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.
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.
Dr. Duncan Stewart
Ottawa Hospital Research Institute
RV/N2 team members
Adaptative platform trial for therapies targeting RVF (CRAVE)
Many of the 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 multiple arm multiple stage (MAMS) design. This type of design allows for multiple treatments/doses and helps to drop losers and select winners early, while allowing for seamless Phase II/III trials and increasing efficiency. 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 would then be used to determine which therapy for each condition can be advanced to the next stage of research (Figure 1).
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.
Partnership and protocol development, as well as stakeholder engagement are in ongoing.
Dr. Jason Weatherald
University of Alberta
Dr. Marie-Alexandre Chaix
Montreal Heart Institute
Dr. Matthieu Ruiz
Montreal Heart Institute
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.
The goals of the RV/N2 metabolomics projetc are:
To reveal specific signatures reflecting disturbances in lipid and glucose metabolism;
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;
To identify changes in the metabolic profile secondary to new cardiac drugs tested on the RV.
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.
Preliminary data for the baseline metabolic profile are currently being analyzed and the team will then establish a final protocol to focus on CHD. The project will involve multiple centers across Canada.