**4. Discussion**

#### **4.1 Etiology, physiopathology and risk factors of SARS-CoV-2 in cardiovascular system**

SARS-CoV-2 is caused by a novel enveloped beta coronavirus that belongs to the Coronaviridae family, a group of positive strand RNA viruses causing human respiratory infections. Named after the crown shaped outer coat seen on the electron-microscopy, it was first discovered in the 1960s, receiving great attention during the 2003 SARS coronavirus (SARS-CoV) outbreak [11]. Seven species of these beta-coronaviruses are known to cause human infections, with four mainly causing mild flulike symptoms and the remaining three resulting in potentially fatal illnesses (SARS, MERS and the ongoing COVID-19) [10].

The transmission of COVID-19 occurs mainly through droplets route. However, there are theories that this can occur by fecal-oral route or/and by airborne. The average incubation time is less than six days (5.1 days), less than three percent of patients (2,5%) develop disease before the third day (2.2 days) after acquiring the virus while the rest (97,5%) develop symptoms 11.5 days after the onset of infection [27].

Although respiratory tract is the primary target for SARS-CoV-2, cardiovascular system (CVS) may get involved in several different ways [10] as destabilized coronary plaque [9], hypoxemia, systemic inflammation and enhanced myocardial oxygen demand, a direct cardiovascular injury, likely develops, initiated by binding of SARS-CoV-2 to angiotensin-converting enzyme 2 (ACE2) (**Figures 2** and **3**). This receptor is widely expressed in lungs, kidney [5] - renal tubules [26], brain, gut [34], gastrointestinal epithelium, Leydig cells in testis [22, 26], but also in the heart, where it is localized to macrophages, vascular endothelium, smooth muscle and myocytes [33].

Experimental study shows that the immune activity levels (innate immune response - NK cells and acquired immune response - B cells, CD8+ T cells and interferon response) in countless human tissues with large number of ACE2 receptors are statistical significant (*P* < 0.05, 0.27 ≤ *r* ≤ 0.78). In the research, the following tissues obtained higher levels of CD8+ T cell - brain, blood vessels, skin and digestive system (pancreas, colon, stomach and esophagus) [3]. On the other hand, high levels of beta 17ß-estradiol have been shown to be important for increasing the number of ACE2 receptors in kidney and adipose tissues in laboratory studies. Interestingly, spontaneously hypertensive male mice, after orchiectomy, have higher levels of ACE2 than females [16].

In fact, the virus shares the ACE2 as the host cellular receptor for virus spike (S) protein according to structural analysis [31, 35] following activation by transmembrane protease serine 2 (TMPRSS2) [34]. The virus produces enzymatic shedding that inactivates ACE2 and prevents conversion of Ang-II [19]. Besides that, virus infection causes damage to pericytes and endothelial dysfunction, especially due to damage to capillary endothelial cells. The increased expression of ACE2 proteins and mRNAs in patients infected by the virus and with basic heart failure disease may have higher risk of critically ill condition and/or heart attack [31] (**Figure 2**).

Laboratory studies have suggested that other intracellular signaling pathways such as Notch could also explain the cytokine storm that ultimately induces heart

#### **Figure 2.**

*The role of ACE2 in COVID-19. The spike protein of SARS-CoV-2 binds ACE2 on a cellular membrane, which triggers 1) endocytosis of the virus and subsequent sequestration of ACE2 or 2) cleavage of the viral spike protein via an enzyme TMPRSS2 leading to the entry of viral contents into the cytoplasm [adapted]. Source: Cheng et al. [11].*

