key: cord-334324-remrcm2q
authors: Kunal, Shekhar; Sharma, Shashi Mohan; Sharma, Sohan Kumar; Gautam, Dinesh; Bhatia, Harnish; Mahla, Himanshu; Sharma, Sandeep; Bhandari, Sudhir
title: Cardiovascular complications and its impact on outcomes in COVID-19
date: 2020-11-04
journal: Indian Heart J
DOI: 10.1016/j.ihj.2020.10.005
sha: 
doc_id: 334324
cord_uid: remrcm2q

BACKGROUND: Coronavirus disease 2019 (COVID-19) has led to a widespread morbidity and mortality. Limited data exists regarding the involvement of cardiovascular system in COVID-19 patients. We sought to evaluate the cardiovascular (CV) complications and its impact on outcomes in symptomatic COVID-19 patients. METHODS: This was a single center observational study among symptomatic COVID-19 patients. Data regarding clinical profile, laboratory investigations, CV complications, treatment and outcomes were collected. Cardiac biomarkers and 12 lead electrocardiograms were done in all while echocardiography was done in those with clinical indications for the same. Corrected QT-interval (QTc) at baseline and maximum value during hospitalization were computed. RESULTS: Of the 108 patients, majority of them were males with a mean age of 51.2 ± 17.7 years. Hypertension (38%) and diabetes (32.4%) were most prevalent co-morbidities. ECG findings included sinus tachycardia in 18 (16.9%), first degree AV block in 5 (4.6%), VT/VF in 2 (1.8%) and sinus bradycardia in one (0.9%). QTc prolongation was observed in 17.6% subjects. CV complications included acute cardiac injury in 25.9%, heart failure, cardiogenic shock and acute coronary syndrome in 3.7% each, “probable” myocarditis in 2.8% patients. Patients with acute cardiac injury had higher mortality than those without (16/28 [57.1%] vs 14/78 [17.5%]; P < 0.0001). Multivariate logistic regression analysis showed that acute cardiac injury (OR: 11.3), lymphopenia (OR: 4.91), use of inotropic agents (OR: 2.46) and neutrophil-lymphocyte ratio (OR:1.1) were independent predictors of mortality. CONCLUSIONS: CV complications such as acute cardiac injury is common in COVID-19 patients and is associated with worse prognosis.

The world is experiencing a never before seen pandemic caused by a novel coronavirus SARS-CoV-2 leading to the coronavirus disease 2019 . Since the first reports of atypical pneumonia originating from Wuhan province of China in December 2019, it was just with few weeks that the virus spread worldwide affecting millions of people. 1 SARS-CoV-2 is a part of the Coronaviridae family and is quite similar to the two other coronaviruses SARS and MERS. 2 COVID-19 predominantly affects the respiratory system with pneumonia and acute respiratory distress syndrome (ARDS) being the predominant manifestation. However, recent reports have highlighted the impact of SARS-CoV-2 on the cardiovascular (CV) system. [3] [4] [5] Patients with cardiovascular disease (CVD) risk factors such as hypertension, diabetes and dyslipidemia are at an increased risk of infection as well as adverse outcomes. 6 Cardiovascular complications such as acute myocardial injury, heart failure (HF), cardiac arrhythmias, myocarditis, pericarditis and venous thromboembolism are increasingly being reported. [2] [3] [4] [5] In addition, use of multiple QT-interval prolonging drugs such as hydroxychloroquine (HCQ) and azithromycin for the treatment of COVID-19 infection may lead to increased incidence of malignant arrhythmias such as torsades pointes (TdP). 2 Data regarding the CV complications especially from developing countries are limited. The present study aims to determine the CV complications in symptomatic COVID-19 patients and its impact on the disease outcomes.

