Apollo Medicine

REVIEW ARTICLE
Year
: 2022  |  Volume : 19  |  Issue : 3  |  Page : 168--176

Cardiovascular manifestations in COVID-19 patients


Jyotsna Maddury, Mani Krishna, Achukatla Kumar 
 Department of Cardiology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India

Correspondence Address:
Jyotsna Maddury
Department of Cardiology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana
India

Abstract

Most important medical challenge during the past 2 years is the COVID-19 pandemic due to SARS-CoV-2 virus. COVID-19 morbidity is increased in the presence of CAD risk factors. Effect of CAD risk factors and COVID-19 infection are bidirectional. Preexisting conditions, such as cardiovascular disease (CVD), hypertension, diabetes, and obesity, increase the severity as well as mortality rate of COVID. COVID-19 disease induces multiple cardiovascular manifestations, such as myocarditis, acute myocardial injury, acute myocardial infarction (MI), stress-induced cardiomyopathy, cardiogenic shock, arrhythmias, and, subsequently, heart failure (HF) and cardiac arrest. Increase of troponin suggests a hyperinflammatory state or may be due to acute myocarditis. Elevated troponin without other laboratory markers elevation suggests aggressive COVID-19 disease than myocardial injury. Stress or takotsubo cardiomyopathy occurred primarily in women with COVID-19 and these women have more severe HF. The patients with COVID-19 positive more frequently have multivessel thrombosis, stent thrombosis, and a higher thrombus when compared to COVID-19-negative STEMIs. Because of higher thrombus burden more usage of glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors and thrombus aspiration and higher heparin doses to achieve therapeutic activated clotting times were also noted. Patients with pulmonary embolism had significantly higher hs-cTnT and NT pro-BNP levels than those without pulmonary embolism. In COVID-19, arrhythmias noticed are atrioventricular/ventricular block, sinus tachycardia, sinus bradycardia, atrial arrhythmias, and ventricular arrhythmias. Consideration for potential drug interactions should be taken when treating CVD patients with COVID-19.



How to cite this article:
Maddury J, Krishna M, Kumar A. Cardiovascular manifestations in COVID-19 patients.Apollo Med 2022;19:168-176


How to cite this URL:
Maddury J, Krishna M, Kumar A. Cardiovascular manifestations in COVID-19 patients. Apollo Med [serial online] 2022 [cited 2022 Dec 3 ];19:168-176
Available from: https://apollomedicine.org/text.asp?2022/19/3/168/353349


Full Text



 Introduction



SARS-CoV-2 produces the coronavirus disease (COVID-19), which antecedent significant mortality in this century and drawn the attention of whole world. Seven types of coronaviruses were known infect human being, out of them, four viruses (HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1) produces upper respiratory tract infections. But SARS-CoV and MERS-CoV produces more severe disease with atypical pneumonia, SARS-CoV-2 after entry into the alveolar epithelial cells, fastly replicates and activates a strong immune response, culminates in cytokine storm syndromes and produces the lung parenchymal and vascular damage. This hypercytokinemia is one of the important mechanisms of acute respiratory distress syndrome (ARDS) and multiple organ failure[1] in COVID-19 disease.

 Cardiovascular Risk Factors and COVID-19 Disease



COVID-19 disease morbidity and mortality are increased in the presence of CAD risk factors. Effect of CAD risk factors and COVID-19 infection are bidirectional [Figure 1] and [Figure 2]. The severity and mortality increase when COVID-19 disease is associated with other comorbid conditions such as cardiovascular disease (CVD), diabetes, hypertension, and obesity.[2],[3] Diabetes can increase the severity of COVID-19 disease by four possible mechanisms. It causes defects in innate and adaptive immunity, viral clearance is delayed, causes increased inflammatory response and renin–angiotensin–aldosterone system[4] is activated. So also the COVID-19 infection predisposed to the thrombotic tendency, macrovascular complications of diabetes may be precipitated in addition to plaque rupture directly due to virus infection and inflammation. Even microvascular complications of diabetes may be exaggerated as COVID-19 infection causes the acute endothelial injury, hypercoagulation, and increased capillary permeability.[5]{Figure 1}{Figure 2}

 Types of Cardiovascular Disease in COVID-19 Disease



COVID-19 disease induces multiple cardiovascular manifestations, such as myocarditis, acute myocardial injury, acute myocardial infarction (MI), stress-induced cardiomyopathy, cardiogenic shock, arrhythmias, and, subsequently, heart failure (HF) and cardiac arrest.

