key: cord-1023500-4jri92pu
authors: Hessami, Amirhossein; Shamshirian, Amir; Heydari, Keyvan; Pourali, Fatemeh; Alizadeh-Navaei, Reza; Moosazadeh, Mahmood; Abrotan, Saeed; Shojaei, Layla; Sedighi, Sogol; Shamshirian, Danial; Rezaei, Nima
title: Cardiovascular diseases burden in COVID-19: Systematic review and meta-analysis
date: 2020-10-16
journal: Am J Emerg Med
DOI: 10.1016/j.ajem.2020.10.022
sha: e5d0972dc394804e91f5fb3dcd08bed1143f16a2
doc_id: 1023500
cord_uid: 4jri92pu

BACKGROUND: High rate of cardiovascular disease (CVD) have been reported among patients with novel coronavirus disease (COVID-19). Meanwhile there were controversies among different studies about CVD burden in COVID-19 patients. Hence, we aimed to study CVD burden among COVID-19 patients, using a systematic review and meta-analysis. METHODS: We have systematically searched databases including PubMed, Embase, Cochrane Library, Scopus, Web of Science as well as medRxiv pre-print database. Hand searched was also conducted in journal websites and Google Scholar. Meta-analyses were carried out for Odds Ratio (OR) of mortality and Intensive Care Unit (ICU) admission for different CVDs. We have also performed a descriptive meta-analysis on different CVDs. RESULTS: Fifty-six studies entered into meta-analysis for ICU admission and mortality outcome and 198 papers for descriptive outcomes, including 159,698 COVID-19 patients. Results of meta-analysis indicated that acute cardiac injury, (OR: 13.29, 95% CI 7.35-24.03), hypertension (OR: 2.60, 95% CI 2.11-3.19), heart Failure (OR: 6.72, 95% CI 3.34-13.52), arrhythmia (OR: 2.75, 95% CI 1.43-5.25), coronary artery disease (OR: 3.78, 95% CI 2.42-5.90), and cardiovascular disease (OR: 2.61, 95% CI 1.89-3.62) were significantly associated with mortality. Arrhythmia (OR: 7.03, 95% CI 2.79-17.69), acute cardiac injury (OR: 15.58, 95% CI 5.15-47.12), coronary heart disease (OR: 2.61, 95% CI 1.09-6.26), cardiovascular disease (OR: 3.11, 95% CI 1.59-6.09), and hypertension (OR: 1.95, 95% CI 1.41-2.68) were also significantly associated with ICU admission in COVID-19 patients. CONCLUSION: Findings of this study revealed a high burden of CVDs among COVID-19 patients, which was significantly associated with mortality and ICU admission. Proper management of CVD patients with COVID-19 and monitoring COVID-19 patients for acute cardiac conditions is highly recommended to prevent mortality and critical situations.

The results of this meta-analysis indicated cardiovascular implications including acute cardiac injury, arrhythmia, coronary heart disease, hypertension and cardiovascular diseases were significantly associated with COVID-19 patient's admission to the ICU. Comparing pooled estimate of OR for CVDs showed odds of ICU admission was significantly higher in acute cardiac injury and arrhythmia than hypertension, but there was no significant difference between other cardiovascular implications.

Investigations have shown that mortality in patients with acute cardiac injury was significantly higher than coronary artery disease, arrhythmia, and hypertension. Comparing estimated frequency of different cardiovascular complications including acute cardiac injury, arrhythmia, cardiomyopathy, coronary heart disease, heart palpitation, hypertension, myocardial damage, heart failure and other cardiovascular diseases did not show any significant difference among them.

Cardiovascular complications have been previously reported in previous respiratory infections with similar etiology and their condition affects severity of the disease (17, 217) ; so that even hospitalization for pneumonia is associated with long-term and short-term risk of CVD (12) . Viral infections cause imbalance between cardiac supply and demand and increase in systemic inflammation. Therefore patients with pre-existing CVD have higher risks for acute cardiac conditions (218) , thrombosis (219) , infection, and develop severe conditions during the infection (220) .

Acute myocardial injury was significantly associated with both ICU admission and mortality. There were several etiologies proposed for acute myocardial injury in these patients. The first possible mechanism is myocardial injury caused by cytokine storm as the results of systematic inflammation mediated by pathologic T-cells (221) (222) (223) . Study by Chen et al. (25) showed elevated myocardial injury biomarkers including NT-proBNP, cTnI and hs-CRP were significantly correlated with COVID-19 severity. The second possible explanation is the imbalance between supply and demand caused by systemic infection along with hypoxia caused by respiratory infection, which lead to acute myocardial injury (221, 223) . There are evidences that shows SARS-CoV-2 binds to human J o u r n a l P r e -p r o o f angiotensin converting enzyme-2 (ACE2) to infect the cells (224) , which being highly expressed in lungs and heart. The binding of SARS-CoV-2 to ACE2 in heart can results acute myocardial injury (221, 225) . COVID-19 has been associated with thrombotic events and coagulations disorders (226) , which might lead to hypercoagulability and coronary thrombosis results in acute myocardial infarction (221, 223) .

