Laboratory Diagnostics of Myocardial Infarction, Myocarditis and Heart Failure

Laboratory Diagnostics of Myocardial Infarction, Myocarditis and Heart Failure

1. PERM STATE MEDICAL UNIVERSITY Academician E. A. Wagner State M edical U niversity of the Ministry of Health of the R ussian Federation Laboratory DIAGNOSTICS of MYOCARDIAL INFARCTION, MYOCARDITIS AND HEART FAILURE ALOOR JOISY JOHNSON FINAL YEAR MEDICAL STUDENT, GENERAL FACULTY

2. MYOCARDIAL INFARCTION Myocardial infarction (MI), commonly known as a heart attack, is defined pathologically as the irreversible death of myocardial cells caused by ischemia. Clinically, MI is a syndrome that can be recognized by a set of symptoms, chest pain being the hallmark of these symptoms in most cases, supported by biochemical laboratory changes, electrocardiographic (ECG) changes, or findings on imaging modalities able to detect myocardial injury and necrosis .

3. According to the WHO criteria as revised in 2000, a cardiac troponin rise accompanied by either typical symptoms, pathological Q waves, ST elevation or depression or coronary intervention are diagnostic of MI. Previous who criteria formulated in 1979 put less emphasis on cardiac biomarkers; according to these, a patient is diagnosed with myocardial infarction if two (probable) or three (definite) of the following criteria are satisfied: Clinical history of ischemic type chest pain lasting for more than 20 minutes. Changes in serial ECG tracings. Rise and fall of serum cardiac biomarkers such as C reatine Kinase-MB fraction and Troponin.

4. APPROACH CONSIDERATIONS: The objectives of laboratory testing and imaging include the following: To determine the presence or absence of myocardial infarction (MI) for diagnosis and differential diagnosis (point–of-care testing and testing in central laboratory of cardiac troponin levels) To characterize the locus, nature (ST-elevation MI [STEMI] or non–ST-elevation MI [NSTEMI]), and extent of MI (i.e, to estimate infarct size) To detect recurrent ischemia or MI (extension of MI) To detect early and late complications of MI To estimate the patient's prognosis

5. LABORATORY TESTS USED IN THE DIAGNOSIS OF MYOCARDIAL INFARCTION (MI) INCLUDE THE FOLLOWING: Cardiac biomarkers/enzymes: The A merican C ollege of Cardiology/American H eart A ssociation (ACC/AHA) and the E uropean S ociety of Cardiology (ESC) guidelines recommend Cardiac T roponin as the only cardiac biomarker that should be measured at presentation in patients with suspected MI, due to its superior sensitivity and accuracy. Troponin is a contractile protein that is not normally found in serum; it is released only when myocardial necrosis occurs. Complete blood cell (CBC) count Comprehensive metabolic panel Lipid profile

6. TIMING OF RELEASE OF VARIOUS CARDIAC BIOMARKER PEAKS AFTER THE ONSET OF MYOCARDIAL INFARCTION SERIAL MEASUREMENT OF CARDIAC TROPONINS AFTER THE INITIAL LEVEL IS OBTAINED AT PRESENTATION, 3 TO 6 HOURS AFTER SYMPTOM ONSET, IS RECOMMENDED. IF INITIAL LEVELS ARE NEGATIVE, ADDITIONAL MEASUREMENTS BEYOND THE 6-HOUR MARK SHOULD BE OBTAINED. CARDIAC TROPONIN Troponin is a contractile protein that normally is not found in serum. It is released only when myocardial necrosis occurs. Of the three troponin subunits, two (troponin I and troponin T) are derived from the myocardium. Serum levels increase within 3-12 hours from the onset of chest pain, peak at 24-48 hours, and return to baseline over 5-14 days.

7. MYOGLOBIN Myoglobin is a low molecular weight iron- and oxygen-binding protein abundantly expressed in the myocardium and skeletal muscle. Myoglobin is rapidly released by the injured myocardium. Its blood levels start to increase within the first 30 min to 2 h after the onset of ischemia, which makes myoglobin an important marker for the early detection/exclusion of cardiac injury. Its levels increase during the first 6–10 h after AMI, reach a peak12 h after the acute event, and return to baseline by 24 h after AMI. Myoglobin is not found in any other tissue than the muscle, making it a sensitive marker for AMI.

