COVID-19-associated myocardial injury

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Main article: COVID-19

For COVID-19 frequently asked inpatient questions, click here

For COVID-19 frequently asked outpatient questions, click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed rizvi, M.B.B.S[[2]]

Synonyms and Keywords: Novel coronavirus, COVID-19, Wuhan coronavirus, coronavirus disease-19, coronavirus disease 2019, SARS-CoV-2, COVID-19, COVID-19, 2019-nCoV, 2019 novel coronavirus, cardiovascular finding in COVID-19, myocardial injury in COVID-19, COVID-19-associated myocardial injury, SARS-CoV2-associated myocardial injury, COVID-19 myocardial injury.

Overview

Coronavirus disease 2019 (COVID-19) is a rapidly expanding global pandemic which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is associated with significant morbidity and mortality. It has been seen to cause myocardial injury, usually in patients requiring hospitalization in more severe cases of SARS-CoV 2 infection. COVID-19 associated myocardial injury is a broad term that is used to describe any cause of myocardial tissue death induced by the SARS-CoV-2 virus. This includes acute coronary syndrome, cardiomyopathy and acute heart failure (with or without cardiogenic shock) and myocarditis. Diagnosis is largely based on an elevated high sensitivity troponin I (hs-TnI) level of > 99th percentile of the upper limit of normal. The exact prevalence of COVID-19 associated myocardial injury is around 5000-38,000 per 100,000 hospitalized individuals worldwide.

Historical Perspective

• COVID-19 (SARS-CoV-2) outbreak initiated and was discovered in December, 2019 in Wuhan, Hubei Province, China.
• January 30, 2020 - World Health Organization(WHO) declared the outbreak as a Public Health Emergency of International Concern.
• March 12, 2020 - WHO declared the COVID-19 outbreak a pandemic.

• January 2, 2020 - first observational study of 41 patients with COVID-19 pneumonia showed that 5 (12%) of the 41 patients had elevated hs-TnI ( high sensitivity troponin) level above the defined threshold (28 pg/ml)
• To view the full historical perspective of COVID-19, click here.

Classification

Following careful clinical evaluation, patients with cTn increases indicative of myocardial injury, including those with COVID-19, should be classified as

• Chronic myocardial injury
• Acute non-ischemic myocardial injury
• Acute myocardial infarction (MI).

Chronic myocardial injury:

• Chronic myocardial injury, a term that applies to patients with chronic stable (<20% change) cTn increases, can be frequently encountered in patients with COVID-19 as the patients are of older age and they have high prevalence of chronic cardiovascular disease.

Acute non-ischemic myocardial injury:

• Acute non-ischemic myocardial injury, a term that applies to patients with dynamic rising and/or falling cTn concentration without clinical evidence of myocardial ischemia, is probably the predominant mechanism for cTn increases in patients with COVID-19.

Acute myocardial infarction (MI):

• Symptoms of acute myocardial ischemia;
• New ischemic electrocardiographic (ECG) changes;
• Development of pathological Q waves;
• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology;
• Identification of a coronary thrombus by angiography including intracoronary imaging or by autopsy
  • To view the classification of COVID-19, click here.

Pathophysiology

The pathophysiology of COVID-19 acute myocardial injury depends on the underlying cause of myocardial tissue death. However, the overall trigger is an exaggerated inflammatory response (hyperinflammation) in response to viral infiltration into cells. SARS-CoV-2 virus gains entry via the ACE-2 (Angiotensin Converting Enzyme 2) receptor that is found abundantly in myocardial tissue and endothelium of blood vessels.

Proposed pathophysiological mechanisms of COVID-19 associated myocardial injury:

• SARS-CoV-2 downregulates ACE-2 expression and subsequent protective signaling pathways in cardiac myocytes
• Hyperinflammation and cytokine storm mediated through pathologic T-cells and monocytes leading to myocarditis
• Respiratory failure and hypoxemia resulting in damage to cardiac myocytes
• Hypercoagulability and development of coronary microvascular thrombosis
• Diffuse endothelial injury and ‘endothelitis’ from direct cell invasion of SARS-CoV-2 and/or resulting from host inflammatory response.
• Inflammation and/or stress causing coronary plaque rupture or supply-demand mismatch leading to myocardial ischemia/infarction.
• Direct invasion of the cardiac tissue by COVID-19.