 Mechanism of Cardiovascular Disease in COVID-19



In COVID-19 infection, cardiovascular involvement may be due to multiple pathways such as nonischemic myocardial injury due to cytokine storm, myocardial demand supply mismatch, plaque rupture and coronary thrombosis, direct viral myocardial injury, microvascular dysfunction, stress-related cardiomyopathy, and various therapy-related adverse effects.[6] In a particular CVD, a combination of the above-said mechanisms may play a role.

 Myocarditis



In a clinically suspected case of myocarditis, laboratory findings may confirm the diagnosis. Lymphocytopenia is a frequently seen abnormality often in up to 83% of cases, followed by leukopenia and thrombocytopenia, which can occur in 33% of cases. Markedly increased levels of inflammatory markers (D-dimer, ferritin, and C-reactive protein) not only suggest severity of the COVID diseases, even this finding in myocarditis suggests more aggressive forms.[7] Isolated troponin elevation occurs in aggressive myocarditis, whereas its elevation along with the other laboratory markers even can occur only in a hyperinflammatory state without myocarditis. If elevated troponin with other inflammatory markers, then the troponin elevation is the component of multiorgan dysfunction than isolated myocarditis.[8] However, elevated NT pro-BNP, whatever may be the reason, is a bad prognostic marker in COVID disease patients. Positive peak high-sensitivity troponin levels in COVID patients were independently associated with acute kidney injury, venous thromboembolism (VTE), development of atrial fibrillation, and death during admission.

Transthoracic echocardiography (TTE) is the first-line investigative modality for myocarditis. Two-dimensional (2D) echo may show regional or global hypokinesia[9] with preserved wall thickness or even hypertrophy, especially in hypertensive patients, as hypertension is an important comorbid factor in COVID-diseased patients. Sometimes, the wall thickness may increase due to myocardial edema also.

CMR is very useful in diagnosis and prognostication of COVID myocarditis. Lake Louise Criteria[10] are used to support the diagnosis of myocarditis by CMR. CMR shows increased T2 values and positive short T1 inversion recovery, which are typical findings for myocarditis [Figure 3]. Myocarditis may be associated with active COVID infection or even latter also.[11]{Figure 3}

 Acute Myocardial Infarction



There is no conclusive data to say that COVID infection can produce ST-elevation MI (STMI), but previous studies demonstrated that there was an association of MI and virus (influenza) and even bacterial infections.[12] COVID disease causes both venous and arterial thrombosis due to procoagulant status [Figure 4].{Figure 4}

Another problem during this pandemic is the mimickers of MI. A small study of 28 patients who had undergone coronary angiogram following MI during this pandemic showed no culprit coronary lesions despite having regional wall motion abnormalities in 7 of them. Hence, the authors were not clear for the cause of clinical presentation.[13]

 Unique Features of Culprit Lesion



The COVID-positive STMI patients had more frequent multivessel thrombosis and more frequent stent thrombosis when compared to COVID-negative STMI patients. The stent thrombosis is not only known to occur during active infection, but also in post-COVID period also. So, there were more frequent usage of GP 2b/3a inhibitor usage and its related complication as well as higher heparin doses to achieve the therapeutic range of APTT. All these resulted in poor left ventricular function as there was less myocardial perfusion and increased mortality.[14],[15] In an Indian study, they have done coronary angiogram in 50 COVID patients (76.92%), of which 23 (35.38%) had single-vessel disease, 14 patients (21.54%) had double-vessel disease, 8 people (12.31%) had triple-vessel disease, and normal coronaries in 5 patients (7.69%).[16]

 Stress-Induced Cardiomyopathy and Heart Failure



Nearly 25% of sick COVID patients who were hospitalized had new onset of HF. Out of them, 33% required intensive care admissions, reflecting the severity of the HF.[7] The probable mechanisms for HF due to COVID-19 disease are explained in [Figure 5]. Increased levels of natriuretic peptides not only bad prognostic marker in the COVID diseases, but also indicates that echocardiographic evaluation is required in this subset of COVID patients.[17] HF due to infection is different from routine HF management. In this, we require cautious administration of fluids and inotropes than vasopressors.{Figure 5}

Cardiac injury-representing biomarkers are elevated more when there is an association with comorbid conditions and are associated with higher mortality. Multiorgan failure can occur due to cardiogenic shock secondary to myocarditis, which can lead to even death.[18] Other causes of HF in COVID disease, other than acute myocarditis, are right HF due to pulmonary thromboembolism (due to prothrombotic state) and stress-induced cardiomyopathy (due to sympathetic activation). Temporary cardiac support machines such as Impella or ECMO are useful in critically ill patients due to HF.[19]

