**3. Acute cardiovascular complications of COVID-19**

#### **3.1 Myocarditis/pericarditis**

It is generally accepted that viral infections, and corona viruses even more, are a common cause of myocarditis, frequently associated with congestive heart failure (CHF), and an increased risk to sudden death due to ventricular arrhythmias [29]. Emerging data suggest an increased association between myocarditis and COVID-19, observed more frequently in hospitalized patients, associated with an increased risk of adverse outcome, including higher mortality rates [30].

According to Dallas criteria, acute myocarditis is defined as "inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical for the ischemic damage associated with coronary artery disease." Proposed pathophysiological pathways are myocardial injury due to the direct action of the virus, mediated via ACE2 receptors, and an intense, prolonged inflammatory response resulting in the release of high amounts of cytokines [29, 31, 32] together with additional factors such as hypoxia, increased metabolic demands, and physiological stress. At biopsy, myocyte and interstitial cells necrosis and mononuclear cell infiltrates were detected.

The real prevalence of acute myocarditis in patients infected with the SARS-CoV-2 virus is difficult to establish. In the medical literature, in these patients, the estimated incidence of acute myocarditis ranges from 12–17% or even 22–31% in ICU patients [33]. The symptoms vary from mild, nonspecific ones: palpitations, breathlessness, chest pain, common in influenza, to the dramatic picture of AHF with dyspnea, arrhythmias, or even sudden cardiac death. On the electrocardiogram (ECG), there are nonspecific ST, PR, and T-wave abnormalities, but signs mimicking an ACS, tachyarrhythmias, and conduction disturbances associated or not with left ventricular echocardiographic alterations and elevated levels of high sensitive troponins are also frequently seen [31, 33]. Another aspect is that the main diagnostic criteria require endomyocardial biopsy and cardiac magnetic resonance imaging (MRI), which are sometimes difficult or even impossible to access in COVID-19 patients due to the increased risk of contamination [33, 34]. It has been discussed that the prevalence of myocarditis rose parallel with the evolving strains of the SARS-CoV-2 virus being higher in patients infected in 2021 than in 2020 [30].

The incidence of pericarditis in COVID-19 patients ranges from 3% to 4.8% [35, 36]. It is often associated with myocarditis in COVID-19 patients with pneumonia and elevated inflammatory markers, as demonstrated by Diaz et al. in a meta-analysis performed on 33 studies, mainly case reports. The principal mechanism seems to be an autoreactive, inflammatory response [36].

Pericarditis manifests itself with a variety of symptoms, such as chest pain, fever, and dyspnea [36]. Pericardial friction rub is seldom encountered (9.3%) [36]. The predominant characteristic of this type of pericarditis is pericardial thickening observed at transthoracic echocardiography (TTE) persisting several weeks during recovery [37]. Over 50% of patients have pericardial effusion, mostly small to moderate in size, with 34% having large pericardial effusion, and even pericardial tamponade developed in about half of this last subset of patients [36]. On the ECG, 60% of patients present the typical four-stage evolution: diffuse ST elevation with depression of the PR segment, normalization of ST elevation, diffuse T-wave inversion, and in the end, normalization of the ECG [66]. Some patients presented unspecific signs, such as diffuse ST elevation, PR depression, and focal T-wave inversion [36].

#### *Impairment of the Cardiovascular System during SARS-CoV-2 Infection DOI: http://dx.doi.org/10.5772/intechopen.103964*

The treatment of acute pericarditis consists in high doses of nonsteroidal antiinflammatory drugs (NSAIDs) such as Ibuprofen, Indomethacin, or Naproxen recommended until symptom relief is achieved, and in addition, colchicine is recommended to be used for 3 to 6 months. Aspirin may be an alternative to NSAIDs [36]. Although low to moderate doses of steroids could be recommended in patients with SARS-CoV-2 infection, in most cases, this therapy is started sooner because of the associated viral myocarditis [36]. Furthermore, steroids can also be added to NSAIDs and colchicine as triple therapy for patients with an incomplete response. In the case of cardiac tamponade, pericardial drainage represents the standard of care [36]. Usually, the evolution of pericarditis associated with COVID-19 is benign.