Hyperinflammation and cytokine storm:

• • Immune dysregulation, including T cell and immune signaling dysfunction, recognized as an important factor in the pathogenesis of vascular disease, may also adversely affect the body's response to SARS-CoV-2 infection
  • CD4(+) CD25(+) FOXP3(+) regulatory T (TREG) cells have played a role in inflammation. TREG cells { T regulatory cells}) plays a vital role in the induction and maintenance of immune homeostasis and tolerance, any dysregulation in the function or regenaration of TREG cells{ Regulatory T cells}) can trigger abnormal immune responses, that can lead to pathology.
  • Naive T lymphocytes can be primed for viral antigens via antigen-presenting cells.
  • The primed CD8+ T lymphocytes migrate to the cardiomyocytes and through cell-mediated cytotoxicity, cause myocardial inflammation and cardio-tropism by heart-produced Hepatocyte Growth Factor (HGF) which interacts with c-Met, an HGF receptor on naïve T lymphocytes.
  • In the cytokine storm syndrome, proinflammatory cytokines such as Interleukin-6 (IL-6) are released into the circulation, which further augments T-lymphocyte activation and causes the release of more cytokines.
  • Cytokine storms result in increased vascular wall permeabilityand myocardial edema.
  • A positive feedback loop of immune activation and myocardial damage is established.
  • Thus cytokine storm activated by T helper cells (Th1 and Th2) and a systemic hyperinflammatory response is triggered.

Role of ACE-2 Receptor :

• ACE-2 is a membrane-bound aminopeptidate receptor expressed on the epithelial cells of the lungs, intestines, kidneys and blood vessels. It has important immune and cardiovascular roles. Angiotensin-converting enzyme (ACE) cleaves angiotensin I to generate angiotensin II (Ang II), which binds to and activates AT₁R, thus promoting vasoconstriction.
• ACE-2 cleaves angiotensin II and generates angiotensin 1–7, a powerful vasodilator acting through Mas receptors
• SARS-CoV-2 has a spike protein receptor-binding domain, similar to SARS-CoV, which interacts with the ACE-2 receptor and acts as the primary functional receptor for pathogenicity and human-to-human transmission. Furthermore, SARS-CoV-2 binding to ACE-2 leads to its down regulation and increases angiotensin II,a pro-inflammatory factor in the lung.
• This subsequently leads to lower amount of angiotensin 1–7. Thus loss of protective signaling pathway in cardiac myocytes. The detrimental effect of ACE-2 downregulation would impede cardioprotective effects of angiotensin 1–7 leading to increased TNFα production, other cytokines release that can result in acute respiratory distress syndrome, acute cardiac injury and multiorgan dysfunction.
• To view the pathophysiology of COVID-19, click here

Pathophysiology of Acute myocardial injury

Causes

• Hypoxemia induced by Acute respiratory distress syndrome (ARDS)
• Hypercoagulability and plaque rupture
• Hyperinflammation and cytokine storm
• Direct invasion of the cardiac tissue by SARS-CoV-2
• To view causes of COVID-19, click here.

Differentiating COVID-19 associated Acute myocardial injury from other Diseases

• COVID-19 associated acute myocardial injury must be differentiated from other causes of myocardial injury not related to COVID-19 infection.
• The signs and symptoms of acute coronary syndrome, acute heart failure and myocarditis induced by COVID-19 cannot be differentiated from non-COVID-19 acute cardiac disease. Laboratory evaluation with hs-TnI, CK and LDH as well as EKG changes are similar and cannot differentiate between the two disease states
• All patients with COVID-19 induced myocardial injury must be PCR positive for SARS-CoV-2
• The majority of patients have other features of COVID-19, primarily fever, pneumonia and/or ARDS at initial presentation
• A small number of patients have been reported to present primarily with COVID-19 associated myocardial injury and minimal to no other pulmonary/systemic symptom
  • For chest pain differential diagnosis Click here
  • For ACS differential diagnosis Click here
  • For heart failure differential diagnosis Click here
  • For myocarditis differential diagnosis Click here
    • For the differential diagnosis of COVID-19, click here.

