Understanding Circadian Mechanisms of Sudden Cardiac Death: A Report From the National Heart, Lung, and Blood Institute Workshop, Part 2: Population and Clinical Considerations

Opportunity: 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.

Many key aspects of the cardiovascular system and its regulation show robust day/night rhythms in healthy people, including increases in catecholamine levels, heart rate, and blood pressure^{15, 29–32} during the beginning of the daily active span. These rhythms provide a biological advantage to healthy individuals, but the rhythmic increases in sympathoadrenal signaling, heart rate, and blood pressure might also contribute to increased risk for myocardial infarction, stroke, arrhythmias, and SCD in unhealthy individuals.^33–38 In other words, circadian rhythms in catecholaminergic signaling that are advantageous in healthy individuals might increase the risk for deleterious events in people living with cardiovascular disease. Further dissection of how these rhythms interact with people living with coronary vascular disease, different types of cardiomyopathies and genetic arrhythmias, as well as other underlying causes of SCD will be an important step for tailoring the timing of disease-specific treatments with circadian-dependent phenomena to achieve optimal therapeutic and preventive effects.³⁹

Opportunity: 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.

The demographics of people living with different types of heart disease span across the spectrum of sex, age, and race. Generally speaking, children have earlier chronotypes (preference for the timing of the sleep and wake routines). The chronotype preference gets progressively later during adolescence until ~20 years of age.⁴⁰ Females on average have shorter intrinsic circadian periods than males, which likely contributes to their earlier entrained circadian phases.^{41, 42} Across adulthood, females continue to have earlier chronotypes than males. In older age, the chronotypes in males shift earlier. However, these changes are not due to changes in the intrinsic period of the circadian system^{41, 43} but rather due to changes in sleep-wake homeostatic processes.^{44, 45}

Some small studies associate differences in the circadian system with racialized categories. African Americans were found to entrain to light phase advances or delays differently than European Americans, and African Americans were reported to show shorter intrinsic circadian periods.⁴⁶ These racialized categories have no biological basis, so it is important to determine whether these differences stem from dynamic environmental factors, such as disparities in socioeconomic status, access to health and education, as well as the impacts of marginalization and discrimination.^{47, 48} Future studies designed to clearly separate how biological, genetic, and environmental factors contribute to the circadian system, and how these factors relate to the risk of SCD, will be important for developing effective mitigation strategies.

Opportunity: Develop new biotechnological tools (e.g., wearables, bioinformatics) to interrogate day-night rhythmic phenotypes.

There are opportunities to develop new technologies and to reimagine existing ones in order to identify heart rhythms and behaviors that reliably predict arrhythmic events and SCD in at-risk populations. For example, there is an increasing use of implantable loop recorders (ILRs) that allow continuous monitoring of people at higher risk for SCD, such as those with hypertrophic cardiomyopathy or long QT syndrome. These devices track clock and calendar time occurrence of arrhythmias, but do not provide understanding of the circumstances that predispose vulnerability to cardiac arrest and SCD. There are opportunities to complement existing ILR monitoring with other assessment technologies to more comprehensively and continuously track key variables. For example, sleep monitoring for sleep architecture, sleep duration, and sleep disorders, obtained in conjunction with ILR monitoring, will help determine if changes in sleep characteristics immediately precede, and perhaps precipitate in, potentially fatal cardiac events.

