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 Table of Contents  
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 67-74

Cardiovascular complications of COVID-19

1 Department of Heart and Vessels, Division of Cardiology, Centro Hospitalar Universitário Lisboa Norte, Cardiovascular Centre of Universidade de Lisboa (CCUL), Lisbon School of Medicine, Universidade de Lisboa, Lisbon, Portugal
2 Department of Heart and Vessels, Division of Cardiology, Centro Hospitalar Universitário Lisboa Norte, Cardiovascular Centre of Universidade de Lisboa (CCUL), Lisbon School of Medicine, Universidade de Lisboa; Department of Intensive Care, Centro Hospitalar Universitário Lisboa Norte, Santa Maria University Hospital, Lisbon, Portugal

Date of Submission16-Jul-2020
Date of Acceptance05-Sep-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Prof. Fausto J Pinto
Department of Heart and Vessels, Division of Cardiology, Santa Maria University Hospital, Av. Prof. Egas Moniz, 1649 028, Lisboa
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/hm.hm_28_20

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Coronavirus disease 19 (COVID-19) has rapidly expanded to a global pandemic, resulting in significant morbidity and mortality. Even though predictors of infection remain unclear, age and preexisting cardiovascular conditions have been clearly identified as predictors of adverse outcomes and higher fatality rates. Since the virus infects host cells through angiotensin-converting enzyme 2 receptors, a key player in the renin-angiotensin-aldosterone system, the interaction between the cardiovascular system and the progression of COVID-19 is nowadays a focus of huge interest. In this review, the authors analyze the available and very recent evidence on the risk factors and mechanisms of the most relevant cardiovascular complications associated with COVID-19, including acute cardiac injury, myocarditis, stress-cardiomyopathy, ischemic myocardial injury, cytokine release syndrome, thrombotic disease, cardiac arrhythmias, heart failure, and cardiogenic shock. Finally, we discuss the cardiovascular impact of the therapies under investigation for COVID-19 treatment.

Keywords: Acute cardiac injury, arrhythmia, cardiovascular diseases, coronavirus disease-19, myocarditis, thromboembolic complications

How to cite this article:
Brito J, Silva BV, da Silva PA, Cortez-Dias N, Silva D, Agostinho JR, Guimar T, Brito D, Pinto FJ. Cardiovascular complications of COVID-19. Heart Mind 2020;4:67-74

How to cite this URL:
Brito J, Silva BV, da Silva PA, Cortez-Dias N, Silva D, Agostinho JR, Guimar T, Brito D, Pinto FJ. Cardiovascular complications of COVID-19. Heart Mind [serial online] 2020 [cited 2023 Jan 30];4:67-74. Available from: http://www.heartmindjournal.org/text.asp?2020/4/3/67/296565

  Introduction Top

At the beginning of 2020, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) was identified as the cause of an outbreak of viral pneumonia in Hubei China. Later on, 11th March, the World Health Organization declared Coronavirus Disease 19 (COVID-19) a global pandemic. As of the end of August, >25 million cases were confirmed, and a death toll >800,000 has been documented worldwide.[1]

COVID-19 most common manifestations are fever and dry cough.[2],[3] However, other symptoms such as fatigue, anorexia, dyspnea, myalgia, and gastrointestinal symptoms have been reported.[2],[3] In atypical cases, the cardiovascular symptoms may be the first manifestation, making the diagnosis more challenging and delaying the recognition of the disease.[4] Usually, symptoms develop 2–14 days after exposure, with a mean incubation period of 4 days.[3]

The disease has a heterogeneous clinical course, ranging from asymptomatic to critical state. In the largest cohort published so far, with over 44,000 people, 81% presented mild-to-moderate disease, 14% severe, and 5% critical.[5] Mild COVID-19 manifests as a common viral respiratory infection associated with lymphopenia, whereas severe disease may present as interstitial pneumonia complicated with acute respiratory distress syndrome. In some patients, massive cytokine release leads to a pro-inflammatory state with multiorgan failure, often times fatal. In a study with 1099 patients, 5% were admitted to the intensive care unit (ICU), and 2.3% required invasive mechanical ventilation.[3] The fatality rate varies among series, ranging from 2% to 4% in the overall population, to 40% in ICU patients.[5]

