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Cardiovascular Manifestations During COVID-19

Author: Dr. R.K. Sujai Nikhil

M.B.B.S., M.D. Gen Med., DM Cardiology, Consultant Interventional Cardiologist, The Pollachi Cardiac and Eye Care Centre

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The outbreak of coronavirus disease 2019 (COVID-19), an infectious disease with harsh acute respiratory syndrome, has now become a worldwide pandemic. In spite of the respiratory complexity, COVID-19 is also linked with serious various organ dysfunction, which comprises of serious cardiac damage. Emerging evidence reveals a direct interplay between COVID-19 and cardiovascular complications, including myocardial injury, heart failure, heart attack, myocarditis, arrhythmias as well as blood clots, which are accompanied with raised risk and unfavourable end results among infected patients, even sudden unexpected death.

Keywords: COVID-19; SARS-CoV-2; Long COVID; Cardiovascular system



Coronavirus disease (COVID-19), formerly known as 2019 novel coronavirus, is result of an infection with serious acute respiratory syndrome coronavirus 2 (SARS-CoV2). It 1st came across in December 2019 among a group of patients showing pneumonia of unrecognised cause in Wuhan, Hubei Province, China [1]. On 11 March 2020, it was declared as a pandemic by the World Health Organisation (WHO), and as of 27 December 2020, more than 79 million cases have been reported across the globe with more than 1.7 million fatalities [2,3]. Like SARS-CoV and MERS-CoV, SARS-CoV-2 is from the genus Betacoronavirus from within the subfamily of Coronavirinae, which emerges from the family of Coronoaviridae. It is an enveloped and non-segmented, positive-sense RNA virus with a length of about 29.9kb with huge genomic diversity [4,5].

COVID-19 has been known to cause cardiovascular complexities such as myocardial injury, thromboembolic events, arrhythmia, and heart failure. Different mechanisms—some overlapping, primarily the role of inflammation and IL-6—potentially underlie these problems.

The noted injury to heart may be an outcome of direct viral breach of cardiomyocytes with subsequent uncontested effects of angiotensin II, surge in metabolic demand, immune triggering, or microvascular disorder. Thromboembolic events have been extensively recorded in both the venous and arterial systems that have allured strong interest in the basal mechanisms. These could probably be due to endothelial dysfunction, secondary to direct viral storming or inflammation. Furthermore, thromboembolic episodes may also be a result of an attempt by the immune system to curb the infection through immunothrombosis and neutrophil extracellular traps. Cardiac arrhythmias have also been addressed with a broad range of suspected contributory factors, varying from direct viral injury to myocardium, as well as other elements, including at-risk individuals with underlying inborn arrhythmia syndromes. Heart failure may also occur as an advancement from cardiac injury, precipitation secondary to the commencement or withdrawal of certain drugs, or the build-up of des-Arg9 -bradykinin (DABK) with exorbitant introduction of pro-inflammatory G protein coupled receptor B1 (BK1). The conferring cardiovascular symptoms include chest pain, dyspnoea, and palpitations. There is currently very high interest in vaccine-induced thrombosis and in the cure of long covid since numerous patients who have survived COVID-19 describe continuous health problems. This article will give a snapshot of the proposed physiological mechanisms of COVID-19-linked cardiovascular complexities [6].


Epidemiology of Cardiovascular Complications

44,672 COVID-19-positive patients in China were screened out of which 81% were mild (having no or mild pneumonia), 4.7% were critical, and mortality rate was 2.3% [7]. Patients who needed ICU care were seen to be of median age, that is, 66 years [8].

SARS-CoV-2 infection has been associated with cardiovascular complications (figure 1), namely myocardial injury and myocarditis (36% of 2736 patients), thromboembolic events (25% of 81 patients), heart failure and cardiomyopathy (29% of 191 patients), arrhythmias (16.7% of 138 patients), and acute coronary syndromes (0.96% of 4702 patients) [6, 8-12].

Figure 1: Cardiovascular Complications of COVID-19 [6]


Pathophysiology of COVID-19-Associated Cardiovascular Complications

Many factors are seen to add up to the cardiovascular complexities which are observed in along with the COVID-19 infections. These may comprise of systemic inflammation, cardiovascular tissue – direct invasion, and medicaments etc. Figure 2 reviews the potential mechanisms as to how cardiovascular complications may arise at various stages of the disease [6].

p38 Mitogen-Activated Protein Kinase (p38 MAPK), Angiotensin II (Ang II); T-helper-1 (Th1); Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2 (Nox2); Neutrophil Extracellular Traps (NETs); von Willebrand factor (vWF); Toll-Like Receptor (TLR); Tissue-Factor (TF); Damage-Associated Molecular Patterns (DAMPs); Factor VIII (VIII); Human Ether-a-go-go-Related gene (hERG); Interleukin (IL); Tumour Necrosis Factor (TNF); Des-Arg-Bradykinin (DABK); G-protein coupled receptor B1 (BK1)

Figure 2: Summary of the possible pathophysiology mechanisms underlying COVID-19 associated cardiovascular complications.