Similarly, incorporation of unobtrusive blood pressure monitoring options would add to the understanding of risk. For example, the day/night pattern of blood pressure is generally characterized by peak values during the late afternoon/early evening and lowest values during sleep. The sleep-period decline in systolic blood pressure relative to wake-period usually amounts to −10 to −20%, and has been termed the sleep-time blood pressure dipping pattern.⁵⁰ However, in sleep apnea and certain other medical conditions the day/night pattern is different such that the sleep-time systolic blood pressure fails to decline (or rises) substantially from wake-time levels. This may indicate a disruption of neuroendocrine and other circadian rhythms that regulate the day/night pattern of blood pressure.^51–55 This sleep-time ‘non-dipping’ blood pressure pattern constitutes an increased risk for myocardial infarction, stroke and other cardiovascular morbid and mortal events.⁵⁶ The role of altered circadian patterning of the blood pressure rhythm and the underlying factors that result in elevating the risk for SCD awaits exploration. It is noteworthy that, in comparison to upon wakening, ingestion of blood pressure-lowering medications before bedtime, particularly angiotensin converting enzyme inhibitors and angiotensin receptor blockers, can normalize the elevated sleep-time systolic blood pressure, improve the 24 hour non-dipping profile, and reduce cardiovascular disease morbidity and mortality.^56–60 This example illustrates the potential for rhythm-based chronotherapy that mitigates SCD risk. We anticipate that identifying circadian vulnerabilities or disruptions in circadian rhythms linked to SCD will inform novel chronopreventive strategies (analogous to those developed for people with ‘non-dipper’ hypertension).^{61, 62}

Opportunity: Develop and validate biomarkers to assess behavioral, central, and peripheral (including cardiac) circadian rhythms and assess correlations with SCD risk.

Current sensor-equipped wearable tracker hardware used in conjunction with interpretative software is capable of accurately monitoring environmental, behavioral and biological variables, including movement/activity, sleep, behaviors such as meal timing, heart rate, heart rate variability, blood pressure, body temperature, and oxygen partial pressure. Herein lies an opportunity for the additional technologies that also allow continuous monitoring of relevant cardiovascular and behavioral variables coded by clock time and calendar date. Such data will generate the databases required for proper investigation of mechanisms for the risk of SCD. As the science develops, the hope is to move from simply assessing time of day events to assessing endogenous circadian time to understand the circadian influence on SCD.⁶³

New technologies that enable the unencumbered non-invasive continuous monitoring of the electrocardiogram, blood pressure and other variables may identify patterns that predict future SCD events. Potentially relevant variables include body temperature, activity, blood glucose, and more unconventional variables that may fluctuate with circadian phase and/or exposure to behavioral/environmental stressors (e.g., the changes in the gut transcriptome and tissue/cellular expression of circadian genes). Technology to ascertain these and other metrics should be developed in order to collect data from large samples of subjects, including children and adults of both sexes.

Opportunity: Create large-scale human datasets that include chronobiological measurements and cardiovascular outcomes.

This opportunity can include projects to obtain data through public-private collaborations and industry-initiated/sponsored trials. For example, the National Institutes of Health All of Us program (https://allofus.nih.gov/) aims to enlist one million participants to build one of the most diverse health databases in history. This database will consist of clinical, genomic and mobile health data to enable exploration of biological, lifestyle and environmental aspects of health, disease pathogenesis, treatment response, and health promotion and disease prevention. Application of advanced computational analyses of large databases, composed of biological and ambient entries properly qualified for circadian time, should involve machine learning-based artificial intelligence methods to identify specific cardiovascular, sleep, and behavioral variables that predict increased risk for SCD. Some of the desired variables can be acquired by currently available consumer-wearable monitoring devices, however, more advanced and standardized high-performance clinical-grade technologies that enable around-the-clock assessment of multiple meaningful biological, behavioral and environmental variables are lacking and urgently required.

Opportunity: Investigate the impact of day/night rhythm misalignment, alteration of circadian period, phase, and/or amplitude on SCD risk.

Data from carefully controlled human studies show that markers of inflammation, coagulation, blood pressure, and heart rate exhibit endogenous circadian variation in healthy young subjects.⁶⁴ Furthermore, analysis of human cardiovascular tissue samples reveals daily variation in the expression of specific cardiac channels and autonomic receptors.^{64, 65} These factors are likely involved in both directly triggering cardiac arrest events in vulnerable individuals and in the long-term development/progression of underlying heart disease. In addition to the role of the circadian system and daily rhythms in the timing of serious adverse cardiovascular events, there is a growing body of evidence indicating that circadian disruption is a risk factor for SCD.⁶⁶

