**2.5 COVID-19 and myocarditis**

Injury of the myocardium and acute myocardial inflammation are well documented complications of acute viral infections. One of the underlying mechanisms of the injury, obtained from the cardiac muscle autopsy specimens are myocytes necrosis with mononuclear cell infiltrates [35]. These findings together with the cases of fulminant myocarditis, lead as to conclude that myocarditis is an important cause of acute myocardial injury in patients with COVID-19 disease. However, the true prevalence, the exact mechanisms and clinical significance of acute myocarditis in COVID-19 patients still remains unclear. We do not have solid evidence of direct myocardial cytotoxic effects of the virus. The real prevalence of this complication still remains unclear. Myocarditis appears in COVID-19 patients after a prolonged period up to two weeks after the symptom's onset.

Clinically, COVID-19 myocarditis may manifest only as mild chest discomfort, palpitation and fatigue, which may be impossible to distinguish from other causes in most patients. In some patients, myocarditis results in fulminant disease, which may be the cause of arrhythmias, conduction block, myocardial dysfunction or even death. In many cases myocarditis is suspected when cardiac injury is present in the absence of ACS [36]. Acute myocarditis diagnosis can be confirmed by the presence of typical acute myocardial injury signals detected by cardiac magnetic resonance imaging (MRI). However Cardiac MRI and EMBs as diagnostic tools are likely to be inappropriate during the current COVID-19 pandemic but should be considered in the later phase to confirm diagnosis.

This cardiac injury in COVID 19 infected patients leads to activation of the innate immune response with release of proinflammatory cytokines. Proteins released through cell lysis might display epitopes similar to the viral antigens and be presented via the major histocompatibility complex [37]. An acquired immune response is the predominant mechanism evidenced by activation of antibodies and T lymphocytes. In the final stage, there is either recovery or low levels of chronic inflammation with concomitant development of left ventricular dysfunction. The most important question for potential therapeutic targets is the extent to which myocardial injury results from viral replication, is immune mediated, or is due to other mechanisms. Patients that develop heart failure have poor prognosis and should be treated based on heart failure guidelines [28]. Clinical follow up, with biomarkers and echocardiography are important for patient's treatment and prognosis [38].

#### **2.6 Arrhythmias and sudden cardiac death**

In-hospital and out-of-hospital sudden cardiac arrests have also been reported in patients with COVID-19 [39]. The contribution of COVID-19 disease for induction of cardiac arrhythmias remains uncertain, having in mind that atrial and ventricular arrhythmias can also be triggered by myocardial injury, other infections, fever, sepsis, hypoxia and electrolyte abnormalities. Arrhythmias can be induced by concomitant antiviral and antibiotic therapy used in patients with COVID-19 disease. Increase heart rate is reported as one of the main symptom in COVID-19 disease patients without other symptoms such as fever or caught. The presence of cardiac arrhythmias was reported in 17% of patient from the cohort of 138 COVID-19 cases in the study from Wuhan, China, and 44% of them were hospitalized in the ICU units [39]. Another study from Wuhan which includes 187 hospitalized COVDI-19 patients, showed that patients with elevated troponin T values were more likely to develop serious arrhythmias, including ventricular tachycardia and fibrillation, comparing to those with normal troponin T levels (12% vs. 5%) [40]. Treatment of all systemic causes and underlying heart injury having in mind drug interactions should remain the arrhythmias management goals in COVID 19 patients [28]. Hospital data from China revealed that hospitalized COVID-19 patients with elevated troponin levels had more frequent malignant arrhythmias (11.5% vs. 5.2%) and higher overall mortality (59.6% vs. 8.9%) [41].

#### **2.7 COVID-19 and coagulation abnormalities**

Thromboembolic complications are highly prevalent in patients with COVID-19 infection. Disseminated intravascular coagulation (DIC) and pulmonary embolism, characterized by increased D-dimer levels and fibrin degradation products, are the most characteristic clinical presentations. DIC has been observed in 71.4% of non-survivors [42]. Pulmonary embolism (PE) has been reported in up to 30% of hospitalized patients [41, 43]. Those percentages might not be surprising given the

#### *COVID-19 and Cardiovascular Disease: Mechanisms and Implications DOI: http://dx.doi.org/10.5772/intechopen.99332*

critical condition of these subjects. The clinical and scientific data we have from several world centers indicates that D-dimer values are highly predictive of adverse events in patients with COVID-19 disease. Results from retrospective cohort study showed that elevated D-dimer values (>1 g/L) are strongly associated with intrahospital mortality, which was confirmed as a relationship in the multivariate analysis (OR 18.4, 95% CI 2.6–128.6; p = 0.003) [44]. Additionally, Chinese and Italian experience emphasizes that in the earlier stage of the disease more discrete D-dimer changes are observed, which precede the rapid rise of D-dimer as disease progresses. Recommended diagnostic algorithms combing pre-test probability assessment and D dimer tests can be used in case of suspected acute PE.

Hypercoagulability caused by inflammation and cytokine release are the underlying cause for pulmonary embolism in COVID-19 infected patients [45]. Advanced age, bedridden, stasis, endothelial injury and hemostatic abnormalities are factors associated with increased risk for venous thromboembolism. Inflammatory activation in COVID-19 leads to frequent abnormalities in the coagulation system [45]. It is assumed that COVID -19 infection lead to generalized endotheliopathy as a one of the underlying mechanisms for impaired vascular function and hypercoagulability. For risk stratification purposes and prognosis as well as identification of the patients with increased thrombotic risk, markers of inflammation and thrombotic risk should be measured at baseline and repeated every 2–3 days if abnormal and whenever clinical deterioration is suspected.

The index of suspicion for VTE should be high in the case of typical deep vein thrombosis (DVT) symptoms, hypoxemia disproportionate to known respiratory pathologies, acute unexplained right ventricular dysfunction, new or unexplained tachycardia and new onset of ECG changes suggestive of PE, fall in blood pressure not attributable to tachyarrhythmia, hypovolemia or sepsis [46].

A diagnostic challenge arises among patients with COVID-19, as imaging studies used to diagnose DVT or PE may not be performed given risk of transmitting infection to other patients or health care workers and potentially due to patient instability. Prophylactic anticoagulation is recommended in all patients admitted with COVID-19 infection. When acute PE is confirmed, treatment should be guided by risk stratification in accordance with the current European Society of Cardiology (ESC) guidelines [28]. The novel oral non-vitamin K antagonists (NOACs) may show some interactions with the some of the drugs used in COVID-19 disease patients, mainly with lopinavir/ritonavir and in those cases NOACs should be avoided. There are no major interactions reported between investigational drugs for COVID-19 and the use of heparin as anticoagulant therapy [47].
