Understanding Circadian Mechanisms of Sudden Cardiac Death

BACKGROUND

Sudden cardiac death is defined as an unexpected death due to cardiac causes that occurs within 1 hour of symptom onset in a person with known or suspected heart disease. It continues to be a major public health problem.  For more than 20 years, it has been known that sudden cardiac death exhibits a time-of-day dependence in settings of acquired and inherited forms of heart disease.  The risk for sudden cardiac death can be understood in terms of a complex interaction between various arrhythmogenic triggers and a vulnerable myocardial substrate.  The circadian system and its disruption can influence the reactivity to certain triggers and/or influence the cardiovascular substrate to promote vulnerability to sudden cardiac death.  An exploration of how daily and intrinsic circadian rhythms interact with and affect the physiological responses to potential extrinsic sudden cardiac death triggers is needed to better understand the mechanisms of sudden cardiac death and to devise strategies to prevent sudden cardiac death.  A lack of appreciation and comprehensive understanding of the circadian physiology and pathophysiology that contributes to the different temporal patterns of sudden cardiac death impedes development of effective therapeutic and prevention strategies, and interferes with the rigor and reproducibility of cardiovascular disease research.  Understanding the underlying mechanisms mediating day-night patterns in sudden cardiac death is expected to improve current clinical management, as well as identify new chronotherapeutic and chronopreventive strategies.

To address these knowledge gaps, the interplay between external and internal timing systems that resonate with the 24-hour day should be explored.  The endogenous circadian clock is a cell-autonomous molecular mechanism with a periodicity of ~24 hours, intrinsic to all cells and organ systems that serves as a molecular timekeeper.  The clock optimizes the timing of cellular and biological functions by regulating gene transcription.  This includes the tissue-specific expression of ‘clock output genes’ to modulate: (1) basal fundamental biological processes (e.g., cellular constituent turnover, metabolism, inflammation, and electrophysiology), (2) the responsiveness of cells/organs to behaviors and stimuli (e.g., extent of β-adrenergic signaling), and (3) pathological responses (e.g., the severity of myocardial damage in response to ischemia).  In addition, human studies have demonstrated that disruptions in circadian clock function contribute to the pathogenesis of cardiovascular diseases, as well as diabetes mellitus, obesity, and sleep-time non-dipping blood pressure patterning (nocturnal hypertension).  We expect that improved understanding of the circadian regulation of arrhythmogenic triggers (e.g., ischemia, neurohumoral stimulation, electrolyte imbalance, etc.) and arrhythmia susceptibility (termed ‘substrate’; e.g., myocardial adverse remodeling, inflammation, etc.) will provide unique opportunities to advance the field.

DISCUSSION

Workshop participants summarized the current state of knowledge in the basic and clinical sciences related to sudden cardiac death and control of cardiovascular physiology by circadian mechanisms.  They also identified gaps in knowledge, proposed novel approaches to advance fundamental and translational sciences, and identified opportunities for future research.

There was unanimous appreciation for the critical need to determine how day-night rhythms, including circadian and behavioral rhythms, confer physiological risks for sudden cardiac death.  Many fundamental basic science questions remain unanswered regarding the mechanisms by which circadian clocks impact cardiovascular physiology. More investigation is needed to understand how circadian clocks in cells, including different cell types (e.g., cardiomyocytes, endothelial cells, fibroblasts, immune cells, platelets, and neurons), influence function of the heart and autonomic nervous system.  Specific areas of focus should include the importance of normal circadian rhythmic synchrony and the potential pathological impact of desynchrony at the cellular, tissue, organ, and organismal levels.  Several challenges to exploring these questions are rooted in the limitations of both animal and cellular models as well as of clinical research.

To overcome these research challenges, greater emphasis on experimental rigor and methodological transparency is needed to control for and assess the influence of circadian factors on cardiovascular physiology.  Many published animal studies do not report the light/dark cycle under which the animals are housed, and human studies often do not report the sleep/wake cycle and meal patterns of participants.  Studying day-night rhythms and circadian clock signaling at the cellular level is further hindered by difficulties maintaining healthy cardiac tissue or differentiated cardiomyocytes in vitro for several days.  Human studies of circadian influences on cardiovascular function are limited by the absence of reliable biomarkers of day-night rhythms.

Human circadian studies have the highest translational value for human physiology and pathophysiology, which are influenced by day-night rhythms.  Greater knowledge of day-night rhythms in healthy populations and how they impact, or are impacted by, disease states that promote sudden cardiac death might enable development of behavioral and environmental interventions and possibly novel preventive strategies.  Identifying disruptions in circadian rhythms associated with vulnerability to sudden cardiac death might lead to new targets for drug therapy and strategies for drug administration and delivery to correct disrupted rhythms that confer risk.  New therapeutic strategies may also blunt the risk of adverse cardiovascular consequences in populations that suffer persistent disruptions to day-night rhythms (e.g., shift workers, sleep disorders).

KNOWLEDGE GAPS AND RESEARCH OPPORTUNITIES

The following scientific gaps in knowledge and research priorities were identified:

Basic/Translation

Gap:

The lack of standardization of animal models and approaches in considering day-night rhythms in experimental measures or design can impair rigor and reproducibility.