COVID-19 associated AMI vs non COVID-19 AMI
Causes	Similar features	Features specific to COVID-19
Acute coronary syndrome -         STEMI, NSTEMI, Unstable Angina -         Type I & II MI	Chest pain Shortness of breath Diaphoresis EKG changes Elevated troponin I level Evidence of coronary occlusion by imaging/PCI	Clinical evidence of SARS-CoV2 infection -         Fever -         Cough -         Dyspnea -         Bilateral ground glass opacities on chest imaging -         Positive SARS-CoV2 PCR (Patients may have nonspecific symptoms such as fatigue and malaise without specific symptoms of cardiac disease)
Acute Heart failure	Chest pain/pressure Shortness of breath Orthopnea Pulmonary edema Jugular venous distention Peripheral edema Elevated BNP Depressed ventricular function on echocardiography
Myocarditis	Chest pain Fatigue S3,S4 or summation gallop Elevated troponin I EKG abnormalities Absence of coronary occlusion
AMI- acute myocardial injury; BNP – Brain Natriuretic peptide; MI – myocardial infarction; NSTEMI - non ST Elevation Myocardial Infarction; PCI – percutaneous intervention; STEMI - ST elevation Myocardial Infarction

Epidemiology and Demographics

Study	Site/ Location	Sample size (n)	Age (years)	Pre-existing cardiac disease	Definition of myocardial injury used in study	Percent with myocardial injury
Huang et al	Wuhan, China	41	Median 49.0	15% cardiovascular disease 15% hypertension	Cardiac injury=troponin I above 99th percentile upper reference limit or new abnormalities on electrocardiography or echocardiography	12
Shi et al	Wuhan, China	416	Median 64.0 (range 21.0–95.0)	4% chronic heart failure 11% coronary heart disease 31% hypertension	Cardiac injury=troponin I above 99th percentile upper reference limit, regardless of new abnormalities on electrocardiography or echocardiography	19.7
Zhou et al	Wuhan, China	191	Median 56.0	8% coronary heart disease 30% hypertension	Cardiac injury=high-sensitivity troponin I above 99th percentile upper reference limit or new abnormalities on electrocardiography or echocardiography	17
Guo et al	Wuhan, China	187	Mean 58.5±14.7	4% cardiomyopathy 11% coronary heart disease 33% hypertension	Myocardial injury=troponin T above 99th percentile upper reference limit	27.8
Wang et al	Wuhan, China	138	Median 56.0	15% cardiovascular disease 31% hypertension	Cardiac injury=troponin I above 99th percentile upper reference limit or new abnormalities on electrocardiography or echocardiography	7.2

Incidence

• The incidence of COVID-19 associated myocardial injury has not been established yet.

Prevalence

• The prevalence of myocardial injury (as reflected by elevation in cardiac troponin levels) is variable among hospitalized patients with COVID-19 and its around 5000-38000 per 100,000 hospitalized individuals worldwide.
• Reported frequencies of 5 to 38 percent
• In a series of 416 patients with COVID-19 who were hospitalized in Wuhan, China, 19.7 percent had high-sensitivity troponin I (hs-TnI) above the 99th percentile upper reference limit on admission.

Case-fatality rate/Mortality rate

• A summary of 44,672 COVID-19 cases documented by the Chinese Center for Disease Control and Prevention demonstrated a case fatality rate of 10.5% with comorbid CVD ( cardiovascular disease) compared to a 2.4% overall case fatality rate
• The mortality rate was also higher in those with myocardial injury (51.2 versus 4.5 percent).

