**2. Cardiovascular PACS: pathophysiology and spectrum of diseases**

PACS describe constellation of new, returning, or persistent symptoms experienced by patients 4 or more weeks after SARS-CoV-2 infection [30]. Patients with this condition can experience potentially wide-ranging symptoms of every organ system with varying impacts on quality of life. COVID-19 caused severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but, in addition to systemic and respiratory complications, may manifest acute cardiovascular syndrome and myocardial involvement (**Figure 2**).

*Perspective Chapter: Cardiovascular Post-Acute COVID-19 Syndrome – Definition, Clinical... DOI: http://dx.doi.org/10.5772/intechopen.109292*

**Figure 2.**

*From COVID-19 to PACS cardiovascular symptoms and cardiovascular disease.*

During the acute phase, several mechanisms have been proposed to directly or indirectly justify myocardial injury:


SARS-CoV-2 binds on transmembrane angiotensin-converting enzyme 2 (ACE2) to enter in the host cells including type 2 pneumocytes, macrophages, endothelial cells, pericytes, and cardiac myocytes, leading to inflammation and multiorgan failure. The infection of endothelial cells or pericytes could lead to microvascular and macrovascular dysfunction with intravascular thrombosis. The immune

over-reactivity contributes to potentially destabilize atherosclerotic plaques and explain the possible development of the acute coronary syndrome. The progression of systemic inflammation and immune cell overactivation, leading to a "cytokine storm" (abnormal elevated level of cytokines) in infection of the respiratory tract and particularly of type 2 pneumocytes, leads to severe acute respiratory syndrome. It has been demonstrated that activated T cells and macrophages may infiltrate infected myocardium, thereby resulting in the development of myocarditis. Similarly, the viral invasion could cause directly myocyte damage and contribute to the development of arrhythmias and left ventricular dysfunction [14]. The pattern of myocardial injury following SARS-CoV-2 infection was initially derived from autopsy. In early autopsy series of 80 consecutive SARS-CoV-2 PCR-positive cases, only four patients (5%) had definition of cardiac injury [35]. In a subsequent autopsy study, a definite diagnosis of myocarditis was demonstrated in 7, 2, to 14% of cases, while interstitial macrophage infiltration was found in 86% of patients, pericarditis and right ventricular injury in 19%, respectively [36, 37]. However, subsequent studies demonstrated that only 1.4% met the well-established histological criteria [38] for myocarditis, suggesting that true myocarditis was relatively rare [39–41]. Lindner et al. [42] demonstrated the presence of SARS-CoV-2 viral particles in the hearts and in particular in interstitial cells including pericytes and macrophages and not within cardiomyocytes.

Cardiac troponin is frequently elevated in COVID-19 patients [43] and indicates myocardial injury. As a consequence of the above-mentioned mechanisms, myocardial injury during COVID-19 includes myocarditis and pericarditis [44], acute coronary syndrome secondary to obstructive coronary artery disease (myocardial infarction type 1) [45] or to oxygen augmented demand (myocardial infarction type 2) [45–49], multisystem inflammatory syndrome in children (MIS-C) and in adults (MIS-A) [50–52], takotsubo/stress cardiomyopathy [53, 54], acute or pulmonale resulting from macro-pulmonary or micro-pulmonary emboli [45, 55], exacerbation of chronic conditions like preexisting heart failure or acute viral infection unmasking subclinical heart disease [56–60]. Since more of these etiologies may coexist, identifying a specific underlying cause during acute phase sometimes may be really challenging.

After the acute phase, PACS may occur in patients who have experienced varying degrees of COVID-19-related disease, from asymptomatic infection to critical illness. Chest pain, dyspnea, and palpitations are some of the key symptoms that draw attention to the cardiovascular system. These symptoms may underlie a COVID-19-related cardiovascular disease that developed or exacerbated during or after infection. For this reason, it is therefore necessary to distinguish cardiovascular complications that can occur during the early post-acute or in chronic phase of COVID-19 (post-acute COVID-19 syndrome with cardiovascular disease, PACS-CVD) from cardiovascular symptoms that extend beyond acute infection, but which are not correlated with a cardiovascular disease (post-acute COVID-19 syndrome with cardiovascular symptoms, PACS-CVS) [61].

Mechanisms for the development of cardiovascular disease after COVID-19 infection are still poorly understood, and several hypotheses have been suggested:

• chronic inflammatory response evoked by persistent viral reservoirs in the heart following the acute infection with consequent tissue damage and chronic myocardial fibrosis that leads to impaired ventricular compliance, perfusion, stiffness, contractility and potential arrhythmias [62].