The most frequent complications are sepsis, respiratory failure, acute heart failure, and septic shock. Unsurprisingly, complication rates are higher in ICU patients and among nonsurvivors.[2] Similarly, the occurrence of co-infection was statistically associated with mortality (16% vs. 1%, P = 0.001).[6]

Cardiovascular complications during respiratory viral infections, such as influenza or respiratory syncytial virus infection, have been well recognized. Similar to SARS-CoV2 other two highly pathogenic coronavirus, SARS-CoV and Middle East Respiratory Syndrome, cause acute severe infections with a high burden of cardiovascular complications.

In this review, we will briefly summarize the impact of SARS-CoV2 on the cardiovascular system.

  Clinical Course of Coronavirus Disease 19 and Predictors of Severity Top

Several case series have allowed identifying predictors of severity in individuals infected with SARS-CoV2, but the evidence on risk factors for infection persists extremely limited.

Regarding disease severity in patients infected with SARS-CoV2, age is the strongest risk factor for adverse outcomes and mortality.[2],[7],[8] In a study with 52 critically-ill patients, mortality was strongly associated with older age (P < 0.001).[6] A mortality rate as high as 14.8% was reported in patients over 80 years old.[9] In contrast, there seems to be no association with gender.[2],[6],[8]

Cardiovascular diseases (CVD) are the most commonly reported comorbidities and are more frequent in patients with severe forms of COVID-19.[10] Whether CVD also predispose to SARS-CoV2 infection needs further investigation. In a cohort with 5700 patients, the most prevalent comorbidities were hypertension (56.6%), diabetes (33.8%), obesity (41.7%), coronary heart disease (11.1%), and congestive heart failure (6%–9%).[11] Considering hypertension, initial studies reported a frequency within the expected prevalence for the overall population. For instance, a Chinese cohort with 1099 COVID-19 patients showed that 15% of patients were hypertensive,[3] in line with the estimated prevalence of hypertension in China, which is 23.2%.[12] In contrast, other study documented higher prevalence of hypertension and CVD in patients with COVID-19 than in controls.[13] Similarly, among 12,594 patients tested for COVID-19, pre-existing hypertension was reported in 39.6% of the overall population as opposed to 59.1% in SARS-CoV2-positive patients.[14]

There is consistent evidence that CVD burden is a significant predictor of COVID-19 severity, being more prevalent in patients admitted to the ICU, requiring mechanical ventilation or nonsurvivors.[3],[6],[7],[10] In a study with critically ill patients requiring ICU admission, 42.9% had previous congestive heart failure diagnosis.[15] According to the report from the Chinese Center for Disease Control and Prevention, the overall COVID-19 mortality is estimated in 2.3%, reaching rates as high as 10.5% in patients with preexisting CVD, 6% in patients with hypertension, and 7.3% in patients with diabetes.[5] Nevertheless, aging associates closely with these comorbidities and it is likely to be a confounding factor for disease severity.

Considering obesity, a strong association between higher body mass index (BMI) and COVID-19 severity has been reported with increased risk of hospitalization (odds ratio [OR] 6.2 for BMI >40 kg/m2),[16] admission to the ICU (OR 3.5 for BMI >35 kg/m2)[17] and mortality (P = 0.005).[18] Moreover, obesity may predispose to infection. A study with >3700 patients detected a significantly higher risk of COVID-19 in obese patients after adjusting for comorbidities and confounding factors.[19] Interestingly, the correlation between BMI and both the risk of infection and disease severity is increased in younger patients.[17],[18],[19]

  Mechanisms of Cardiovascular Involvement in Coronavirus Disease 19 Top

Current evidence supports an overlap between pathways leading to CVD and immune dysregulation. Aging is associated with immune dysfunction, and it is the single strongest risk factor for CVD. Therefore, CVD burden is considered as a marker of immune dysregulation, strengthened by the presence of other comorbidities such as diabetes or dyslipidemia. This may explain the increased susceptibility to COVID-19 severe infection in patients with preestablished CVD. Even though a higher incidence of cardiovascular complications is seen in patients with previous CVD, the virus itself may induce cardiovascular damage. The exact pathophysiological mechanism is still unknown, and multiple pathological pathways may be implicated.

