HFpEF is a major public health problem that is rising in prevalence with the aging population and the ongoing epidemics of obesity, diabetes, and hypertension. HFpEF accounts for nearly half of all heart failure (HF) cases with a prevalence of at least 3 million in the U.S. alone and may be under-diagnosed in the general population. Whereas HFpEF was previously termed “diastolic HF”, it is now well known that HFpEF is a multi-organ, systemic syndrome that involves multiple pathophysiologic abnormalities beyond left ventricular diastolic dysfunction. HFpEF is associated with high morbidity and mortality. After HF hospitalization, the 5-year survival of HFpEF is a dismal 35%, which is worse than most cancers. In addition, quality of life in HFpEF is as poor or worse than HF with reduced ejection fraction (HFrEF) and is associated with physical activity levels that are similar to moderate-to-severe chronic obstructive pulmonary disease.
There are currently no effective therapies for HFpEFas most current therapies for HFrEF have been demonstrated to be ineffective for HFpEF. Recent studies have highlighted both the systemic nature of the HFpEF syndrome and the presence of “sub-phenotypes” within the heterogeneous HFpEF syndrome, highlighting the potential need for better-targeted therapies to specific HFpEF subtypes as a way to improve the track record of HFpEF clinical trials. Furthermore, while myocardial fibrosis, abnormal cardiomyocyte calcium handling, increased passive myocardial stiffness due to altered titin phosphorylation states, impaired cGMP-protein kinase G activity, cardiac and extracardiac metabolic derangements, and other mechanistic hypotheses have been implicated in HFpEF, basic science studies have been limited both by the heterogeneity of human HFpEF and by frequently equating diastolic dysfunction alone with the HFpEF syndrome, with a consequent lack of accepted animal models. Finally, because HFpEF is difficult to treat and carries a poor prognosis once it presents as overt volume overload requiring hospitalization, preventing HFpEF and limiting disease progression is critical.
Division of Cardiovascular Sciences
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.
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.
The Working Group will develop a report of the meeting for publication in an appropriate professional journal.