**4. Subacute and long-term cardiovascular sequels following the infection with the SARS-CoV-2 virus**

The important contribution of COVID-19 in the pathogenesis of acute cardiovascular involvements is now well established, but because this pandemic is a new disease, long-term data on post-COVID-19 complications were not available [63, 64]. However, more and more studies revealed that the infection with the SARS-CoV-2 virus also causes chronic cardiac complications, even when the viral load is normalized [63, 64], explaining the persistence of symptoms during recovery observed in an increasing number of individuals [65]. In some patients, myocarditis, subacute pericarditis, persisting arrhythmias, pulmonary hypertension, or heart failure have been observed raising serious concerns and indicating that in symptomatic patients, a comprehensive evaluation and a regular long-term follow-up are needed for effective therapeutic regime and to prevent a worse evolution of these cardiovascular complications.

#### **4.1 Pulmonary hypertension**

It is well known that pulmonary hypertension (PH) may occur during the acute phase of the SARS-CoV-2 infection as a consequence of extensive lung injury and of altered pulmonary circulation, frequently leading to right heart failure (RHF), shearing common pathophysiological mechanisms with other complications encountered in this illness, and significantly increasing the mortality [66, 67].

In COVID-19 patients, the prevalence of PH varies wildly, depending on the studied population, ranging from 7.69% to 12–13,4% or even 22% in severe COVID-19 cases [67, 68]. While this topic was largely debated in the medical literature, information over its outcome is less available. It has been observed that some patients are predisposed to develop interstitial lung disease (ILD) frequently associated with persisting PH and explaining, at least partially, the persisting symptoms observed in patients with subacute and long COVID-19 [69, 70]. The backgrounds of this disease are complex and multifactorial, including a large variety of pathophysiological types, ranging from arterial PH (group 1), PH of group 3 – due to ILD, to chronic thromboembolism (group 4 PH) or even of group 2 PH (secondary left heart disease) [70, 71]. In their study, Suzuki et al., observed a unique hystopathological finding identified only at the autopsy of COVID-19 patients, namely thickened pulmonary vascular walls, considered an important hallmark of arterial PH [71]. This finding suggests that COVID-19, depending on the severity of the lung injury and the inflammatory responses, could favor the development of PH, and some of these patients may develop in the future signs and symptoms of PH and RHF [71].

The diagnosis of PH is difficult and implies right heart catheterization, which is limited during the pandemic considering the risk of contamination and shortness of personal and resources. In patients infected with SARS-CoV-2, TTE allows an accurate estimation of the systolic pressure in the pulmonary artery, being the most utilized method for the diagnostic and follow-up of these patients. A specific therapy for this type of PH has not been described, and future studies are needed to clarify its management.

#### **4.2 Heart failure**

AHF may appear precocious in the evolution of the SARS-CoV-2 infection, in some cases being even the first manifestations. Since COVID-19 and AHF/ worsening of CHF shear similar symptoms, distinguishing these two pathologies is challenging, the more so as these two conditions may coexist. Some studies describe an increased prevalence of ACH (23% or even 33%) in patients hospitalized for COVID-19 being associated with an increased risk of mortality [63]. In many cases, it is difficult to establish if AHF is the consequence of a new myocarditis/cardiomyopathy or it represents the exacerbation of previously undiagnosed CHF. Responsible pathophysiological mechanisms of AHF in COVID-19 may include acute myocardial injury due to inflammation (myocarditis), tachyarrhythmia or ischemia, or to acute respiratory failure, acute kidney injury, and hypervolemia [9, 29, 31]. Importantly, RHF may also be present especially in patients with severe pulmonary injury and PE contributing to the increased mortality of these patients [37].

Diagnosis may be difficult, but clinical presentation, history of preexisting cardiovascular comorbidities, evidence of cardiomegaly, and/or bilateral pleural effusion on chest radiography are suggestive. Increased levels of B-type natriuretic peptide (BNP)/N-terminal B-type natriuretic peptide (NT-proBNP) could be an important clue for AHF/worsened CHF, although elevated BNP/NT-proBNP values were also found in COVID-19 patients in the absence of AHF. An important contribution offers TTE demonstrating enlarged cardiac cavities, impaired systolic performance, and other important signs [34, 49, 72].