SARS-CoV2 enters the host cell by binding its spike protein to the angiotensin-converting enzyme 2 (ACE2), a transmembrane protein expressed in multiple cell types. Despite COVID-19 tropism for the respiratory system, multiorgan failure has been reported. This phenomenon may be partially explained by the tissue distribution of ACE2, a ubiquitous membrane-bound aminopeptidase with a significant presence in type II alveolar epithelial cells, myocardial, and endothelial cells. Endocytosis of SARS-Cov2-ACE2 complexes allows virus access to the intracellular compartment and simultaneously decreases the ACE2 abundance at the cell surface, decreasing the ACE2 enzymatic activity. ACE2 is the main counter mechanism of angiotensin-2, by inducing its cleavage into angiotensin 1–7 and consequently attenuating its effects on vasoconstriction, sodium retention, fibrosis, and inflammation.[20] Furthermore, angiotensin 1–7 has specific anti-inflammatory and vasodilator properties that protect the angiotensin-2-producing tissues from excessive local action.[21] It has been proposed that the downregulation of ACE2 at pulmonary endothelial cells induced by the SARS-CoV2 internalization causes a local angiotensin 1–7/angiotensin-2 imbalance and that unimpaired angiotensin-2 increases lung vascular permeability causing lung edema and respiratory failure.[22],[23] In a cohort of 12 COVID-19 patients, angiotensin 2 serum levels were markedly elevated and correlated with viral titters with a tendency to worsened the PaO2/FiO2 ratio, reinforcing that imbalanced renin-angiotensin-aldosterone system (RAAS) activation may be a key factor in disease severity.[24] Another study described high incidence of hypokalemia in COVID-19 patients and reported that the degree of hypokalemia was directly correlated with disease severity.[25] This ionic disturbance was not clearly related to gastrointestinal loss and seemed to be due to increased kaliurese, suggesting that the upregulation of RAAS may be critical in the severe forms of COVID-19. SARS-CoV also enters cardiac host cells host through ACE2 biding. In a postmortem study, viral genome was detected in 35% of autopsied hearts with co-existent inflammation, pathological hypertrophy and decreased ACE2 levels.[26] Patients with cardiac involvement presented a more aggressive disease course and higher mortality.[26] These findings provide a direct pathway of viral-induced cardiomyocyte injury.

Endothelial inflammation is a key factor for microcirculatory dysfunction and associated end-organ lesion. In COVID-19, two mechanisms may be expected: (1) direct endothelial infection with viral particles causing endothelitis;[27],[28] and (2) systemic inflammation, enhancing coagulation and platelet activation, contributing to endothelial dysfunction and predisposing to thrombotic events.[29] In fact, a report of lung autopsies in COVID-19 patients showed a significant increase in pulmonary angiogenesis and microvascular thrombosis when compared to influenza patients.[28]

Finally, infectious diseases induce hypoxia and increased cardiometabolic demand, reducing oxygen supply and favoring myocardial ischemia. Increased right ventricular (RV) overload in the context of hypoxia, metabolic acidosis, and mechanical invasive ventilation may also trigger ischemia.[30] Atherosclerosis is a chronic inflammatory state, and the progression of disease has been described in the set of systemic infections. In acute infections, abrupt inflammatory changes in coronary arteries may also induce plaque destabilization and rupture, culminating in acute coronary events.[30]

  Hypertension and Renin-Angiotensin-Aldosterone Antagonists Top

Taking into account that SARS-CoV2 uses the ACE2 receptor to invade host cells and recognizing that ACE2 is a key player in the RAAS, it is tempting to hypothesize that RAAS blockers may impact the propensity to SARS-CoV2 infection or to modulate the progression and severity of COVID-19. In this context, it is of paramount relevance to discuss the available evidence, aiming to clarify if there exists any association between RAAS antagonists' treatment and COVID-19 and to evaluate if such putative interaction is favorable or deleterious.

