COVID-19-associated myocardial injury

Overview Acute myocardial injury may be defined across studies as any of the following

Elevated troponin levels [1]. 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..[2] Elevated cardiac biomarker levels to > 99th percentile of upper reference limit.[3] Electrocardiographic and echocardiographic abnormalities.[4] Coronavirus disease 2019 (COVID-19) is a rapidly expanding global pandemic which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) , resulting in significant morbidity and mortality. Some hospitalized patients can develop an acute COVID-19 myocardial injury, which can manifest with a variety of clinical presentations but often presents as an acute cardiac injury with cardiomyopathy, ventricular arrhythmias, and hemodynamic instability, acute coronary syndrome, cardiogenic shock. patents with preexisting cardiovascular disease have higher morbidity and mortality.

Historical Perspective One of the first reports of myocardial injury associated with SARS-CoV-2 was a study of 41 patients diagnosed with COVID-19 in Wuhan, China, wherein 5 patients (12%) had a high-sensitivity troponin I above the threshold of 28 pg/mL [5] Classification There is no established system for the classification of Acute myocardial injury.

Pathophysiology The pathophysiology of myocardial injury include, Hyperinflammation and cytokine storm mediated through pathologic T-cells and monocytes leading to myocarditis[6] Respiratory failure and hypoxemia resulting in damage to cardiac myocytes[7] Down regulation of ACE2 expression and subsequent protective signaling pathways in cardiac myocytes Hypercoagulability and development of coronary microvascular thrombosis[8] Diffuse endothelial injury and ‘endotheliitis’ in several organs, including the heart as a direct consequence of SARS-CoV-2 viral involvement and/or resulting from host inflammatory response.[9] inflammation and/or stress causing coronary plaque rupture or supply-demand mismatch leading to myocardial ischemia/infarction.[10] Electrolyte imbalances and adverse medication effects may disproportionately challenge a diseased heart, with special consideration for the regimen of hydroxychloroquine and azithromycin treatment due to the potential for QTc prolongation [11] Direct invasion of the cardiac tissue by COVID-19.[12] 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[13] The role of CD4(+)CD25(+)FOXP3(+) regulatory T (TREG) cells in the modulation of inflammation and immunity has received increasing attention. Given the important role of TREG cells in the induction and maintenance of immune homeostasis and tolerance, dysregulation in the generation or function of TREG cells can trigger abnormal immune responses and lead to pathology. Evidence from experimental and clinical studies has indicated that TREG cells might have an important role in protecting against cardiovascular disease, in particular atherosclerosis and abdominal aortic aneurysm. The role of TREG cells is evident in the pathogenesis of a number of cardiovascular diseases, including atherosclerosis, hypertension, ischaemic stroke, abdominal aortic aneurysm, Kawasaki disease, pulmonary arterial hypertension, myocardial infarction and remodelling, postischaemic neovascularization, myocarditis and dilated cardiomyopathy, and heart failure.[14] Role of ACE 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-1, which interacts with the ACE-2 receptor and acts as the primary functional receptor for pathogenicity and human-to-human transmission.[15] 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 syndrome, acute cardiac injury and multiorgan dysfunction.[16] Causes Acute respiratory distress syndrome. (ARDS) Pneumonia. Hypercoagulability and plaque rupture. Hyperinflammation and cytokine storm. Electrolyte imbalances and adverse medication effects Direct invasion of the cardiac tissue by COVID-19. Myocarditis and myocyte necrosis. Epidemiology and Demographics 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[17] The frequency of myocardial injury (as reflected by elevation in cardiac troponin levels) is variable among hospitalized patients with COVID-19, with reported frequencies of 7 to 28 percent[18] [19]. Some studies have identified greater frequency and magnitude of troponin elevations in hospitalized patients with more severe disease and worse outcomes [20] 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 [21]. 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. The mortality rate was also higher in those with myocardial injury (51.2 versus 4.5 percent). The risk of death starting from the time of symptom onset was more than four times higher in patients with evidence of myocardial injury on admission. Risk Factors A meta-analysis of 6 studies inclusive of 1,527 patients with COVID-19 examined the prevalence of cardio vascular disease (CVD) and reported the prevalence of hypertension, cardiac and cerebrovascular disease, and diabetes to be 17.1%, 16.4%, and 9.7%, respectively [22]

Screening There is insufficient evidence to recommend routine screening for acute myocardial injury in COVID-19 patients. Natural History, Complications, and Prognosis The disease also contributes to cardiovascular complications, including Acute coronary syndromes Arrhythmias Myocarditis Pericarditis Heart failure Cardiogenic shock Death. 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.[23] Diagnosis Diagnostic Study of Choice Cardiac Biomarkers and Acute Cardiac Injury he 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).10 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).[24] 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[25] History and Symptoms Patients with COVID-19 can present with the typical symptoms and signs of SARS-CoV-2 nfection such as fever, cough, dyspnea, and bilateral infiltrates on chest imaging can present with chest pain, dyspnea, dysarrhythmia, and acute left ventricular dysfunction [26] [27] Physical Examination Laboratory Findings 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) X-ray Echocardiography or Ultrasound CT scan MRI Other Imaging Findings Other Diagnostic Studies Treatment Treatment of Acute myocardial injury depends upon the complication the