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. Author manuscript; available in PMC: 2020 Dec 18.
Published in final edited form as: Curr Sleep Med Rep. 2019 Nov 29;5(4):234–242. doi: 10.1007/s40675-019-00157-8

Short Sleep, Insomnia, and Cardiovascular Disease

Caleb G Hsieh 1, Jennifer L Martin 2,*
PMCID: PMC7747467  NIHMSID: NIHMS1544930  PMID: 33344144

Abstract

Purpose of Review:

This review summarizes key findings linking insomnia, short sleep duration, and cardiovascular health.

Recent Findings:

Early studies associations between insomnia with short sleep and cardiovascular disease Recent studies have incorporated objective data to assess sleep and identify comorbid sleep disorders (e.g. sleep apnea). Use of objective metrics has facilitated understanding of the impacts of insufficient sleep on autonomic dysregulation, metabolic syndrome, coronary artery disease and overall cardiovascular mortality. Emerging research suggests treatment of insomnia (CBT-I) may be beneficial in terms of reducing cardiovascular disease risk.

Summary:

From short term effects on the autonomic nervous system to lasting effects on metabolic syndrome and coronary artery disease, there is growing evidence to support a physiologic pathway by which insomnia with short sleep contributes to cardiovascular disease. More research is needed to understand the effect of insomnia treatment on cardiovascular risk.

Keywords: Insomnia, Short Sleep, Cardiovascular disease, Insomnia, CVD risk

INTRODUCTION

Cardiovascular disease (CVD) is the leading cause of death in the United States and worldwide1, and via one of its many potential manifestations, affects nearly half of all adults over the age of 20 in the US and costs an estimated $351.2 billion annually.2 These figures are projected to continue rising over time.2 In recognition of the enormous impact that sleep disturbance has on health, and the ongoing need to address such modifiable risk factors early, the American Heart Association has added a category for “sleep” to its list of core health behaviors and health factors that contribute to cardiovascular health.2

Over one-third of Americans report inadequate sleep or regular sleep disturbance.3 That number is projected to grow as work habits and lifestyles change.4 In the modern era, the average individual faces an increasing number of daily challenges and potential threats to maintaining healthy sleep. From increasing demands and stressors in the work place,5,6 to increasing distraction and blue-light disturbance from pervasive electronic devices,7,8 “poor sleep” is an escalating burden on health and society.9,10 In this review, we aim to define components of sleep specifically related to insomnia and short sleep duration and to summarize the emerging evidence and pathways through which insomnia and short sleep duration may contribute to cardiovascular disease.

Terminology for Describing Insufficient and Poor-Quality Sleep

When describing “poor sleep”, the umbrella phrase “sleep disturbance” can refer to any number of a heterogeneous components of disease. While sleep-disordered breathing (e.g. obstructive sleep apnea, central sleep apnea) is a crucial component to sleep disturbance, there is emerging evidence that other sleep-related disturbances are worthy of consideration as well. One challenge in drawing conclusions from the many studies on short sleep duration and insomnia may be attributed to inconsistencies in how insomnia and short sleep duration are defined and measured across studies.

In 2013 and 2014, the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) and the International Classification of Sleep Disorders, third edition (ICSD-3) respectively released updated criteria for the diagnosis of insomnia disorder.11,12 In both nosologies, a diagnosis of chronic insomnia disorder requires dissatisfying sleep (i.e., difficulty initiating, maintaining, or early awakening) that occurs at least 3 nights per week, for at least 3 months. The sleep disruption must be sufficiently severe to cause significant functional impairment or distress. Current classifications also note that insomnia disorder should not be diagnosed if another sleep-wake disorder, substance abuse, comorbid psychiatric illness or medical illness fully explain the sleep complaint;11,12 however, it is notable that insomnia disorder can still be diagnosed in the context of comorbid conditions. These changes lengthened the time period required for diagnosis (from 1 month to 3 months) and allowed for easier diagnosis of insomnia in the context of comorbid conditions, and this may alter estimates of prevalence and morbidity.

