Serial cardiac markers

It has also been reported to be more sensitive in detecting small injuries to the myocardium that occur in patients with non-ST elevation ACS. These interferences have no such effects when mass assays are used because the antibodies are specific for CK-MB and do not cross-react with these compounds. This sensitivity and specificity changes with the time of presentation after symptom onset.

Measurement of CK-MB activity is most reliable in the hours period after symptom onset. Studies comparing the utilisation of these assays for the early diagnosis of AMI have shown that CK-MB mass reaches the cut-off point in serum several hours before CK-MB activity and have claimed its superiority within 4—8 hours after symptom onset.

This observation has been substantiated by different groups. Severe skeletal muscle damage e. In these situations, the CK-MB to CK ratio or cardiac troponins can be used to differentiate cardiac and non-cardiac pathologies. They were discovered by Weavers in This isoenzyme is converted into other forms by the action of the plasma enzyme carboxypeptidase N CPN according to the following reaction: Therefore, in the event of myocardial injury, it will require a several-fold increase in the marker before it exceeds the upper limit of the reference range.

CK-MB, being a relatively large molecule, may take even longer to reach the circulation and become important diagnostically. When myocardial injury occurs, there is a sudden release and rise of the tissue isoforms, i. By using CK-MB isoforms effectively each patient acts as his own control, and a release of only a small amount of the marker is required to raise the ratio much earlier to a significant level. Creatine kinase MB isoforms are reported to be released within 1 hour after symptom onset and peak at 4 hours.

One study reported a sensitivity and specificity of The test was also positive in patients with hypothyroidism and rhabdomyolysis. A study by Laurino et al. Myoglobin is a small heme protein 17 K Da that functions in oxygen binding and transport. It stores oxygen in red muscles skeletal and cardiac and, under conditions of severe oxygen deprivation, it releases the oxygen to be used by muscle mitochondria for synthesis of adenosine triphosphate ATP.

The myoglobin content of heart muscle is reported to be 2. Males have higher levels than females because they have bigger body size and muscle bulk. Myoglobin is one of the best available early markers of AMI within 3 hours after symptom onset. The relationship between AMI and high myoglobin levels was first reported in Several investigators have confirmed a significant role for myoglobin in the early diagnosis of AMI, the most promising role being in the early exclusion of AMI in patients presenting within 6 hours after symptoms onset.

However, a positive result should be used with caution, as there are many situations that could give rise to myoglobin elevation in the absence of AMI. Myoglobin is a non-specific marker protein for myocardial injury. Serum myoglobin is raised in skeletal muscle damage including intramuscular injection, exhaustive exercise, muscle trauma, direct current shock cardioversion, and also in patients and carriers of genetic muscle disease.

Severe renal disease leads to failure of clearance of myoglobin from the circulation. The concentration tends to rise and the circulation time is prolonged in these patients. Although these factors interfere with the specificity of the test, in clinical practice most of them could be ruled out by careful attention to history taking and simple blood tests.

Coronary angiography is the most definitive method to assess the success of thrombolytic treatment, but this procedure is invasive, carries morbidity and mortality risks, requires a catheterisation laboratory team, and is not widely available. Biochemical markers like myoglobin among others offer an alternative non-invasive, safe and potentially sensitive method for the detection of reperfusion.

This can be done by monitoring the changes in serum concentration immediately before and 60 or 90 minutes after initiation of thrombolysis. Patients who successfully reperfuse their occluded artery show a higher and early concentration peak of the biochemical marker compared to those who fail to reperfuse.

Thus a patent artery does not invariably indicate tissue reperfusion. Accurate markers of tissue reperfusion are required. The combination of serial lead ECG, clinical features, and serial cardiac markers testing offer a practical alternative to coronary angiography for assessment of reperfusion status. It is composed of amino acids.

It was introduced by Glatz et al. This makes the plasma estimation of H-FABP a suitable indicator for the early detection and quantification of myocardial tissue injury. Heart-type FABP is released into plasma within 2 hours after symptom onset and is reported to peak at about 4—6 hours and to return to normal base line level in 20 hours.