As SARS-CoV2 uses ACE2 to facilitate cell entry, it has been postulated that patients taking RAAS blockers would present increased susceptibility to infection if the chronic use of such drugs would induce ACE2 overexpression. The concept of ACE2 up-regulation with RAAS blockers resulted from animal studies.[31] However, proof of the direct effect of RAAS inhibition on lung-specific ACE2 levels is missing. More importantly, the effect found on preclinical studies may not readily translate to humans, as results from clinical studies regarding the effect of RAAS inhibition in ACE2 levels are conflicting.[20] Accordingly, large observational studies did not find an association between RAAS inhibitors and increased risk of infection or adverse outcomes.[13],[14] Conversely, a positive association between COVID-19 and the use of diuretic therapy was found.[13] These results may not suggest a pharmacological interaction, but rather an increased susceptibility in patients with serious comorbidities requiring diuretics, such as heart failure or chronic kidney disease.[13]

Therefore, scientific societies have urged not to discontinue RAAS blockers in stable patients with COVID-19, as their benefit on myocardial and kidney function is well established and withdrawal may trigger decompensation, particularly in high-risk patients.[32]

Recently, the concept that enhanced RAAS activity may play a key role in determining disease severity has risen the interest in counteracting Ang-2 activity. In animal models of in severe viral infection, it was shown that RAAS blocker treatment may reduce the extent of lung injury.[33],[34],[35] Relevantly, losartan (NCT04311177 and NCT04312009) and exogenous ECA2 administration (NCT04287686) are being evaluated in ongoing clinical trials.

  Acute Cardiac Injury Top

Acute cardiac injury is the most common cardiovascular event reported in COVID-19, with rates ranging from 7.2% to 36%.[36],[37] Myocardial injury in patients with COVID-19 could be due to plaque rupture, cytokine storm, hypoxic injury, coronary spasm, microthrombi, direct endothelial, or vascular injury. The criteria applied for diagnosis differed among cohorts, while the majority considered only a rise in serum troponin (Tn) above the upper threshold, others also included electro or echocardiography changes. The etiology of the underlying myocardial injury was not clarified in most studies. A wide range of mechanisms may mediate myocardial injury besides acute coronary syndrome and should be considered in the differential diagnosis, such as myocarditis, stress cardiomyopathy, cytokine release syndrome, acute heart failure, arrhythmias, renal impairment, and toxic injury.[38]

Acute cardiac injury has been consistently associated with worse clinical outcomes in COVID-19, being 13 times more frequent in patients with severe disease.[10] Recent cohorts reported a positive correlation between acute cardiac injury and elevation of inflammatory biomarkers, respiratory failure requiring mechanical ventilation, renal failure, and coagulation disorders.[37],[39],[40] Moreover, in a cohort with 3096 individuals, it was recognized as an independent risk factor for in-hospital mortality after adjusting for age, comorbidities, and disease severity (P < 0.001). The fatality risk was directly correlated with the magnitude of Tn elevation.[37]

Older individuals and patients with preexisting CVD are more likely to suffer myocardial injury.[37],[39] Guo et al. reported the highest mortality rates in patients with preexisting CVD who developed myocardial injury.[39] Interestingly, patients with CVD but without Tn rise presented more favorable outcome than individuals without CVD who developed myocardial injury (mortality, 13.3% vs. 37.5%). In addition, Tn rise, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and the incidence of malignant arrhythmias were strongly associated, and both the magnitude of Tn and NT-proBNP elevation and their dynamic changes during hospitalization were correlated with mortality.[39] These results suggest that myocardial injury plays a critical role in fatality, eventually greater than previous CVD.

