Task Force members of the Council of Cardiomyopathy and Cor Pulmonale:

Chairman:  Gary Lopez MD

Members:   Oliver Sansano MD

                   Charisse Mendoza-Aldea MD

                   Aileen Divinagracia-Alban MD

                   Alma Fides Mallabo MD

                   Juan Armando Diaz MD

                   Claudia Alcancia MD

                   Gilbert Florentino MD

                   Jose Ernesto Adea MD

                   Joseph Cuaresma MD

                   Karl Chavez MD

                   Michael Rome MD

                   Michelle Maliwat MD

                   Rona Leonor MD

                   Ryan Andal MD

                   Shaula Cabreros MD

The Council of Cardiomyopathy and Cor Pulmonale issues the following statements with regard to Cardiomyopathy, Cor Pulmonale and COVID-19:

• Proposed mechanisms of development of Cardiomyopathy in COVID-19 are the following: (1) ischemia from Acute Lung Injury with or without ARDS from cytokine storm, (2) catecholamine or stress-induced with or without tachycardia, (3) acute coronary syndrome (if with preexisting coronary artery disease), (4) acute microvascular thrombosis and (5) viral myocarditis.
• Preexisting cardiac risk factors including the diagnosis of cardiomyopathy is associated with a worse prognosis in patients with COVID-19.
• Elevated levels of myocardial markers predict risk for in-hospital death
• Myocardial injury is associated with older age, inflammatory response and cardiovascular-related comorbidities
• Diagnostic workup for cardiomyopathy in COVID-19 include: laboratory (Troponin or cardiac enzymes, BNP or NT-proBNP) and imaging tests (Chest xray, 12 lead ECG, 2DEchocardiogram, cardiac MRI). These should be taken with caution regarding benefits vs. risks and impact on management.
• Patients who were diagnosed to have cardiomyopathy and maintained on ACEI/ARB, who tested positive for COVID-19, should continue taking ACEI/ARB in the outpatient setting to prevent recurrence of heart failure symptoms.
• Patients who were diagnosed to have cardiomyopathy and maintained on ACEI/ARB, presently hospitalized due to COVID-19, may continue taking ACEI/ARB to prevent deterioration of cardiac dysfunction.
• Heart failure symptoms in patients with COVID-19 disease are treated with the use of guideline-directed medical therapy.
• Acute Cor Pulmonale can occur in COVID-19 disease due to enhanced thromboembolic phenomena.
• Prophylactic anticoagulation with heparin is oftentimes given if no contraindication because of hypercoagulability. Doses are increased to therapeutic doses if thrombus and/or embolism are documented or highly suspected.
• No evidence that antiviral and immunomodulatory therapy will prevent the development of Cardiomyopathy in patients with COVID-19.
• In the use of ECMO , its role as a bridge to recovery, cost, available blood products, possible exposure of more personnel and availability of personal protective equipment should all be taken into consideration.

The Coronavirus disease-2019 (COVID-19  or SARS-CoV2) , now known to be a global pandemic as it has spread across the world, leading to significant loss of life.  This is primarily known to affect the respiratory system, but severe and critical cases have shown to possibly involve multiple organs including the Cardiovascular system.

COVID-19 as a new cause of viral myocarditis requires identification of histologic findings of active myocarditis ,identification of the SARS-CoV-2 genome in heart tissue, identification of viral particles in cardiomyocytes, and exclusion of known cardiotropic viruses (21).

Cases regarding the occurrence of acute myocarditis have been reported in COVID-19 disease since early March, 2020, and it is observed that the evidence of cardiac involvement such as acute myocarditis is associated with a worse prognosis in COVID-19 disease.  These  patients were older, has more comorbities and had greater abnormalities  in their laboratory and radiographic findings (20).  The initial studies from Wuhan, China showed that fulminant myocarditis occurs in severe COVID-19 disease and is often fatal (1).

The presence of ACE2 receptors in the vessels and the heart may lead to direct viral myocardial damage but no sufficient data is available to confer or refute such possibility for SARS-CoV-2.  Still no reports of biopsy proven SARS-CoV2 viral myocarditis with viral inclusions/viral DNA detected in myocardial tissue. Infection-mediated vasculitis could also be another mechanism. ACE2 is highly expressed in arterial and venous endothelial cells. Direct viral entry into the myocardial endothelial cells could trigger Vasculitis. The presence of the virus leads to indirect immunological response resulting to hypersensitivity reaction.

