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Diffused Myocardial Inflammation in COVID-19 Associated Myocarditis Detected by Cardiac Magnetic Resonance Imaging in Post-COVID Patients

Objective: To determine the frequency of myocarditis in patients recovered from COVID-19 infection. Study Design: Analytical Cross-sectional study.


INTRODUCTION
SARS-CoV-2 causes Coronavirus Disease 2019 (COVID- 19), an infectious disease. In December, 2020 the first known case was reported in Wuhan city of China. 1 Since then, the disease spread worldwide and became a pandemic. Fever, headache, cough, breathing difficulty, exhaustion, and loss of taste and smell were common symptoms of COVID-19. 2 81% of symptomatic patients developed only mild to moderate symptoms (up to mild pneumonia), while 14% developed severe symptoms (dyspnea, hypoxia or more than 50% involvement of lungs on imaging) and 5% of patients suffered critical symptoms (shock, respiratory failure, or multi organ dysfunction). Despite being a minor cause of all viral myocarditis cases, human coronaviruses have been linked to myocarditis in patients of all age groups. 3 Reports show an association of multiple organs including heart. 4 The viral RNAs of Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV, which are close relatives of SARS -CoV-2, were found in the heart tissues of infected animals, suggesting that these coronaviruses possess cardio tropism. Raised serum troponin levels are often allied with acute respiratory infections and sepsis, which is a reason of mortality even after recovery. 5 Similarly, in hospitalized COVID-19 patients, serum troponin levels are elevated, and 30% cases reported cardiac injury which is associated with adverse outcomes. 6 40% deaths were caused due to this. 7 Troponin rise have been reported in multiple disease mechanisms like acute coronary syndrome, arrhythmias, myocarditis, underlying cardiovascular disease and systemic inflammatory syndrome.
Myocardial injury related to COVID-19 is a common complication and has dire implications on prognosis of disease. The advanced stage of COVID-19 associated with systemic hyper inflammation likely contributes to myocardial injury. The non-invasive imaging modality includes echocardiogram being less sensitive so, Cardiac magnetic resonance imaging (CMR) can be used preferably for the diagnosis of increased troponin from unclear etiology, 8 and evaluation of acute myocarditis, enabling risk stratification and prognostication. COVID-19 related myocarditis is one of important complication and early detection will help in better management of patient.
The COVID patients have been reported to have myocarditis as a possible clinical presentation or complication. Significant proportion of recovered patients has evidence of ongoing myocardial inflammation. Although the long-term consequences of this finding are uncertain, COVID-19 individuals are likely to have persistent residual cardiac damage and possibly heart failure in the long run. The diagnostic tests include; echocardiography and CMR.
During the recent decade, CMR (where available) has become gold standard non-invasive diagnostic imaging tool in cardiovascular medicine but only in tertiary care centers of patients with evidence for acute non ischemic myocardial injury. Suspected myocarditis is one of the most frequent indications for CMR scans and, in Europe, represents about one third of CMR referrals. 9 In patients with suspected myocarditis, CMR is the most complete and accurate diagnostic tool available, with no deterministic and minor stochastic effects. It allows for the verification or exclusion of myocardial inflammation and reversible/irreversible injury, as well as the assessment of myocarditis activity and severity. The high specificity and positive predictive value of CMR, especially when employing the Lake Louise Criteria, are its key advantages. As a result, it's particularly well-suited to verifying suspected myocarditis in patients with a high pre-test score.
The prognostic significance of these findings needs more information, and for the follow up and monitoring of residual abnormalities CMR (Cardiac magnetic resonance) mapping techniques should be considered as first line investigation to asses post COVID myocardial injury. Parametric T1 and T2 maps are the quantitative evaluation of infarction and edema respectively. This study will be helpful for medical practitioners. Regardless of knowing this possibility among physicians, there is lack of information about prevalence, mechanism, diagnosis, prognosis and treatment of myocarditis in the context of COVID-19. A contemporary study from Wuhan has stated that more than half of recovered COVID-19 patients with stand cardiac edema and fibrosis. 10 No literature has been found on role of CMR for screening of myocarditis in recovered patients of COVID-19 in context of Pakistan therefore, the purpose of present research is early identification or screening of myocarditis by using CMR in post COVID-19 patients in Pakistan. Aim of current study was to determine the frequency of myocarditis in patients recovered from COVID-19 infection.

METHODOLOGY
This was a single center cross-sectional study.

