**2.1 Cardiac injury caused by COVID-19 infection**

The data from published studies showed that patients with myocardial injury (elevated cardiac troponin), have up to three times higher hospital mortality [12]. Increased hospital values of the high-sensitivity cardiac troponin I are found in over 50% of fatal COVID-19 disease cases. Elevation of the troponin values parallel the elevation of N-terminal pro-B-type natriuretic peptide and C-reactive protein and markers of cardiac injury and inflammation. Data showing the rise of the troponin in the same time with other inflammatory biomarkers (D-dimer, ferritin, interleukin-6 (IL-6), lactate dehydrogenase), lead to conclusion that isolated myocardial injury mediated through ACE-2 is not the only mechanism of COVID-19 induced

cardiac lesions [13]. One of the explanations is the presence of cytokine storm. The curves of troponin values changes show slow elevation during the first 2 weeks, with steep elevation during the third week in severely and critical ill patients with severe disease forms. Follow up studies showed that hs- Troponin I value in survivors have no significant changes [14].

Many patients' cases with of ST segment elevation myocardial infarctions (STEMI) with normal coronary angiography findings are published [15] which is explained as injury caused by stress cardiomyopathy or acute myocarditis. However, so far there are no published data of the signs of direct virus infiltration of the myocardium. The scientific data we have indicates inflammation as a cause of multi-organ damage, not only myocardial damage. Use of cardiac magnetic resonance imaging may give more answers to these questions.

There are evidences of impaired heart function due to myocardial injury in patients who recover from COVID-19, mostly due to myocarditis. Based on all data we have we can evaluate troponin levels as markers on disease severity and myocardial injury, also related to the underlying mechanisms such as cytokine storm, tissue hypoxia, and coagulation disturbances [16]. Management of the myocardial injury and their consequences are of great clinical and prognostic importance in critically ill individuals. We should not initially use invasive diagnostic procedures in patients with COVID-19 disease and isolated troponin elevation in absence of other signs and symptoms suggesting the presence of acute coronary syndrome.

#### **2.2 Which biomarkers should we measure?**

As in patients without COVID-19, cardiac troponin T and troponin I values should be measured based on clinical presentations when T1 type myocardial infarction (MI) is suspected [17]. Normal high -sensitive cardiac troponin values depend on gender and essay analyses used. Diagnostic algorithms for rapid rule out and/or rule-in of MI in patients with acute chest discomfort such as the high-sensitivity cardiac troponin (hs-cTn) T or I 0/1 hour algorithm is expected to provide comparable performance and add to diagnosis in other challenging subgroups with higher baseline concentrations such patients with renal dysfunction: very high safety for rule-out and high accuracy for rule-in, but reduced efficacy with a higher percentage of patients remaining in the observe zone [17, 18]. Clinical assessment including chest pain characteristics, hs-cTn T or I measurement at 3 hours, and cardiac imaging using echocardiography are the key elements for the identification of STEMI in the setting of COVID-19 infection. Hs-cTn I should be measured in patients with confirmed pulmonary embolism, as a marker for risk stratification and prognosis [19].

Similarly, B-type natriuretic peptide (BNP) and NT-proBNP should be measured whenever clinically heart failure is suspected [19]. Rule-in cut-offs for heart failure (HF) maintain high positive predictive value even in patients with pneumonia, who are not critically ill. Having in mind that most of the critical ill patients have significantly higher BNP/NT-proBNP values, it is therefore not recommended to use current cut-off values applied for heart failure patients. Increased BNP/NT-proBNP levels in severely ill patients with COVID-19 disease are explained by the presence of hemodynamic stress and myocardial injury leading to heart failure [20]. Cardiac injury, as assessed by several serum analysis parameters (lactate dehydrogenase, cardiac troponin I, creatine kinase (-MB) and myoglobin), were associated with poor prognosis in COVID-19 infection, assessed in. the retrospective multicenter study from Xie and coworkers, as shown in **Figure 2** [21].

