key: cord-0793761-vx5jwfvg
authors: Li, Jialing; Guo, Tao; Dong, Dandan; Zhang, Xinxin; Chen, Xi; Feng, Yujia; Wei, Baozhu; Zhang, Wei; Zhao, Min; Wan, Jing
title: Defining heart disease risk for death in COVID-19 infection
date: 2020-08-13
journal: QJM
DOI: 10.1093/qjmed/hcaa246
sha: 323936fbdfe696e5a2462967e1aeb7c54722a45d
doc_id: 793761
cord_uid: vx5jwfvg

BACKGROUND: Cardiovascular disease (CVD) was in common in Coronavirus Disease 2019 (COVID-19) patients and associated with unfavorable outcomes. We aimed to compare the clinical observations and outcomes of SARS-CoV-2-infected patients with or without CVD. METHODS: Patients with laboratory-confirmed SARS-CoV-2 infection were clinically evaluated at Wuhan Seventh People’s Hospital, Wuhan, China, from January 23 to March 14, 2020. Demographic data, laboratory findings, comorbidities, treatments and outcomes were collected and analyzed in COVID-19 patients with and without CVD. RESULTS: Among 596 patients with COVID-19, 215 (36.1%) of them with CVD. Compared with patients without CVD, these patients were significantly older (66 years vs 52 years) and had higher proportion of men (52.5% vs 43.8%). Complications in the course of disease were more common in patients with CVD, included acute respiratory distress syndrome (22.8% vs 8.1%), malignant arrhythmias (3.7% vs 1.0%) including ventricular tachycardia/ventricular fibrillation, acute coagulopathy(7.9% vs 1.8%), and acute kidney injury(11.6% vs 3.4%). The rate of glucocorticoid therapy (36.7% vs 25.5%), Vitamin C (23.3% vs 11.8%), mechanical ventilation (21.9% vs 7.6%), intensive care unit admission (12.6% vs 3.7%) and mortality (16.7% vs 4.7%) were higher in patients with CVD (both p < 0.05). The multivariable Cox regression models showed that older age (≥65 years old) (HR 3.165, 95%CI 1.722-5.817) and patients with CVD (HR 2.166, 95%CI 1.189-3.948) were independent risk factors for death. CONCLUSIONS: CVD are independent risk factors for COVID-19 patients. COVID-19 patients with CVD were more severe and had higher mortality rate, early intervention and vigilance should be taken.

For this retrospective study，we recruited patients diagnosed with laboratory-confirmed COVID-19 in the Wuhan Seventh People's Hospital from January 23, 2020 to March 14, 5 2020. All COVID-19 patients were diagnosed according to WHO interim guidelines 8 

The electronic medical records of the patients were reviewed by a team of well-trained physicians worked in the two hospitals during the epidemic time. Patient demographical, epidemiological, clinical, laboratory, treatment and outcome data were collected with standardized data collection forms shared by the international Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. The researchers were responsible to contact the patients or their families in case of uncertainties about the data to maximum the accuracy of the data.

Real-Time Transcription Polymerase Chain Reaction (RT-PCR) Assay for COVID-19.

Throat swabs from the inpatients were collected at multiple time points after COVID-19 related symptom remission according to their treating physicians. SARS-CoV 2 in respiratory samples was qualitatively detected by Real-Time Transcription Polymerase Chain Reaction (RT-PCR) Assay according to publicly released COVID-19 sequence, as described previously 4 .

Diagnostic criteria are based on the recommendations by National Institute for Viral Disease 6 Control and Prevention (China) 10 . Routine blood examinations were performed for COVID-19 inpatients, including complete blood count, coagulation profile, blood lipids and electrolytes, liver and renal function, cardiac biomarkers (Troponin T, creatine kinase-MB, myoglobin, NT-proBNP), inflammatory biomarkers and arterial blood gas analysis. The frequency of tests was determined by the treating physicians according to the clinical condition of the individuals.

Discharge and cure standards according to the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia released by the National Health Commission of the PRC 11 . Acute respiratory distress syndrome (ARDS) was defined according to the Berlin Definition 12 .

Malignant arrhythmia was diagnosed when rapid ventricular tachycardia lasting more than 30 seconds, inducing hemodynamic instability and/or ventricular fibrillation. Acute myocardial injury was defined if serum levels of troponin T(TnT) were above the 99th percentile upper reference 2 . Acute coagulopathy was determined as all prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimer and platelet count were abnormal, while excluded anticoagulant effect. Acute kidney injury was identified according the Kidney Disease: Improving Global Outcomes definition 13 .

Treatment decisions for COVID-19 patients were made in accordance with the Chinese Diagnosis and Treatment Protocol of Coronavirus Pneumonia from first to seventh versions.