  Ischemic Myocardial Injury Top

Viral infections may be a trigger for plaque disruption, as reported by Kwong et al., who detected an incidence ratio of acute type 1 myocardial infarction (MI) after influenza infection of 6.05 (95% confidence interval [CI]: 3.86–9.50) when compared to healthy controls.[40] However, it is critical to notice that myocardial necrosis in the setting of viral infections is more frequently due to type 2 mechanisms, justifying the need for therapeutic strategies completely different from those used in type 1 MI.[30] In addition, SARS-CoV2 tropism for endothelial cells induces microvascular dysfunction, and therefore, MI with nonobstructive coronary arteries may occur. This reinforces the necessity of an individualized invasive strategy, depending on the mechanism of myocardial damage.[41]

Currently, there are only a few reports of ischemic myocardial injury in COVID-19 patients.[27] Recently, in a case series of 18 COVID-19 patients with ST-segment elevation, nine patients underwent coronary angiography, and coronary obstructive disease was found in six of them.[42] Therefore, it seems that MI with nonobstructive coronary is a more prevalent cause of ST-segment elevation when compared to the general population.[38]

Consideration of the acute coronary syndrome mechanism has a great impact on clinical management. Due to the pandemic, in some centers have encouraged the use of fibrinolysis before coronarography.[43] Considering the risks of fibrinolysis, this treatment modality should be only considered in patients, in whom the diagnosis of type 1 MI is certain. In fact, European Society of Cardiology (ESC) recommendations reinforce that primary percutaneous coronary intervention is the gold standard intervention, leaving fibrinolysis only when the primary approach is not feasible.[44]

  Myocarditis and Stress Cardiomyopathy Top

During acute viral infection, nonischemic myocardial injury may occur due to stress-cardiomyopathy or myocarditis, either due to direct cardiomyocyte damage or activation of the immune system. So far, only case reports of myocarditis have been published, and the actual prevalence remains unclear.[45],[46],[47] Interestingly, myocardial damage may not correlate with respiratory severity, as indicated by the case of acute myopericarditis presenting with mild respiratory symptoms published by Inciardi et al.[46]

The distinction between stress-cardiomyopathy and myocarditis requires cardiac magnetic resonance imaging and endomyocardial biopsy (EMB), which may be limited in the setting of the ongoing pandemic. Magnetic resonance imaging provides a noninvasive morphological and functional evaluation that supports myocarditis suspicion; nevertheless and alike all imaging exams it should only be used when the results are expected to impact management and prognosis. Moreover, short protocols for image acquisition are recommended.[48]

EMB is the gold standard for establishing the diagnosis of myocarditis. However, in the setting of SARS-COV2 infection, EMB should only be considered in life-threatening conditions after Acute coronary syndrome (ACS) and other causes of acute myocardial injury have been ruled out.[41] Two reports of EMB in COVID-19 patients were published, and one of them fulfilled criteria for myocarditis, with acute inflammatory T-lymphocyte infiltration, cardiomyocyte necrosis, and diffuse edema, but importantly without detection of SARS-CoV2 genome.[47] Indeed, so far, no viral particles have been detected in EMB in COVID-19 patients. Since myocardial injury develops late after the onset of symptoms (10–15 days), it has been proposed that immune-mediated lesion is the prevailing pathway in myocardial inflammation.[2]

The diagnosis of fulminant myocarditis has been suggested in some cases.[41],[42],[49],[50] Tavazzi et al. reported a case of fulminant myocarditis with cardiogenic shock requiring mechanical circulatory support, although EMB only revealed mild inflammation, and the COVID-19 RNA was only detected in the inflammatory cells.[51]

There is no consensus regarding a specific treatment for SARS-CoV2 myocarditis. Of note, a case of fulminant myocarditis successfully treated with intravenous glucocorticoids, immunoglobulins, and mechanical support was recently reported.[52]

  Heart Failure and Cardiogenic Shock Top

Zhou et al. reported heart failure in 23% of COVID-19 patients (52% in nonsurvivors vs. 12% in survivors), although echocardiography data were not reported.[2] In another study, among patients with a previously normal left ventricle ejection fraction admitted to ICU, one-third evolved with acute heart failure and cardiogenic shock.[15] Importantly, cardiogenic shock may dominate the clinical course. In a retrospective analysis of 68 COVID-19 diseased patients, 7% were due to myocardial damage with circulatory failure, and circulatory dysfunction was a contributing factor to mortality in one-third of the cases.[7]