 Acute Pulmonary Thromboembolism



The most common complication of COVID-19 infection is acute pulmonary thromboembolism (PTE). In most of the studies, pulmonary thromboembolism was found in up to 25%–30% of cases in people with COVID active infection with high mortality.[20] However, in an Indian study, PTE was found in 4.6% of patients post-COVID illness. Patients with PE had significantly higher hs-cTnT and NT pro-BNP levels than those without PE.[21] Endothelial dysfunction in diabetic patients may be a confounding factor for the increased COVID mortality. An already weakened endothelium with added jeopardy from increased thrombogenicity and cytokine cascade activation may be a precursor for pulmonary thrombosis–embolism. Special attention to the women of child-bearing age, who are on oral contraceptives, is higher risk of developing PTE.

Risk factors for the development of venous thromboembolism (VTE) was discussed in many studies,[22] whereas Whyte et al. showed that the Wells score on CTPA is not efficient to detect the PTE. First line of treatment for COVID-19 disease-related VTE/PTE is anticoagulation, even though there are other modalities such as catheter-directed thrombolysis. [Appendix 1] shows the recommendations by different associations for this VTE.[INLINE:1]

 Cardiac Arrhythmias



Wang et al. first described COVID-19-related cardiac arrhythmia. The incidence of cardiac arrhythmias is more frequent in the patients who were admitted to intensive coronary care unit (ICCU) (44%) with overall incidence of 17%. According to Guo et al., the incidence of malignant arrhythmias (ventricular tachycardia [VT] and fibrillation) in COVID-19 was 5.9%.[23] According to Du et al.'s study in death due to COVID, the common cause of death was cardiac arrest (8.64%) and malignant arrhythmias accounts for up to 2.47%. Multiple pathways are described for the occurrence of arrhythmias in COVID-19 disease [Figure 6].{Figure 6}

The reported incidences of atrioventricular/ventricular block, sinus tachycardia, sinus bradycardia, atrial arrhythmias, and ventricular arrhythmias were 11.8%, 7.5%, 8%, 7%, and 4%, respectively. Most frequent arrhythmia according to these studies was atrioventricular/ventricular block.[24]

 Women Heart Disease and COVID-19



Worldwide literature mentioned that COVID-19 pandemic effected the women and men equally, but as 70% of health-care providers are female and mental as well as social suffering is more in females, the cardiovascular morbidity in females needs to see separately.[25] Hence, this pandemic opens Pandora's box of new cardiac problems in women, in addition to increasing incidence of CAD in women in this decade.[26] It was found that the incidence of stress cardiomyopathy in COVID era increased by 17.85% compared to pre-COVID period. Stress cardiomyopathy occurred primarily in women with COVID-19 and these women have more severe HF. In general population, there is great predilection (as much as 90%) for takotsubo to affect female gender. Similarly, in COVID-19 patients presenting with takotsubo are women and their clinical course is more stormy than men. Hence, early recognition and aggressive management will result in better outcomes.

 Investigations to Detect the Cardiovascular Disease in COVID-19 Disease



Electrocardiography

Even though the most common abnormality on electrocardiogram (ECG) is sinus bradycardia, other arrhythmias such as sinus tachycardia and atrial and ventricular arrhythmias are also reported. ST-T changes are the frequent changes seen on ECG in up to 40% of ICCU-admitted COVID patients.[27] In addition, interval and axis changes on ECG are also seen. Atrial fibrillation, QT interval prolongation, ST-segment and T-wave changes, and VT/fibrillation on ECG are associated with poor outcome. Not only the basal QT interval estimation is required in COVID patients to detect likely possibility to deteriorate into ventricular arrhythmia, it also important in the starting and maintenance therapy with HCQ prophylaxis. Along with basal ECG, repeat ECG is required if the patient develops cardiovascular symptoms such as palpitations, chest pain, or syncope or taking HCQ beyond 8 weeks.