Therapy of AHF in COVID-19 patients should be performed according to guidelines [63] based on the same recommendation as in subjects without COVID-19, with special attention to early detection and treatment of complications, especially hypoxia, thrombotic/bleeding events, and cardiac arrhythmias. It is important to consider AHF/CHF when administering intravenous fluids avoiding excessive fluid replacement and to be conscious on the cardiac adverse effects of medications used in the treatment of COVID-19 [9, 31, 64].

Referring to patients already diagnosed with CHF, it is well known that they are predisposed to develop more severe forms of COVID-19, being predisposed to a higher mortality. The SARS-CoV-2 infection may also unmask a latent CHF, particularly heart failure with preserved ejection fraction (HFpEF) which is common among elderly overweight, hypertensive patients. In addition, as a consequence of myocardial injury, cardiac fibrosis may occur, explaining the increased frequency of diastolic dysfunction identified on TTE. The risk to develop overt CHF is present both during the acute phase of COVID-19 and during the recovery from the acute illness in survivors [31, 33, 72, 73].

Another aspect is that the COVID-19 pandemic negatively impacted the outcome of patients with CHF who avoided or delayed hospital controls or admissions due to fear of contamination. They presented themselves to the hospital only when their condition was severe, which lead to an increased mortality worldwide [9, 74].

### **4.3 New onset or aggravation of systemic hypertension**

The relationship between the infection with the SARS-CoV-2 virus and systemic hypertension is very complicated and difficult to establish. While it is generally accepted that COVID-19 patients with a history of cardiovascular diseases, especially

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

systemic hypertension, have a worse outcome and increased mortality [29, 75], it is very difficult to establish if there is a new onset or a worsening of a chronic hypertension in the context of this illness, since a previous comprehensive evaluation is not available in the majority of cases. A meta-analysis of Lippi et al. evidenced a nearly 2.5-fold increase of severity and mortality of severe COVID-19 in patients with associated systemic hypertension, especially in those older than 60 years with other comorbidities [75].

Other large meta-analyses focused on the impact of hypertension's severity and its control and the outcomes but failed to document significant connections [76]. It was concluded that hypertension is associated with endothelial dysfunction strongly impacted in COVID-19, and patients with more severe forms have more advanced atherosclerosis and consecutive complications, thus increasing the morbidity and mortality. As the concerns regarding therapy with ACE inhibitors were not found to be justified, treatment should be given according to guidelines to optimize blood pressure values [77].

#### **4.4 Postural orthostatic tachycardiac syndrome**

The postural tachycardia syndrome (POTS) is the result of an autonomic dysregulation which determines increased vasoconstriction when standing, resulting in blood pooling within the splanchnic vasculature and limbs, with reduced venous return to the heart. An excessive compensatory tachycardia and increased plasma noradrenaline levels contribute to symptoms, the commonest of which are fatigue, palpitations, light-headedness, headache, and nausea symptoms reported by many of patients with long-COVID (between 15% and 50% according to some studies) [78]. Although orthostatic intolerance is common among patients recovering from a COVID-19 infection, not all have POTS, some of them have only orthostatic hypotension [78].

The exact pathophysiological mechanism of POTS is not fully clarified, and there are several mechanisms involved, including hypovolemia, autonomic denervation, hyperadrenergic stimulation, and autoimmune pathology. It is not well established whether the same recognized pathophysiology of POTS is also present in patients with long COVID further studies being necessary [78].

