Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)

IMPORTANCE Increasing numbers of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) are occurring in several countries and continents. Information regarding the impact of cardiovascular complication on fatal outcome is scarce. OBJECTIVE To evaluate the association of underlying cardiovascular disease (CVD) and myocardial injury with fatal outcomes in patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS This retrospective single-center case series analyzed patients with COVID-19 at the Seventh Hospital of Wuhan City, China, from January 23, 2020, to February 23, 2020. Analysis began February 25, 2020. MAIN OUTCOMES AND MEASURES Demographic data, laboratory findings, comorbidities


C
oronavirus disease 2019 (COVID-19) is a newly recognized infectious disease that has spread rapidly throughout Wuhan, Hubei, China, to other provinces in China and several countries around the world.The number of fatalities owing to COVID-19 is escalating.][3][4] With the increasing number of confirmed cases and the accumulating clinical data, in addition to the common clinical presentation of respiratory failure caused by COVID-19, the cardiovascular manifestations induced by this viral infection has generated considerable concern.Huang et al 5 reported that 12% of patients with COVID-19 were diagnosed as having acute myocardial injury, manifested mainly by elevated levels of high-sensitive troponin I. From other recent data, among 138 hospitalized patients with COVID-19, 16.7% had arrhythmias and 7.2% had acute myocardial injury. 6However, at present, specific information characterizing whether patients with COVID-19 with underlying cardiovascular disease (CVD) who develop myocardial injury during hospitalization face greater risk and have worse in-hospital outcomes remains unknown.The present study investigated the association of underlying CVD and myocardial injury with fatal outcomes of patients with COVID-19.

Study Design and Participants
This single-center, retrospective, observational study was performed at the Seventh Hospital of Wuhan City, China, which is a designated hospital to treat patients with COVID-19 and supervised by the Zhongnan Hospital of Wuhan University in Wuhan, China.We retrospectively analyzed patients with COVID-19 who were diagnosed according to the interim guidance of the World Health Organization 7 from January 23, 2020, to February 23, 2020, and who were either treated and discharged or died during hospitalization.Clinical information was collected on admission and during hospitalization by attending physicians.
This study complied with the edicts of the 1975 Declaration of Helsinki 8 and was approved by the institutional ethics board of Zhongnan Hospital of Wuhan University and the Seventh Hospital of Wuhan City (no.2020026).Consent was obtained from patients or patients' next of kin.

Data Collection
The electronic medical records of the patients were reviewed by a trained team of physicians who worked in Seventh Hospital of Wuhan City during the epidemic period.Patient data including demographics, medical history, laboratory examinations, comorbidities, complication, treatment measures (antiviral, antibiotic, corticosteroid therapies, immune glucocorticoid therapy, and respiratory support), and outcomes were collected and analyzed.

Outcome
The end point was incidence of COVID-19-associated death.Successful treatment toward hospital discharge comprised relieved clinical symptoms, normal body temperature, significant resolution of inflammation as shown by chest radiography, and at least 2 consecutive negative results shown by realtime reverse transcription-polymerase chain reaction assay 6 for COVID-19.
Acute respiratory distress syndrome was defined according to the Berlin Definition. 9Malignant arrhythmia was defined as rapid ventricular tachycardia lasting more than 30 seconds, inducing hemodynamic instability and/or ventricular fibrillation.Patients were considered to have acute myocardial injury if serum levels of troponin T (TnT) were above the 99th percentile upper reference limit. 5

Statistical Analysis
Categorical variables are shown as frequency rates and percentages, and continuous variables as mean (SD) and median (interquartile range [IQR]).The means for continuous variables were compared using independent group t tests when the data were normally distributed, otherwise, the Mann-Whitney test was used.The Pearson correlation coefficient and Spearman rank correlation coefficient were used for liner correlation analysis.Proportions for categorical variables were compared using the χ 2 test, although the Fisher exact test was used when data were limited.Wilcoxon rank sum matched-pair tests were used to assess differences among the admission, hospitalization, and impending death.All statistical analyses were performed with SPSS, version 19.0 (IBM Corp) for Windows.A 2-sided P < .05 was considered statistically significant.Analysis began February 25, 2020.

Clinical Characteristics on Admission
Data were collected in consecutive patients hospitalized with COVID-19, including 211 patients who were successfully treated and discharged and 45 patients who died.We excluded 67

Key Points
Question What is the impact of underlying cardiovascular disease (CVD) and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19)?
Findings In this case series study of 187 patients with COVID-19, 27.8% of patients had myocardial injury, which resulted in cardiac dysfunction and arrhythmias.Myocardial injury has a significant association with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury were relatively favorable.
Meaning It is reasonable to triage patients with COVID-19 according to the presence of underlying CVD and evidence of myocardial injury for prioritized treatment and even more aggressive strategies.discharged patients and 2 patients who died because of incomplete data, leaving 144 discharged individuals and 43 individuals who died included for final analysis.Of 187 patients, 66 (35.3%) had underlying CVD including hypertension, coronary heart disease, and cardiomyopathy, and 52 (27.8%) exhibited myocardial injury as indicated by elevated TnT levels.
On admission, none showed evidence of acute myocardial infarction, chronic liver disease, thromboembolic diseases, or rheumatism.In patients with elevated plasma TnT levels who eventually were discharged or died, the median (IQR) duration from illness onset to discharge or death was 28 (22-33) and 23.5 (18.25-34.5)days, respectively.Mortality was markedly higher in patients with elevated plasma TnT levels than in patients with normal TnT levels (31 [59.6%] vs 12 [8.9%])(Table 1).
Compared with patients with normal TnT levels (