Two-dimensional echocardiography

TTE (transthoracic echo off-axis views or contrast) is preferred over transesophageal echo (TEE). Measurements for LV, RV, and LA should be performed. If LAA clot is suspected, computed tomography (CT) or magnetic resonance imaging (MRI) is a preferred modality of investigation over TEE. As already sympathetic activation is there in COVID patient if ischemia detection tests are required then pharmacological stress is recommended than treadmill stress. 2D echo evaluation is mandatory for the diagnosis, detection of complications, for response to therapy and follow-up in COVID-19 disease-related CVD. Patients with COVID-19 have shown an impaired LV systolic and diastolic function. RV dysfunction is the most common echocardiographic finding. Moreover, patients with RV dysfunction have higher mortality than patients without. When worsening RV dysfunction is suspected and for the diagnosis of RV clots, then repeat echo may be required.[28] LV wall motion abnormalities and findings similar to stress cardiomyopathy like apical ballooning are noted, especially in females with COVID-19 infection.

CTPA

In COVID-19 patients, PTE affects the segmental arteries and more so in the right lung. CT severity, lower level of saturation, and a rise in D-dimer levels are the indications for a CTPA. According to Takkar et al., there are diagnostic challenges in a patient with COVID-19 for VTE.[29] The challenges are transportation of patient to the CT lab (increase the chance of infection spreading to healthcare workers) and difficult to image (either CTPA or Doppler for DVT) when the patient is in prone position (recommended in severe ARDS).

CARDIAC magnetic resonance imaging

This is the investigation of the choice when COVID myocarditis is suspected. As already in describe in a previous patient the finding on MRI suggestive of myocarditis are myocardial edema and late gadolinium enhancement.

Positron emission tomography scan

Positron emission tomography scan cannot be routinely used in emergency setting. Currently, it has a potential to increase our understanding of the mechanism of COVID-19 for research purpose. It is very useful to know the activity of myocarditis [Figure 7].{Figure 7}

 Drug Interactions of COVID-19 Diseases with Cardiovascular Disease



So many drugs used in the treatment of COVID-19 can interact with many cardiovascular drugs.[30] Few important interactions are summarized in [Appendix 2] and [Appendix 3].[INLINE:2][INLINE:3]

 Recommendations for Detection, Diagnosis, and Management OD Cardiovascular Disease in COVID-19 Disease



In recently published Consensus Scientific Statement on Advisory Working Guidelines and Recommendations for the Female Population in COVID-19 Era by WINCARS, mentioned the recommendations for CVD, VTE and drug–drug interactions in females.[29] CVD in females with COVID-19, more association with diabetes than men, same risk of myocardial injury as men, ACS presentation in females more confounded by still more delayed presentation, diagnosis and treatment [Appendix 4].[31] Even though the VTE was less prevalent in females, women already on oral contraceptives are more prone to VTE. Thromboprophylaxis recommendations same as men even during menstrual period also [Appendix 5]. This scientific paper cautioned in giving hydroxychloroquine for breastfeeding women, tocilizumab may be given to pregnant women if benefit is more and favipiravir requires monitoring when women with COVID-19 disease is taking estrogen receptor modulators for breast cancer [Appendix 6].[INLINE:4][INLINE:5][INLINE:6]

 Conclusion



COVID-19 infection can have variety of cardiovascular manifestations. Early identification of cardiovascular involvement by serum biomarkers, point of care echocardiography, and cardiac MRI can decrease mortality and morbidity in COVID-19 patients. Consideration for potential drug interactions should be taken when treating CVD patients with COVID-19. Gender differences in cardiovascular manifestations of COVID-19 such as more severe HF in women should also be given importance when treating female patients.

Conflicts of interest

There are no conflicts of interest.

Funding

Nil.

Authors contribution

Prof. Maddury Jyotsna: Conception of the idea, Drafting the article, Critical revision of the article and Final approval of the version to be published. Dr. Mani Krishna: Drafting the article, & Critical revision of the article. Dr. Achukatla Kumar: Critical revision of the article.