“Short sleep” has been defined by most epidemiological studies as a habitual sleep duration of less than 6 hours.13 That said, the 2015 American Academy of Sleep Medicine (AASM) and Sleep Research Society (SRS) guidelines jointly recommend at least 7 hours of sleep per night for adults 18 to 65 years of age to “promote optimal health”.14 This is similar to the recommendation of 7 to 9 hours from the National Sleep Foundation.15 In addition to this minor terminological difference, there have also been various methodological heterogeneities with regards to how sleep duration and quality are measured. Large epidemiologic studies generally utilize subjective quantification via recall-based questionnaires. Some studies have used daily sleep diaries to compute sleep duration. Although subjective reports are less resource intensive, there may be more susceptibility to reporting biases. Objective measures of sleep duration (e.g. at-home actigraphy or in-lab polysomnogram (PSG)) are more resource intensive and generally limited to smaller cohorts, although these approaches have the advantages of measuring actual sleep time and are not subject to recall biases. Few studies to date have utilized or compared both subjective and objective measurements,13,16,17 and more research on meaningful discrepancies between self-reported and objectively measured sleep duration is needed.

Within the subset of individuals habitually sleeping less than 6–7 hours a night, there are also some without the sleep insufficiency, dissatisfaction, or functional impairments characteristic of insomnia disorder. These individuals may represent outliers on the spectrum of typical sleep duration and can be difficult to identify in epidemiologic studies due to the lack of symptoms. Conversely, there are also individuals with insomnia that do not necessarily experience short sleep. Combining both subjective and objective elements, Vgontzas and colleagues studying the Penn state cohort were better able to identify the compound effects of insomnia and short sleep duration on medical morbidity and mortality, with findings having since been replicated in several other studies.16,1822

INSOMNIA, SLEEP AND CARDIOVASCULAR DISEASE

Insomnia, Short Sleep and Autonomic Dysregulation

Autonomic dysregulation in insomnia has been implicated in the initiation and propagation of sleep disturbance associated CVD (see Figure 1). Increases in sympathetic tone and decreases in parasympathetic tone portend overall increases in cardiovascular risk.23 Heart rate variability (HRV) is a complex surrogate for autonomic tone and sympatho-vagal balance that measures the variance of time intervals between consecutive heart beats.24,25 Fourier transform can be used to convert this information into a frequency spectrum with the high- frequency (HF) domain HRV reflecting vagal activity. Higher HF power indicates increased parasympathetic influence. HF power may often be greater at night and lower during the day. Interpretation of low-frequency HRV remains controversial.24,25 Although well-accepted in the cardiology literature, use of HRV in studies of sleep insufficiency or sleep disorders has been relatively limited with mixed results.26

Figure 1:

Figure 1:

The relationship between insomnia, short sleep duration and cardiovascular disease is complex with many overlapping and interacting components.

Grimaldi et al. subjected a small cohort of 26 young, healthy volunteers aged 20–39 years to sleep deprivation and circadian disruption. Participants had normal baseline sleep behavior and schedules as confirmed by baseline PSG and actigraphy. They were then subjected to 3 days of 10-hours bedtimes (22:00h – 08:00h), followed by 8 days with 5-hour bedtimes. The circadian-alignment group slept from 00:30h – 05:30h on all 8 days, while the circadian misalignment group slept from 09:00h −14:00h on days 2,3,5 and 6 and 00:30h – 05:30h on remaining days. HRV and urinary norepinephrine (NE) were measured at regular intervals. They found that the combination of short sleep and circadian misalignment significantly increased urinary NE and decreased HRV, suggesting increased sympathetic and decreased parasympathetic tone.27 This was similar to earlier studies by Takase et al.28

As part of the Multi-Ethnic Study of Atherosclerosis (MESA), Castro-Diehl et al. performed a cross-sectional analysis of baseline HRV and HRV response to additional mental and physical stress challenges. Sleep duration was assessed with 7-day actigraphy manually adjusted based on data from sleep diaries; Sleep quality was assessed via Women’s health initiative insomnia rating scale; and sleep disordered breathing was screened for via 1-night home polysomnogram. With regard to the combined effect of short sleep and insomnia, the authors found greater high-frequency HRV reactivity in response to stress thus implicating higher sympathetic and lower parasympathetic tone.29

With regard to chronic insomnia, Jarrin et al. separated a small cross-sectional cohort of 180 patients by objective sleep duration as measured by a 3-night PSG and subjective sleep duration as measured by a 14-day sleep diary, and found that objective short sleepers had dampened parasympathetic activation compared to the near normal sleep duration cohort. Interestingly, there was no significant difference when subjective sleep duration was analyzed.30