Since there were no effective antiviral drug or vaccine at present, most treatments were symptomatic and supportive. For mild and moderate patients, main treatment is symptomatic support and antifebrile. For severe and critical patients, on the basis of symptomatic treatment, complications should be proactively prevented, underlying diseases should be treated, secondary infections also be prevented, and organ function support should be provided timely.

COVID-19 patients were used of oseltamivir, ribavirin or arbidol for antiviral therapy Most patients received a broad-spectrum antibiotic (moxifloxacin) to prevent secondary bacterial infection. Patients with PaO2/FiO2 and chest radiographs showing rapid deterioration were given respiratory support, vitamin C, and low-dose glucocorticoids (methylprednisolone). The long-term medications prior to admission such as anti-hypertensive drugs and hypoglycemic drugs were not discontinued.

Continuous variables were expressed as mean (SD) or median (interquartile range) if appropriate. One-sample Kolmogorov-Smirnov test was used to verify the normality of distribution of continuous variables. Comparison of the means of continuous variables between two groups were made with Mann-Whitney U test. Categorical variables were expressed as frequencies (percentages). Comparison of categorical variables between two groups were made using Chi-square test or Fisher exact test if appropriate. Survival curves were plotted using Kaplan-Meier method with the log-rank test and compared between COVID-19 patients with vs without cardiovascular disease. Multivariate Cox regression models were uses to identify the independent risk factors for death in-hospital death. The number of possible predictors 8 entering into Cox regression was limited due to small number of death cases (n=54) and to avoid overfitting in the model. Five variables, including sex, age, cardiovascular disease, diabetes and malignancy were chosen for the final regression models. The statistical analysis was performed using the SPSS package for Windows (v.22.0, Chicago, IL) and GraphPad Prism(version8.0). A two-tailed P value < 0.05 was considered statistically significant. and malignancy (7.4% vs 2.9%; p = 0.010) in the patients with CVD was higher than patient without CVD. There were no significant differences in chronic obstructive pulmonary disease, hepatic dysfunction, renal dysfunction and smoking history between the two groups (Table1).

The laboratory findings on admission are shown in Table 2 

Antivirus therapy (78.4%) and antibiotic therapy (74.8%) were the most common treatments in both groups. The rate of glucocorticoid therapy (36.7% vs 25.5%; p = 0.004), Vitamin C (23.3% vs 11.8%; p < 0.001), mechanical ventilation (21.9% vs 7.6%; p < 0.001) were higher in patients with CVD compared with those without CVD. There were significant differences between two groups in noninvasive mechanical ventilation (11.6% with CVD vs 4.2% without CVD; p = 0.001) and invasive mechanical ventilation (10.2% with CVD vs 3.4% without CVD; p = 0.001) (Table1).

In-hospital complications, including acute respiratory distress syndrome (22.8% vs8.1%; p < 0.001), malignant arrhythmias (3.7% vs 1.0%; p = 0.034) including ventricular 11 tachycardia/ventricular fibrillation, acute coagulopathy(7.9% vs 1.8%; p < 0.001), and acute kidney injury(11.6% vs 3.4%; p < 0.001) developed more frequently in patients with CVD.

Patients with CVD vs those without CVD had no statistically differences in the hospitalization days and the duration from illness onset to discharge or death. Patients with CVD more likely to require intensive care unit (ICU) admission (12.6% vs 3.7%; p < 0.001).

The mortality rate of patients with CVD was 16.7%, which was markedly higher than patients without CVD (4.7%, p < 0.001) and overall study population (9.1%). The survival curves of COVID-19 patients with CVD vs without CVD are shown in Figure. 1. As summarizes in were independent risk factors for in-hospital death. After analysis of the classification of cardiovascular diseases, we found that hypertension (HR 2.606, 95%CI 1.443-4.706) and coronary heart disease (HR 2.330, 95%CI 0.985-5.512) were related to death.

This study described the characteristics of COVID-19 patients with vs without CVD and identified risk factors associated with in-hospital mortality. In this study, patients with CVD accounted for 36.1% and hypertension accounted for the highest proportion, which was consistent with previous studies 2-7 . Patients with CVD were more likely to have complications in the course of the disease, requiring glucocorticoid therapy and mechanical ventilation for a larger proportion, and had a higher rate of ICU admission and death. Old age (≥65 years) and cardiovascular diseases, especially hypertension and coronary heart disease, were independently associated with in-hospital death.

CVD was the most common comorbidity in patients with coronavirus. CVD was an independent risk factor for death or other adverse outcomes in patients with severe acute respiratory syndrome (SARS) [14] [15] , about 50% of patients with Middle East respiratory syndrome coronavirus (MERS) had hypertension and diabetes mellitus Error! Reference source not found. . It had been confirmed that SARS-CoV-2 infection depends on the binding of spike glycoprotein on the surface of and angiotensin-converting enzyme 2 (ACE2) Error! Reference source not found. , ACE2 plays a key role in regulating the invasion of coronavirus into human cells.