A cohort with 100 patients was evaluated with serial echocardiography during COVID-19 progression. At baseline, the most common changes were RV dilation and reduced pulmonary acceleration time.[53] These findings are suggestive of increased pulmonary artery resistance, which may occur due to pulmonary or vascular disease.[53] Of note, further progression of the RV parameters was observed in the patients who evolved with clinical deterioration.[53]

  Cytokine Release Syndrome Top

Similar to previous coronavirus infections, COVD-19 course may be complicated with cytokine release syndrome, a systemic pro-inflammatory state that may cause multisystem organ failure. This inflammatory state appears to be triggered by an imbalance between type 1 and type 2 T-helper cells response.[54] Several studies reported high pro-inflammatory cytokine levels in COVID-19 patients and described a direct correlation between cytokine serum concentration and disease severity.[2],[54] Furthermore, interleukin-6 and ferritin levels were found increased in COVID-19 nonsurvivors.[2]

Recently, immune dysregulation, as measured by lymphocyte counts, C-protein reactive level, and procalcitonin concentration, was independently associated with myocardial injury.[55] From a cardiovascular standpoint, cytokine release syndrome-related cardiotoxicity may manifest with hypotension, dysrhythmias, left ventricular dysfunction, and cardiogenic shock.[56]

  Cardiac Arrhythmias Top

During SARS-CoV and MERS outbreaks, a higher prevalence of both bradyarrhythmia and tachyarrhythmia events was detected; thus, it is likely that in the SARS-CoV2 pandemic the same phenomenon occurs.[57] Furthermore, cardiac arrhythmias may be the first presentation in COVID-19 patients, as found in a cohort of 137 patients, in which palpitations constituted the presenting symptom in 7.3% of patients.[58] The underlying pathophysiology is multifactorial and includes increased automaticity and enhanced triggered activity induced by hypoxemia, electrolyte derangements, and neuroinflammatory stress. In addition, heart failure decompensation and myocardial ischemia both predispose to arrhythmic events.

Wang et al. reported arrhythmic events in 16.7% of COVID-19 patients, with a significantly higher frequency in ICU patients (44.4% vs. 6.9%, P < 0.001).[36] However, the type of arrhythmia was not discriminated in that study. Recently, in a study with 138 hospitalized patients, malignant arrhythmias with associated myocardial injury were detected in 5.9% of patients.[39]

Nevertheless, to the time being, a thorough description of the arrhythmia in the context of COVID-19 is yet to be published.

  Thrombotic Disease Top

Multiple mechanisms predispose to thrombotic events during systemic viral infections, with emphasis on the hypercoagulability induced by endothelial dysfunction, hypoxia, cytokine storm, and immobilization related to illness.

Similar to other infections, thrombotic complications are more common in COVID-19 patients suffering from severe disease. Klok et al. reported thromboembolic events in 31% of patients with pulmonary embolism (PE), accounting for 85% of cases.[59] In a cohort of patients undergoing computed tomography pulmonary angiography, PE was detected in 24%, one-third of them presenting proximal PE.[60] Importantly, the rate of PE was even higher among ICU admitted patients, reaching 50%, and this impressive high prevalence was seen even though all patients were under prophylactic anticoagulation.[60] In addition, case reports of massive PE with acute RV dysfunction have also been published.[61],[62]

Disseminated intravascular coagulopathy (DIC) is a marker of severe sepsis complicated with excessive thrombotic and bleeding events. DIC has been described in COVID-19 and associates with increased mortality (71.4% vs. 0.6% P < 0.001).[63] In a cohort of 191 patients, D-dimer levels at admission >1 μg/mL were strongly associated with in-hospital mortality (adjusted hazard ratio: 18.4; 95% CI: 2.6–128.6; P = 0.003).[2] Other coagulation disturbances, such as increased fibrin degradation product levels and prolonged prothrombin time, have been associated with mortality.[63] It has been suggested that DIC may cause myocardial injury. Supporting this theory, coronary artery thrombosis with myocardial necrosis was observed in autopsies of COVID-19 patients with DIC, and the elevation of D-dimer was detected in COVID-19 patients with MI.[42]

The high prevalence of thrombotic events in COVID-19 and the association with adverse outcomes may support the rational of therapeutic anticoagulation in patients with elevated D-dimer, aiming to prevent microvascular thrombosis. Nevertheless, so far only one small study suggested the benefit of therapeutic anticoagulation in patients with high sepsis-induced coagulopathy score or markedly elevated D-dimer.[64]

Due to the lack of definitive data, scientific societies recommend advise on the use of empirical anticoagulation and give preference to the conventional prophylactic doses.

