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: Sara Zand, M.D.[2] 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). Myocardial injury presented by high level of cardiac troponin is a common manifestation in COVID-19. The exact pathogenesis of myocardial injury in COVID-19 is not clear yet. However, systemic inflammation, hypoxemia, vasopressor requirement, thrombophilia have been proposed as the underlying mechanisms of myocardial injury. Factors associated with myocardial injury including age, creatinine, multisystem organ failure were similar in both COVID-19 and non COVID-19 patients. Myocardial injury was less common in severe COVID-19 in comparisson with ARDS without COVID-19. However, it was associated with poor outcome in critically ill COVID-19 patients and increased risk of intubation and death. So, Myocardial injury can be the manifestation of underlying critically illness and multisystem organ dysfunction, especially concomitant renal dysfunction, as well as thrombotic complications among COVID-19 patients.

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

• Common causes of high troponin level in COVID-19 are:
• Thrombotic , plaque rupture events
• Supply-demand mismatch
• Direct cardiac viral toxicity
• Older age
• Acute renal dysfunction
• Chronic renal dysfunction
• High serum lactate level
• Inflammation, prothrombothic state in COVID-19
• High level of ferritin as a marker of inflammation
• Low level of fibrinogen as a marker of consumption, microvascular thrombi, endothelial dysfunction

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
• Table below shows the differentiating diagnosis of elevated troponin level:

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 is known to be approximately 5,000-38,000 per 100,000 hospitalized individuals worldwide.
• Reported frequencies range from 5% to 38%
• 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% ).

Age

• Patients with this marker of myocardial injury were older and had more comorbidities (including chronic heart failure, 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

• There is no racial predilection in myocardial injury associated COVID-19.

Gender

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

Risk Factors

Predictors of elevated troponin level in hospitalized COVID-19 were:

• Age
• Female sex
• Low systolic blood pressure
• High level of creatinine

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

• Myocardial injury in severe COVID-19 was associated with underlying comorbidities, older age, multisystem organ dysfunction similar to non COVID-19 critically ill patients.
• COVID-19 critically ill patients with increased level of troponin were more likely to be intubated.
• Myocardial injury was less common among COVID-19 patients compared with ARDS without COVID-19 after adjusting confounders including age, renal dysfunction, degree of critical illness.
• Myocardial injury was estimated to be approximately in 50% of intubated patients. However, mortality risk decreased after adjustment for the degree of critical illness.

Complications

• Mycardial injury 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 and was associated with multisystem organ involvement and critical illness.
• Mortality was higher among intubated COVID-19 patients with highest level of troponin compared with troponin below the ULN (61.5% vs 22.7%).

• 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.

Diagnosis

• The diagnosis is made when the level of cardiac troponin is above the 99th percentile.
• Clinical evaluation and obtaining ECG for diagnosis the causes of cardiac injury including acute myocardial infarction, myocarditis, Takotsubo syndrome, direct injury from covid-19, as well as noncardiac condition such as pulmonary emboli, critical illness, sepsis, ACS with normal or near normal coronary artery should be considered.

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 chest pain diagnostics 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 related 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), is 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)
  • An 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 findings on COVID-19, click here.
  

Ultrasound/Echocardiography

• Concomitant myocardial injury and echocardiography abnormalities]] were associated with high mortality. However, mortality was not increased in the presence of myocardial injury without echocardiography abnormalities.(ACC,2020)

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

• Cardiac MRI can be used for evaluation of myocardial injury associated COVID-19.
• Findings of CMR among recovered COVID-19 with myocardial injury include:

  Myocardial edema

  Myocardial fibrosis

  Impaired right ventricular function

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

The mainstay of therapy in myocardial injury is:

• Antiviral therapy: favipiravir, remdesivir, chloroquine
• Treatment of cytokine storm associated with SARS-COV-2 infection: antishock therapy, steroid, neutralized antibodies
• Treatment of underlying cardiovascular comorbidities: use of statin, betablocker, ACEI, aspirin for plaques stabilization, heart failure treatment, ECMO
  • 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

• Effective measure for primary prevention strategy in myocardial injury associated COVID-19 is vaccination.
• Other primary prevention strategies include measures to reduce the occurrence of myocardial injury among COVID-19 patients.

Secondary Prevention

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

References

COVID 19