COVID-19 Regime which has Ill Effects on CVD Profile

Suggested COVID-19 remedies and their probable cardiovascular complexities (table 1) [9, 13-20]. Hydroxychloroquine (HCQ); Chloroquine (CQ); Acute Kidney Injury (AKI); Cytochrome P450 2D6 (CYP2D6); Cytochrome P450 3A4 (CYP3A4).


Table 1: Proposed COVID-19 therapies and their potential cardiovascular complication

Sr No

Proposed Therapy

Potential Cardiovascular Effects

Possible Mechanisms




  • QT Prolongation
  • Cardiotoxicity
  • Blockage of hERG K+ channels
  • Toxic HCQ/CQ accumulation secondary to AKI
  • Lysosomal dysfunction → glycogen/ phospholipid accumulation


HCQS + Azithromycin


  • QTc Prolongation (especially those with elevated transaminases)
  • Azithromycin prolongs QT interval
  • Elevated transaminases indicative of pro-inflammatory cytokines which prolong QT


HCQS + Loop Diuretics


  • QTc Prolongation
  • Electrolyte derangement by loop diuretics might be a contributory facto


Lopinavir + Ritonavir


  • Thrombosis (in clopidogrel users)
  • Arrythmias
  • CYP3A4 inhibition thus decreased active metabolites of clopidogrel
  • CYP2D6 inhibition → CQ accumulation



  • Bradycardia
  • Unclear


Future Therapeutic Regimen - Consideration of CVD Protection in COVID-19

Cardiovascular complexities are well confirmed in COVID-19 and also the cardio toxic effect of anti-COVID-19 drugs is known [21]. Hence, there arises an unfulfilled need for a drug that can show a cardio protective outcome along with an anti-COVID-19 outcome. If we think for the new drug development, it will be a time consuming and costly process, and therefore reusing of current cardio protective agents with possible anti-viral and anti-inflammatory effects will be a better strategy [22].

Amidst number of cardio protective drugs, statins are very widely explored drugs with a good safety characteristic on long-term usage [23]. Studies have proposed statins as a possible cardio protective drugs among the patients who are infected by COVID-19, as it displays a hybrid mechanism of action [24–26]. Statins exhibit anti-hyperlipidemic, antioxidant, anti-inflammatory, anti-thrombotic, and immunomodulatory effects [26]. Additionally, it was found that nCoV-19 accelerates the MYD88 signalling pathway giving rise to hyper inflammation in addition to cardiotoxicity, and curiously, statins inhibits this signalling pathway [26].

In addition to statins, sodium-glucose cotransporter-2 (SGLT-2) inhibitor is a noted cardio protective agent which is seen as a drug of choice in diabetic cardiomyopathy for quite a long time [27]. SGLT-2 inhibitors also found to show cardio protective effect among non-diabetic patients and reduced the mortality rate and hospitalization frequency among heart failure patients [28]. Interestingly, SGLT-2 inhibitors have been reported to inhibit the viral entry of nCoV-19 via inhibiting lactate pathways and by increasing the cytosolic pH [29]. Studies have also shown that increased expression level of ACE2 eventually leads to anti-oxidant, vasodilation and anti-fibrosis effect and reduces ARDS, cytokine storm and exhibits cardio protective effect [30]. Thus, taking into account the multiple benefits of SGLT-2 inhibitor, a metacentric phase III clinical trial is being conducted (DARE-19, NCT04350593) where predominantly, therapeutic effect of Dapagliflozin is being assessed along with its cardio safety effect. In addition to this, an undesired invasive procedure such as cardiac catheterization and transthoracic procedures should not be used until its very necessary. In the case of ST-elevation, patients should be treated with thrombolytic drugs such as tenecteplase, whereas in the case of pulmonary embolism or venous thrombosis, anticoagulants should be used as per the standard dose regimen [31].



SARS-CoV-2 is more than just a respiratory illness; it has shown a preponderance to those with underlying cardiovascular co-morbidities. In addition, even after days and months after infection, cardiovascular complexities have occurred. These cardiovascular complexities include myocardial damage and myocarditis, acute coronary syndromes, HF, arrhythmias, and thromboembolic episodes. Some of the medicaments used to treat COVID-19 also have possible cardiac complications. In addition, cardiac symptoms, such as palpitations, chest pain, and dyspnoea and CMR changes, have been noticed in patient’s weeks to months after the initial infection in what has been termed Long-COVID. Autonomic dysfunction could be a reason for the underlying pathophysiological mechanism of these manifestations. Chronic myocarditis leading to myocardial fibrosis and then giving rise to the development of arrhythmias which may probably account for few of these symptoms as well. The importance of the noticed cardiovascular changes is still not well understood; nor do we know if there will be more to be detected. The accurate pathophysiological mechanisms underlying the disease and its cardiovascular sequelae are still largely hypothetical. Some more research must be carried out to better recognize COVID-19 and its long-term complexities.




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