This was a single center retrospective observational study among COVID-19 patients at a designated tertiary care COVID-19 hospital. Consecutive symptomatic laboratory confirmed COVID-19 patients were enrolled in the study. Asymptomatic patients as well as J o u r n a l P r e -p r o o f those subjects without documentation of cardiac biomarkers including cardiac troponin and creatinine kinase-myocardial band (CK-MB) were excluded. Data regarding demographic features, medical history, laboratory findings, treatment and outcomes were collected and evaluated. In all these patients, a baseline neutrophil to lymphocyte ratio (NLR) defined as ratio of absolute neutrophil count to absolute lymphocyte count was computed. Apart from routine laboratory investigations, cardiac biomarkers such as serum CK-MB/cardiac troponins were done in all patients. Two-dimensional (2D) echocardiography was done selectively based on clinical indication. In addition, a 12-lead electrocardiogram was done in all patients and QTc interval were computed both at admission as well as during the course of hospitalization. All the ECG parameters were measured using electronic calipers (EP Calipers v1.6). QT intervals were corrected using the Fridericia method. Delta QTc was determined as difference of maximum QTc during hospitalization to QTc as baseline.

Tisdale 7 risk scoring was used retrospectively for prediction of drug-associated QT prolongation in these patients. All the data were collected and analyzed by two independent cardiologists.

In all these patient assessments were done to determine the presence of acute cardiac injury as well other cardiac complications such as acute coronary syndrome (ACS), myocarditis, pericarditis, pericardial effusion, cardiac tamponade, cardiac arrhythmias and CS. Acute cardiac injury was defined as blood levels of cardiac biomarkers above the 99thpercentile upper reference limit irrespective of new findings on ECG or echocardiography. 3 A diagnosis of myocarditis was based on the three-tiered clinical classification on the basis of level of diagnostic certainty (definite, probable and possible). 8 A definite diagnosis requires a histological or immunohistological evidence of myocarditis while probable myocarditis is defined based on the "clinical context of possible myocardial injury with cardiovascular symptoms and at least one of the following: (i) raised cardiac biomarkers; (ii) ECG findings J o u r n a l P r e -p r o o f suggestive of cardiac injury, or (iii) abnormal cardiac function on echocardiogram or cardiac MRI even in the absence of histopathological confirmation". 8 Based on the presence or absence of acute myocardial injury, patients were divided into two groups: Group 1: patients with acute myocardial injury and Group 2: patients without acute myocardial injury. A written informed consent was waived off keeping in mind the retrospective nature of this study. The inclusion and use of data complied with the Declaration of Helsinki.

The end point in this study was the occurrence of COVID-19 related death.

Successful treatment was defined as improvement in clinical symptoms, normal body temperature, radiological resolution as well as two consecutive negative results on RT-PCR assay for COVID-19.

Descriptive statistics was obtained for all the study subjects with continuous data being expressed as mean ± SD while categorical data represented as proportions. Comparison of means of continuous variables was done using Student's t-test while χ2 test was used for categorical variables. Multivariate logistic regression analysis was done to determine factors associated with worse outcomes. Receiver operating characteristic (ROC) curve was plotted for Tisdale QT risk scoring system predicting QT prolongation and a cut-off score was then determined along with sensitivity and specificity. All statistical analyses were performed on SPSS, version 24.0 (IBM Corp). A P-value of < 0.05 was considered to be statistically significant.

A total of 108 symptomatic patients were included in the final analysis (28 patients excluded in the absence of documentation of cardiac markers). Of the 108 patients, there were 70 males (64.8%) with a mean age of 51.2 ± 17.7 years. The most common presenting J o u r n a l P r e -p r o o f symptoms were fever in 82 (75.9%), cough in 60 (55.6%) and dyspnea in 57 (52.8%) with a mean duration of symptoms being 3.9 ± 2.4 days. Chest pain on presentation was reported in 9 (8.3%) patients of whom four had typical anginal symptoms (all of them had an evidence of raised biomarkers and ECG or echocardiographic changes). Among those with atypical chest pain, raised biomarkers or ECG changes were observed in two of them. A majority of subjects (75.9%) had a history of travel to/resided in an endemic area while international travel was reported in 10 (9.3%) patients. History of contact with a known COVID-19 positive patient was documented in 40 (37.3%) subjects. Co-morbidities were present in 50 (46.3%) patients with hypertension being most common (38%) followed by diabetes (32.4%) and CVD (13%). Chronic lung diseases in the form of chronic obstructive pulmonary disease (COPD) was present in 6 (5.6%), asthma and post-tubercular sequalae in 3 (2.8%) each while interstitial lung disease and bronchiectasis in one patient each. History of smoking was reported in 10 (9.3%) patients. The clinical and demographic profile has been tabulated in Table 1 . 