#### **Figure 3.**

*Renin–angiotensin system inhibition (RAS) by Angiotensin converting enzyme/Ang-II receptor blockers (ACEI/ARBs) and SARS-CoV-2 binding to ACE2 receptors [adapted]. Source: Gonzallez-Jamarilo et al. [19].*

and lung disease caused by SARS-CoV-2 direct damage to tissues [23]. Besides that, other theory is that the "cytokine storm" - term for increasing various interleukins and chemokines as TNF-α, IFN-γ, GCSF, MCP-1, MIP-1-α, IL-10, IL-6 and IL-2 contributes to cardiac injury. These situations are analogous to cardiotoxicity in the setting of CAR- T cell (chimeric antigen receptor - T cell) therapy. In this paper, left

#### *Cardiovascular System and SARS-CoV-2: Etiology, Physiopathology and Clinical Presentation… DOI: http://dx.doi.org/10.5772/intechopen.97076*

ventricular systolic dysfunction, cardiac injury and cardiovascular events (troponin elevation) post-CAR-T have been demonstrated [17].

Therefore, the exact mechanism of cardiac involvement in COVID-19 remains under investigation but it seems the SARS-CoV-2 can (a) cause cardiac injury indirectly due to a probable overwhelming immune inflammatory response and cytokine storm; (b) cause invasion of cardiomyocytes and direct damage via this process; (c) cause Severe hypoxia from acute respiratory damage caused by the virus may result in oxidative stress and myocardial injury from increased myocardial oxygen demand in the presence of severe hypoxia due to acute lung injury (ARDS) [25].

Cardiovascular disease patients are at particularly high risk for mortality from SARS-CoV-2 due to their frailty and susceptibility for a myocardial involvement [36], perhaps due to the virus's affinity for ACE2 (**Figure 3**) mainly due to the interaction with the renin-angiotensin-aldosterone system (RAAS).

RAAS has an important role in regulating blood pressure and electrolyte balance. This system compromises two pathways: ACE2/Ang (1–7)/Mas receptor and ACE/Ang II/AT1R. In physiological situations, these two metabolic pathways function harmoniously, maintaining the normal function [7] (**Figure 3**). Hence, RAAS is widely implicated in Diabetes mellitus (DM), hypertension, heart failure [21] and Coronary heart disease [29].

Patients with COVID-19 are often diagnosed with coronary artery disease (2.5–8%), diabetes (7.3%–18.8%), hypertension (15%–30.4%) and other cardiovascular disease (4%–14.6%). In addition, of the patients who had been admitted to the intensive care unit (ICU), those with cardiovascular diseases compared to those who had not had a worse prognosis [9, 14, 24].

Another fact to be considered is that COVID-19 is more aggressive in elderly patients. The literature tells us that the elderly and male have more ACE2 receptors than the general population [29]. About that, Li et al. [3] refer that, when studying the expression of ACE2 receptors in various tissues of the body and its correlation with immunogenicity, in the thyroid, lungs, adrenal gland, liver, and kidneys, ACE2 expression levels showed significant positive correlations with CD8+ T cell enrichment levels solely in males.

Finally, patients with chronic kidney and those who have received renal transplant - and have a higher cardiovascular risk - are at increased risk of COVID-19 infection and severity. Moreover, there are frequent renal function abnormalities and increased incidence of acute kidney injury in patients with COVID- 19 [26].

#### **4.2 Clinical presentation, laboratory markers and imagenological aspects of SARS-CoV-2 in cardiovascular system**

There appears to be two clinical stages to the disease. The first stage is the replicative stage, when SARS-CoV-2 is replicating over the course of several days and the patient presents with relatively mild symptoms [25] such as fever, cough, and myalgia or fatigue; less common symptoms were sputum production, headache, hemoptysis, and diarrhea [32]. The adaptive immunity stage is the second stage. The body produces antibodies against the virus and, as there is viral clearance, the antibody titers will return to baseline values and an infection solves. This creates an "Immune memory". However, a minority of patients becomes critically ill and have high mortality rates [25]. It is important to remember that some symptoms in patients with COVID-19 pneumonia suggest cardiovascular diseases. Fatigue, dyspnea, cough is typical in COVID-19, but these symptoms may also result from exacerbation of chronic heart failure [14].