Serial measurements of H-FABP in the first 24 hours after onset of symptoms may be potentially useful for: the diagnosis of AMI; to identify patients who need early reperfusion treatment; to identify patients who reperfuse their infarct related artery; to detect re-infarction if it occurs early and for estimation of infarct size. Heart-type FABP exists in high concentrations in the heart only.

However, this protein is not totally cardiac specific and occurs in other tissues although in much lower concentrations. Gorski et al. The concentrations of these markers were not affected by dialysis. H-FABP is increased in the plasma of healthy volunteers after strenuous exercise.

Myoglobin and H-FABP share many key features: 1 low molecular weight proteins 17 and 15Kda, respectively ; 2 abundant concentrations in the cytosol of myocardial cells; 3 substrate for mitochondrial oxidation oxygen and fatty acids, respectively and 4 both are released within 2 hours after symptom onset, peak early 6 hours and return to normal baseline concentration within 24 hours.

Both proteins are present in the heart and skeletal muscle in different concentrations. The concentration of myoglobin in heart and skeletal muscle is 2. The myoglobin content of skeletal muscle is twice that of the heart.

H-FABP is therefore more cardio-specific than myoglobin. The normal ratio of myoglobin: H-FABP in the myocardium is about , whereas the ratio in skeletal muscle is in the order of depending on muscle type.

A myoglobin: H-FABP ratio that is around is considered to be specific for the heart and a ratio that is between is more specific to skeletal muscle damage.

However, the use of this ratio should not be a rigid criterion as overlaps do occur. The troponin complex is found on the thin filament actin of all types of striated muscle fast, slow, and cardiac. Its function is to regulate calcium dependent contraction of muscles. They are designated with a letter that refers to the function of the troponin protein; TnC binds calcium; TnI inhibits the action of the enzyme actomyosin adenosine triphosphatase; TnT binds to tropomyosin. Cardiac TnT has more tissue distribution and more free cytoplasmic concentration and is released as a complex with the other cardiac troponin T-I-C.

Cardiac TnI is released more in the binary form troponin I-C complex. The half-life of cTnT in circulation is minutes and this long diagnostic window is thought to be due to the continuous release of the marker from myocardial cells after necrosis, and not due to slow clearance from the circulation. It was found that the group that had elevated concentrations of cTnT had an increased risk of cardiac events and the higher the cTnT the more frequent the complications.

Patients were followed-up for 6 months for cardiac complications. The risk of further AMI and death was 4. The incidence of complications in this group was very high: cardiac death 12 patients , coronary revascularisation 22 patients , death and non-fatal AMI 18 patients.

Cardiac-TnT measurement can help select the appropriate patients for treatment with antithrombotics. However, patients with cTnT greater than or equal to 0. Elevated cTnT concentration has been reported in a significant numbers of patients with chronic renal failure. These levels do not seem to be affected by haemodialysis, with elevations persisting after treatment. There is however, a slightly higher rate of positive results with cTnT assays in some patients with chronic renal failure and acute or chronic muscle disease.

During foetal development both sTnI and cTnI are expressed in the myocardium; however, at birth, the cTnI remains as the only isoform present in the human myocardium. Cardiac-TnI was first reported as a biochemical marker of myocardial injury in and has since been shown to be a very sensitive and specific marker for the diagnosis of AMI. Cardiac-TnI is cardiac specific and its concentration in normal and disease free populations is undetectable or very low.

This makes it a suitable marker for the detection of myocardial injury in patients with Non-ST elevation MI as well as other situations where myocardial injury is expected, but the amount released could be small, e. Those patients showing higher levels at admission have more complications increased mortality and AMI on subsequent follow-up. Cardiac-TnI was not found in patients who underwent uncomplicated angioplasty.

Thus, there is a lack of standardisation of methodology for cTnI assays. However, cTnI has been reported to show slightly better specificity in situations where there is severe skeletal muscle injury and renal failure. Cardiac-TnI was not elevated in patients who underwent non-cardiac surgery, but was raised in patients undergoing CABG due to surgical injury of the myocardium.