Laboratory Findings on Admission
Patients with elevated TnT levels presented with significantly higher white blood cell count  Plasma TnT levels in patients with COVID-19 correlated significantly with both plasma high-sensitivity C-reactive protein levels (β = 0.530, P < .001)(Figure 1A) and plasma NT-proBNP levels (β = 0.613, P < .001)(Figure 1B).

Comparison of Complications and Treatment During Hospitalization
Patients with underlying CVD were more likely to exhibit elevation of TnT levels (36 [54.5%]) compared with patients without CVD (16 [13.2%]).During hospitalization, patients with elevated TnT levels developed more frequent complications (Table 1), including acute respiratory distress syndrome (30 [57.7%] vs 16 [11.9%]),malignant arrhythmias (6 [11.5%] vs 7 [5.2%])including ventricular tachycardia/ventricular fibrillation, acute coagulopathy (25 [65.8%] vs 17 [20.0%]),and acute kidney injury (14 [36.8%] vs 4 [4.7%]), compared with those with normal TnT levels.However, there was no significant differences in incidence of acute liver injury between the 2 groups.Antiviral (oseltamivir, 75 mg twice a day; ribavirin, 0.5 g twice a day; umifenovir, 0.2 g 3 times a day), antibacterial (moxifloxacin, 0.4 g every day), glucocorticoid (methylprednisolone, 40-80 mg every day), and respiratory support were the main treatment approaches for the hospitalized patients (Table 1).During hospitalization, the majority of patients underwent antiviral and antibacterial therapy, with no significant difference in such therapies between patients with normal and elevated TnT levels.However, the rates of glucocorticoid therapy and mechanical ventilation were much higher in patients with elevated TnT levels compared with those with normal TnT levels.
Long-term outpatient medications prior to admission, such as antihypertensive drugs and hypoglycemic drugs, were not discontinued.Notably, the use of angiotensinconverting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) was higher in patients with elevated TnT levels (11 [21.1%] vs 8 [5.9%];Table 1), reflecting the higher rates of CVD.The mortality rates of patients with and without use of ACEIs/ARBs was 36.8% (7 of 19) and 21.4% (36 of 168) (P = .13).

Mortality of Patients With COVID-19 With/Without CVD and With/Without Elevated TnT Levels
Among 187 patients, 7.62% (8 of 105) with normal TnT levels without underlying CVD, 13.33% (4 of 30) with normal TnT levels with underlying CVD, 37.50% (6 of 16) with elevated TnT levels without underlying CVD, and 69.44% (25 of 36) with elevated TnT levels with underlying CVD died during hospitalization (Figure 2).

Dynamic Changes of TnT and NT-proBNP Levels During Hospitalization
Figure 3 shows the dynamic escalation of TnT and NT-proBNP levels for patients who died and those who were successfully treated and discharged.Both TnT and NT-proBNP levels increased significantly during the course of hospitalization in those who ultimately died, but no such dynamic changes of TnT or NT-proBNP levels were evident in survivors.

Association of Myocardial Injury With Prognosis
This report provides detailed cardiovascular information of the association between underlying CVD, myocardial injury, and fatal outcomes of patients with COVID-19.The Chinese Center for Disease Control and Prevention recently published the largest case series to date of COVID-19 in mainland China; the overall case fatality rate was 2.3% (1023 deaths among 44 672 confirmed cases), but the mortality reached 10.5% in patients with underlying CVD. 10 In the current study, among 187 patients with COVID-19, 52 (27.8%) exhibited myocardial injury as demonstrated by elevation of TnT levels, and the mortality was markedly higher in patients with elevated TnT levels than in patients with normal TnT levels (59.6% vs 8.9%).The median (IQR) duration from illness onset to death was 23.23 (8-41) days in the group with elevated TnT levels.Patients with underlying CVD and escalation of TnT levels had the highest mortality (69.44%) and the shortest survival term.However, patients with underlying CVD but with normal TnT levels during the course of dis- ease experienced a more favorable prognosis, compared with patients with elevated TnT levels but without underlying CVD (mortality, 13.3% vs 37.5%).The dynamic escalation of NT-proBNP and increased incidence of malignant arrhythmias during the course of disease in patients with elevated TnT levels is evidence that myocardial injury played a greater role in the fatal outcome of COVID-19 than the presence of underlying CVD itself.NT-proBNP elevation and malignant arrhythmias were significantly more common in patients with elevated TnT levels, and NT-proBNP was significantly correlated with TnT levels (Figure 1).This suggests that those with myocardial injury were more likely to experience impairment in cardiac function.