References

1Villar J, Zhang H, Slutsky AS. Lung repair and regeneration in ARDS: Role of PECAM1 and Wnt signaling. Chest 2019;155:587-94.
2Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;231:1259-61.
3Maddury J, Paramjyothi GK. Need of the hour- COVID-19 for cardiologists. Indian J Cardiovasc Dis Women WINCARS 2020;5:4-7.
4Bloomgarden ZT. Diabetes and COVID-19. J Diabetes 2020;12:347-8.
5Kaur M. COVID-19 outbreak: Key considerations for safety of health care workers. Indian J Cardiovasc Dis Women WINCARS 2020;5:278-81.
6Vipperla S, Mahapatro AK. Cardiovascular disease and COVID-19: Issues in women. Indian J Cardiovasc Dis Women WINCARS 2020;5:195-9.
7Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet (London, England) 2020;395:1054-62.
8Calabrese LH. Cytokine storm and the prospects for immunotherapy with COVID-19. Cleve Clin J 2020;87:389-93.
9Bonow RO, Fonarow GC, O'Gara PT, Yancy CW. Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality. JAMA Cardiol 2020;5:751-3.
10Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang G, Alakija P, Cooper LT, et al. Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J Am Coll Cardiol 2009;53:1475-87.
11Cooper LT Jr., Keren A, Sliwa K, Matsumori A, Mensah GA. The global burden of myocarditis: Part 1: A systematic literature review for the Global Burden of Diseases, Injuries, and Risk Factors 2010 study. Glob Heart 2014;9:121-9.
12Musher DM, Abers MS, Corrales-Medina VF. Acute infection and myocardial infarction. N Engl J Med 2019;380:171-6.
13Stefanini GG, Montorfano M, Trabattoni D, Andreini D, Ferrante G, Ancona M, et al. ST-elevation myocardial infarction in patients with COVID-19: Clinical and angiographic outcomes. Circulation 2020;141:2113-6.
14Choudry FA, Hamshere SM, Rathod KS, Akhtar MM, Archbold RA, Guttmann OP, et al. High thrombus burden in patients with COVID-19 presenting with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2020;76:1168-76.
15Saleh MA, Ambrose JA, Poosti K, Rajyaguru C, Sargsyan M, Najafi A, et al. Misdiagnosis of type II myocardial infarction. J Am Coll Cardiol 2019;74:1732-3.
16Rashid M, Wu J, Timmis A, Curzen N, Clarke S, Zaman A, et al. Outcomes of COVID-19-positive acute coronary syndrome patients: A multisource electronic healthcare records study from England. J Intern Med 2021;290:88-100.
17Gao L, Jiang D, Wen XS, Cheng XC, Sun M, He B, et al. Prognostic value of NT-proBNP in patients with severe COVID-19. Respir Res 2020;21:1-7.
18Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID- 19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46:846-8.
19Scally C, Abbas H, Ahearn T, Srinivasan J, Mezincescu A, Rudd A, et al. Myocardial and systemic inflammation in acute stressinduced (Takotsubo) cardiomyopathy. Circulation 2019;139:1581-92.
20Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-9.
21Srikanth K, Maddury J. Incidence of cardiovascular events and mortality in COVID-19 patients admitted in NIMS intensive unit during second wave. Indian J Cardiovasc Dis Women WINCARS 2020;5:125-8.
22Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;231:1259-61.
23Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061.
24Du Y, Tu L, Zhu P, Mu M, Wang R, Yang P, et al. Clinical features of 85 fatal cases of COVID-19 from Wuhan. A retrospective observational study. Am J Resp Crit Care Med. 2020;201:1372-9.
25Chaudhary A. Women in COVID pandemic: Beyond morbidity and mortality. Indian J Cardiovasc Dis Women WINCARS 2020;5:274-7.
26Kapoor PM. Women in COVID-19 pandemic: Influential leadership is the need of the hour. Indian J Cardiovasc Dis Women WINCARS 2020;5:271-3.
27Li Y, Liu T, Tse G, Wu M, Jiang J, Liu M, et al. Electrocardiograhic characteristics in patients with coronavirus infection: A single-center observational study. Ann Noninvasive Electrocardiol 2020;25:e12805.
28Spyropoulos AC, Lipardi C, Xu J, Lu W, Suh E, Yuan Z, et al. Improved benefit risk profile of rivaroxaban in a subpopulation of the MAGELLAN study. Clin Appl Thromb Hemost 2019;25:1076029619886022.
29Takkar S, Jyotsna M, Goyal P, Chaudhary A, Vipperla S, Hemalatha Y, et al. Consensus Scientific Statement on Advisory Working Guidelines and Recommendations for the Female Population in COVID-19 Era by WINCARS. Indian J Cardiovasc Dis Women WINCARS 2020;5:175-94.
30Chhabra ST, Goyal P. Venous thromboembolism in COVID-19: Are women different? Indian J Cardiovasc Dis Women WINCARS 2020;5:200-8.
31Spyropoulos AC, Lipardi C, Xu J, Lu W, Suh E, Yuan Z, et al. Improved benefit risk profile of rivaroxaban in a subpopulation of the MAGELLAN study. Clin Appl Thromb Hemost 2019;25:107602961988602.