Environmental circadian misalignment occurs as a consequence of disruptions in the temporal relationship between the circadian system relative to environmental cycles. Behavioral circadian misalignment occurs because of a disruption in the temporal relationship between the circadian system relative to behavioral cycles. Internal misalignment occurs because of a disruption in the temporal relationships between different circadian oscillators (e.g., the central circadian pacemaker and peripheral oscillators and/or misalignment between different peripheral oscillators). Environmental, behavioral and internal circadian misalignment are not mutually exclusive. For example, if the timing of the light/dark cycle and the eating/fasting cycle are disturbed, internal misalignment can develop. In this case, the timing of food intake alters certain peripheral clocks, such as in the liver or skin, while the clock in the SCN maintains synchronization by the light/dark cycle.^{67, 68} In healthy human subjects, highly-controlled studies demonstrate that misalignment between the central circadian pacemaker relative to the behavioral and environmental cycles worsens several parameters associated with increased risk of cardiovascular disease, including increases in blood pressure and inflammatory markers (hsCRP, IL-6, TNF-α).^{24, 66, 69–72} Epidemiologic studies of shift workers showing increased risk for diabetes, hypertension, and myocardial infarction are consistent with these data. However, key gaps in the current state of science revolve around being able to reliably quantify the influence of circadian disruption on SCD risk remain. This includes but is not limited to distinguishing and understanding the mechanisms mediating the SCD risks resulting from environmental and behavioral circadian misalignment as opposed to the SCD risks resulting from the internal circadian misalignment.

Opportunity: Determine if biomarkers that reflect circadian disruption are robust predictors of SCD and whether restoring circadian rhythm synchrony lowers risk for SCD.

The study of circadian misalignment requires a basis for defining normal circadian alignment. One of the key barriers in advancing the science of chronobiology is the lack of an accepted clinical biomarker for circadian phase. In laboratory and controlled field settings, dim light melatonin onset (DLMO) is the gold-standard biomarker for assessing the phase of the central clock in the SCN. However, the measurement of DLMO requires repeated samples over a span of several hours while participants remain in dim light conditions. Another limitation is that it does not reveal the phase of the circadian clocks in different cell populations. As the use of β-blockers can suppress the secretion of melatonin,⁷³ this already difficult test is often inappropriate for use in populations with underlying cardiac disease, including those most at risk for SCD. Moreover, even in the laboratory setting there are no established, easily accessible, markers defining circadian phase in the different tissues and organs relevant to cardiac disease.

Several research groups are actively searching for alternative biomarkers that require fewer samples, are robust to various diets, medications, and genomic backgrounds, and do not require dim light conditions. Preliminary studies on blood based molecular circadian biomarkers have been reported.^74–76 However, none have been validated across a wide variety of patient populations, clinical conditions, and behavioral perturbations (e.g., shift work, altered mealtimes, etc.). In addition, to date, none of the proposed diagnostics focused on the markers for the circadian clock or circadian molecular outputs in peripheral tissues that are most relevant to SCD (e.g., vasculature, heart muscle, sino-atrial node, His-Purkinje system).

Beyond the assessment of circadian phase, measures of circadian disruption are particularly important for clinical study. Circadian disruption is most common in the setting of night shift work but can occur in almost any setting. This is especially true with the widespread use of light at night which shifts the SCN central phase quickly, while peripheral clocks may take longer to re-synchronize to the new central circadian phase (about 1 hour per day, depending on the intensity and circadian timing of light exposure).^{19, 77}

The discrepancy between biomarker estimated central circadian phase and behavioral and/or environmental cycles is a natural measure of molecular, behavioral and environmental circadian misalignment. However, measures of local clock function in cardiac tissue or measures that better describe the period, phasing and amplitude of specific processes may have more utility in predicting and explaining risk. Ultimately the specific molecular rhythms important to SCD development and the measures of circadian dysfunction that best predict risk will require dedicated clinical studies. Similar studies are required to identify the underappreciated impacts of existing risk factors (e.g., geographical setting, alcohol, drugs, smoking/vaping, etc.) or interventions that improve these circadian measures on cardiovascular outcomes.