As a separate measure of autonomic function, systolic blood pressure (SBP) generally decreases by approximately 10% during sleep, a phenomenon referred to as “dipping.” Lanfranchi et al compared 13 patient with chronic insomnia to normal sleeping controls and found that self-reported chronic insomniacs had blunted SBP dipping, higher nighttime SBP, and overall higher average 24-hour SBP compared to “good sleepers”.31 Similar to non-dipping HR profiles, elevated nighttime SBP and non-dipping blood pressure may be associated with increased cardiovascular risk3133

Insomnia, Short Sleep and Atrial Fibrillation

Until recently, the effects of insomnia and sleep duration on atrial fibrillation (AF) were largely overshadowed by the association between sleep apnea and AF.34 Analysis of approximately 18,755 physicians from the Physicians’ Health Study found that while self-reported sleep duration of ≤6 hours was associated with higher incidence of AF; however, this effect was nullified when accounting for concomitant sleep apnea.35 Similarly, Kwon et al. evaluated 2,048 individuals in the MESA cohort with objectively measured sleep duration via actigraphy and found no association between sleep duration and AF.36 These studies used self- reported sleep duration; however, Genuardi et al. reviewed 31,079 diagnostic polysomnograms and found that every 1-hour decrement in total sleep time was associated with 1.17-fold increased odds for prevalence of AF, and a 1.09-fold increased odds of incidence AF. These associations held even when controlling for SDB.37 This suggests a relationship between objective sleep time, but not reported sleep time, and AF.

To further evaluate the link between sleep quality and AF independent of SDB, Christensen et al. analyzed cross-sectional data on 4,553 participants in the Health eHeart cohort, longitudinal data from 5,703 participants in the Cardiovascular Health Study (CHS) and clinical data from over 14 million patients in the California HCUP databases. Even after controlling for SDB, they found that longer sleep onset latency and more frequent nighttime awakening were independently associated with prevalent AF in the Health eHeart cohort; frequent nighttime awakening, early morning awakening and decreased REM sleep were associated with increased incident AF in CHS; and a diagnosis of insomnia predicted subsequent diagnosis of AF in clinical settings.38

Mechanistically, while the MESA cohort analysis had found a protective effect from increased stage N3 or slow wave sleep time,36 and analysis of the CHS suggested a protective effect from REM sleep,38 Genuardi et al. suggest that all stages of sleep were protective.37

Insomnia, Short Sleep and Metabolic Syndrome

Hypertension, diabetes, dyslipidemia and obesity are a set of interrelated metabolic disorders that directly promote and increase the risk for cardiovascular disease.39 While metabolic syndrome is largely influenced by known factors such as genetics, nutrition, physical activity, and more recently, SDB,40 the role of insomnia and short sleep independent of SDB is not as established.

In short-term laboratory settings, pathophysiologic studies have suggested a mechanistic foundation for an association between short sleep and metabolic syndrome. In animal models used to simulate shift work, circadian misalignment and disruption of normal circadian activity shifted energy homeostasis towards increased feeding, impaired glucose metabolism and obesity.41 Indeed, similar findings have been demonstrated in human studies.42 Experimental sleep restriction has been shown to cause hormonal imbalance - decreases in the satiety hormone (Leptin) and increases in the appetite stimulating hormone (Ghrelin) - and inflammatory cascade43,44 resulting in increased appetite45,46 and increased insulin resistance.47

Longitudinally, a number of meta-analyses have found increased risk for metabolic syndrome among individuals with self-reported short sleep,4851 but lack of consideration of SDB and insomnia led Fernandez-Mendoza et al. to analyze the effects of objective short sleep duration amongst individuals within the Penn State Cohort with and without metabolic syndrome. After a mean follow up 16.7 years, the authors found that while differences in mortality among normal (>6h) sleepers with and without metabolic syndrome was essentially negligible, objective short sleepers with metabolic syndrome had a 2-fold increased mortality risk compared to short sleepers without metabolic syndrome. This was largely driven by patients with diabetes and/or hypertension.52 Thus, in addition to potentially contributing towards development of metabolic syndrome, short sleep may also modify amplify mortality risk.