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

#### **Figure 2.**

*Dynamic changes in laboratory markers of severely ill patients with COVID-19 disease hospitalized in the intensive care units (ICU). The figure describes changes in the arterial pO2 ("P") from the ABG divided by the FIO2 ("F") (P/F ratio) which includes the values of lymphocytes, high sensitive C reactive protein (hs-CRP), D-dimer, lactate dehydrogenase (LDH) and high sensitive troponin I (hs-troponin I) (a-f). At all-time points shown, there were significant differences between survivors and non-survivors. Intensive care medicine volume 46, pages1863–187, 2020 (ref [21].*

#### **2.3 COVID-19 and Heart failure**

COVID-19 infection might present as new or worsened previously established heart failure. It is a challenge for every physician to make differential diagnoses between decompensated heart failure (HF), often complicated with pulmonary infection and COVID-19 infection, prior to laboratory-confirmation. There are significant similarities between chest computer tomography (CT) findings of the patients with heart failure and those with COVID-19 disease. Higher ratios of central ground glass opacity are found in patients with heart failure, comparing to the more peripheral gradient distribution in patients with COVID-19 infection [22].

Scientific data reports up to 25% of case fatality rate in patients with extreme elevation of NTproBNP levels caused by heart failure and cardiac arrest [23]. In a large cohort from China, heart failure was reported in 23% of infected patients and the prevalence was significantly higher among non-survivors (52% vs. 12%, p < 0.0001) [23].

From the evidences we have so far, patients with previous heart failure will have more complicated pulmonary disease and COVID-19 infection course. Acute heart failure and myocarditis might be one of the clinical presentations of COVID-19 disease. Some of the explanations of the underlying mechanisms of the heart dysfunction are initial structural changes in the early stage of the disease with preserved left ejection fraction in parallel with pulmonary complications and the development of acute heart failure with reduction of systolic function in the later stage of the disease as a response to cytokine storm.

Heart failure has been reported as an outcome in 23% of COVID subjects in a recent report from in-hospital Chinese subjects. Approximately 52% of

non-survivors had heart failure as compared with 12% of survivors [24, 25] Mechanisms underlying myocardial injury remain unknown and it is unclear whether they reflect systemic, local, ischemic or inflammatory process. It is still not known whether acute injury is a primary infective phenomenon or secondary to lung disease.

Elderly patients with heart failure may have left ventricular hypertrophy, diastolic dysfunction or systolic dysfunction and are prone to higher pulmonary vascular pressure in case of overload with fluid infusions and administration of parenteral therapy. Myocardial injury is observed in more than 20% of hospitalized patients with COVID-19 [26]. Increased levels of brain natriuretic peptide or N-terminal pro brain natriuretic peptide may be found in COVID-19 patients and may suggest concomitant impairment of cardiac function and poorer clinical course. Patients with elevated troponin levels have higher rates of major complications, including cardiac arrhythmias, acute kidney injury, ARDS, need for mechanical ventilation, and death [26].

Most patients with heart failure have elevated C-reactive protein, erythrocyte sedimentation rate and other indexes of inflammation and thrombogenicity, such as ferritin, interleukin-6, lactate dehydrogenase, fibrinogen, and D-dimer. An increase in these markersis associated with high mortality [27]. All these markers are higher with continuing increase during the hospitalization in high risk patients who do not survive the disease. Contrary in lower risk stable patients who survive all these parameters remains stable and relatively low. Procalcitonin must be measured when bacterial superinfection is suspected. Echocardiography must be considered in all patients with HF and suspected or confirmed COVID-19 infection to assess cardiac function and to detect concomitant causes of HF, either pre-existing or COVID-19-related (e.g. right ventricular dysfunction secondary to pulmonary embolism). Treatment of heart failure patients should be based on the latest guidelines from several cardiology societies [17, 28].