Acute cardiac injury was the most common cardiovascular complication reported in 28 (25.9%) subjects followed by HF, cardiogenic shock (CS) and ACS in 4 (3.7%) patients each, "probable myocarditis" in three patients (2.8%) while pericardial effusion was reported in two patients (1.9%). Patients who presented with acute cardiac injury were significantly older, had greater frequency of co-morbidities including hypertension, diabetes and cardiovascular diseases, higher total leucocyte count, liver enzymes, cardiac troponins and CK-MB levels. In addition, these patients had greater D-dimer positivity, higher lactate dehydrogenase (LDH) levels and increased use of IMV (Table 2) 

Other complications reported in this cohort of patients included sepsis in 25 (23.1%), ARDS in 12 (11.1%) and acute kidney injury was present in 8/108 patients. In addition, three patients developed diabetic keto-acidosis while one had an intracranial hemorrhage.

A total of 30 (27.8%) symptomatic critically ill patients died during the course of hospitalization. The patients in the deceased group as compared to the survivors were older, had significantly higher frequency of co-morbidities, hypertension, diabetes, chronic lung diseases, acute cardiac injury, cardiogenic shock and VT/VF. In addition, non-survivors had J o u r n a l P r e -p r o o f higher levels of ESR, NLR, troponin T, serum LDH and CK-MB levels ( Table 3 ). There was no significant difference in outcomes in those using ACEi/ARBs than those without [5 (17.8%) vs 8 (10%); P=0.27].

Univariate logistic regression analysis showed that age and hypertension (OR:0.33; 95% CI:0.09-1.21; P=0.95) were not found to be independent predictors of mortality.

This study provides a detailed understanding of cardiovascular implications of COVID-19 infection and its impact on the outcomes. Patients with co-morbidities such as hypertension, diabetes and CVD are often prone to COVID-19 infection and portends a bad prognosis. 6, 9 In the series of 44,672 COVID patients, hypertension was documented in 2683 (12.8%), diabetes in 1102 (5.3%) while CVD in 873 (4.2%) subjects. 10 Similarly, in a metaanalysis, most common comorbidities reported were hypertension (17%), diabetes (8%) and CVD (5%). 11 In our series too, hypertension, diabetes and CVD were most common comorbidities associated with COVID-19.

In this study, acute cardiac injury was the most common cardiovascular complication in COVID-19 patients. Previous studies have documented prevalence of acute cardiac injury to be 7-44% 3,4,12-15 . Shi et al. 3 had documented that acute cardiac injury was independently associated with increased mortality in COVID-19 patients. Similarly, Guo et al. 4 reported myocardial injury in 52 (27.8%) of his 187 COVID-19 patients. Mortality rates were significantly higher in patients with increased cardiac troponins than those with normal levels (59.6% vs 8.9%). In addition, patients with co-morbidities such as hypertension, coronary artery disease and diabetes had higher troponin-T levels, a finding seen in our study too.

There is no clarity regarding the exact mechanisms responsible for acute cardiac injury with the plausible hypothesis being i) direct viral invasion of the myocardium, ii) hypoxemia leading to acute cardiac injury, iii) "cytokine storm" and immune mediated cardiac injury and iv) stress cardiomyopathy. 2 Other cardiovascular complications include myocarditis, ACS, HF, pericarditis, venous thromboembolism. 2 The data on myocarditis in COVID-19 is sparse with the reported prevalence ranging up to 12%. 5, 16, 17 while in our series "probable myocarditis" was present in 2.8%. HF in COVID-19 patients can either develop de novo as a result of myocardial injury or can be an exacerbation of pre-existing HF. In our series, 3.7% of patients had HF while Zhou and colleagues 14 documented HF in 23% patients. CS was reported in 3.7% of our patients and was associated with a poor outcome. Often these patients may have right sided cardiac involvement which can go unnoticed. 18 CS in these patients is associated with poor prognosis and a veno-arterial ECMO may be the last resort in these cases. 19 VTE is increasingly being recognised in COVID-19 patients and is often due to an underlying coagulopathy. Grillet et al. 20 recently reported the prevalence of acute pulmonary embolism on CTPA in 23% of severe cases. We too had a case of acute pulmonary embolism in an J o u r n a l P r e -p r o o f elderly male however, the exact prevalence might be underrepresented in our series as only 15 patients underwent CTPA.