8. B-TYPE NATRIURETIC PEPTIDE B-type natriuretic peptide (BNP) is a 32-amino acid polypeptide secreted by the ventricles of the heart in response to excessive stretching of cardiomyocytes . Measurement of BNP or N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) for the diagnosis of acute myocardial infarction (MI) is not recommended for diagnosis of MI, but these biomarkers have utility in risk stratification and prognostication of patients with acute MI who may have congestive heart failure. OTHER LABORATORY STUDIES COMPLETE BLOOD CELL COUNT A platelet count is necessary if a IIB/IIIA agent is considered; furthermore, the patient's white blood cell (WBC) count may be modestly elevated in the setting of MI, signifying an acute inflammatory state. The platelet count may become dangerously low after the use of heparin because of heparin-induced thrombocytopenia (HIT). The leukocyte count may be normal initially, but it generally increases within 2 hours and peaks in 2-4 days, with predominance of polymorphonuclear leukocytes and a shift to the left. Elevations generally persist for 1-2 weeks. LIPID PROFILE A lipid profile may be helpful if obtained upon presentation, because levels can change after 12-24 hours of an acute illness.

9. CHEMISTRY PROFILE (COMPREHENSIVE METABOLIC PANEL) In the setting of MI, closely monitor potassium and magnesium levels. Blood glucose levels are important to measure, as many patients are first diagnosed with diabetes when they present with MI. Although not routinely measured, the erythrocyte sedimentation rate (ESR) rises above reference range values within 3 days and may remain elevated for weeks. The serum lactate dehydrogenase (LDH) level rises above the reference range within 24 hours of MI, reaches a peak within 3-6 days, and returns to the baseline within 8-12 days. HISTOPATHOLOGY Histopathological examination of the heart may reveal infarction at autopsy. Gross examination may reveal signs of myocardial infarction. A ONE-WEEK-OLD MYOCARDIAL INFARCTION OF THE POSTERIOR LEFT VENTRICLE, WITH FOCAL RUPTURE, IN FRESH STATE (LEFT) AND AFTER FORMALIN FIXATION (RIGHT). THE INFARCTED AREA IS PALE WHEREAS THE RUPTURE IS HEMORRHAGIC (DARK RED).

10. CROSS-SECTION OF THE HEART, SHOWING AN OLD MYOCARDIAL INFARCTION OF THE POSTERIOR WALL OF THE LEFT VENTRICLE (SEEN AS PALE AREAS). A COLOR-ENHANCED ANGIOGRAM OF THE HEART LEFT SHOWS A PLAQUE-INDUCED OBSTRUCTION (TOP CENTER) IN A MAJOR ARTERY, WHICH CAN LEAD TO MYOCARDIAL INFARCTION (MI). MIS CAN PRECIPITATE HEART FAILURE. UNDER THE MICROSCOPE, MYOCARDIAL INFARCTION PRESENTS AS A CIRCUMSCRIBED AREA OF ISCHEMIC, COAGULATIVE NECROSIS (CELL DEATH). ON GROSS EXAMINATION, THE INFARCT IS NOT IDENTIFIABLE WITHIN THE FIRST 12 HOURS.

11. BIOMARKERS OF PLAQUE DESTABILIZATION AND MYOCYTE RUPTURE Myeloperoxidase (MPO), a component of neutrophil granules, is abundantly released from unstable atherosclerotic plaques and plays a critical role in myocardial inflammation and oxidative stress. When used alone, MPO does not seem to be appropriate for AMI diagnosis. However , when combined with TnI and CK-MB, MPO appears to improve the early diagnostic accuracy of AMI. Biomarkers, including lipid markers (lipoprotein A, apolipoproteins A and B), endothelial cells- ( endocan ) and platelet- (mean platelet volume, mean platelet volume- toplatelet count ratio, beta- thromboglobulin , platelet miR-126) related markers have been proposed as AMI biomarkers. Non-coding RNAs, including microRNAs ( miRNAs ), circular RNAs, and long noncoding RNAs ( lncRNAs ), act as strong, tissue- and cell-specific epigenetic regulators of cardiac gene expression, homeostasis, and function, and have recently emerged as promising biomarkers in a wide variety of cardiovascular diseases.

12. MYOCARDITIS Also known as Inflammatory C ardiomyopathy, is an Acquired C ardiomyopathy due to inflammation of the cardiac muscle. Myocarditis is most often due to a viral infection . Other causes include bacterial infections, certain medications, toxins and autoimmune disorders . A diagnosis may be supported by an electrocardiogram (ECG), increased troponin, heart MRI, and occasionally a heart biopsy . An ultrasound of the heart is important to rule out other potential causes such as heart valve problems .