SARS-CoV-2 binding to ACE2 causes activation of renin-angiotensin system and its complications including hypertension, heart failure, and atherosclerosis (220, 227, 228) as we resulted in our metaanalysis. These data could also suggest a reason for high prevalence of hypertension in our pooled estimate. Underlying CVDs like hypertension could higher the risk of infection and developing more severe symptoms in COVID-19 patients (229) . We showed in our meta-analysis that hypertension was significantly associated with ICU admission and mortality; therefore blood pressure control could be potentially beneficial to reduce disease burden (230) . Using Angiotensin Receptor Blockers (ARBs) and ACE inhibitors in order to control hypertension have raised question in the era of the COVID-19 pandemic. Studies suggested that using ARBs and ACE inhibitors could potentially be harmful as they can cause up-regulation of ACE2, SARS-CoV-2 receptor, and lung injury (230, 231) ; so, they should be carefully considered in COVID-19 patients (229) . This meta-analysis also indicated that mean age of COVID-19 patients admitted to ICU was significantly higher that non-ICU. An explanation to this condition by AlGhatrif et al. (232) suggested that elderly patients with hypertension are more likely to have down-regulation of ACE2 expression, due to viral binding, and up-regulated angiotensin II, which exaggerates pro-inflammatory condition, predisposing them to severe conditions and mortality (233) .

Arrhythmia was significantly associated with ICU admission and mortality in our meta-analysis. There are pathophysiological mechanisms suggested for arrhythmia among COVID-19 patients; however, whether these patients had pre-existing arrhythmia or secondary to COVID-19 remains unknown (234) . First, as any systematic infection COVID-19 can cause electrolyte imbalance, especially J o u r n a l P r e -p r o o f hypokalemia (235) , which might contribute to arrhythmia in susceptible patients (221) . Second, as we have discussed earlier myocardial injury has been an important subject in COVID-19 patients. It has been suggested that myocardial damage can be potentially triggers arrhythmia (236, 237) . Third, pharmacological therapies prescribed for these patients can be potential risk factors for arrhythmia.

Hydroxychloroquine, as one the most common drugs which had been used in COVID-19, can triggers QT prolongation (237, 238) . Fourth, arrhythmia could also occur secondary to myocarditis by disrupting cardiomyocyte membrane and electrolyte imbalance, myocardial fibrosis, proinflammatory cytokines and edema of pericardium (234) .

In our meta-analysis the prevalence of heart palpitation was relatively high and it has been reported as one the initial symptoms of the disease (239) . National Health Commission of China (NHC) reported that some patients have presented with heart palpitations and chest tightness instead of cough and fever as initial symptoms of COVID-19 (229) ; so, heart palpitations in outpatients setting needs to carefully considered as potential symptom of COVID-19.

Heart failure was significantly associated with mortality in our meta-analysis, ranked after acute cardiac injury. The incidence of heart failure might be as the consequence of myocardial injury or myocarditis (240) , which has been previously discussed. Increasing systemic metabolic demand as the results of systemic infection could also exacerbate previous stable heart failure (221) . Right heart failure and pulmonary hypertension should be also carefully considered in patients with acute respiratory distress syndrome (ARDS) and parenchymal lung disease (236) .

Cardiomyopathy has been also observed in COVID-19 patients in various forms. Takotsubo syndrome (TTS) or stress cardiomyopathy, characterized by transient left ventricular dysfunction, is triggered by emotional and physical stresses following to natural disasters (241), like COVID-19 pandemic.

There were number of studies reported TTS in COVID-19 patients (242) (243) (244) (245) (246) . Mechanism of stress cardiomyopathy in COVID-19 patients might be due to emotional distress caused by pandemic along with inflammatory and metabolic distress (244) . Inflammatory cardiomyopathy or myocarditis was J o u r n a l P r e -p r o o f previously described in viral infections (247) as well as COVID-19 (248, 249) . Cardiomyocytes expresses ACE2 which is the receptor for SARS-CoV-2, so this virus could infects human heart which can even exacerbate in case of heart failure (234) .

Coronary artery disease was significantly associated with mortality of COVID-19 patients in our study. In patients with previous coronary artery disease, inflammatory state and hemodynamic changes in infection can potentially increase the risk of plaque rupture (18, 236, 250) . Coagulopathy in COVID-19 patients (226) can also cause acute coronary syndrome in these patients. Hypertension, acute cardiac injury, coronary heart diseases in COVID-19 patient needs to be carefully monitored and managed in case of acute conditions. Other cardiovascular implications, including arrhythmia and heart failure also need to be considered since they can be fatal. Therefore, careful consideration and management of cardiovascular disease among these patients are necessary. Results of this study could help policy makers, physicians and healthcare workers in front line to make evidence-based decisions and reduce the mortality and morbidity of this 21 st century pandemic.

Ethics approval and consent to participate. Not applicable.

Funding. Student Research Committee, Mazandaran University of Medical Sciences (code number: 7396). J o u r n a l P r e -p r o o f 

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We acknowledge Student Research Committee of Mazandaran University of Medical Sciences for supporting this project (code number: 7396).