Insomnia, Short Sleep and Hypertension

An association between insomnia, short sleep and hypertension has been reported for decades, but there remains a significant element of confounding from comorbidities, inconsistent definitions, and study heterogeneity that has limited the interpretation and application of this information. In a thorough systematic analysis and review on this subject, Jarrin et al.53 found significant heterogeneity across 64 studies in term of definitions for insomnia (e.g. DSM, ICSD, or ICD), subdivisions of insomnia (i.e. onset, maintenance, or early morning awakening), measurement of insomnia (i.e. subjective vs objective), measurements of hypertension (e.g. self-report, physician report, ambulatory monitoring), duration of study, and direction of proposed causality.53 In a meta-analysis of 11 studies including nearly 60,000 patients and mean follow up of 5.5 years for sleep duration analysis and 8.2 years for insomnia analysis, Mong et al. found that studies used a mix of subjective and objective sleep duration measurements, subjective and objective hypertension measurements and varying degrees of control for confounding factors. The overall relative risk for short sleep was 1.21 (1.05 – 1.40). There were no statistically significant differences within the various subgroup analyses, however the authors did note that shorter follow-up durations, adjustment for psychological factors, self-reported blood pressures and self-reported sleep durations contributed to a lack of significant findings across studies.54

Another large meta-analysis by Wang et al. included data from 13 cross-sectional studies (some overlap with Meng et al.), with approximately 350,000 participants. Adjusting for age and gender, the authors stratified sleep duration by <5h, 6h, 7h, 8h and >9g, and found a U-shaped distribution for the pooled odds ratios for hypertension. Sleep duration of <5h was highest risk for hypertension. In their subgroup analyses, they found that association between shorter sleep and hypertension was stronger for women and weaker for elderly patients. It was also noted that they did not control for sleep disordered breathing or additional comorbidities.55

In view of the challenges presented by the above large-scale meta-analyses and reviews, it is worth noting a few studies attempting to address these issues. Fernandez- Mendoza and Vgontzas were among the first to use objective short sleep duration in the study of insomnia and hypertension.56 In a repeat analysis, 1,741 patients with objectively measured short sleep based on single overnight PSG and mean follow-up of 15.5 years, they found a dose-response pattern with increasing risk of hypertension (and mortality) corresponding to decreased objective duration of sleep.57 Notable limitations, however, included an oversampling of SDB patients, and lack of consecutive nightly recordings. Thus, Ramos et al. performed a cross sectional study evaluating 2,148 patients who underwent one full week of wrist actigraphy. After accounting for SDB (defined as AHI > 15), there was no significant association between total sleep duration, reported insomnia severity and hypertension; however, patients with hypertension did have significantly increased sleep fragmentation and decreased sleep efficiency compared to those without hypertension.58 Finally, in an attempt to minimize contribution from covariates, authors of the HUNT-3 trial conducted a large (approximately 50,000) epidemiological study and multivariate analysis adjusting for sociodemographic and lifestyle factors (e.g. physical activity, chronic pain, depression and anxiety), established CVD risk factors (e.g. diabetes an hyperlipidemia) and SDB.59 In contrast to prior studies, there was a small inverse association between insomnia symptoms and blood pressure which, authors concluded was of limited clinical significance after adjustment for covariates.59

From a mechanistic perspective, it has been noted that decreased stage N3 or slow wave sleep may be associated with increased incidence of hypertension.60,61 Analysis of data from the Sleep Heart Health Study suggested that this association persists even after controlling for SDB, sleep duration, and fragmented sleep.60 This may be due to increases in parasympathetic activity during slow wave sleep that may be protective and lead to sustained lower blood pressures. That said, if increased total duration of all stages of sleep can be protective with regards to AF,37 this may also be true for hypertension.

In summary, while strong association between insomnia with short sleep duration and hypertension has been implicated by many cross sectional and prospective studies, the interpretation and implications of these studies is somewhat limited. Future studies would benefit from thorough exclusion of SDB, the use of more objective sleep parameters and blood pressure measurements over longer follow-up periods, and more systematic control of covariates.

