Heart rate variability and adrenal size provide clues to sudden cardiac death in hospitalized COVID-19 patients
Introduction There may be an association between Coronavirus Disease 2019 (COVID-19) and sudden cardiac death (SCD), sudden death from a cardiac cause . The etiology of SCD in COVID-19 is not clearly defined and in the absence of precipitating causes such as myocarditis, pulmonary embolism, or acute coronary syndrome, the differential diagnosis may include stress cardiomyopathy refractory to exogenous vasopressors. Several factors contribute to the difficulty of determining the potential pathomechanism of SCD in COVID-19. Screening and diagnostic procedures such as transthoracic echocardiograms were dramatically decreased  (due to risk of COVID-19 exposure to healthcare workers), replaced by reliance on clinical intuition. For example, stress cardiomyopathy has been associated with sudden cardiac death  and is typically diagnosed by echocardiogram and coronary catheterization. The role of stress cardiomyopathy or other identifiable etiologies of SCD in hospitalized patients with COVID-19 has not been fully elucidated. We hypothesized that the cardiac telemetry of inpatients who died with clinically identified SCD would show decreased parasympathetic activity, measured as root mean square of successive differences (RMSSD), consistent with acute stress cardiomyopathy . Given a possible link between stress cardiomyopathy and adrenal insufficiency,  we hypothesized that critically ill COVID-19 patients were more likely to have adrenal insufficiency either because of or despite corticosteroid therapy. 

Methods We included adult COVID-19 patients admitted to a telemetry-bed at Columbia University Irving Medical Center, who died between 4/25/2020 and 7/14/2020 and had an autopsy. Clinical criteria for SCD using chart review was: unexplained rapidly progressive cardiovascular collapse (i.e., despite increasing vasopressors) in patients who had stabilized. Three clinicians (2 intensivists [BR and SP] and 1 cardiologist [HY]), blinded to autopsy results, reviewed charts for SCD ( ). Disagreement on SCD labels was determined by majority. RMSSD was generated from ectopy-free, non-overlapping 5-min segments of continuous telemetry, acquired at 240 samples a second from Philips Intellivue MX800 monitors (Amsterdam, Netherlands). Demographics and comorbidities between groups (non-SCD or SCD) were compared using Wilcoxon rank-sum or Fisher's exact test as appropriate. Mann–Whitney two-sample statistic was used to compare adjusted organ weights between groups (non-SCD and SCD). This study was approved by the Columbia University Institutional Review Board. 

Results Thirty COVID-19 patients were included and 12 had SCD ( ). The agreement by pairwise-kappa statistics between SP-HY (0.45) and HY-BR (0.52) was “moderate” while the agreement between SP & BR was “very strong” (0.92). One patient was missing adrenal weights. Autopsy reports were examined for pulmonary embolism, myocarditis, and coronary artery occlusion or myocardial infarction. In non-SCD patients, three patients had focal mild/borderline lymphocytic myocarditis and one patient had acute myocardial ischemia. One had medium-sized pulmonary artery thrombus and two had non-occlusive thrombus. One had an acute right ventricle infarct. In the SCD patients, one patient had mild ischemic damage to the right ventricle, and one had myocardial infarction occurring at least 3–4 weeks before death. No patients had pulmonary embolism or myocarditis. The RMSSD over 7 days without vs with SCD was median 0.0129 (IQR 0.0074–0.026) versus 0.0098 (IQR 0.0056–0.0197), p < 0.0001 ( ). All organ weights were equivalent between groups (including heart, lungs, spleen, liver, kidney and thyroid) except for adrenal weights. The total adjusted adrenal weight of the non-SCD group was 0.40 g/kg (IQR 0.35–0.55) versus 0.25 g/kg (IQR 0.21–0.31) in the SCD group, p = 0.0007. Four (22%) non-SCD and three (25%) SCD patients received at least 14 days of steroids ≥25 mg of prednisone equivalents in the 30 days prior to death. 

Discussion Hospitalized patients with COVID-19 who experienced SCD had lower parasympathetic activity (RMSSD) and smaller sized adrenal glands. Lower RMSSD has been associated with sudden unexplained death in epilepsy (SUDEP) , SCD in congenital cardiac disease , neurocardiogenic injury in patients with subarachnoid hemorrhage , and stress cardiomyopathy . Additionally, COVID-19 patients admitted to the ICU have been shown to have lower RMSSD compared to sepsis patients without COVID-19 admitted to the ICU . Our findings of lower RMSSD in SCD patients could be explained by acute stress cardiomyopathy. Acute stress cardiomyopathy is a clinical/imaging diagnosis, and echocardiograms were limited during the pandemic to minimize exposure . It is notable that the SCD patients had significantly smaller adrenals, suggesting either adrenal atrophy from steroids or lack of adrenal hyperplasia in response to prolonged critical illness. The smaller adrenal gland size coupled with stress cardiomyopathy may have led to refractory cardiovascular collapse. Further work is needed to confirm these findings in additional cohorts. 4.1 Limitations This retrospective case-control study enrolled patients who had autopsies ordered by the clinicians, a potential source of selection bias. Additionally, the definition of sudden cardiac death has some subjectivity. 

Limitations This retrospective case-control study enrolled patients who had autopsies ordered by the clinicians, a potential source of selection bias. Additionally, the definition of sudden cardiac death has some subjectivity. 

This study was supported by the 10.13039/100000002 National Institutes of Health , R21NS113055 (Dr. Park), the 10.13039/100000968 American Heart Association , 20POST35210653 (Dr. Megjhani), and the 10.13039/100000133 Agency for Healthcare Research and Quality , T32HS026121 (Dr. Ranard). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. 

Benjamin Ranard: Data Curation, Formal analysis, Writing – Original Draft and Review & Editing; Murad Megjhani: Methodology, Formal Analysis, Writing – Review & Editing; Kalijah Terilli: Data Curation, Writing – Review & Editing; Hirad Yarmohammadi: Conceptualization, Writing – Review & Editing, John Ausiello: Conceptualization, Writing – Review & Editing, Soojin Park: Conceptualization, Methodology, Formal analysis, Investigation, Data Curation, Writing-Original draft preparation and Reviewing and Editing, Supervision, Management and coordination responsibility for the research activity planning and execution. Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Supervision; Validation; Visualization; Roles/Writing – original draft; Writing – review & editing. Please format with author name first followed by the CRediT roles: for an example and more details see authorship of a paper section here . 

The authors declare no conflicts of interest. 

