Introduction

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global pandemic. As of January 10, 2021, more than 90 million worldwide cases had been reported, and ~1.9 million deaths had been attributed to this entity.¹ The condition has received considerable attention in the cardiovascular community because persons with established cardiovascular disease or a high burden of cardiovascular risk factors seem to be particularly vulnerable during infection.^2-6 The infection itself may also increase the risk of a variety of cardiovascular events and complications.^7,8

The Yale COVID-19 Cardiovascular Registry

The Yale COVID-19 Cardiovascular Registry is an ongoing registry comprising data from adult patients who are admitted (or transferred) to Yale New Haven Hospital with a positive SARS-CoV-2 test.⁹ Patients could be included in cases of SARS-CoV-2 infection detected by a reverse-transcriptase polymerase chain reaction assay or high-throughput sequencing or if they were discharged with a diagnosis of COVID-19 using the International Classification of Diseases, Tenth Revision code, U07.1.

Study data were collected through manual chart review. We obtained information related to demographics (including prevalent cardiovascular risk factors, conditions, and medications), presenting symptoms, vital signs, laboratory test results at admission, imaging findings, electrocardiograms, and in-hospital events (including cardiovascular and COVID-19-specific medication use, supportive measures, ICU admission, cardiovascular events, other pertinent clinical events, and mortality).

The primary endpoint was in-hospital death. The main secondary endpoint was in-hospital MACE (a composite of type 1 or 2 myocardial infarction, stroke, new acute decompensated heart failure or cardiogenic shock, venous thromboembolism, new-onset ventricular arrhythmia, new-onset atrial fibrillation or flutter, pericardial effusion or cardiac tamponade, or aborted cardiac arrest). Cardiac events were adjudicated by experienced physicians.

Clinical Presentation and Laboratory Findings

The current study results were derived from 586 COVID-19-positive patients who were admitted between March 1 and May 31, 2020, and who had a final disposition (i.e., either in-hospital death or survival to hospital discharge). The median age was 67 years, 47% were female, and 49% identified as Non-Hispanic White, 31% identified as Non-Hispanic Black, and 16% identified as Hispanic. Prior clinical cardiovascular disease was reported in 37%, and 60% had hypertension, 40% had diabetes mellitus, and 39% had hyperlipidemia. With respect to antihypertensive medications, 33% were receiving angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers, 30% were on beta-blockers, and 28% were on diuretics.

The median time from symptom onset to admission was 4 days, and the median length of hospital stay was 13 days. In descending order, the most common presenting symptoms were cough (59%), fever or chills (59%), dyspnea (55%), and fatigue or malaise (34%). Laboratory findings stratified for mortality status are presented in Table 1.

Table 1: Laboratory Findings at Admission in Patients With COVID-19 Who Survived and Did Not Survive to Hospital Discharge

Laboratory Study		Survived to Hospital Discharge (n = 504)	Did Not Survive to Hospital Discharge (n = 82)	P-value for Difference
Hematology (n = 545)
	Hemoglobin (g/dl)	13.0 (11.5-14.1)	12.4 (10.6-13.7)	0.03
	White blood cell count (per mm3)	6.4 (4.9-8.4)	7.45 (5.5-11.5)	0.005
	Absolute lymphocyte count (per mm3) (n = 529)	1.0 (0.7-1.4)	0.8 (0.5-1.1)	<0.001
	Absolute neutrophil count (per mm3) (n = 535)	4.6 (3.1-6.5)	5.8 (3.9-9.6)	<0.001
	Platelet count (per mm3)	204 (161-262)	164 (127-232)	0.002
Renal (n = 549)
	Creatinine (mg/dl)	1.0 (0.8-1.4)	1.4 (1.0-2.1)	<0.001
Liver (n = 497)
	Alanine aminotransferase (units/l)	26 (19-44)	26.5 (20-42)	0.76
	Aspartate aminotransferase (units/l)	41 (30-63)	53.5 (37-79)	0.002
	Lactate dehydrogenase (units/l) (n = 293)	304 (245-439)	358 (285-439)	0.16
	Total bilirubin (mcmol/l) (n = 485)	0.4 (0.3-0.6)	0.5 (0.4-0.8)	0.002
	Albumin (g/dl) (n = 481)	3.7 (3.3-4.0)	3.4 (3.0-3.8)	<0.001
	International normalized ratio (n = 511)	0.99 (0.93-1.06)	1.06 (0.99-1.12)	<0.001
Inflammation
	High-sensitivity C-reactive protein (mg/l) (n = 512)	68 (18-139)	119 (52-161)	<0.001
	Procalcitonin (ng/ml) (n = 517)	0.12 (0.06-0.28)	0.29 (0.12-0.94)	<0.001
	Ferritin (ng/ml) (n = 503)	499 (222-1012)	623 (368-1470)	0.02
	D-dimer (mg/l) (n = 498)	0.99 (0.56-1.79)	1.56 (0.82-2.90)	<0.001
	Fibrinogen (mg/dl) (n = 488)	511 (383-617)	531 (405-619)	0.70
Circulatory
	Troponin T (ng/ml) (n = 504)	<0.01 (<0.01 to <0.01)	0.03 (<0.01 to 0.08)	<0.001
	N-terminal prohormone of B-type natriuretic peptide (pg/ml) (n = 335)	223 (68-848)	2775 (613-8401)	<0.001

Morbidity and Mortality

In all, 82 (14%) patients died in-hospital, 196 (33%) were admitted to the intensive care unit, and 111 (19%) required mechanical ventilation. The risk of in-hospital death was 8% among those not admitted to the intensive care unit and 26% among those admitted to the intensive care unit. A total of 135 (23%) patients experienced in-hospital MACE (Table 2).

