NEWS & EVENTS

Enhancing Resilience for Cardiovascular Health and Wellness

July 11 - 12 , 2018
Rockville, MD

Description

The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group meeting on July 11-12, 2018, in Rockville, MD, to discuss the role of resilience to enhance cardiovascular health and wellness. The goal for the Working Group was to discuss the state of the art and emerging concepts, identify opportunities and barriers, and develop recommendations for immediate and longer-term research to help enhance resilience for cardiovascular health.

Multiple mechanisms operate to maintain normal cardiovascular physiology and health. For example, optimal management of energy and substrate diversity is essential to cardiovascular tissues, as is a robust immune system that safeguards tissue homeostasis. However, there is heterogeneity in how these factors react to acute and chronic perturbations/insults between individuals. In some instances, biochemical tolerance and beneficial response and adaptation is successfully achieved to maintain tissue homeostasis and normal physiology. In other instances, there is not such a beneficial response or adaptation but rather a dysregulation of tissue hemostasis, which in turn initiates pathology. The Working Group considered a number of factors that could contribute to cardiovascular resilience and agreed on a working definition of resilience for the meeting — “Resilience is the ability of living systems to successfully maintain or return to homeostasis in response to physical, molecular, individual, social, societal, or environmental stressors or challenges.” Current knowledge gaps limiting our understanding of this phenomenon include a lack of information on the role of social, physiologic and other contributors. Additionally, we require more information on the identity of the molecular determinants and other processes that are responsible for biochemical tolerance and protection from subsequent cardiovascular disease.

Recap

Summary of discussions

The Charge for the working group was to identify research gaps in the field of cardiovascular resilience and to identify research opportunities in other science areas for incorporating the concept of resilience. Discussions also included the potential to identify “static” biomarkers of resilience, and the significance of defining and quantifying resilience in the context of specific stressors or perturbation.

Molecular basis of resilience

It is important to understand if resilience resides at the cellular/organ/tissue levels, to discriminate between aging and resilience, and to also clarify underlying mechanisms for each. An intriguing question is whether aging of the vascular system compromises tissue/organ resilience, and through this pathway compromises cardiovascular health. To address this question, genetics-based approaches could provide insights into the molecular basis of resilience and could use existing databases to search for naturally-occurring loss of function mutations that are protective for cardiovascular health. This question could also be addressed by identifying and studying individuals who harbor mutations of known childhood-onset diseases, but who manifest no clinical disease. Integrative analysis of genetic, genomic, and electronic medical record (EMR)-based data also might be informative in identifying and characterizing individuals in the general population who manifest extreme resilience.

It will be critical to gain insights into the molecular pathways and mechanisms involved in cardiovascular (CV) resilience and to differentiate them from pathways involved with vulnerability (predisposition to pathophysiology). The interaction of micro- and macro-environments with the organism is of importance in the regulation of cell-autonomous and non-cell-autonomous resilience pathways. Investigating transcriptional flexibility thresholds (elasticity) might be one measure of resilience at the cellular level that could prove useful.

Modulating factors in resilience

Understanding the role of pro-resolving mediators, such as the resolvins, lipoxins, protectins and maresins, their biosynthetic pathways and pro-resolving receptors in countering inflammation and stimulating resolution might shed light on how tissue resilience occurs. The role of mitochondrial nuclear communication, bioenergetics, and metabolism also merit exploration as systemic modulators of tissue resilience. Adaptive factors may confer resilience in other processes and characteristics of exceptional adaptive agers (individuals who don’t respond adversely to stress) that might lend insights into pathways of CV tissue resilience. The role of mitochondrial stress, DNA damage, and other quality control measures all might play important roles in CV resilience. Exceptional longevity, recovery from incident strokes with no cognitive decline, and differences in the effect of risk factors are some unique opportunities to help explore possible additional mechanisms of CV resilience.

Populations, risk and resilience

Group comparisons between populations may mask individuals or subgroups within a group who maintain good CV health despite the presence of adverse risk exposures. Consequently, the theme of ‘an enhanced state of functioning’ is an important contributor to CV resilience. Understanding the environmental and individual promoters of CV resilience and health in populations exposed to broadly adverse environmental conditions could provide insights into physiologic and tissue resilience. One unique opportunity would be to focus on the geographic areas of unexpectedly good CV health in larger neighborhoods with otherwise unfavorable CV health outcomes.