*Perspective Chapter: Cardiovascular Post-Acute COVID-19 Syndrome – Definition, Clinical... DOI: http://dx.doi.org/10.5772/intechopen.109292*

#### **Figure 3.**

*PACS cardiovascular symptoms and PACS cardiovascular disease.*

• autoimmune response to cardiac antigens through molecular mimicry [63]. In fact, Wang et al. identify a wide range of autoantibodies against humoral and tissue antigens in patients with severe COVID-19 [64–66]; in other studies, autoantibodies against cholinergic and adrenergic receptors were found [67, 68]. Moreover, cytokine profile analysis and proteomic studies revealed increased expression of prothrombotic factors beyond acute infection [69, 70], thereby justifying increased rate of thrombo-embolic events and/or pulmonary hypertension.

**Figure 3** shows differences between PACS with cardiovascular symptoms and cardiovascular disease as well as different clinical scenarios and disease spectrum of cardiovascular PACS.

#### **2.1 PACS-cardiovascular disease**

CVD refers cardiovascular conditions that manifest 4 weeks after SARS-CoV-2 infection and includes all forms of myocardial involvement that can be development during acute phase of infection:


Discerning whether PACS-CVD began in acute infection, during illness resolution, or as a new condition post-recovery may be challenging.

	- Laboratory: elevated cardiac troponin;
	- Electrocardiogram (ECG): abnormal electrocardiographic findings (diffuse T-wave inversion and ST segment elevation);
	- Echocardiography: left ventricular wall motion abnormalities in noncoronary distribution;
	- cardiac magnetic resonance (CMR) patterns: non-ischemic late gadolinium enhancement pattern (usually sub-epicardial) with prolonged native T1 and T2 relaxation times;
	- Histopathologic findings on biopsy or postmortem evaluation: inflammatory myocardial infiltrates associated with myocyte degeneration and necrosis;
	- Absence of critical epicardial coronary artery disease (defined using noninvasive coronary imaging and or coronary angiography).

Prevalence and incidence of myocarditis in COVID-19 infection are highly variable [71]. Autopsy results among COVID-19 patients showed mixed data. In a study by Halushka et al, classic myocarditis was identified in 7.2%, nonmyocarditis inflammatory infiltrate in 12.6%, single-cell ischemia in 13.7%, and acute myocardial infarction in 4.7% [72]. Regarding echocardiographic data in patients hospitalized for COVID-19 suggest that myocardial dysfunction may be present in up to 40% [73, 74]. On the other hand, cardiac magnetic resonance (CMR), the most sensitive imaging modality for identifying myocardial (and pericardial) involvement, has been used in several studies to evaluate symptomatic and asymptomatic individuals with COVID-19, in both hospital and ambulatory settings. In a study of 100 patients (33% hospitalized), non-ischemic LGE was found in 20% and prolonged native T1 and T2 relaxation times in 73% and 60%, respectively [75]. Similar findings have been observed in other CMR studies, with variable degrees of LGE and mapping abnormalities [76–81]. When performed in athletes as screening protocol, various abnormalities have been noted with 0.6–3% of subjects meeting modified Lake Louise criteria for clinical myocarditis [82–84]. Variability in observed findings with CMR likely reflects differences in the populations studied, in timing of CMR relative to infection onset as well as in the specific imaging protocols that could affect interpretations of imaging data. Several

*Perspective Chapter: Cardiovascular Post-Acute COVID-19 Syndrome – Definition, Clinical... DOI: http://dx.doi.org/10.5772/intechopen.109292*

mechanisms have been proposed by which SARS-CoV-2 may contribute to myocarditis such as direct virus invasion, host inflammatory or immune responses, and microvascular angiopathy. Moreover, emerging data seem to indicate other mechanisms such as a maladaptive host immune response with excessive activation of innate immune pathways, a surge of pro-inflammatory cytokines, a deregulated thrombo-inflammation, a thrombotic microangiopathy, an endothelial dysfunction, and a mechanism of molecular mimicry [85–88]. Other hypotheses may include augmented demand ischemia, stress cardiomyopathy, and hypoxia-induced myocardial injury [89]. While the acute inflammation and myocardial injury have been well attended, the longterm effects of myocarditis are completely unknown. Most infected patients experience mild form of myocarditis with self-limiting symptoms and without persistence of LGE; other patients, in the chronic phase, experience various degrees of systolic dysfunction (with symptoms related to heart failure) and/ or cardiac arrhythmias (e.g. atrial fibrillation, supraventricular, and/or ventricular tachyarrhythmias) because of extensive myocardial fibrosis [90, 91].