Insomnia, Short Sleep, Coronary Artery Disease and Mortality

If insomnia and short sleep does indeed increase risk for autonomic dysfunction, hypertension and metabolic dysregulation as above (see Figure 1), one might expect an association with coronary artery disease, and by corollary, mortality. Early studies focusing on sleep duration alone showed mixed results, which prompted Chandola et al. to evaluate the additive effects of short sleep and “sleep disturbance” in the Whitehall II Cohort – a prospective study of >10,000 individuals with a mean follow up of 15 years.62 Although SDB was not evaluated, the authors point to a prevalence of 14–21% for sleep disturbance in their study compared to up to 1.5% for OSA in their local population. Even after adjusting for hypertension, diabetes and other potential confounders, short sleep and sleep disturbance contributed to a significantly elevated risk of CAD (HR 1.45, 1.24–1.70).62

In the HUNT study cohort, Laugsand et al.63 separated symptoms of insomnia into difficulty initiating sleep, difficulty maintaining sleep and non-restorative sleep and found a dose dependent relationship between insomnia symptoms and relative risk for acute myocardial infarction. The risk was most notable for those with difficulty initiating sleep and was more pronounced if patients using sleep aids were excluded. Data on mortality was not collected in this study.

In the Sleep Heart Health Study, Bertisch et al.18 re-produced similar results in a slightly older population (mean age: 64.±11.1 years) of ˜4500 individuals with objectively measured sleep duration and self-reported difficulty initiating sleep, difficulty maintaining sleep, or early morning awakening. In regard to incident CVD (including CVA), neither insomnia nor short sleep alone increased risk of events; however in combination, there was a dose-dependent response with a 29% increase in events (HR 1.29, 1.00–1.66) for <6h and 52% increase (HR 1.52, 1.08–2.14) for <5h. Interestingly, in the mortality analysis, while short sleep alone conferred a modest increased risk of all-cause mortality, insomnia with short sleep did not.18 This is in contrast to earlier findings from the Penn State Cohort,64 which noted an increased mortality in men. Authors of both studies suggest that the increased mortality in men within Penn State Cohort may be attributable to an increase in baseline diabetes prevalence (21% in men vs. 8% in women) as the odds ratio was not significant after accounting for diabetes and hypertension18,64.

In a recent epidemiological study of the Women’s Health Initiative Cohort, which incorporated self-reported and subjective measures of sleep duration and insomnia from >150,000 women over a median of 17.8 years, Kabat et al. found that short sleep duration (>5h) was associated with increased CVD related mortality regardless of concomitant insomnia. In fact, the authors reported that insomnia had a small inverse effect on mortality. That said, in addition to the lack of objective sleep measurement, a couple notable limitations to these findings are that the use of sleep medications or alcohol (i.e. sleep aids) – which did confer an increased mortality risk – was separated from insomnia and that there was no adjustment or information with regards to existing SDB.

Despite using non-standard criteria for insomnia, the above studies suggest that insomnia or sleep disturbance coupled with short sleep duration likely increases the risk for CAD and CVD. The somewhat paradoxical finding that sleep duration alone confers increased risk for CVD mortality, but not necessarily CVD itself supports results published by Cappuccio et al. in a prior meta-analysis.65 In addition to more objective and standardized assessment of sleep duration and disturbance, the above findings suggest that future studies should attempt to better elucidate the compounding effects of insomnia on CVD-related mortality, better assess the role and effect of sleep medications, and potentially reassess the modifying effects of gender.

TREATMENT OF INSOMNIA AND EFFECTS ON CVD

Beyond interventions that address comorbidities (e.g. treatment of depression/anxiety, encouraging diet and exercise), current therapeutic modalities aimed directly at insomnia and sleep duration utilize cognitive behavioral therapy for insomnia (CBTI), hypnotics, or some combination of the two. While these interventions can be effective in improving sleep iteslf,66 given the wide array of conditions that contribute to insomnia and short sleep duration and the bidirectional nature of their respective relationships, the end effect of insomnia treatment on cardiovascular risk remains uncertain.