#### **3.2 Acute coronary syndrome**

An increased incidence of ACS has been reported in several viral infections such as influenza, SARS, and MERS, being associated with a 3- to 10-fold increased risk, but in COVID-19 exact data are lacking [31, 32]. As principal potential pathophysiological pathways are considered: destabilization of atherosclerotic plaques due to systemic inflammation with an increased release of pro-inflammatory cytokines, the "cytokine storm," associated microangiopathy, activation of prothrombotic factors, as well as other specific changes of immune cell polarization toward more unstable phenotypes. Contributing factors also are myocardial oxygen supply/demand mismatch in the context of increased metabolic demands due to tachycardia/arrhythmias, fever, and hypoxia. These factors probably represent also the best explanation for the increased troponin levels observed in many patients with acute COVID-19 in the absence of typical cardiovascular manifestations (chest pain, specific ischemic electrocardiographic modification, and parietal hypokinesia at TTE) [31, 32], the more so as some other complications such as myopericarditis may have similar symptoms, and often patients with COVID-19 may not have typical angina symptoms.

Patients already suffering with coronary artery disease and heart failure may be exposed in a greater extent to ACS as a consequence of coronary plaque rupture or stent thrombosis in the context of systemic inflammation [31, 32]. For this reason, it is strongly recommended that in patients with a previous history of coronary artery disease and especially in those with coronary interventions, antiplatelet therapy should be continued, eventually even intensified, together with other plaque stabilizing agents such as statins, beta-blockers, and angiotensin-converting enzyme inhibitors [27, 30, 38, 39].

In this global health systems crisis, an adequate diagnosis and management of ACS is complicate and health care institutions worldwide have reexamined their protocols considering the increased risk of contamination of healthcare personal and the high requirements for protective equipment [34, 40, 41]. However, risk stratification is difficult due to limited bedside approach for an accurate ECG and TTE examination [31, 42]. The treatment of acute myocardial infarction (AMI) in COVID-19 patients is even more controversial. While in patients diagnosed with non-ST elevation myocardial infarction (non-STEMI), the result of a PCR testing could be expected prior to cardiac catheterization, in cases with ST elevation myocardial infarction (STEMI), the American College of Cardiology (ACC) recommends reconsidering fibrinolysis in patients with "low-risk STEMI" such as inferior without right ventricular extension, or lateral STEMI without altered hemodynamic. Thus percutaneous coronary intervention (PCI) remains the most indicated therapy, remaining the best option also in non-STEMI patients who are hemodynamically unstable [34, 42, 43].

In a large meta-analysis, DeLuca et al. concluded that COVID-19 pandemic has significantly impacted the therapy of patients with STEMI, with a 19% reduction in PCI procedures leading to increased morbidity and mortality, aspects evidenced also in other studies [34, 40, 43].

### **3.3 Increased risk of arrhythmias**

Arrhythmias were observed precociously in COVID-19 patients worldwide, several centers reporting a large spectrum of electrocardiographic abnormalities [31, 32]. In most cases, sinus tachycardia due to multiple, concomitant causes (hypoperfusion, fever, hypoxia, and anxiety) was observed, but also atrial tachycardia and fibrillation (AF), and less frequently atrioventricular block (AVB) and polymorphic ventricular tachycardia (VT), significantly increasing the morbidity and mortality, and explaining at least in part, the increased number of cardiac arrests noticed in out-of-hospital patients [44, 45]. It was considered that underlying mechanisms are myocardial injury, inflammation, coexisting hypoxia, electrolytic (especially hypokalemia) and acid–base imbalances, and activation of the sympathetic nervous system, which is contributing the medication used to treat this disease such as hydroxychloroquine, azithromycin, and antivirals that prolong the QT interval [46, 47].

Perhaps the most comprehensive study written on this topic is the one of Coromilas et al. who analyzed data collected from over 4000 patients with COVID-19 and arrhythmias, from 4 continents and 12 countries, and concluded that the majority of them (81.8%) developed supraventricular arrhythmias including AF and atrial flutter, 21% of subjects had ventricular arrhythmias, and 22.6% developed bradyarrhythmias [47]. They also observed that arrhythmias were more frequent in patients over 60 years old, male gender prevailed, and frequently systemic hypertension and diabetes mellitus were associated comorbidities [33, 46, 47].