Opportunities:

• Establish guidelines and best practices for reporting and controlling day-night variables in animal studies of sudden cardiac death and cardiac arrhythmias.
• Consider time of day as a biological variable in such studies.

Gap:

There is a lack of understanding regarding the contributions of circadian clocks in cells critical for normal heart function, and uncertainty regarding the molecular and physiologic rhythms at the cellular, tissue, and whole organism levels that are most relevant to sudden cardiac death.

Opportunities:

• Apply contemporary genomic, biochemical, and molecular tools to interrogate circadian signaling (including transcription, translation, and post-translational modification) in cardiovascular cells and tissues relevant to sudden cardiac death.
• Determine the importance of circadian synchronization (phase) in central and peripheral clock signaling among cells and tissues relevant to sudden cardiac death (including neuronal and cardiac cells).

Gap:

There is uncertainty regarding the importance of maintaining normal circadian rhythmic synchrony and the potential pathological impact of desynchrony in terms of sudden cardiac death risk.  Can circadian biology be targeted to modify risk of sudden cardiac death?

Opportunities:

• Determine how perturbations in circadian rhythms can impact sudden cardiac death risk in animal models.

• Investigate the impact of timing for feeding, exercise, and drug administration on alleviating sudden cardiac death risk.

Clinical/Population

Gap:

There is uncertainty regarding how circadian rhythms confer risk for sudden cardiac death and how to explain evolving epidemiology of day-night rhythm in the incidence of sudden cardiac death.

Opportunities:

• Identify and investigate subsets of at-risk persons distinguished by sex, race, age, cardiac pathology, treatments, genetics, circadian disruption, etc. and determine in which subsets physiological changes across the circadian cycle confer sudden cardiac death risk.
• Determine how innate circadian rhythms interact with and modify the physiological responses to extrinsic arrhythmia triggers to create time-of-day vulnerability to sudden cardiac death.

Gap:

There is a lack of methodology to quantify circadian health in people and human tissues that are needed to assess the impact of deviations from normal on sudden cardiac death risk.

Opportunities:

• Develop new biotechnological tools (e.g., wearables, bioinformatics) to interrogate day-night rhythmic phenotypes.
• Develop and validate biomarkers to assess behavioral, central, and peripheral (including cardiac) circadian rhythms and assess correlations with sudden cardiac death risk.
• Create large-scale human datasets that include chronobiological measurements combined with cardiovascular outcomes.

Gap:

There is a lack of understanding of the impact of circadian rhythm disruption on risk for sudden cardiac death.

Opportunities:

• Investigate the impact of day-night rhythm misalignment, alteration of circadian period, phase, and/or amplitude on sudden cardiac death risk.
• Determine if biomarkers that reflect circadian disruption are robust predictors of sudden cardiac death and whether restoring circadian rhythm lowers risk for sudden cardiac death.

Publication Plans: A white paper outlining the recommendations that arose from the deliberations for the workshop is in preparation.

NHLBI CONTACTS:

Ravi Balijepalli, Ph.D., Division of Cardiovascular Sciences (DCVS)/Heart Failure and Arrhythmia Branch (HFAB)

Bishow Adhikari, Ph.D., DCVS, HFAB

George Sopko, M.D., DCVS, HFAB

Renee Wong, Ph.D., DCVS, HFAB

Michael Twery, Ph.D., National Center on Sleep Disorders Research (NCSDR), Division of Lung Diseases (DLD)

Workshop Members:

CHAIRS:

Alfred George, M.D., Northwestern University, Chicago, IL.

Brian P. Delisle, Ph.D. University of Kentucky, Lexington, KY.        

MEMBERS:

Michael Smolensky, Ph.D., University of Texas-Austin, TX             

Jeanne F. Duffy, MBA, Ph.D., Harvard Medical School, Boston, MA          

Joseph Bass, M.D., Northwestern University, Chicago, IL   

Jeanne Nerbonne, Ph.D., Washington University, St. Louis, MO.

Ron Anafi, MD, Ph.D., University of Pennsylvania, Philadelphia, PA.

Mukesh Jain, M.D. Case Western Reserve University, Cleveland, OH.      

Kalyanam Shivkumar, M.D. Ph.D., University of California, Los Angeles, CA.        

Martin Young, Ph.D., University of Alabama, Birmingham, AL.       

Steven Shea, Ph.D., Oregon Institute of Occupational Health Sciences, Portland, OR.           

Virend Somers, MD, Ph.D., Mayo Clinic, Rochester, MN.                

Christine E. Garnett, Pharm.D., FDA, Silver Spring, MD                  

Frank A.J.L. Scheer, Ph.D, Harvard Medical School, Boston, MA

Prince J. Kannankeril, M.D., Vanderbilt University, Nashville, TN   

Joshua Goldhaber, M.D., Cedars-Sinai Medical Center, Los Angeles, CA

Martica Hall, Ph.D., University of Pittsburgh, Pittsburgh, PA

Tracey Hermanstyne, Ph.D., Washington University, St. Louis, MO           

Crystal Ripplinger, Ph.D., University of University of California, Davis, CA