CBTI remains the first-line treatment for chronic insomnia disorder.67 In 2015, Conley and Redeker revised studies aimed at determining the effect of CBTI on CVD as reviewed by in 2015,68 and additional work has been published after their review. Jarrin et al. conducted a secondary analysis of a 6 week CBTI program on nocturnal HRV in a cohort of 65 patients with chronic insomnia (based on DSM-IV criteria), excluding individuals with comorbid SDB.69 Participants kept 2-week sleep diaries and had both pre- and post- intervention PSGs. Contrary to what the authors expected, patients with improved sleep onset latency had reduced HF HRV suggesting less parasympathetic activity. That said, authors acknowledged the small sample size and lack of a control group.70

In the Sleep to Lower Elevated blood Pressure trial (SLEPT), McGrath et al71 conducted a randomized, investigator-blinded trial evaluating the effects of an 8-week self-guided internet- based sleep hygiene and CBTI program on 24-hour ambulatory systolic blood pressure. Volunteers had baseline systolic blood pressure between 130–160 mmHg (mean 141 mmHg), were on one or fewer medications for blood pressure and had self-reported sleeping difficulties. Those with prior sleep-related diagnoses were excluded. Of 67 patients randomized to receive the online intervention, only 58 registered, and of those, only 29 patients completed all sessions. Those that completed the intervention had improved subjective measures of sleep, but no significant difference in blood pressure. Additional studies on this topic are underway.72

Finally, Redeker et al.73 published a pilot randomized control trial evaluating the effect of CBTI on autonomic function and hypothalamic-pituitary axis (as measured by urinary biomarkers) among patients with existing heart failure. Patients with untreated sleep-disordered breathing were excluded. The authors note that while this small pilot study was not powered to detect an effect of CBTI on biomarkers, there were trends for improvements in sleep disturbance, objective sleep characteristics, and biomarkers which may be evaluated in future studies.

SHIFT WORK AND SLEEP DURATION:

Some forms of behaviorally-induced sleep disturbances are more readily identifiable, likely to increase in prevalence, and thus deserve special mention. One seldom discussed cause of insufficient sleep is shift work. The rise of the “24/7 economy” has increased the length of the average working day and the prevalence of so-called “shift workers” whose often dis-circadian work schedules are associated with increased morbidity.5,7476

Data from the Nurses’ Health Study published in 2016 and collected over 24 years found that >5 years of rotating night shift work was associated with an approximately 12% increased risk of CVD. In subgroup analyses, CVD risk decreased after cessation of night shift work, while longer spans of night shift work (5–9 years and >10 years) further increased risks (19% and 27% respectively).77 Ongoing research on the effects of shift work aims to identify factors that may help predict an individuals’ vulnerability to shift work sleep disturbance or shift work tolerance.78

CONCLUSION

The link between insomnia, short sleep and CVD is complex and multidirectional. The relationship remains challenging to study and isolate from comorbid medical, psychiatric, and sleep-related diagnoses. This has resulted in a trend towards incorporation of objective sleep data to exclude SDB and more reliably quantify sleep duration and insomnia. That said, there remains utility in both subjective and objective qualification of sleep in considering the clinical utility of the findings.

Poor sleep affects many independent factors of cardiovascular health. Over time, autonomic dysregulation and sympathetic-parasympathetic imbalance are likely to increase incidence of arrhythmia, hypertension, metabolic syndrome, coronary artery disease and cardiovascular events. Non-pharmacologic treatment of insomnia, namely CBTI, may help improve subjective perceptions of sleep and improve sleep duration; however, more studies are needed to detect any potential impact on CVD, both in terms of reducing risk for subsequent disease, and in improving symptoms in those with diagnosed CVD.

As the awareness and understanding of insomnia, short sleep, and sleep disturbance improves, so hopefully will the ability to address the resulting burden on society. Future studies could benefit from measurements of HRV, biomarkers, and potentially integration of wearable technology as it may become more feasible to both quantify and track objective sleep duration during intervention studies. It may also be important for future studies to further evaluate which particular aspects of insomnia have the greatest impact on CVD.

Support:

This work was supported by K24 HL143055 (PI: Martin) and VA Greater Los Angeles Healthcare System, Geriatric Research, Education and Clinical Center.

Jennifer Martin reports a grant from NIH/NHLBI during the conduct of the study.

Footnotes

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of a an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

Conflict of interest

Caleb G. Hsieh declares no conflicts of interest.

Human and Animal Rights Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors

Contributor Information

Caleb G. Hsieh, University of California, Los Angeles.

Jennifer L. Martin, VA Greater Los Angeles Healthcare System, University of California, Los Angeles, 16111 Plummer St #200, North Hills, CA 91343.

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