Cardiac-TnI or cTnT may be the preferred markers of choice to detect myocardial injury in patients who undergo non-cardiac surgery. In the situation of non-cardiac surgery, cTnI or cTnT , being specific to the myocardium, will also help to distinguish elevation of CK-MB due to skeletal muscle damage alone from elevation due to myocardial injury. Although all have been shown to be excellent sensitive early markers, there are still significant issues concerning its specificity.

CK-MB mass measurement is suitable in the 6—24 hours interval; CK-MB based on activity measurement is more sensitive in the 12—24 hours interval, and the other cardiac markers like total CK, cTnT, and cTnI are most reliable after 12 hours from symptom onset. The prolonged diagnostic window of cardiac troponins of several days that is highly sensitive and specific obviates the needs for less specific markers with long diagnostic window like aspertate aminotransferase ALT and CK.

Decision-making regarding triage and treatment of patients should not be based on a single measurement of cardiac markers alone because of the time delay required for the marker to exceed the upper limit of reference range.

CK-MB preferably mass is the second best marker in the absence of troponins assays. Patients who present with acute chest pain suspicious of ACS are best managed within specifically designated units that have rapid access to specific equipment ECG, echocardiogram and facilities point of care instruments to measure cardiac markers , and with appropriate staffing. Acute chest pain units attached to emergency departments can accommodate patients for 12 hours, so that appropriate investigations can be carried out quickly after presentation in order to identify patients with evolving infarction who are at increased risk.

A serial combination testing of a sensitive early marker e. Two serial testings within a minimum of 12 hours e. This 12 hour strategy also identifies patients at low-risk for acute ischaemic events. National Center for Biotechnology Information , U. Sultan Qaboos Univ Med J.

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Abstract Chest pain is a non-specific complaint and is the most frequent reason for patients seeking urgent medical attention. Characteristic Features of Biochemical Markers of Myocardial Injury The ideal characteristics of a marker of myocardial injury are: 1 it should be abundant in the myocardium and not present in other tissues.

The sensitivity and specificity of cardiac markers for the early diagnosis of AMI is influenced by several factors such as: Time of presentation: Early presentation after symptom onset is likely to show a relatively increased sensitivity for markers like myoglobin, which is released very early in the course of AMI, and less sensitivity for markers like CK-MB or cTnI, which are released slightly later.

Myoglobin Myoglobin is a small heme protein 17 K Da that functions in oxygen binding and transport. H-FABP AND MYOGLOBIN Myoglobin and H-FABP share many key features: 1 low molecular weight proteins 17 and 15Kda, respectively ; 2 abundant concentrations in the cytosol of myocardial cells; 3 substrate for mitochondrial oxidation oxygen and fatty acids, respectively and 4 both are released within 2 hours after symptom onset, peak early 6 hours and return to normal baseline concentration within 24 hours.

Cardiac Troponins The troponin complex is found on the thin filament actin of all types of striated muscle fast, slow, and cardiac. References 1. The burden of cardiovascular disease mortality in Europe. Eur Heart J. Trends in coronary care. A retrospective study of patients with myocardial infarction treated in coronary care units. Acta Med Scand. Alpert JS, Thygesen K. Cohn PF. Silent myocardial ischemia.

Ann Intern Med. Ann Emerg Med. The initial electrocardiogram during admission for myocardial infarction. Use as a predictor of clinical course and facility utilization. Arch Intern Med. Biochemical markers of myocardial injury. Is MB creatine kinase the choice for the s? Use of cardiac enzymes identifies patients with acute myocardial infarction otherwise unrecognized in the emergency department. Analytical and clinical evaluation of creatine kinase MB mass assay by IMx: comparison with MB isoenzyme activity and serum myoglobin for early diagnosis of myocardial infarction.

Clin Chem. Value of myoglobin, troponin T, and CK-MB mass in ruling out an acute myocardial infarction in the emergency room. Early monitoring of serum cardiac troponin I for assessment of coronary reperfusion following thrombolytic therapy.