	- pericardial chest pain;
	- pericardial friction rub;
	- PR depression and or diffuse concave upward ST elevation on ECG;
	- new or worsening pericardial effusion during infection.

In some cases, it may be associated with myocardial involvement (myo-pericarditis). The pathogenesis of acute and chronic pericarditis and myo-pericarditis in COVID-19 patients is not still understood. Direct virus-mediated cytotoxicity and dysregulation of the immune system are the key in the pathogenesis of SARS-CoV-2 infection leading to an overproduction of pro-inflammatory cytokines resulting a cytokine storm, an immune-mediated inflammation that affects myocardium and pericardium and an ACE 2 receptor downregulation in acute and long COVID-19 play a fundamental role in pericardial involvement [93, 94]. Data on pericardial disease are relatively scarce. A systematic review including studies on adult patients undergoing any type of cardiac assessment after COVID-19 recovery reported a prevalence of pericardial enhancement in 63/758 patients (8%) and of pericardial effusion in 99/758 patients (13%) [95]. Only few studies reported a formal clinical diagnosis of myo-pericarditis (2%) and pericarditis (0.5%) [96]. Based on studies, pericarditis appears to be common in the acute infection but rare in the post-acute period of COVID-19, while small pericardial effusions may be relatively common in the post-acute phase of COVID-19 [97]. In hospitalized patients with COVID-19, diffuse acute ST changes consistent with pericarditis were present in 12% of subjects [98]. In competitive athletes screened after COVID-19, pericarditis was present in 0.3% of cases [99]. In the post-acute period of COVID-19, a pericardial effusion was identified in a proportion of patients ranging from 5 to 20% [100, 101].


*Perspective Chapter: Cardiovascular Post-Acute COVID-19 Syndrome – Definition, Clinical... DOI: http://dx.doi.org/10.5772/intechopen.109292*

and atrial and ventricular arrhythmias. It is also known that recovery of ventricular function can be variable over time and that, in the long-term, myocardial fibrosis can be observed despite complete recovery of the systolic function of the left ventricle [115]. In post-COVID-19 phase, patients may experience persistence of signs and symptoms of heart failure with or without complete recovery of systolic function and the onset or persistence of arrhythmias often linked to the presence of myocardial fibrosis.


with some similarities to Kawasaki disease, macrophage activation syndrome, or cytokine storm. The diagnostic criteria of both syndromes are similar: a previous SARS COV2 infection and hyperinflammatory state associated with dysfunction of at least two between cardiovascular, pulmonary, gastrointestinal, cutaneous, nervous, hematological, and renal systems [130, 131]. The exact incidence of MIS-A and MIS-C is largely unknown.

• **Arrhythmias:** Arrhythmias are frequently reported in COVID-19 patients. Atrial fibrillation (AF) being the most common form. The pathophysiology of COVID-19-related AF is not well understood. Proposed mechanisms include reduction in angiotensin-converting enzyme 2 (ACE2) receptor availability, cytokine storm, direct viral endothelial damage, electrolytes, and acid base abnormalities in the acute phase of severe illness and increased adrenergic drive [132]. Based on literature data, among COVID-19 patients, AF was detected in 19–21% of all cases [133–135] and in patients with severe pneumonia, ARDS) and sepsis, the incidence of during hospitalization is usually higher [136, 137]. The real incidence of atrial fibrillation in post-COVID-19 period is unknown. Increased postinfectious adrenergic tone, any persistent cardiac involvement during infection (e.g. myocarditis and chronic pulmonary heart) or the presence of predisposing illness (e.g. arterial hypertension, ischemic heart disease, mitral regurgitation, and hypertensive heart) represent the most important predisposing factors. Management of AF should be set up according to current guidelines [138, 139]. Ventricular arrhythmias are less frequent during infection and may be caused by myocardial injury secondary to myocarditis or ischemic myocardial damage, by the presence of electrolyte or acid base imbalances or by the concomitant use of QTc-interfering drugs, especially in intensive care. In post-COVID-19 period, ventricular arrhythmias, at rest or during exercise, should represent "red flags" of cardiac involvement, even in asymptomatic patients.