Treatment of arrhythmias should follow the standard guidelines for the management of arrhythmias focusing on the underlying pathophysiological mechanisms, and addressing as much as possible the reversible causes, especially electrolyte abnormalities. In the case of recurrent, uncontrolled ventricular arrhythmias not responding to antiarrhythmic therapy, implantable cardioverter defibrillators may be recommended, and for persistent high-degree AVB transvenous pacemaker insertion [48].

## **3.4 Thromboembolic events and bleeding risk**

As the pandemic unravels, medical literature has provided robust insight into the unique mechanisms of and specific propensity for COVID-19 thrombogenicity, identified as considerably different from other severe infectious and non-infectious diseases. The relationship between SARS-CoV-2 infection and subsequent dysregulation of coagulation homeostasis is reflected in the various rates of occurrence of major venous and arterial thromboembolic/thrombotic events, which, in more extreme cases, have been documented to occur concomitantly. A recent comparative study, which retrospectively evaluated thromboembolic risk in large patient cohorts of COVID-19 and Influenza, found that COVID-19 was independently associated with a higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared to Influenza, with secondary analysis showing a similar risk for ischemic stroke and myocardial infarction, and a higher risk for deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with COVID-19 [49].

#### *Impairment of the Cardiovascular System during SARS-CoV-2 Infection DOI: http://dx.doi.org/10.5772/intechopen.103964*

In spite of early thromboprophylaxis, most frequently, VTE negatively impacts clinical outcomes in COVID-19 hospitalized patients, and the risk seems to be greatest in the intensive care unit (ICU) setting, among the critically ill [50]. Major arterial thrombotic events and VTE have been reported at a higher frequency, in COVID-19 ICU patients, as compared to non-ICU patients, over a 30-day period, despite a thromboprophylaxis rate of 85–90% [51]. Moreover, a recent meta-analysis of 12 studies, in which all patients were under thromboprophylaxis, with either low molecular weight or unfractionated heparin, still showed a 31% pooled prevalence of VTE for ICU admissions [52]. Very recently, an overall incidence of 17.3% for VTE among hospitalized COVID-19 has been reported (~2/3 DVT), with significant discrepancies between pooled incidences of VTE for ICU admissions as compared to general ward patients (27.9% vs. 7.1%, respectively), while including catheter-associated thromboembolism, isolated distal DVT, and isolated pulmonary emboli reached the highest incidence rates. Even so, VTE incidence was higher when assessed within a screening strategy (33.1% vs. 9.8% by clinical diagnosis), meaning that, in clinical practice, it is very likely that many COVID-19 patients with subclinical VTE remain undiagnosed [53]. Moreover, VTE prevalence in COVID-19 patients varies widely depending on the subpopulation evaluated, seemingly correlating well with disease severity and preexisting metabolic and cardiovascular comorbidities, a statement reflected by the variability of occurrence rates reported: <3% in non-ICU patient [51], >30% for ICU cases, with DVT and subsequent PE representing the most common thrombotic complication in the ICU setting [54], while autopsy findings of COVID-19 fatalities suggest it may reach nearly 60% [55].

Interestingly, amounting data suggest that the majority of so-called PE diagnoses occur without a recognizable source of venous embolism and may be better defined as primary in situ pulmonary arterial thrombosis, a direct consequence of the SARS-CoV-2 pulmonary disease, entailing thrombotic occlusion of small−/mid-sized pulmonary arteries, which will result in the infarction of afferent lung parenchyma [56]. This may explain why PE is the most prevalent thrombotic event seen in COVID-19 patients [54] and why screening yielded a higher incidence of VTE than clinical evaluation of asymptomatic patients. In a recent investigation, duplex ultrasound was performed for clinical suspicion of DVT, reporting 41.58% confirmed DVT, 6.93% superficial thrombophlebitis and, surprisingly, 23.76% PE (mostly involving distal pulmonary vessels), yet only 7.92% had PE and concomitant, associated DVT, meaning that 2/3 of PE occurred in the absence of a recognizable DVT, suggesting a causal mechanism of primary thrombosis rather than embolism [56]. Additionally, postmortem analyses of COVID-19 fatalities have frequently documented thrombosis of small- and mid-sized pulmonary arteries, a lesion capable of causing hemorrhagic necrosis, fibrosis, disruption of pulmonary circulation, acute pulmonary hypertension (PH), and ultimately death [55]. Other severe morphopathological modifications of pulmonary tissue architecture have also been frequently reported in COVID-19 autopsy reports, such as severe endothelial injury, with disruption of cell membranes, rampant vascular thrombosis, and significant angiogenesis [25], while other organs also showed microthrombotic lesions on autopsy, but at a lower rate (cardiac thrombi, epicardial coronary artery thrombi and microthrombi in myocardial capillaries, arterioles, and small muscular arteries) [55].