#### **2.4 COVID-19 and Coronary artery disease**

Patients with coronary artery disease, stabile or unstable, are prone to complications during COVID-19 infection, due to coronary plaque rupture or stent-thrombosis secondary to pro-coagulant effects of systemic inflammation [28]. Around 6% of patients with severe COVID-19 disease report the history of previous coronary artery disease (CAD), comparing with 1.8% prevalence of CAD in patients with non-severe disease forms [18].

It is important to underline that many individuals with COVID-19 disease initially presents with chest pain, palpitation and dyspnea instead of cough, fever and other related respiratory symptoms. Normal coronary angiography in patients presenting with chest pain and suspected acute coronary syndrome, should raise the first suspicion of infection with COVID-19. However, elevated troponin during COVID-19 infection, if followed by typical symptoms and signs of myocardial infarction should lead to guideline-directed interventions, fibrinolysis, or coronary angioplasty in designated hospitals [18, 28]. There are evidences of high expression of angiotensin II receptors in the heart muscle [29]. These findings explain the SARS-CoV-2 infection repercussion on the myocardium in the form of locally induced microvascular inflammation and dysfunction leading to myocardial infarction without the obstruction of the coronary arteries (MINOCA). All these pathophysiological mechanisms could explain the scientific data we have obtained concerning the clinical course of patients presenting with myocardial infarction signs during the COVID-19 disease [30]. Additionally, cytokine storm significantly contributes for the development of the endotheliopathy through well described mechanisms. The global finding during

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

the COVID-19 pandemic is significant reduction of number of acute myocardial infarction by 30–50%, mostly due to fear for on time search of medical help [31]. The late patient's presentation leads to significant increase of acute myocardial infarction complications, especially heart failure.

Several pathways associated with viral diseases may contribute to destabilize plaques in COVID-19 patients [32]. Viral illness can potentially destabilize atherosclerotic plaques through systemic inflammatory responses, cytokine storm, as well as specific changes of immune cell polarization towards more unstable phenotypes. In patients with viral infections, type 2 myocardial infarction is the most common subtype, were the usefulness of invasive treatment with coronary revascularization is limited.

In patients with acute coronary syndrome (ACS) and COVID-19 disease the final treatment decision weather invasive or medical management is applied should be carefully considered. Primary percutaneous coronary intervention (PCI) is the standard treatment for patients presenting to PCI centers within 90 minutes of first medical contact [28, 33]. It is important to underline that all patients presenting with a suspected STEMI should be considered COVID-19 possible. Testing for SARS-CoV-2 should be performed as soon as possible following first medical contact, irrespective of treatment strategy, in order to allow to implement adequate protective measures and management pathways [28]. Some of these patients may have a "STEMI-mimicker" such as focal myocarditis or stress cardiomyopathy known to be associated with COVID-19 illness.

Treatment of patients with non-ST segment elevation myocardial infarction non-STEMI should be guided by risk stratification. Patients with Troponin rise and no acute clinical signs of instability (ECG changes, recurrence of pain) might be managed with a primarily conservative approach. For patients at high risk, medical strategy aims at stabilization whilst planning an early (< 24 hours) invasive strategy.

The use of timely reperfusion in STEMI patients should not be compromised by the COVID-19 pandemic. Based on the recommendations from the latest guidelines of the European Society of Cardiology (ESC), reperfusion therapy is indicated in STEMI patients with ischemia symptoms in duration <12 hours and persistent ST segment elevation in at least 2 ECG leads, and these recommendations remain the same for COVID -19 disease patients with STEMI. The maximum delay from STEMI diagnosis to reperfusion of 120 minutes should remain the goal for reperfusion therapy with primary PCI when feasible within this time frame and performed in facilities approved for the treatment of COVID-19 patients [28]. If primary PCI performing hospital is no not available or target time cannot be met and fibrinolysis is not contraindicated, fibrinolysis should then become first line therapy [28, 34].
