Research Priorities in Heart Failure with Preserved Ejection Fraction (HFpEF)

The Working Group identified 5 areas of focus for discussion based on their potential impact to advance HFpEF therapeutics over the next 5-10 years: (1) clinical definition, diagnosis, and progression; (2) organ level pathophysiology; (3) molecular pathophysiology; (4) new research tools and methods; and (5) strategies to monitor, prevent, and treat HFpEF.  To facilitate and prepare for thoughtful exchange of ideas, the Working Group developed a set of pre-meeting survey questions designed to identify major research gaps and emerging opportunities.  Additionally, the Working Group members were asked to provide preliminary recommendations and submit a brief outline of their presentation prior to the meeting.

The presentations and discussions during the meeting reflected the same themes as the survey responses. There was uniform recognition that HFpEF is a multi-organ, systemic disorder requiring a multipronged investigative approach in both humans and animal models to improve understanding of mechanisms and treatment of HFpEF.  It was recognized that advances in understanding of basic mechanisms and the roles of inflammation, microvascular dysfunction, fibrosis, and tissue remodeling are needed.  The discussion emphasized the need for improved animal models, including large animal models, which incorporate the effects of aging, exercise, and associated co-morbid conditions.  It was thought that a multi-model approach that is validated should be shared and made available to all researchers.  The working group thought that repositories of deeply-phenotyped human tissue (e.g., left ventricle, right ventricle, adipose, and skeletal muscle tissues; urine; blood; stool samples; etc.) should be developed and made accessible to researchers to enhance collaboration and research advances.

The Working Group emphasized the need for interactions between basic, translational, and clinical scientists and across organ systems and cell types, leveraging different areas or research focus, and between research centers.  The Working Group members suggested that future studies focus on pathobiological mechanisms and treatments with systemic/pleiotropic effects that are expected to target multiple organ limitations, in animal models as well as in humans.  The importance of understanding the fundamental mechanisms underlying heart-kidney cross talk and how these two organs affect each other or other organ systems bi-directionally was stressed.  It is well known that HFpEF is associated with multi-organ reserve dysfunction (i.e., lack of adequate response under stress or during exertion).  Therefore, assessment of the response of various organs to stressors and/or exercise reserve—rather than resting function alone—in human HFpEF and relevant animal models was felt to be of high importance.  Thus, future HFpEF research should include a stressor, not only for the heart but also for other involved organs including the vasculature, skeletal muscle, kidneys, lungs, and endocrine and adipose tissues.

A network of collaborative research centers to accelerate basic, translational, and clinical understanding of pathobiological mechanisms and treatment strategies in HFpEF was discussed as an example of a strategy to advance research progress.  This resource would facilitate a comprehensive and deep phenotyping of a multi-center HFpEF patient cohort with standardized protocols and a robust biorepository.  It was felt that the roles of metabolic dysfunction, obesity, and cGMP/PKG signaling should be included in future research studies.  There was strong consensus to include small proof-of-concept clinical trials, ideally including characterization of tissues from skeletal and cardiac muscle, blood, and imaging data with and without exercise.  Several examples of novel strategies were discussed, which included machine learning approaches, home-based telemonitoring, and patient-specific systems modeling to predict how patients will respond to interventions.  Aging, cognitive impairment, and frailty were identified as important factors to evaluate and include in future HFpEF studies.  To facilitate sharing and collaborations, the Working Group stressed the need for centralized databases to house both clinical and animal model data.

Additional discussions focused on the need to develop validated monitoring methods with strong correlation to invasive hemodynamic measurements to accurately evaluate exercise or stress effects, and high-definition phenotyping of HFpEF patients over time as disease progresses to correlate changes in clinical status with patient outcomes longitudinally.

Recommendations:

The Working Group made the following recommendations to address the identified knowledge gaps and advance prevention and treatment strategies in HFpEF that are categorized by scientific priorities, strategies, and funding mechanisms.