Chinese study shows large number of patients (81%) with mild symptoms of COVID-19 between (no pneumonia and mild pneumonia). These patients with more aggressive symptoms, 14% has more severe clinical conditions (lung infiltrates >50% within 24 to 48 hours, partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300, blood oxygen saturation ≤ 93%, respiratory rate ≥ 30/min and dyspnea) and 5% critical medical conditions (septic shock, respiratory failure and/or multiple organ dysfunction or failure) [37]. Others publishing and anecdotal reports indicate manifestations of arrhythmia [28], cardiac arrest, acute heart failure [23] and theoretically fulminant myocarditis [17, 32].

COVID-19 virus enters cells through the angiotensin converting enzyme II (ACE2) receptor, resulting in down-regulation of ACE2 receptor function. This leads to an increase of angiotensin II activity, activation of the renin-angiotensin-aldosterone system (RAAS) following a decrease in ACE2, an increase in vasoactive, proliferative, and profibrotic Ang-II leads to cardiopulmonary damage through hemodynamic changes such as pulmonary hypertension and interstitial edema followed by respiratory failure in the most severe cases (**Figure 3**) [19].

In laboratory markers, definitive diagnosis of SARS-CoV-2 Infection is based primarily on nucleic acid amplification tests, such as real-time reverse transcriptase–polymerase chain reaction (rRT-PCR) [27].

The laboratory alterations found in COVID-19 include in descending level elevated concentrations of serum creatine kinase (7%–13.7%), total bilirubin (10.5–18%), transaminases (21–28%), D-dimer concentration (36%–46.4%), lactate dehydrogenase (41–76%), C-reactive protein (60.7–93%), thrombocytopenia (17%–36.2%) and lymphopenia (35%–82.1%). It is important to note that the first three have been rarely reported [14].

Interesting to note that elevated D-dimer values are common in COVID-19 patients, even in the absence of thrombophlebitis and acute pulmonary embolism and it seems to correlate with acute pulmonary embolism [18], arterial thrombosis, acute respiratory distress syndrome and death [15]; elevated cardiac troponin I (cTnI) levels [32] and N terminal pro B type natriuretic peptide (NT-proBNP), with the cut-off value of 88.64 pg./mL [20] are correlate with cardiovascular injury, hospitalization and death. Including, plasma TnT levels in patients with COVID-19 correlated significantly with both plasma high-sensitivity C-reactive protein levels, NT-proBNP elevation and malignant arrhythmias [20].

According to Clerkin et al. [9] the rise in elevated high sensitivity cTnI tracks with other inflammatory biomarkers (D-dimer, ferritin, interleukin-6 (IL-6), lactate dehydrogenase and elevated creatinine kinase, raising the possibility that it may reflect on cytokine storm or secondary hemophagocytic lymphohistiocytosis more than isolated myocardial injury.

Transthoracic echocardiography is routinely recommended in patients with complicated COVID-19 due to the high prevalence of heart failure or/and myocarditis. This measure is useful to differentiate dyspnea of pulmonary origin from dyspnea of cardiac origin and monitor the sequelae of ARDS. Another useful use of echocardiography in the medical practice of ICU is monitoring treatments such as extracorporeal membrane oxygenation and fluid management in shock. Ultrasound evaluation of the lung may be a sensitive marker of fluid accumulation in the interstitial space and it useful for show the most common changes present in lungs how consolidation, B-line artifacts (the earliest signs in the disease course) and pleural line abnormalities like >1 mm, loss of continuity and irregularity [27].

Cardiovascular Magnetic Resonance (CMR) is useful in mapping of the extent of myocardial injuries, impact on ventricular function and differentiating a etiologies

(ischemic from non-ischemic). It stills helps in differentiating the between myocarditis and other acute myocardial injury that can elevate myocardial enzymes (eg. Troponin) and alter electrocardiographic (ECG) patterns [13].