Sample Size:
We recruited all COVID-19 patients who underwent CMR with a suspicion of myocarditis from July 2020 till April 2022. Non-probability consecutive sampling technique was used for sample selection.
The study was carried out after approval by Institutional Review Board and Hospital Ethical and Research Committee (IERB letter # 9/2/R&D/2022/152).
Inclusion Criteria: Used was: (1) All PCR positive cases of COVID 19 who recovered from COVID 19 and completed their 12 days of isolation not exceeding 60 days of 1st PCR positive, (2) who have any symptoms of shortness of breath, fatigue and chest pain with reduced left ventricular ejection fraction (LVEF) on 2D echocardiogram.
Cardiovascular magnetic resonance scanning protocol; Siemens 3.0 Tesla Magnetom Skyra scanner was used to scan the patients. Scanning protocol consists of functional images, morphological assessment images, parametric mapping and delayed enhancement images. Standard long axis images are of single slice while, multiple almost 9 slices were obtained in short axis view covering the whole heart from base to apex. Native T1 and T2 mapping was performed in short axis view with 3 slices at base, mid and apex. Early and late gadolinium enhancement (EGE & LGE) images were taken in both short and long axis view. Short axis view of EGE and LGE is similar to cine short axis while in long axis we acquired 4 slices of each 2, 3 and 4 chamber view.
All images were obtained in breath hold with ECG gating, some sequences with retrospective gating and some with prospective gating. Intravenous contrast (Gadovist 1.0 mmol/ml, Bayer Healthcare, Berlin, Germany) was given with a dose of 0.15 mmol/kg and images were acquired after 10 mins of contrast administration.
• Native T1 maps: voxel size was 1.4x1.4x6.0mm 3 , TR and TE was set to be at 279.12ms and 1.1ms respectively, flip angle of 35 o , TI of 180ms, and 1 trigger pulse with a delay of 497ms.
• High resolution LGE: voxel size was 1.4x1.4x6.00 mm 3 with TR, TE and flip angle of 800ms, 2.75ms and 25 o respectively. Time to invert (TI) depends upon scout image usually ranging from 230-330ms. 2 trigger pulses were applied with trigger delay of 0ms.
• Overview LGE: 1.8x1.8x6.0mm 3 was the voxel size with TR of 700ms, TE of 1.09ms and a flip angle of 55 o . Trigger pulses were two with a delay of 0ms.
CMR post processing; Images were analyzed on syngovia software. LV function and volumes were calculated on SSFP cine images. Native T1 and T2 times were estimated by drawing an ROI (region of interest) on the myocardium. Enhancement pattern either subendocardial, mid myocardial and subepicardial or transmural were assessed by the consultant Cardiologists on phase sensitive inversion recovery (PSIR) late gadolinium enhancement images.
Data analysis procedure; Descriptive statistics were applied with the help of SPSS ver 21. Continuous variables were reported as Mean±SD. Categorical variables were reported as frequency and percentage. Association between the variables was find out by using Chi Square/Fischer Exact test by taking p-value <0.05 as significant.

RESULTS
Total 83 patients were included in this study who recovered from COVID-19 and underwent CMR. Mean age of the patients was 39.17±12.9 years. Mean height and weight was 170.37±8.2cm and 75.42±15.7 kg respectively in Table-I    Forty two (50.6%) cases of myocarditis were males while only 8 (9.6%) were females that showed male population was more effected by post COVID-19 myocarditis, as shown in Figure-2.

Figure-2: Gender distribution with Myocarditis
The Pearson's Chi Square test results presented in given Table-II is showing statistically significant association of all the findings (CMR-EF, T1 MAP, T2 MAP  and LGE) with Myocarditis (p<0.05) except ST-changes (p>0.05) at 95% confidence interval and 5% margin of error.

DISCUSSION
Current study showed statistically significant association of all the findings (CMR-EF, T1 MAP, T2 MAP and LGE) with Myocarditis (p-value <0.05). Many studies supporting the given result have been discussed in following sections.
The COVID patients have been reported to have myocarditis as a possible clinical presentation or complication. Significant proportion of recovered patients has evidence of ongoing myocardial inflammation. Although the long-term consequences of this finding are uncertain, COVID-19 individuals are likely to have persistent residual cardiac damage and possibly heart failure in the long run.
A study has been carried out in China on patients recovered from COVID-19 who had presented with cardiac symptoms showed that there was evidence of myocarditis on cardiac MRI in 58% of the patients, revealing that there is high incidence of involvement of myocardium with COVID-19 disease. A cohort study of German patients recovered recently from COVID-19 infection, reveals that there was involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%) on CMR, independent of severity, preexisting conditions, time from original diagnosis and overall acute illness course. This study resembles with them showing 50 patients (60%) having cardiac involvement of myocarditis after recovered from COVID- 19. 5 Myocarditis has a strong association with variety of viral diseases but the true incidence of myocarditis among them is unknown. 16 Autopsy reveals inflammatory myocardial infiltrates in COVID-19 patients but the real prevalence was unknown. 17 19 Recent studies reported elevated T1 and T2 times in septum suggesting fibrosis and edema respectively.
According to the scale of COVID-19, long term follow-up with cardiac MRI is not feasible. However, a small group should be targeted and evaluated with CMR as LGE had a crucial role in pathophysiology of dilated cardiomyopathy. 20 Long term presence of scar is associated with cardiac involvement of myocarditis. For such evaluations, follow-up studies are recommended.

LIMITATIONS OF STUDY
It was a single centre study with limited number of COVID-19 patients enrolled for research as the institute in which study was conducted was cardiac rather than medical facility where COVID-19 patient inflow comparatuively less.

CONCLUSION
The Coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 is a highly contagious Viral disease. Myocardial injury related to COVID-19 is a common complication and has dive implications on prognosis of disease, early detection of COVID-19 related myocarditis will help in better management of patient.
The non-invasive imaging modality includes echocardiogram being less sensitive so, Cardiac magnetic resonance imaging (CMR) can be used preferably for the diagnosis of Post COVID myocarditis and evaluation of acute myocarditis, enabling risk stratification and prognostication. MRI is an important imaging technique which permits non-invasive assessment of myocardial injury and edema as well as identification of potentially treatable underlying causes of inflammation in suspected patients of myocarditis and myocardial inflammation, to guide management and improve patient outcomes. It can also be helpful in asymptomatic patients of myocarditis after getting infected with COVID-19.

ACKNOWLEDGMENT
I am deeply grateful to my supervisor for his guidance, patience and support who provided insight and expertise that greatly assisted my research project. I also want to share my gratitude for Comdt Exec Dir AFIC/NIHD & HoD R&D