A. Scientific Concepts, Priorities, and Goals:

1. Improve diagnosis and identification of HFpEF by encouraging innovative approaches, such as machine learning to sub-classify distinct phenotypes of HFpEF.  Validate the phenotypes with longitudinal progression of clinical status and outcomes in the same subject, for example, from Stage B and C, by utilizing multimodality imaging assessments, provocative testing (e.g. exercise stress), and serial analyses of blood, cell, and tissue samples.  Employ multiscale modeling and systems biology methods to integrate the data in models to advance understanding of disease mechanisms and predict disease cause, risk, and progression.
2. Conduct large-scale interrogation of specific basic mechanisms: inflammation, microvasculature, fibrosis, metabolism, cGMP-PKG, mechanobiology (e.g., fibroblasts), including developing tools and banking human HFpEF tissue samples (e.g., cardiac, skeletal, adipose tissues).  Focus on discovery of new mechanisms and how they correlate to specific HFpEF phenotypes.
3. Develop improved HFpEF small and large animal models and resources that more accurately reflect the systemic, multi-organ nature of human HFpEF, including the distinct HFpEF phenotypes and make these models available to researchers.
4. HFpEF is a multi-organ reserve dysfunction syndrome.  It is therefore essential to stress the system, not just the heart but also vascular, skeletal, renal, pulmonary, endocrine, and adipose systems in both humans and animal models.  Assessments should be standardized, and may be invasive or non-invasive (assuming the non-invasive test is robust and validated with the invasive reference standard).
5. Pursue pathobiological mechanisms and treatments with systemic/pleiotropic effects that are expected to target multiple organ limitations, in animal models that mimic the human HFpEF phenotype as well as in humans.  Examples include, heart-kidney cross-talk and the obese-metabolic link in HFpEF.
6. Identify pathobiological mechanisms of, and trials testing interventions targeted to endophenotypes (e.g., combined pre- and post-capillary pulmonary hypertension; natriuretic peptide deficiency syndrome; obesity/metabolic HFpEF; microvascular dysfunction; hypertensive; cardiorenal, etc.) in human HFpEF patients, as well as animal models of HFpEF.  Coordinate the human and animal assessments in such studies.
7. Develop novel dissemination and implementation techniques to identify patients with HFpEF (e.g., natural language processing of electronic health records and automated analysis of cardiac imaging data) and apply proven interventions such as exercise training and diet.  Develop patient-centered medical home and multi-disciplinary coordinated care models for HFpEF.

B. Specific Strategies:

1. Emphasize key links between basic and clinical findings and across organ systems and cell types, leveraging different areas of research focus.
2. Develop collaborative teams with both basic and clinical investigators across disciplines working together within centers and across centers. 
3. Perform small proof-of-concept clinical trials as part of a specific HFpEF clinical research network.
4. Encourage simpler home-based trials with innovative trial designs that go beyond drugs to diet and exercise.
5. Encourage patient-specific, “high-definition” phenotyping and systems modeling approach with the potential for automated methods for quantification of phenotypic data, and serial phenotypic measurements over time.
6. Characterize mechanisms and test novel therapies targeting HFpEF patients with natriuretic peptide levels below traditional cut points.
7. Consider heavier use of Phase T1 or 2A proof-of-concept trials of novel or established therapies that will provide new mechanistic insight by leveraging additional testing for discovery (biomarkers, imaging, phenomics, physiologic assessments, etc.).
8. Determine and develop methods to detect what causes the transition of HFpEF from Stage B to C, and from C1 to C2.
9. Adjudicate HF events in existing large-scale comorbidity trials and stratify by EF to inform prevention of HFpEF.

C.  Funding Mechanisms

1. Establish a Translational HFpEF Network of collaborative research centers to accelerate basic understanding of the pathobiological mechanisms and develop and test novel treatment strategies in HFpEF.  The Translational HFpEF Network will be an efficient mechanism to optimally pursue the strategies listed under section B above.  Although there is an existing Heart Failure Network (HFN), the proposed Translational HFpEF Network will have a very different focus and composition.  This is needed because:  (1) the Translational HFpEF Network will build collaborative, translational teams to develop novel approaches using the full range of translational research, from molecular to large clinical trials; (2) it is now well established that HFpEF is a distinct entity from classic HFrEF, not merely an early stage in the transition to HFrEF; (3) there are numerous, marked, fundamental differences between HFpEF and HFrEF, which has been the traditional focus of the HFN; (4) treatment strategies that attempted to simply apply proven HFrEF treatments to HFpEF have been largely unsuccessful; (5) groups of investigators keenly focused on HFpEF have relatively modest overlap with investigators who are focused on advanced HFrEF, mechanical circulatory support, and cardiac transplantation; and (6) an HFpEF network can generate the critical mass of scientists needed  to ensure rapid communication, exchange of ideas, development and conduct of pivotal studies, and dissemination of novel techniques and strategies. 
2. Consider competitive seed-to-R01 type of awards to attract and test new research hypotheses (basic and clinical) in HFpEF.  These awards would start out with 1 year of limited funds in a competitive format with the top performers moving on to a larger-scale R01 grant. 
3. Encourage use of the full range of NIH funding mechanisms (e.g., networks, multi-institute funding, HFpEF RFAs, multi-PI grants, R01, R03, R21, multi-institute P50s, PPGs, etc.) to help advance the HFpEF field.  While the Translational HFpEF Network would be an effective means to promote advances, it is not the sole mechanism, and use of the full range of funding mechanisms will best ensure inclusion of the broad range of scientists capable of generating important discoveries. 

Publication Plans:

The Working Group will develop a report of the meeting for publication in an appropriate professional journal.