Although one could posit direct invasion of cardiomyocytes by SARS-CoV2 underlies cardiac impairment, a recent pathological study documented scarce interstitial mononuclear inflammatory infiltrates in heart tissue without substantial myocardial damage in a patient with COVID-19.(11) Due to limited evidence, to date it is unproven if SARS-CoV2 can directly impair the heart.

Those with underlying cardiovascular disease such as coronary artery disease, hypertension, congestive heart failure history, and arrhythmias, are particularly susceptible to cardiovascular complications and mortality with COVID-19.

The concept of cytokine storm in COVID-19 releasing inflammatory cytokines from immune cells has been theorized to greatly contribute to the development of acute myocarditis.(7) SARS-CoV2 can elicit intense release of cytokines and chemokines. Cytokine storm is an immunopathological response caused by hyperinduction of proinflammatory cytokines such as IL-1, IL-6, T helper 1 cytokine interferon-gamma, and TNF-alpha. These cytokines are thought to depress myocardial function via activation of neural sphingomyelinase pathway and via nitric oxide-mediated blunting of beta-adrenergic signalling. This has been evidenced by the presence of elevated LDH, ferritin, C-reactive protein and other inflammatory markers during the acute phase of the disease.

Cardiomyopathy may develop from SARS-COV-2 with myocarditis, profound systemic inflammation, and/or microvascular dysfunction.  In an early report of clinical outcomes in 21 patients with severe COVID-19 disease, approximately 33% had evidence of de novo cardiomyopathy.(4-5)

Mechanism of cardiac injury were hypothesized to be because of: (a) demand-ischemia, (b) toxicity from direct viral injury , (c) stress, (d) inflammation and (e) microvascular dysfunction/plaque rupture.

Diagnostic workup for cardiomyopathy in COVID-19 includes laboratory (Troponin or cardiac enzymes, BNP or NT proBNP) and imaging tests (chest xray, 12 lead ECG, 2decho, cardiac MRI). These should be taken with caution regarding benefits vs. risks and impact on management. A normal or low level BNP favors ARDS versus acute cardiogenic pulmonary edema with a sensitivity of 27% and specificity of 95%. Elevated levels can neither confirm heart failure nor exclude ARDS.

There is no evidence-based guideline in the treatment of cardiomyopathy in patients with COVID-19 disease, therefore we follow the existing guideline-directed medical therapy.

The use of ACEI/ARB in patients with Covid 19 has not been shown to have deleterious effects despite the possibility of direct viral myocardial damage to the ACE2 receptors.(3,6) Based on this uncertainty regarding overall effect of RAAS inhibitors in COVID-19, multiple specialty societies currently recommend that RAAS inhibitors be continued in patients in otherwise stable condition. (16)

Severe COVID disease may present with hypercoagulability and right-sided myocardial dysfunction leading to fatal arrhythmias and death, presumably due to acute Cor Pulmonale.(2) Patients with COVID-19 are at significantly higher risk of acquiring VTE due to prolonged immobilization, hypercoagulable status, active inflammation and propensity for DIC. These patients have been shown to have elevated D-dimer, FDPs and Fibrinogen. Taking this into account, prophylactic anticoagulation with heparin is oftentimes given if no contraindication because of hypercoagulability. Doses are increased to therapeutic doses if thrombus and/or embolism are documented or highly suspected. A study of Zhou et al showed that D-dimer >1ug/mL on admission associates with in-hospital death. In critically ill COVID-19 patients who deteriorate, VTE should be considered.

Endothelial injury and inflammatory cytokines (IL-6 and TNF-alpha) upregulate tissue factor expression leading to a prothrombotic state. Dysregulation of Antithrombin III, Plasminogen activator inhibitor I and Protein C in the setting of inflammation and sepsis promote an anticoagulated state. Platelet activation could be activated in the setting of sepsis and inflammation.