An aforementioned study, analyzing 184 COVID-19 ICU cases, all receiving thromboprophylaxis, demonstrated a 31% cumulative incidence of the defined vascular complication composite outcome (PE, DVT, ischemic stroke, ACS, or systemic arterial embolism). The main independent predictors of thrombotic

complications identified were age, with an adjusted hazard ratio (aHR) of 1.05/per year, and coagulopathy [54]. Conversely, regarding VTE, an extensive meta-analysis (44 studies/14,866 hospitalized COVID-19 patients), on the topic acute complications and mortality, reported a much lower prevalence of 15% for VTE, than previously reported. This value may be influenced not only by cohort size but also by other factors such as heterogeneous reporting between the studies evaluated and increased risk of bias, resulting in very low-quality evidence [57].

On the other hand, as seen in the above-mentioned studies, VTE can still occur in noncritically ill COVID-19 patients; therefore, rigorous elaboration of adequate screening and risk stratification protocols for VTE, especially for mild and moderate COVID-19 phenotypes, will be essential, as these patients are much less likely to undergo tromboprophylaxis.

Regarding arterial thromboembolism (ATE), incidence rates among COVID-19 diagnosed patients have consistently been reported as being much lower than for VTE, since the early days of the pandemic (3.7%) to date [54]. Unsettlingly, largevessel strokes in young and generally healthy people, which became infected with SARS-CoV-2, have been consistently reported [25, 55]. Early retrospective studies, seemingly corroborated these findings, claiming that acute, new-onset, cerebrovascular disease was not uncommon in COVID-19 patients – out 219 consecutive COVID-19 patients, 10 (4.6%) developed acute ischemic stroke and 1 (0.5%) had intracerebral hemorrhage [58] –,and that SARS-CoV-2 infection carried an increased risk of ACS, especially via coronary stent thromboses [59]. Nevertheless, investigations involving a much larger sample size showed that the actual incidence of ATE (thrombotic/ embolic) is, in fact, much lower than initially reported in earlier studies [51, 60]. A large cohort retrospective study, evaluating 1114 COVID-19 patients with independently adjudicated thrombotic/embolic events, found stroke and ACS incidence were 0.1% (1/1114) and 1.3% (14/1114), respectively [51]. Most authors agree that thrombotic events occur early in the evolution of COVID-19, and in order to combat the hypercoagulable and prothrombotic state, administration of anticoagulants is recommended to reduce this risk [27].

Of great importance is the fact that, due to several factors such as thrombocytopenia, hyperfibrinolytic state, consumption of coagulation factors, which initiate their action later on, after 1 to 3 weeks, COVID-19 patients may also become prone to bleeding. This must be taken into account, especially in severe COVID-19 cases, where concomitant administration of anticoagulants as thromboprophylaxis is very likely to occur [61]. Additionally, critically ill COVID-19 patients have an even more increased bleeding risk, due to thrombocytopenia/platelet dysfunction or coagulation factor deficiencies, or both [62], which are frequent occurrences in this clinical population. Thus, it has become increasingly difficult to establish an adequate, integrative, anticoagulant prophylaxis strategy for COVID-19.

As opposed to the numerous investigations debating over thromboembolic events, there are much fewer articles focusing on major bleedings and just a few case reports on hematomas in COVID-19. Al-Shamkary et al. reported an overall incidence of 4.8–8% referring to bleeding events, and of 3.5% for major bleedings [62], being mostly associated with advanced age, comorbidities and apparently, more frequent in males.

All in all, thromboembolic events are a frequent morbidity encountered in COVID-19 patients, especially in those with severe forms and comorbidities. For their prophylaxis/treatment anticoagulant therapy is recommended, thus increasing the risk of bleedings. Both thromboembolic events and hemorrhagic complications

aggravate the evolution of these patients, representing significant negative prognostic factors and increasing the morbidity and mortality associated with COVID-19.