Potential Mechanism Underlying Myocardial Injury
The current study demonstrates that patients with underlying CVD and other comorbid conditions are more prone to experience myocardial injury during the course of COVID-19.For patients with underlying CVD, including hypertension, coronary heart disease, and cardiomyopathy, viral illness can further damage myocardial cells through several mechanisms including direct damage by the virus, systemic inflammatory responses, destabilized coronary plaque, and aggravated hypoxia.Therefore, patients with CVD are more likely to experience myocardial injury after COVID-19 infection and higher risk of death.However, it is also notable that the 16% of patients with underlying CVD but with normal TnT levels had a relatively favorable outcome in this study.These data suggest that myocardial biomarkers should be evaluated in patients with CVD who develop COVID-19 for risk stratification and possible early and more aggressive intervention.
Although the exact pathophysiological mechanism underlying myocardial injury caused by COVID-19 is not fully understood, a previous report showed that in 35% of the patients with severe acute respiratory syndrome coronavirus (SARS-CoV) infection, the SARS-CoV genome was positively detected in the heart.This raises the possibility of direct damage of cardiomyocytes by the virus. 11SARS-CoV-2 may share the same mechanism with SARS-COV because the 2 viruses are highly homologous in genome. 12,13In the current study, plasma TnT levels were significantly positively linear correlated with plasma high-sensitivity C-reactive protein levels (Figure 2), indicating that myocardial injury may be closely associated with inflammatory pathogenesis during the progress of disease.Viral particles spread through respiratory mucosa and simultaneously infect other cells, which could precipitate a cytokine storm and a series of immune responses.Huang et al 5 highlighted that in patients with COVID-19, the imbalance of T helper 1 and T helper 2 responses resulted in a cytokine storm, which may contribute to myocardial injury.The release of inflammatory cytokines after infection may cause reduction in coronary blood flow, decreases in oxygen supply, destabilization of coronary plaque, and microthrombogenesis.

Consideration of Prevention and Treatment for Myocardial Injury
Unfortunately, until now, no specific antiviral drugs or vaccines have been recommended for COVID-19 except for symp-tomatic supportive treatment and intervention.As patients with underlying CVD are more likely to develop more severe adverse outcomes when myocardial injury occurs after COVID-19 infection and face higher risk of death, it may be reasonable to triage patients with COVID-19 according to the presence of underlying CVD and evidence of myocardial injury for prioritized treatment and even more aggressive treatment strategies.Other cardiac biomarkers such as NT-proBNP and electrocardiograms should be closely monitored for early warning and intervention.
There remains controversy concerning the use of ACEI/ ARB for COVID-19.In this study, with a limited number of patients, the mortality of those treated with or without use of ACEI/ARB did not show a significant difference in outcome.Concerns about ACEI/ARB have been raised since angiotensinconverting enzyme 2 (ACE2) is a potential target for COVID-19 infection, and the increased ACE2 expression induced by ACEI or ARB would aggravate lung injury of patients with COVID-19.However, a previous study 14 showed a beneficial effect of ACEI/ARB in patients admitted with viral pneumonia, as it significantly reduced the pulmonary inflammatory response and cytokine release caused by virus infection.The beneficial effect of ACEI/ARB may be related to a compensatory increase in ACE2. 15However, the evidence regarding the use of ACEI/ ARB in patients with COVID-19 infection is still emerging, and larger clinical studies are required.At present, for patients with COVID-19 who previously used ACEI/ARB, the use of these drugs may not need to be discontinued based on current data.

Limitations
Our study has several limitations.First, only 187 patients with confirmed COVID-19 were included, and a larger cohort study is needed to verify our conclusions.Second, as a retrospective study, some other specific information regarding cardiovascular complications and inflammation such as echocardiography and interleukin 6 were not presented in the study because the data were incomplete owing to the limited conditions in the isolation ward and the urgency of containing the COVID-19 epidemic.Third, the data in this study permit a preliminary assessment of the clinical course and outcomes of patients with COVID-19.The causes of death may involve multiple organ dysfunction in most cases, and it is difficult to differentiate the myocardial injury as the main and direct cause in an individual case.Long-term observation and prospective study design on the effectiveness of treatments specific for the myocardial injury are needed.

Conclusions
Myocardial injury has a significant association with fatal outcomes of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury appears relatively favorable.Myocardial injury is associated with impairment of cardiac function and ventricular tachyarrhythmias.Inflammation may be associated with myocardial injury.Aggressive treatment may be considered for the patients with myocardial injury.

Figure 1 .
Figure 1.Correlation Between Plasma TnT and NT-proBNP With hsCRP

Table 1 .
Demographics and Clinical Characteristics of Patients With COVID-19 a Statistical differences between the normal TnT and elevated TnT groups.b Duration indicates days from onset of symptoms to death or discharge.Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19) Original Investigation Research jamacardiology.com(Reprinted) JAMA Cardiology July 2020 Volume 5, Number 7 813 Downloaded From: https://jamanetwork.com/ on 09/24/2023

Table 2 .
Laboratory Results Among Different Groups