Table 2: Cardiovascular Events in Patients With COVID-19

Endpoint		All patients (n = 586)
MACE (%)		135 (23%)
Ischemic
	Type 1 myocardial infarction	3 (1%)
	Type 2 myocardial infarction	44 (8%)
	Isolated myocardial injury	64 (11%)
	Stroke	11 (2%)
Heart Failure
	New acute decompensated heart failure	31 (5%)
	Worsening acute decompensated heart failure	35 (6%)
	Cardiogenic shock	12 (2%)
	Myocarditis	0
	Stress (takotsubo) cardiomyopathy	4 (1%)
Arrhythmia
	New-onset atrial fibrillation or atrial flutter	46 (8%)
	New-onset ventricular arrhythmia	19 (3%)
Venous
	Pulmonary embolism or deep vein thrombosis	34 (6%)
Other
	Pericardial effusion or cardiac tamponade	5 (1%)
	Aborted cardiac arrest	21 (4%)

Predictors of mortality in a multivariable logistic regression model adjusted for demographic characteristics, clinical presentation, and laboratory findings were age (odds ratio [OR] 1.28 per 5 years; 95% confidence interval [CI], 1.13-1.45; p < 0.001), prior ventricular arrythmias (OR 18.97; 95% CI, 3.68-97.88; p < 0.001), use of P2Y12 receptor inhibitors (OR 7.91; 95% CI, 1.64-38.17; p = 0.01), C-reactive protein (OR 1.81 per standard deviation [SD]; 95% CI, 1.18-2.78; p = 0.007), albumin (OR 0.64 per SD; 95% CI, 0.47-0.86; p = 0.003), and troponin T (OR 1.84 per SD; 95% CI, 1.39-2.46; p < 0.001).

In a similarly adjusted multivariable logistic regression model, predictors of MACE were altered mental status at presentation (OR 2.94; 95% CI, 1.38-6.24; p = 0.005), respiratory rate (OR 1.31 per 5 bpm; 95% CI, 1.05-1.65; p = 0.02), absolute lymphocyte count (OR 0.66 per SD; 95% CI, 0.50-0.87; p = 0.003), total bilirubin (OR 1.39 per SD; 95% CI, 1.05-1.84; p = 0.02), albumin (OR 0.65 per SD; 95% CI, 0.49-0.85; p = 0.002), and troponin T (OR 1.85 per SD; 95% CI, 1.43-2.39; p < 0.001).

First and Second Waves

Several treatment advances were made as the pandemic progressed, including studies showing benefits of dexamethasone, tocilizumab, and, to some extent, remdesivir. We found that patients admitted during the so-called "second wave" (between October 1 and December 31, 2020) had a significantly lower rate of in-hospital mortality at 9% (34 deaths/386 admissions) compared with 14% during the initial wave (p = 0.006).

Conclusions

The individuals in our study presented in a similar fashion to in-hospital patients described in earlier reports of COVID-19.^2-6,10 Our overall conclusions also support prior studies that proposed cardiovascular disease as being an adverse risk marker.^2-6,11 Similar inferences can be drawn for various biomarkers, particularly cardiac troponin.^7,8,12-14 Still, our study stands out given its fairly large sample size, data collection through manual review of electronic health records, and event adjudication.¹⁵ Overall cardiovascular event rates were high but lower than initially thought after events were adjudicated. Major limitations include the observational design, use of a composite cardiovascular endpoint, and the limited power for assessing individual cardiovascular outcomes.

Several questions remain unanswered, most of which pertain to optimal management of patients with elevations of certain biomarkers (e.g., D-dimer and troponin). Although some institutions have adopted biomarker-guided algorithms, the evidence for these strategies remains unclear, and we have yet to examine whether these interventions have affected patient prognosis positively at our institution. It is also unknown whether any specific measures are available in the acute setting to lower the higher risk among patients with pre-existing cardiovascular disease. Nevertheless, our findings in the context of a global pandemic may be used as an incentive to optimize management of cardiovascular risk factors and known cardiovascular disease.

Acknowledgements

The authors would like to thank Maxwell Eder, Justin Pacor, Jakob Park, Zaniar Ghazizadeh, Alex Heard, Ana Sofia Cruz-Solbes, Roozbeh Nikooie, Chad Gier, Zain V. Ahmed, James V. Freeman, Judith Meadows, Kim G. E. Smolderen, Rachel Lampert, Eric J. Velazquez, and Tariq Ahmad for their invaluable contributions to the study.

References

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Clinical Topics: Arrhythmias and Clinical EP, COVID-19 Hub, Dyslipidemia, Heart Failure and Cardiomyopathies, Pericardial Disease, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Hypertension, Noninvasive Imaging

Keywords: COVID-19, Coronavirus, Coronavirus Infections, severe acute respiratory syndrome coronavirus 2, Cardiovascular Diseases, Antihypertensive Agents, Hospital Mortality, Patient Discharge, Troponin T, C-Reactive Protein, Purinergic P2Y Receptor Antagonists, Shock, Cardiogenic, Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Antagonists, Logistic Models, Cardiac Tamponade, African Americans, Pericardial Effusion, Hyperlipidemias, International Classification of Diseases, Venous Thromboembolism, Albumins, Bilirubin, Respiratory Rate, Pandemics, Atrial Fibrillation, Reverse Transcriptase Polymerase Chain Reaction, Confidence Intervals, Laboratories, Risk Factors, Stroke, Heart Failure, Diabetes Mellitus, Hypertension, Registries, Heart Arrest, Dyspnea, Hospitals, Lymphocyte Count, Fatigue, High-Throughput Nucleotide Sequencing, Intensive Care Units, Electrocardiography, Dexamethasone, Reference Standards

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