ACE2 was highly expressed in the heart as well as in lung cells Error! Reference source not found. . It protected the cardiovascular system by counteracting the over activation of angiotensin II (AngII) in the renin angiotensin system 16 . Therefore, the increase of ACE2 activity in patients with cardiovascular disease was considered to be the mechanism of high prevalence in patients with CVD.

The remarkably increase in coagulation profiles such as D-dimer and prothrombin time were observed in patients with CVD. Early stage of CVD was usually accompanied by vascular endothelial dysfunction and organic lesions, while oxidative stress and blood pressure can damage vascular endothelium. The vicious cycle of them aggravated vascular endothelial damage, and endothelial damage can cause hypercoagulability 20 . In our study, patients with CVD were mostly in severe, they were more likely to form venous thrombosis of lower 13 extremities in need of respiratory support and long-term bed rest, which caused the increase of D-dimer. ACE2 was also expressed in vascular endothelial cells. Previous studies showed that the expression of ACE2 on the cell surface can be reduced after SARS-CoV infection 21 , which led to the activation of renin-angiotensin system, promoted vascular contraction and endothelial injury. The injury of endothelium caused the up-regulation of tissue factor expression and imbalance of fibrinolysis system 22 . In the pneumonia model of bacterial infection, the level of ACE2 was critical for the severity of inflammation. ACE2 reduction promoted the release of inflammatory factors, which results in the infiltration of a large number of neutrophils, leading to excessive inflammatory response and immune damage 23-24 . Therefore, it was speculated that ACE2 is a key regulatory factor of inflammatory reaction and coagulation dysfunction in patients with COVID-19.

Combining CVD caused the reduction in the function of cardiac reserve, bad tolerance to severe pneumonia, and acute cardiovascular events were more likely to occur in cases of viral infection. In this study, the levels of myocardial biomarkers in patients with CVD was significantly higher than that of patients without CVD on admission, and the rates of acute myocardial injury in hospital was remarkably increased. The infection of SARS-CoV-2 may cause direct primary myocardial injury or aggravate the original myocardial injury. Previous reports showed that ACE2 expression was significantly decreased in the myocardium of mice infected with SARS-coronavirus (SARS-CoV), resulting in ACE2-dependent myocardial injury 25 . In addition, SARS-CoV 2 had a stronger interaction with ACE2 than SARS-CoV 26 , and may directly or indirectly cause heart damage through ACE2-related pathways. Ribose nucleic acid (RNA) of SARS-CoV was detected in the hearts of dead SARS patients and viral inclusion bodies were found in cardiac myocytes in pathological examination. It proved that SARS-CoV can directly infect the heart. Pathological findings of COVID-19 patients showed degeneration and necrosis of the cardiomyocytes 27 , so the same mechanism could not be ruled out for SARS-CoV 2. Autopsy report showed interstitial mononuclear inflammatory infiltrates in heart tissue. In this study, inflammatory biomarkers were significantly increased in patients with CVD, indicating that inflammatory cell necrosis promoted inflammatory response and led to cytokine storm damage to the myocardium, which can be severe and even lead to fulminant myocarditis [28] [29] .

Lesions of COVID-19 patients were mainly focus on the lung, but other organs may also have different degrees of damage. Patients with CVD had higher rate of acute liver injury and acute renal injury in hospitalization. A study reported that specific expression of ACE2 in bile duct cells may lead to liver injury after SARS-CoV 2 infection 30 . Patients with CVD had poor compensatory ability of cardiac function and inflammatory storm, which exacerbated microcirculation ischemia and hypoxia of liver cells and further aggravated liver function injury. As the organ with high expression of ACE2, kidney was the primary target of injury. This study has several limitations. First, this is a single-center descriptive study, the patients included in this study were early stages of the epidemic, coronaviruses at this stage 15 were more virulent. Data from more centers and more patient populations are needed to further confirm the relationship between CVD and COVID-19. Second, due to limited medical resources and time for diagnosis in the outbreak, there was a lack of some important laboratory data for the patients, such as echocardiography, electrocardiogram and cytokines. Finally, this study only observed the starting point and results of patients, lacking dynamic observation of disease progression.

Older age (≥65 years old) and CVD are independent risk factors for COVID-19 patients.

COVID-19 patients with CVD were more severe and had higher mortality rate, early intervention and vigilance should be taken. 

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Platelets×10^3/μL

HDL, high-density lipoprotein

LDL, low-Cardiac biomarkers Creatine kinase-MB fraction

Liver and renal function ALT, U/L 21

We acknowledge all health-care workers involved in the diagnosis and treatment of patients at Wuhan Seventh People's Hospital, and Liu Lei for statistical consultation.