13. LABORATORY STUDIES USE TO EVALUATE SUSPECTED MYOCARDITIS MAY INCLUDE THE FOLLOWING: Complete Blood Count: Leukocytosis (may demonstrate eosinophilia ). Erythrocyte Sedimentation R ate L evel (and that of other acute phase reactants [e.g., C-Reactive P rotein]) Rheumatologic Screening Cardiac Enzyme L evels (e.g., C reatine K inase or Cardiac T roponins) Serum V iral Antibody T iters Viral Genome T esting in Endomyocardial B iopsy Electrocardiography

14. Cardiac Enzymes and Natriuretic Peptide: Elevated Creatine Kinase or Cardiac Troponins (in Fulminant Myocarditis, an e levated Serum Cardiac Troponin [CTN] is a lmost a lways p resent, but t he a bsence o f i ts e levation d oes n ot r ule o ut Myocarditis.) Elevated cardiac enzymes are an indicator for cardiac myonecrosis. Cardiac troponin (troponin I or T), in particular, is elevated in at least 50% of patients with biopsy-proven myocarditis . MYOCARDITIS. HEMATOXYLIN AND EOSIN STAINING. HIGH POWER. TOXOPLASMOSIS (NUMEROUS PURPLE GRANULAR-LIKE STRUCTURES WITHIN A MYOCYTE) IS DEMONSTRATED.

15. Antimyosin scintigraphy (using antimyosin antibody injections) can identify myocardial inflammation with high sensitivity (91-100%) and negative predictive power (93-100%) but has low specificity (31-44%) and low positive predictive power (28-33%). Positron emission tomography (pet) scanning has been used in selected cases (e.g., sarcoidosis) to assess the degree and location of inflammation. Gadolinium-enhanced magnetic resonance imaging (MRI) is used for assessment of the extent of inflammation and cellular edema, although it is still nonspecific. Delayed-enhanced MRI has also been used to quantify the amount of scarring that occurred following acute myocarditis . Endomyocardial biopsy (EMB) is the criterion standard for the diagnosis of myocarditis. However, endomyocardial biopsy has limited sensitivity and specificity, as inflammation can be diffuse or focal.

16. HEART FAILURE Heart failure develops when the heart, via an abnormality of cardiac function (detectable or not), fails to pump blood at a rate commensurate with the requirements of the metabolizing tissues or is able to do so only with an elevated diastolic filling pressure . Symptoms result from a structural and/or functional abnormality of the heart, that disrupts its filling with blood or its ejecting of it during each heart beat. Careful evaluation of the patient's history and physical examination (including signs of congestion, such as jugular venous distention) can provide important information about the underlying cardiac abnormality in heart failure. However, other studies and/or tests may be necessary to identify structural abnormalities or conditions that can lead to or exacerbate heart failure. Endomyocardial biopsy is indicated only when a specific diagnosis is suspected that would influence therapy in patients presenting with heart failure.

17. Clinical practice guidelines on the diagnosis and management of heart failure by the European Society of Cardiology (ESC) were published in August 2021. Recommendations include the following: HFPEF ( H eart F ailure with Preserved E jection F raction) diagnosis requires evidence of cardiac structural or functional abnormalities as well as elevated plasma NP (natriuretic peptide) concentrations consistent with LV diastolic dysfunction and increased LV filling pressures. A diastolic stress test is recommended if these markers are equivocal. Basic tests such as serum urea and electrolytes, creatinine, full blood count, and liver and thyroid function tests are recommended to differentiate HF from other conditions, to provide prognostic information, and to guide potential therapy .

18. Genetic testing should be considered in individuals who have a clinical diagnosis of ARVD based on the diagnostic criteria. A case can be made to offer genetic testing to all with a clinical diagnosis of ARVD with a negative family history based on the high rate of reduced penetrance thus far identified with the ARVD genes. Molecular genetic testing is available on a clinical basis for TGFB3, RYR2, TMEM43, DSP, PKP2, DSG2, DSC2, and JUP.

19. LIVER FUNCTION TESTS In severe cases of acute right ventricular (RV) or left ventricular (LV) failure, frank jaundice may occur . Acute hepatic venous congestion can result in severe jaundice, with a bilirubin level as high as 15-20 mg/dL, elevation of AST to more than 10 times the upper reference range limit, elevation of the serum alkaline phosphatase level, and prolongation of the prothrombin time. Patients with severe heart failure, particularly those on large doses of diuretics for long periods, may have elevated BUN and creatinine levels indicative of renal insufficiency owing to chronic reductions of renal blood flow from reduced cardiac output. RENAL FUNCTION TESTS