Age

• Patients with this marker of myocardial injury were older and had more comorbidities (including chronic heart failure in 14.6 versus 1.5 percent), greater laboratory abnormalities (including higher levels of C-reactive protein, procalcitonin, and aspartate aminotransferase), more lung radiographic abnormalities, and more complications compared with those without myocardial injury.

Race

• As of June 12, 2020, age-adjusted hospitalization rates are highest among non-Hispanic American Indian or Alaska Native and non-Hispanic black persons, followed by Hispanic or Latino persons. CDC
  • Non-Hispanic American Indian or Alaska Native persons have a rate approximately 5 times that of non-Hispanic white persons,
  • non-Hispanic black persons have a rate approximately 5 times that of non-Hispanic white persons,
  • Hispanic or Latino persons have a rate approximately 4 times that of non-Hispanic white persons

Gender

• .There is no data on gender predilection to acute myocardial injury in COVID-19.

Region

• COVID-19 is a pandemic.

Risk Factors

• A meta-analysis of 6 studies inclusive of 1,527 patients with COVID-19 examined the prevalence of cardiovascular disease (CVD) and reported the prevalence of hypertension, cardiac and cerebrovascular disease, and diabetes to be 17.1%, 16.4%, and 9.7%, respectively
• To view the risk factors of COVID-19, click here.

Screening

• There is insufficient evidence to recommend routine screening for acute myocardial injury in COVID-19 patients.
• To view screening for COVID-19, click here.

Natural History, Complications, and Prognosis

Complications

• The disease also contributes to cardiovascular complications, including
  • Acute coronary syndromes
  • Arrhythmias
  • Myocarditis
  • Pericarditis
  • Heart failure
  • Cardiogenic shock
  • Death

Prognosis

• Prognosis of COVID-19 myocardial injury patients is generally poor.
• A retrospective analysis of the cause of death in Chinese patients infected with COVID-19 revealed that 40% of patients died at least in part because of myocardial injury and circulatory collapse.
• In another study, patients hospitalized for COVID-19 infection developed cardiac injury in roughly 20% of cases; thus leading to greater than 50% mortality.
• Older patients with preexisting cardiovascular comorbidities and diabetes are prone to develop a higher acuity of illness after contracting SARS-CoV-2 associated with higher risk of myocardial injury and a markedly higher short-term mortality rate.
  • To view natural history, complications, and prognosis of COVID-19, click here.

Diagnosis

Initial evaluation of suspected acute myocardial injury in COVID-19

History

Chest pain, diaphoresis Dyspnea is a nonspecific symptom and usually secondary to pneumonia/ARDS

Physical exam

No specific findings in ACS JVD, pulmonary edema

EKG changes

ST elevation/depression Q wave T wave inversion QT prolongation Left bundle branch block

Laboratory evaluation

Serial Troponin l CK BNP

Imaging studies

Echocardiogram

Diagnostic approach to chest pain in COVID-19

For diagnosing of chest pain Click here

History and Symptoms

• Patients with COVID-19 present with the typical symptoms and signs of SARS-CoV-2 infection such as fever, cough, dyspnea. Acute myocardial injury in COVID-19 presents similar to non COVID-19 realted ACS and heart failure.
• For ACS sign and symptoms please Click here
• For Heart failure sign and symptoms please Click here
• To view the history and symptoms of COVID-19, click here.

Physical Examination

• To view the complete physical examination in COVID-19, click here.
• To view physical exam of ACS Click here
• To view physical exam of Heart failure Click here

