Recent Grant Awards
Targeting metabolism to reverse RV dysfunction in PAH.
Principle Investigator: Dr. Yuchi Han at the University of Pennsylvania.
Summary:
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.
Summary:
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.
Specific Aims:
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.
Development of a Right ventricular Assist Device for Patients with Advanced Pulmonary Hypertension
Awarded to Circulite, Inc.
The CMREF has approved a grant to Circulite, Inc for the development of a right ventricular assist device to be developed as a treatment of advanced pulmonary hypertension refractory to medical therapy. In the current scheme of medical treatments, the only treatment for patients who have failed approved medical therapies, including intravenous prostacyclins, is lung transplantation. However, due to the strict criteria for listing patients, and the severe shortage of donor lungs, the majority of these patients will never be transplanted. It is the hope of Circulite that the right ventricular assist device will fill this unmet medical need. This grant provides necessary funding required to complete preclinical studies and initiate a clinical study in patients with refractory IPAH.
The project will:
- Utilize the same pump and outflow graft used for left heart support
- Develop a new inflow cannula fitted with cage to guard against right atrial collapse
- Utilize a small pump size that will permit subcutaneous placement
- Conduct two 90-day animal studies to show feasibility
- Conduct a preliminary cadaver fit study
Establish the Pulmonary Circulation Journal
Awarded to the Pulmonary Vascular Research Institute
The inaugural issue of Pulmonary Circulation, the official journal of the Pulmonary Vascular Research Institute (PVRI), was published in spring 2011. The launch of this journal has already received a warm welcome from clinicians and scientists around the world who are engaged in research in the pulmonary vascular field. The scope of the journal is wide and will provide a home for clinical, translational and basic research in the field. This will be the only peer-reviewed international journal dedicated to furthering the science and treatment of pulmonary vascular disorders.
http://www.pulmonarycirculation.org
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:
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
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.
http://www.thoracic.org/assemblies/pc/grover-conference/index.php
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.