Psychosocial, environmental, and lifestyle factors

Psychological resilience may be best understood and measured as an adaptive response trajectory that compares favorably to other possible response trajectories after exposure to severe stressors or trauma. There are many different stress models and theories that collectively suggest that achieving psychological resilience is dependent upon the source of stressor, the controllability of the stressor, the resulting cognitive appraisal of the stressor, the behavioral response to the stressor, and the time course of these stress responses. It is possible that psychological or cognitive resilience sometimes bypasses the central nervous system and operates on more instinctual levels, whereas at other times, resilience does require processing at the central nervous system. Information emerging from the creation of a Human Resilience Project (Chen et al, 2016) designed to collect and integrate physical, molecular, individual, social, societal, or environmental data, in response to human stressor exposure, could be a valuable source of insights regarding psychological, tissue, and CV resilience to stressor exposure.

Measures of midlife CV tissue and psychological resilience might serve as a determinant or indicator of current and future healthspan and/or lifespan. One measure of global resilience might be to assess how well and how quickly one recovers from a surgical or medical intervention. Experimental model systems can help identify molecular phenotypes of resilience. As we investigate ways to intervene upon resilience, exercise and caloric restriction appear to confer benefits over a range of subdomains of resilience and may be useful to improve human resilience. Understanding the underlying mechanisms for these interventions may yield generalizable principles that inform further research and interventions.

Recurrent themes in the discussion included the necessity of assessing resilience over time and throughout the lifespan, thus the need for longitudinal data. The concept of a simple clear definition and the need to clearly define and tease apart the differences between resilience, disease-free aging, and adaptation was discussed. Also, the need to integrate data and measures of resilience from the cellular to the population level was a recurrent theme.

Recommendations

  • Adopt the following simplified working definition for resilience — ‘Resilience is the ability to resist and recover from a stressor’
  • Integrate high-dimensional data derived from existing longitudinal studies, mobile apps, EMR information, and genetic resources to create a quantitative measure of a ‘resilience index’
  • Focus on age-dependent resilience analyses and a lifecourse approach. Introduce interventions into studies to investigate resilience as a dynamic process.
  • Measure allostatic load and changes over time in response to defined stressors by employing a systems approach to characterize the determinants that confer resilience, the ‘resiliome’
  • Assess vascular and capillary health as a marker of CV resilience at the individual organismal level
  • Investigate mitochondrial health, genetics, mitochondrial-nuclear interaction, and mitochondrial-cellular energetics as determinants of cell/tissue/organ/individual resilience
  • Support quantitative measures of inflammation resolution factors and real time measurements of the ability of the immune (M2 macrophages) and lymphatic systems to clear debris
  • Probe recovery of functional capacity and physical/cognitive function after exposure to stressors over time
  • Build a cloud-based platform to house and facilitate integration of data from and across multiple domains
  • Leverage existing cohorts to accommodate more visits over time to address resilience (i.e., cognitive function, cardiovascular health, microbiome, etc.)
  • Identify molecular drivers of resilience that can subsequently inform therapies
  • Develop quantitative cell/organ/systems models to identify resilience mechanisms involving resolution/response pathways and the role of their pro-resolving receptors and signaling.
  • Train the next generation of researchers to adopt cross-domain models for resilience research

Reference

Chen, R., et al. (2016). "Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases." Nature Biotechnology 34: 531.

Publication Plans

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

Participating Division

Division of Cardiovascular Sciences

Staff Contacts

Pothur Srinivas, PhD, MPH
srinivap@nhlbi.nih.gov
301-402-3712

Zorina Galis, PhD
Zorina.galis@nih.gov
301-435-0560

Working Group Members

Co-Chairs

  • Herman Taylor Jr, MD, Morehouse School of Medicine
  • Toren Finkel, MD, PhD, University of Pittsburgh School of Medicine

Members

  • Charles Serhan, PhD, Brigham and Women’s Hospital
  • Karina Davidson, PhD, Columbia University
  • Luisa Iruela-Arispe, PhD, UCLA
  • Martin Picard, PhD, Columbia University Irving medical Center
  • Michelle Odden, PhD, Stanford University
  • Nathan Lebrasseur, PhD, Mayo Clinic
  • Rong Chen, PhD, Mount Sinai School of Medicine
  • Scott Ballinger, PhD, University of Alabama School Of Medicine

NHLBI Staff

  • Eser Tolunay, PhD
  • Cashell Jaquish, PhD
  • Diane Reid, MD
  • Joni Snyder, RM
  • Michael Wolz, MA
  • Michelle Olive, PhD
  • Myron Waclawiw, PhD
  • Olga Tjurmina, PhD
  • Rebecca Campo, PhD
  • Shu Hui Chen, PhD
  • Sonia Arteaga, PhD
  • Yunling Gao, PhD