Linked by the heart
The Right Ventricle Network of Networks (RV/N2)
The RV/N2 collaborative project is led by Dr. Duncan Stewart of the Ottawa Hospital Research Institute, Ottawa, ON, Canada.
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The right ventricle (RV) is critical for functional capacity and clinical outcomes in a variety of cardiovascular diseases, including pulmonary hypertension (PH) and various forms of congenital heart disease (CHD). However, the RV has received much less attention than the left ventricle (LV). The RV has a remarkable capacity to undergo profound adaptations to accommodate volume or pressure overload; however, there is tremendous interindividual heterogeneity in the ability of the RV to adapt. In many patients, maladaptive RV remodeling leads to right ventricular failure (RVF) and ultimately to death or transplantation. Therapies that have proven effective in LVF have not worked in RVF. The RV/N2 will leverage the tremendous strengths and resources across Canada, as well as strategic international collaborations, to identify novel therapeutic strategies for RVF and build a clinical trial platform that spans the life continuum to shed light on different RVF subtypes.
Team Lead
Dr. Duncan Stewart
Ottawa Hospital Research Institute
RV/N2 team members
Adaptative platform trial for therapies targeting RVF (CRAVE)
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Many of the previous trials in RVF have enrolled small numbers of patients, and a number of them have been prematurely terminated or underpowered. The CRAVE platform trial, led by Dr. Jason Weatherald, a respirologist at the University of Alberta, aims to address this issue using a platform trial. This type of design allows for multiple treatments/doses that are compared to a common control, increasing efficientcy. The same therapies can then be evaluated simultaneously in different disease states, such as pulmonary arterial hypertension (PAH), pulmonary hypertension associated with lung disease, and congenital heart disease (CHD). Interim analyses can set parameters for early termination or to be advanced to the next stage of research.
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Populations that will be studied in the CRAVE platform include: PAH, heart failure with preserved or reduced ejection fraction with RV dysfunction, pulmonary hypertension associated with lung disease, and CHD.
At this stage, the protocol for a CRAVE feasibility study has been developed. This will be a 5-centre Canadian trial of 30 participants with pulmonary hypertension and right ventricular dysfunction randomized to placebo, ranolazine, or empagliflozin. The team will assess: 1) the proportion of eligible participants approached for consent; 2) the proportion of participants who consent who are randomized; 3) average enrollment rate of participants per centre per month; 4) loss to follow-up or death; and 5) ability to capture data for secondary outcomes. Submission to Health Canada is expected in May 2024 with an ethics approval and first site activation by September 2024. This feasibility trial will inform the design and number of centres required for the larger phase 2 CRAVE adaptive platform trial.
This project received funding support from the CIHR, the Accelerating Clinical Trials Consortium and the University of Ottawa Heart Institute Foundation ORACLE Precision Medicine Fund.
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Dr. Jason Weatherald
University of Alberta
Dr. Marie-Alexandre Chaix
Montreal Heart Institute
Dr. Matthieu Ruiz
Montreal Heart Institute
Dr. Lisa Mielniczuk
University of Ottawa Heart Institute
RV/N2 metabolomics
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To date, the RV has been understudied and the underlying mechanisms of RV adaptation and maladaptation are poorly understood. The stress-adaptative pathways of the RV differ from those of the LV. One of these adaptations is a chronic metabolic switch from fatty acid to high glycemic metabolism. Although initially good, this will eventually have deleterious effects with chronic stress. Therefore, this part of the RV/N2 project, led by Dr. Marie-Alexandre Chaix, a cardiologist at the Montreal Heart Institute, aims to better understand this metabolomic adaptation to stress in the RV.
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The goals of the RV/N2 metabolomics projetc are:
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To reveal specific signatures reflecting disturbances in lipid and glucose metabolism;
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To identify correlations between the most significant metabolites identified by principal component analysis and a) clinical status (NYHA, heart failure, diuretics), b) RV function and dilation by imaging (TTE and MRI), c) other biomarkers such as NT-proBNP and troponin;
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To identify changes in the metabolic profile secondary to new cardiac drugs tested on the RV.
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Identification of new putative therapeutics.
The project is initially focusing on CHD and will investigate other diseases such as PAH and RVF associated with LVF.
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To achieve these goals, the team has created a platform for the recruitment process for various projects such as RV/N2. The CCP3 is an integrative registry and biobank at the Montreal Heart Institute, with a prospective data collection dedicated to adult congenital heart disease (CHD) patients with heart failure or at risk for developing heart failure. Patients with Tetralogy of Fallot, Ebstein’s Disease, systemic right ventricle with biventricular physiology (Mustard and ccTGA), Fontan surgery univentricular left and univentricular right are targeted for the recruitment.
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The objectives of the CCP3 platform are:
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To better understand the heterogeneous and specific phenotype of congenital heart disease with heart failure
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To study the lifestyle habits of patients with complex CHD,
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To identify the metabolic and genetic biological factors of progression to heart failure,
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To identify new therapeutic targets by studying the metabolomic and genetic profile.
The CCP3 biobank is currently in the enrollment phase, which will allow the RVN2 project to be carried out and facilitate preliminary analyses.
RV/N2 team members
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Dr. Duncan Stewart – Cardiologist, Professor, University of Ottawa Heart Intitute, University of Ottawa
Dr. Jason Weatherald – Respirologist, Associate Professor, University of Alberta
Dr. Marie-A. Chaix - Cardiologist, Clinical Assistant Professor, Montreal Heart Institute, Université de Montréal
Dr. Lisa Mielniczuk – Cardiologist, Assistant Professor, University of Ottawa Heart Institute, University of Ottawa
Dr. Matthieu Ruiz - Scientist, Assistant Professor, Montreal Heart Institute, Université de Montréal
Dr. Seema Mital - Cardiologist, Professor, The Hospital for Sick Children, University of Toronto
Dr. Patrick Lawler – Cardiologist, Associate Professor, McGill University Health Center, McGill University
Dr. Anthony Tang – Electrophysiologist, Professor, London Health Science Centre, Western University
Dr. Harm Jam Bogaard – Expert in Heart Failure and Right Ventricular Dysfunction, Amsterdam University Medical Centre
Dr. Roham Zamanian – Expert in pulmonary hypertension clinical trials and digital health endpoints, Stanford University
Dr. Haley Hedlin – Statistician, Expert in adaptive and platform trials, Stanford University
Peter Greenstreet – PhD candidate, Lancaster University
Dr. Brandon Budhram – Resident Physician, University of Calgary
Jamie Myrah – Patient Advisor, Executive Director, Pulmonary Hypertension Association of Canada
Courtney Gubbels – Project Leader, Canadian VIGOUR Centre, University of Alberta, Coordinating Centre.