#### **4.5 Aggravation of preexisting cardiovascular pathologies**

From the early stages of the infection with the SARS-CoV-2 virus, it became evident that underlying cardiovascular diseases, obesity, diabetes mellitus, and more advanced age are associated with a higher risk for severe COVID-19 infection [34]. Individuals already suffering from cardiovascular diseases were more likely to be infected with the virus, and the virus infection was likely to determine the deterioration of basic heart disease [79]. Apparently, among COVID-19 patients, there were almost 50% diagnosed with chronic diseases, 40% of them with cardiovascular and cerebrovascular disorders, chronic kidney failure, and chronic obstructive pulmonary disease, having an increased risk of morbidity or even death related to this infection. A large study from the USA reported that the most common comorbidities among patients with COVID-19 were systemic hypertension (56.6%), obesity (41.7%), diabetes (33.8%), coronary artery disease (11.1%), and CHF (6.9%) [33], and a retrospective cohort study in China conducted on patients with cardiovascular comorbidities evidenced a fivefold higher mortality risk (10.5%). Based on these results, hypertension and cardiovascular comorbidities can be considered as risk factors for persons with severe symptoms of the disease.

In COVID-19 cases, it is important to recognize the clinical characteristics of infected persons to identify and effectively treat the associated comorbidities and the newly developed cardiovascular complications as well to reduce patients' morbidity and mortality. Since many antiviral drugs may determine cardiac insufficiency, arrhythmia or other cardiovascular disorders, therefore, during the therapy of this illness, especially with antiviral therapy, the risk of cardiac toxicity needs to be closely monitored [79].

Another aspect is that of the long-term outcome of patients who suffered from a SARS-CoV-2 infection. In a recent and comprehensive study realized on over 150000 individuals recovering from COVID-19 [80], Xie et al. highlighted that beyond the first month after infection, people with COVID-19 experienced at 12 months an increased morbidity risks and burdens of cardiovascular diseases, including cerebrovascular disorders, dysrhythmias, inflammatory heart disease, ischemic heart disease, heart failure, thromboembolic disease, and other cardiac disorders [80]. These risks were obvious regardless of age, race, gender, and associated cardiovascular risk factors, including obesity, hypertension, diabetes, chronic kidney disease, and hyperlipidemia, being evident even in individuals without history of cardiovascular pathology before the SARS-CoV-2 virus infection, raising concerns that these risks might be present even in people at low risk of cardiovascular disease [80]. These risks and associated burdens increased parallel to the severity of the acute phase of COVID-19: from non-hospitalized individuals – who were the majority – to hospitalized patients, especially to those admitted to the intensive care units [80].

#### **4.6 Cardiovascular effects of medication used to treat COVID-19**

It has been observed that many of the medications used for the treatment of COVID-19 strongly interfere with other medications used in the therapy of cardiovascular diseases, such as anticoagulants, antiplatelets, statins, antihypertensives, and especially antiarrhythmics favoring the occurrence of arrhythmias [31]. Some antibiotics (azithromycin), corticosteroids, antimalarials (chloroquine, hydroxychloroquine), newly developed therapies, still under study such as antivirals (remdesivir, ribavirin, lopinavir/ritonavir, and favipiravir), and biologics (tocilizumab) determine cardiotoxicity, interact with electrolyte metabolism, and many of them, especially Lopinavir/ritonavir, may cause QT and PR prolongation favoring the occurrence of arrhythmias or conduction disturbances, mainly in patients already treated with drugs prolonging the QT interval. Data over the mechanism of action and potential effects of main medication used in the treatment of COVID-19 is presented in **Table 1** [31].

#### **4.7 Cardiovascular effects related to vaccination**

After the introduction of mRNA COVID-19 vaccines a higher incidence of myocarditis in vaccine recipients. A study performed on the data basis from an Israeli national database concluded that the incidence of myocarditis after two doses of the BNT162b2 mRNA vaccine was reduced (risk ratio = 3.24), significantly lower than after COVID-19 (risk ratio = 18.28), but higher than in unvaccinated individuals. The risk of myocarditis was higher after the second dose of vaccine and in young male recipients [81].

Similar results were also reported by other researcher, with an elevated risk of myocarditis, pericarditis, and myopericarditis observed particularly among young males with 39–47 expected cases of per million second mRNA COVID-19 vaccine


**Table 1.**

*Interactions of medications used in the treatment of COVID-19.*

doses administered [82]. They reported an increased risk of myocarditis after the first dose of ChAdOx1 and BNT162b2 vaccines and the first and second doses of the mRNA-1273 vaccine [82].