ECG abnormalities reported in patients with COVID-19 include ST-T changes, QT prolongation and cardiac arrhythmias. 2 Sinus tachycardia has been reported as the most common ECG finding in COVID-19 patients, a finding seen in our series too. 21 First degree AV block was documented in five of our patients while one had sinus bradycardia. Recently, Peigh et al. 22 reported sinus node dysfunction among two COVID-19 patients and proposed "myocardial inflammation or direct viral infiltration" as a plausible hypothesis.

to an increased risk of QT-interval prolongation and drug-induced TdP. 23 In a series of 84 patients receiving HCQ/azithromycin, there was a significant prolongation of QTc. 24 In nine patients, there was a severe prolongation of QTc to >500 msec however, none had an evidence of TdP. Similarly, in our series too, there was a significant increase in QT-interval following therapy with HCQ/ azithromycin and 6.5% patients reported a severe prolongation of QTc >500 msec. Patients on HCQ and azithromycin combination had far more greater QTinterval prolongation than on HCQ alone, a finding similar to that reported by Bessière et al. 25 and Mercuro et al. 26 

Previous studies have reported elderly patients with multiple co-morbidities had a poor outcome. In our study too, elderly patients with diabetes, hypertension had a worse prognosis. In addition, lymphopenia, leucocytosis, serum LDH, elevated cardiac biomarkers, D-dimer, interleukin-6 (IL-6) and serum creatinine have been considered as poor prognostic markers. 2, 9 Patients with acute cardiac injury have been shown to have a worse outcomes. 3, 4 Similar findings were observed in our series too. In our series, NLR was significantly higher J o u r n a l P r e -p r o o f among non-survivors and was an independent predictor of mortality. Similar findings have been reported by Yan et al. 27 and Liu et al. 28 wherein they found NLR to be an independent risk factor for in-hospital mortality. There has been lots of concern and speculation regarding the use of ACEi in these patients since the initial reports of an adverse outcomes with these medications. 29, 30 However, we did not find any relationship between the usage of ACE inhibitors/ARBs and cardiac injury or worse outcomes, a finding which has been replicated in multiple studies. 2, 31 This was a single centre observational study including symptomatic patients over a short period of time with relatively small sample size. In addition, being retrospective in nature, not all laboratory investigations such as serum IL-6 were done in all patients. Owing to the resource limitations, only single measurements of cardiac troponins were obtained in our patients. Logistic issues hampered our ability to perform echocardiography in all patients and was limited to only those with a clinical indication for the same. A lack of cardiac magnetic resonance imaging and an endomyocardial biopsy owing to the logistic issues further prevented us to better characterise the patients with myocarditis. Larger multi-centric studies are further warranted to further characterise the CV outcomes and to confirm the role of cardiac injury in these patients.

Recent clinical and epidemiological studies have suggested that CV complications are common in COVID-19 patients however, the exact mechanism regarding the cardiovascular involvement is still unclear. Acute cardiac injury is a frequently encountered complication in COVID-19 patients and is associated with an increased mortality. Cardiac biomarkers can be used for risk stratification of critically ill patients in order to identify those who need intense monitoring. Currently advocated treatment regimens comprise QT-interval prolonging drugs such as HCQ and azithromycin which calls for strict cardiac monitoring especially in those J o u r n a l P r e -p r o o f who are critically ill. Risk stratification needs to be done to identify those with an increased risk for QT prolongation. J o u r n a l P r e -p r o o f Troponin-T (µg/L)

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ECG: electrocardiogram; F: female; gm/dl: gram per deciliter; LDH: Lactate dehydrogenase; M: male; µg/L: microgram per litre; mg/dl: milligram per deciliter; mL: milliliter; SOFA: sequential organ function assessment

U/L: units per liter; VT/VF: ventricular tachycardia/ventricular fibrillation

Disclosures: None

J o u r n a l P r e -p r o o f