Laboratory Findings

• Cardiac Biomarkers:
  • The upper reference limit for the high-sensitivity troponin I (hs-TnI) test (0.04ng/mL), based on the 99th percentile of measurements reported in healthy population without the occlusion of coronary arteries.
  • In the recently published retrospective study of 191 COVID-19 patients from two separate hospitals in China, the incidence of elevation in high-sensitivity cardiac troponin I (cTnI) (>28 pg/ml) was 17%, and it was significantly higher among non-survivors (46% versus 1%, p<0.001).
  • Furthermore, elevation of this biomarker was noted to be a predictor of in-hospital death (univariable OR 80.07, 95% CI [10.34–620.36], p<0.0001). The most abrupt increase in cTnI in non-survivors was noted beyond day 16 after the onset of disease. In the same study, the incidence of acute cardiac injury was 17% among all-comers, but significantly higher among non-survivors (59% versus 1%, p<0.0001).
  • CK-MB >2.2 ng/mL
  • Guo et al¹¹ provide additional novel insights that TnT levels are significantly associated with levels of C-reactive protein and N-terminal pro-B-type natriuretic peptide (NT-proBNP), thus linking myocardial injury to severity of inflammation and ventricular dysfunction

Inflammatory biomarkers:

• Elevated levels of inflammatory markers including erythrocyte sedimentation rate, C reactive protein, and procalcitonin are usually seen in myocarditis but they are non-specific and do not confirm the diagnosis. Increases levels of Interleukin-6 (IL-6), d-dimer, serum ferritin, prothrombin time were seen in COVID-19 patients.
  • To view the laboratory findings on COVID-19, click here.

Electrocardiogram

• The electrocardiogram (ECG) can demonstrate a range of findings
  • In some cases mimicking acute coronary syndrome (ACS).
  • The ECG abnormalities result from myocardial inflammation and include non-specific ST segment-T wave abnormalities.
  • T wave inversion.
  • PR segment and ST segment deviations (depression and elevation)
  • The ECG can help to find previous cardiac abnormalities and triggering factors, such as acute myocardial infarction, and arrhythmias.
    • To view the electrocardiogram findings of ACS Click here
    • To view the electrocardiogram findings heart failure Click here
    • To view the electrocardiogram findings on COVID-19, click here.

X-ray

• There are no specific X-ray findings in COVID-19 associated myocardial injury.
• To view the x-ray finidings on COVID-19, click here.
  

Ultrasound/Echocardiography

• There are no specific ultrasound/ echocardiographic findings related to COVID-19-associated acute myocardial injury
• To view the echocardiographic findings on COVID-19, click here.
  

CT Scan

• There are no specific CT scan findings related to COVID-19-associated acute myocardial injury.
• To view the CT scan findings on COVID-19, click here.

MRI

• There are no specific MRI findings related to COVID-19-associated acute myocardial injury.
• To view the MRI findings on COVID-19, click here.
  

Other Imaging Findings

• There are no other imaging findings related to COVID-19-associated acute myocardial injury.
• To view other imaging findings on COVID-19, click here.
  

Other Diagnostic Findings

• There are no other diagnostic studies related to COVID-19-associated acute myocardial injury.
• To view other diagnostic studies for COVID-19, click here.
  

Treatment

Medical Therapy

• There are no specific treatments, and treatment varies depending upon presentation, please click on the conditions to see the management.
  • (COVID-19-associated myocarditis
  • COVID-19-associated myocardial infarction
  • COVID-19-associated heart failure
  • COVID-19-associated arrhythmia and conduction system disease
  • COVID-19-associated cardiogenic shock
  • COVID-19-associated cardiac arrest
  • COVID-19-associated pericarditis
  • COVID-19-associated spontaneous coronary artery dissection
  • To view medical treatment for COVID-19, click here.

Surgery

• There is no established surgical intervention for the treatment of COVID-19-associated acute myocardial injury.

Primary Prevention

• There are no available vaccines against COVID-19 and studies are going on for finding an effective vaccine.
• Other primary prevention strategies include measures to reduce the occurrence of myocardial injury among COVID-19 patients. Recent studies have suggested the use of medications improving microcirculation, especially for the high-risk group such as males, smokers, diabetic patients, and patients with established cardiovascular disease comorbidities.
  • For Risk factors associated with COVID-19 please click here

Secondary Prevention

• There are no established measures for the secondary prevention of COVID-19-associated myocardial injury.

References

COVID 19