  Coronavirus Disease 19 Therapy Top

To date, no target therapy for COVID-19 has proven to be successful. Experimental and empirical treatments have been used worldwide, although their effectiveness remains controversial, and the side effects, particularly of cardiovascular nature, are considerable.

Chloroquine and hydroxychloroquine, a group of antimalarial drugs, were initially used extensively off-label due to promisingin vitro results that were not confirmed on clinical trials, revealing no benefit in a randomized trial that included hospitalized patients.[65] These drugs are, on the other hand, associated with concerning side effects, like potential direct myocardial toxicity[66] and pro-arrhythmic effect due to potential prolongation and early afterdepolarizations, with the risk of initiating atrial and ventricular arrhythmias that may be severe, sometimes even fatal.[57] The risk seems to be higher when used in combination with azithromycin since both drugs prolong the QT interval.[67]

The protease inhibitor lopinavir/ritonavir did not show any benefit when compared to placebo in severe patients.[68] In addition, it may prolong the QT interval, cause conduction disturbances[66] and induce multiple drug interaction by inhibiting CYP3A4 and P-glycoprotein, particularly with most P2Y12 inhibitors and anticoagulant drugs.[69]

Regarding antivirals, remdesivir, an RNA-dependent RNA polymerase inhibitor, obtained the most favorable results. The preliminary results of a double-blind, placebo-control, randomized trial with 1063 hospitalized individuals revealed a significant reduction in time to recovery with a 10-day course treatment.[70] Importantly, the effect on survival is still unknown, as well as the impact on the cardiovascular system.[66]

Alternative classes of drugs besides antivirals are being evaluated for the management of COVID-19. Treatment with convalescent plasma is undergoing investigation with contrasting results so far. A multicenter study with 115 patients reported significant improvement defined by reduction in length of stay and necessity of invasive ventilation,[71] while a randomized trial with 103 patients detected no significant clinical improvement within 28 days, although there are concerns that the study may have been underpowered.[72]

On the rational of the increased cytokine release observed on severe patients, monoclonal antibodies targeting inflammatory mediators, such as interleukin-6 inhibitors (tocilizumab and sarilumab) are under investigation. The published preliminary results from randomized trials are controversial, as CORIMUNO-19[73] and COVACTA[74] report opposite outcomes regarding clinical improvement and risk of death; however, final results are pending. The impact on the cardiovascular system is still unclear.

Finally, the randomized control trial RECOVERY provided evidence that dexamethasone reduced 28-day all-cause mortality in patients requiring ventilation or oxygen support and with a disease course longer than 7 days. However, no benefit was observed in patients not requiring oxygen.[75] In addition, there are concerns of potential unreported side effects due to the short follow-up duration, particularly in patients with CVD.[76]

  Long-Term Consequences Top

Evaluation of the long-term impact of COVID-19 on the cardiovascular system is still pending. On the follow-up of recovered patients from SARS-CoV infection, poor life-quality has been reported. When compared with healthy controls, patients presented a tendency to cardiovascular and glucose metabolism abnormalities, as well as other metabolic derangements such as an increase in serum phosphatidylinositol and lysophosphatidylinositol, known to play a role in glucose homeostasis.[77] Given the known similarities between the two viruses, it will be relevant to evaluate the chronic CVD burden after SARS-CoV2 infection.

  Conclusions Top

Age and pre-existing CVD are the most important predictors of COVID-19 severity. The disease is associated with a high inflammatory burden and a propensity to cardiovascular complications. The most prevalent being acute myocardial injury, which was directly associated with disease severity and mortality. Multiple possible mechanisms may be accountable for this injury and when considering the ischemic injury, the nonobstructive coronary disease seems to be predominant. A better understanding of the virus pathophysiology, particularly the interaction with RAAS, may lead to new potential therapies.

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