Information on cardiac complications is limited among COVID-19 patients, cardiac impairment has been demonstrated as a direct or underlying cause of death in 27% of pneumonia-associated deaths. Even after adjustment for baseline risk, cardiac complications are associated with a 60% increase in pneumonia-associated short-term mortality. (8)

References:

1. ^{Chen C, Yiwu Z, et al, SARS-CoV-2: a potential novel etiology of fulminant myocarditis. Herz 45, 230-232 (2020)}
2. ^{Creel-Bulos C, Hockstein M, et al, Acute Cor Pulmonale in Critically Ill Patients with Covid 19; New Eng Jour Med, May 6, 2020}
3. ^{Mehra, M, Desai S, et al, Cardiovascular Disease, Drug Therapy in Covid 19, New Eng Jour Med, May 1, 2020}
4. ^{Schilling JD et al, Management of the Hospitalized COVID-19 Patient with Cardiomyopathy or Heart Failure, Cardiology Magazine, April 16, 2020}
5. ^{Arentz M, Yim E, et al, Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State, JAMA, March 20,2020; 323(16):1612-1614}
6. ^{Oudit GY, Kassiri Z, Jiang C, et al, SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS; Eur J Clin Invest 2009; 39: 618-25}
7. ^{Yufang S, Ying W, et al, COVID-19 infection: the perspectives on immune responses, Cell Death Differ, 2020 May; 27(5): 1451-1454}
8. ^{Shi S, Qin M, et al, Characteristics and clinical significance of myocardial injury in patients with severe Coronavirus disease 2019; Eur Heart J (2020) doi:10.1093/eurheartj/ehaa408}
9. ^{Xiong T, Redwood S, et al, Coronaviruses and the cardiovascular system: acute and long-term implications 2020, Eur Heart J (2020) doi:10.1093/eurheartj/ehaa231}
10. ^{Atri D, Siddiqi HK, Lang J, Nauffal V, Morrow DA, Bohula EA, COVID-19 for the Cardiologist: A current Review of the Virology, Clinical Epidemiology, Cardiac and other Clinical Manifestations and Potential Therapeutic Strategies, JACC: Basic to Translational Science (2020), doi:https://doi.org/10.1016/j.jacbts.2020.04.002}
11. ^{Xu Z, Shi L, Wang Y , Zhang J, Huang L, Zhang C, Liu S et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. pii: S2213-2600(20)30076-X. doi:10.1016/S2213-2600(20)30076-X.}
12. ^{Madjid M, Vela D, Khalili-Tabrizi H et al. Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes. Tex Heart Inst K 2007;34:11-18.}
13. ^{Klok FA, Kruip MJHA, Van der Meer NJM et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020. doi:10.1016/j.thromres.2020.04.013. [Epub ahead of print: 10 Apr 2020].}
14. ^{Shanghai Clinical Treatment Expert Group for COVID-19. [Comprehensive treatment and management of coronavirus disease 2019:expert consensus statement from Shanghai]. Chin J Infect 2020.}
15. ^{Kang Y, Chen T, Mui D, et al. Heart Epub ahead of print: [18 May 2020]. doi: 10.1136/heartjnl-2020-317056}
16. ^{Vaduganathan M, Vardeny O, Michel T, et al. Renin-Angiotensin-Aldosterone system inhibitors in patients with Covid-19. N Engl J Med doi:10.1056/ NEJMsr2005760. [Epub ahead of print: 30 Mar 2020].}
17. ^{Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269–71.}
18. ^{Sahraei Z, Shabani M, Shokouhi S, et al. Aminoquinolines against coronavirus disease 
2019 (COVID-19): chloroquine or hydroxychloroquine. Int J Antimicrob Agents 
2020;105945.}
19. ^{Thachil, et al. International Society of Thrombosis and Hemostasis (ISTH) Interim guidance on recognition and management of coagulopathy in COVID-19. Journal of Thrombosis and Haemostasis. 25 March 2020.}
20. ^{Shi S, Qin M, et al.; Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol. 2020}
21. ^{Caforio AL, Pankuweit S, Arbustini E; et al; Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013 Sep;34(33):2636-48, 2648a-2648d. Epub 2013 Jul 3.}