiency virus, liver disease, autoimmune and connective tissue diseases, obesity, sleep disordered breathing and chronic pulmonary disease from smoking and air pollution.1-3 PH is difficult to diagnose and there is no equivalent to the sphygmomanometer used to detect systemic hypertension. PH is advanced when symptoms of exercise intolerance appear and the outcomes of therapy are not as good as treatment of milder disease.4 The global scale of the problem is enormous. There is a huge and pressing unmet need for a device to non-invasively measure PA pressure as a screening tool to diagnose PH. It would also be valuable during outpatient visits to evaluate the results of therapy or drug trials and for use continuously in the critically ill. In addition, this device would add immeasurably to our understanding of the natural history of pulmonary vascular disease by permitting frequent measurements of pulmonary artery pressure.
The Grover Conference, which is held on a biennial basis, is the only international meeting in North America that repeatedly focuses on subjects relevant to lung vascular biology and medicine. Initiated in 1984 and named in honor of Robert Grover, the Conference is held in a secluded, rural setting in the Rocky Mountains. Participation of young scientists is particularly encouraged. The setting has been proven many times to be an excellent meeting that has led to fruitful collaborations between investigators young and old and often in different fields. In addition to the scholarly review of topics, each conference has resulted in a publication that has been notable in its contribution to science.
Since 2000 the Grover Conference has included the following topics:
The CMREF is proud to be a co-sponsor for the 2013 Grover Conference that will focus on the topic “Adaptive and Maladaptive Coupling of the Right Ventricle and Pulmonary Circulation”, a particularly timely issue in pulmonary vascular diseases.
Interactions of Blood and the Pulmonary Circulation.
Cell signaling in vascular inflammation.
Genetic and Environmental Determinants of Pulmonary Endothelial Cell Function.
Rho Family GTPases in Pulmonary Vascular Pathophysiology.
Membrane Receptors, Channels, and Transporters in Pulmonary Circulation: Role in the Development of Pulmonary Vascular Disease.
Risk Factors in Pulmonary Hypertension
Robyn Barst Pediatric Research and Mentoring Fund
The Pulmonary Hypertension Association is proud to announce that we have reached our Phase I fundraising goal of $1 million, enabling us to begin making the first pediatric pulmonary hypertension grants in the world through the Robyn J. Barst Pediatric Research and Mentoring Fund. This achievement is due, in large part, to the generous donation from the Cardiovascular Medical Research and Education Fund.
In January of 2011, the Robyn Barst Pediatric Research and Mentoring Fund was founded through two initial contributions from Robyn Barst, MD, and generously supported over time by members of the PHA community. It is Dr. Barst’s objective, shared by the Pulmonary Hypertension Association, that this fund be used to expand research and related mentoring opportunities in the field of pediatric pulmonary hypertension.
As one of the pioneers in developing the field of pulmonary hypertension research and clinical practice, Dr. Barst’s desire now is to seed similar developments for pediatric pulmonary hypertension practice. She understands the importance of this goal from her widely recognized position as one of the leading physicians in pediatric pulmonary hypertension clinical practice.
Responses of EGLN1/VHL and HIF1AN/CBP: The factual oxygen sensor molecules at high-altitude.
Principal Investigator: Qadar Pasha, PhD. Institute of Genomics and Integrative Biology
Summary of the proposed Research
High-altitude (HA) is responsible for low partial pressure of air and as a consequence reduced blood arterial oxygen saturation (SaO2) in the body. The hypobaric hypoxia environment at HA is the chief driving force for acclimatization and adaptive processes. In order to maintain O2 availability to the tissues, various physiological pathways are activated that bring about the functional and phenotypic differences. For example, O2 sensing pathway plays a cardinal role in maintaining the vascular and adaptive homeostasis by transcribing the genes required for either increasing O2 availability of the body or mediating responses to O2 deprivation such as reduction of ATP turnover rate. Understandably, any kind of perturbation in the regular O2 supply results in malfunctioning of the system and hence the O2 sensor molecules gain significance. Among the several O2 sensors, the two HIF-hydroxylases, HIF-Prolyl hydroxylase (EGLN1) and HIF-1, alpha subunit inhibitor (HIF1AN) are of particular importance. We hypothesize that individually and together these two play a crucial role in the regulation of body physiology, especially the cumulative influence due to their interactions. EGLN1 catalyzes hydroxylation of proline residues of hypoxia inducible factor-1α (HIF-1α) so that it gets recognised by VHL for polyubiquitination and proteasomal degradation. On the other hand, HIF1AN hydroxylates asparagine residue of HIF-1α thereby blocking the interaction of this molecule with the coactivators required for functional transactivation of HIF-signaling pathway. Further to highlight, under normoxic condition, the protein levels of HIF-1α and its transactivational activity are regulated by EGLN1 and HIF1AN, respectively. However, under hypobaric hypoxia, these molecules are inhibited to allow proper functioning of HIF-1α for maintenance of O2 and cellular homeostasis. Thus a great potential of these HIF-hydroxylases with respect to hypobaric hypoxia physiology is envisaged, especially for their crosstalk. This study is therefore formulated to serve the objectives of (i) finding the association of HIF1AN and EGLN1 variants with HA adaptation and maladaptation, (ii) to find interactions between them and (iii) the various correlations between these two hydroxylases and other biomarkers like NO and ROS. Further, (iv) the methylation study will add to understanding the epigenetic role. It would thus be significant to add that this investigation would be first of its kind to evaluate EGLN1 and HIF1AN, the imperative oxygen-sensing molecules in relation to hypobaric hypoxia. It holds great promise in delivering encouraging results.
Pulmonary Vascular Research Institute: Business Plan for the future.
Principal Investigator: Martin Wilkins, M.D., Imperial College
Summary of the proposal
The Pulmonary Vascular Research Institute (PVRI) was established in 2007 by academics as an independent medical association devoted to increasing awareness and knowledge of pulmonary vascular diseases, and to facilitating advances in the treatment of affected people worldwide. It is a non-profit international medical organization and its activities focus on the traditional triad of research, education, and clinical care related to pulmonary vascular disease and heart failure, with an emphasis on countries with healthcare disparities. The PVRI faculty has grown to a global network of over 600 members on 6 continents. All are volunteers with academic careers in pulmonary vascular medicine and related fields. Their combined expertise allows them to collaborate at a level that no single academic institution could accomplish.
The PVRI holds its international scientific sessions each year (in successive years, Spain, Mexico, Portugal, Panama, South Africa and Turkey) as well as supporting local meetings arranged by others (India, Middle East and North Africa, Brazil and, China), where experts from PVRI attend and provide research seminars and teaching sessions. Research and educational material are collated and provided through a web site (www.pvri.info), curated by junior fellows from each region. Funding to support the overseas training of scientists and physicians from underdeveloped countries and support for pilot research projects in those countries are also used to deliver its mission.
The PVRI has had success in several areas in its 6 years of existence. Some notable examples are:
- Research Projects: Schistosomiasis
- Establishing a journal, Pulmonary Circulation
- Classification of pulmonary vascular disease for the pediatric age group
- Pulmonary Hypertension Academic Research Consortium (PH-ARC) : a think tank comprising input from academia, pharma and regulatory bodies
The Business Plan will allow the PVRI to establish new initiatives while increasing revenues from its activities to establish financial independence and stability.