Myocarditis in Patients with COVID-19

Abstract

SARS-CoV-2 is an enveloped RNA beta coronavirus, identified as the pathogen responsible for coronavirus disease 2019 (COVID-19). It primarily affects the respiratory system; however, cardiovascular complications have been found in 30% of hospitalized patients, associated with worse outcomes. The virus can invade human host cell by binding with high affinity the Angiotensin Converting Enzyme 2 (ACE 2) receptor, which is expressed especially in the lungs and heart, where the human immune response can lead to an inflammation of the myocardium itself. Patients with myocarditis commonly experience nonspecific signs and symptoms; laboratory tests often revealed elevated marker of myocardial necrosis and inflammation while electrocardiogram in most patients have demonstrated features similar to an acute coronary syndrome. Echocardiography is the first method of investigation to evaluate the left ventricular systolic function. In suspected case, Cardiac Magnetic Resonance Imaging (CMRI) is acknowledged as the non-invasive gold standard test for myocarditis, also useful in assessing prognosis. Endomyocardial biopsy (EMB), although considered a gold standard for the diagnostic confirmation of myocarditis, is an invasive procedure that cannot be performed in all patients. Current management is mainly supportive in association with glucocorticoids.

Keywords: Myocarditis; SARS-CoV-2; COVID-19; Cardiac Magnetic Resonance Imaging

Introduction

Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV- 2) is an enveloped RNA with positive polarity beta coronavirus, identified as the pathogen responsible for coronavirus disease 2019 (COVID-19) [1]. This pathology was first reported in Wuhan (China) in December 2019 and, then, in March 2020 the World Health Organization (WHO) declared a COVID-19 global pandemic [2]. SARS-CoV-2 primarily infects the lung epithelium causing flu-like symptoms (headache, anosmia, dysgeusia, cough, fever, myalgia, and dyspnea) as the most common clinical manifestation; however cardiovascular complications have been found in 30% of hospitalized patients, sometimes associated with worse outcomes [3].

Pathogenesis

SARS-CoV-2 through the receptor-binding domain on the S protein can invade the human host cell by binding with high affinity the Angiotensin Converting Enzyme 2 (ACE 2) receptor. ACE-2 is widely expressed throughout the body, especially in the lungs and heart where the TMPRSS2 co-expression is required for SARSCoV- 2 entry. After penetration, viral RNA enters the cell nucleus for replication and apoptosis [4]. The human immune response to the virus is variable as the clinical presentation. Several mechanisms have been proposed to explain the underlying pathophysiology of COVID- 19-related acute myocarditis but the main biomolecular mechanism responsible for heart damage is thought to be the abnormal state of systemic inflammation, causing low oxygen levels and thrombosis and the cell-mediated cytotoxicity in which CD8+ T lymphocytes migrate to cardiomyocytes with an inflammation of the myocardium itself [5]. Furthermore, myocardial damage may be due to the direct viral action on the tissue or to extrapulmonary migration of infected alveolar macrophages through the bindings of the ACE2; these bindings in turn cause downregulation of ACE2 receptors with increases type 1 angiotensin II receptors expression, which leads finally to endothelial damage and vasoconstriction in both lung and heart [6]. Lastly, the hyperactivation of the autoimmune system with possible interferon mediated activation of the innate and adaptive immune system has also been proposed as possible mechanism [7].

Signs and Symptoms

Patients with myocarditis commonly experience dyspnea and fever, followed by cough and chest pain. Other reported symptoms include nausea, fatigue, myalgia, diarrhea and headache, all flulike symptoms which hamper the clinical diagnosis of myocarditis especially in the setting of COVID-19 pandemic [8].

Laboratory and Instrumental Findings

In many COVID-19 patients elevated levels of troponin, Creatine Kinase Myocardial Band (CKMB), Brain Natriuretic Peptide (BNP) and also of C-Reactive Protein (CRP) were reported; however, these are nonspecific findings as normal levels did not exclude myocarditis [9].

Electrocardiogram (ECG) in most patients with myocarditis have demonstrated features including sinus tachycardia, ST-segment elevation, T-wave abnormalities and occasional atrioventricular or branch blocks [10], findings often similar to acute coronary syndrome.

Imaging Findings

Echocardiography it is the first and most available method of investigation, demonstrating mainly the presence of pericardial effusion, global left ventricular systolic dysfunction and regional wall motion abnormalities [11]. Even if the coronary angiography is considered the gold standard for the visualization of coronary tree, Coronary Compute Tomography coronography plays a central role as a non-invasive instrument that allows the differential diagnosis between acute myo-pericarditis and ischemic heart disease [12].

Cardiac Magnetic Resonance Imaging (CMRI) is acknowledged as the non-invasive gold standard test for myocarditis; the reference diagnostic criteria are those of Lake Louis where the diagnosis of myocardial inflammation is based on at least one T1-based criterion (non-ischemic late enhancement, increased myocardial T1 relaxation times, increased extracellular volume fraction) with at least one T2-based criterion (noticeable myocardial edema, global signal intensity ratio myocardium/skeletal muscle ≥2, increased myocardial T2 relaxation times) (Figure 1) [13]. Moreover, CMRI provides important prognostic information in myocarditis; in fact, the presence of Late Gadolinium Enhancement (LGE) is correlated with cardiac mortality with a hazard ratio of 12.8 [14] and with left ventricular dilatation and reduced Ejection Fraction (EF) [15]. The distribution pattern of LGE also matters because major cardiac event and heart failure hospitalization occurred more frequently in patients with an antero-septal involvement [16].

    

    

    Figure 1: Cardiac magnetic resonance image short-axis view fulfilling Lake
Louis criteria for myocarditis. A, B) Balanced steady-state free-precession
sequences during diastole and systole showing no alteration of the kinetics
at the level of the inflamed myocardium. C) T2w short tau inversion recovery
sequences showing myocardial edema of the mid lateral wall with a nonischemic
distribution (sub-epicardial) (arrow). D) Phase-sensitive inversion
recovery sequences showing late enhancement with same pattern of C
(arrow).