Am J Clin Pathol. Henderson AR, Bhayana V. A modest proposal for the consistent presentations of ROC plots in clinical chemistry. Wu AHB. In: Wu AHB, editor. Cardiac Markers. Molecular heterogeneity of creatine kinase isoenzymes. Biochim Biophys Acta. Serum creatine phosphokinase in acute myocardial infarction. Increased creatine kinase MB in the absence of acute myocardial infarction. Creatine Kinase, Isoenzymes, and variants. Mass concentration and activity concentration of creatine kinase isoenzyme MB compared in serum after acute myocardial infarction.

The mass concentrations of serum troponin T and creatine kinase-MB are elevated before creatine kinase and creatine kinase-MB activities in acute myocardial infarction. Eur J Clin Chem. Acute myocardial infarction and MB creatine phosphokinase. Relationship between onset of symptoms of infarction and appearance and disappearance of enzyme.

Risk stratification in suspected acute myocardial infarction based on a sensitive immunoassay for serum creatine kinase isoenzyme MB. Creatine Kinase-MB protein mass is a better indicator for the assessment of acute myocardial infarction in the lower range of creatine kinase level.

Jpn Heart J. Increased CK-MB mass concentration in patients without traditional evidence of acute myocardial infarction. A risk indicator of coronary death.

Cardiac troponin-T and CK-MB mass release after visually successful percutaneous transluminal coronary angioplasty in stable angina pectoris. Am Heart J. Factors associated with the release of cardiac troponin T following percutaneous transluminal coronary angioplasty. Clin Cardiol. Post-synthetic changes in creatine kinase isoenzymes EC 2.

Identification of the carboxypeptidase responsible for the post-synthetic modification of creatine kinase in human serum. Clin Chim Acta. Creatine kinase MB isoforms: sensitive markers of ischemic myocardial disease. Early diagnosis of acute myocardial infarction based on assay for subforms of creatine kinase-MB. Use of a rapid assay of subforms of creatine kinase-MB to diagnose or rule out acute myocardial infarction. N Engl J Med. Diagnostic Marker Cooperative Study for the diagnosis of myocardial infarction.

Rather than the enzyme activity of CK and CK-MB, the CK mass estimated is found to be of better diagnostic value, but the costs being considerable is not easily available. Because there is a lag period for the elevation of CK-MB levels after onset of chest pain, other potential markers such as myoglobin and troponins were pursued. Troponins are the contractile proteins in muscle cells, which present very early in the bloodstream, 3 to 9 hours post infarct.

Cardiac-specific isoforms have been identified, and among the three troponins in the contractile component of the myocardium, troponin-I and troponin-T are widely used. Cardiac troponin cTn I, increases in 4 to 6 hours, peaks at 12 hours, and returns to basal levels in 3 to 10 days, whereas troponin-T stays elevated for 12 to 48 hours and falls to normal in 10 days. The introduction of a high-sensitivity troponin hs-Trop assay has been very useful in patients with non—ST-elevation myocardial infarction NSTEMI , which allows diagnosis by a single blood test, thus permitting early treatment than otherwise might be advised.

The hsTn assays are also of value in prognostication in patients with acute heart failure AHF if seen in detectable values, as seen in a study by Xue et al. Thus tropinins play a significant role in assessment of cardiac dysfunction. The small heme protein that assists in oxygen transport in all muscle tissues, is released within 1 hour and rises more rapidly than cTn or CK-MB, peaks in nearly 8 to 10 hours, and returns to normal within 24 hours.

Thus, it is a sensitive early indicator of cardiac damage, and though nonspecific to the myocardium, it has found use as an excellent negative predictor of myocardial injury.

When the circulating serum albumin comes into contact with the ischemic heart tissue, a novel marker of ischemia is produced by the structural modification of albumin at the N-terminal end, which is used for the estimation. IMA rises within 6 hours of an infarct and remains elevated for 12 hours. The drawback with IMA is that it is induced by conditions such as extracellular hypoxia, acidosis, etc. It is a very stable low-molecular-weight 14—15 kDa protein present in the myocardial cytoplasm.

These are involved in the transport of fatty acids from the cell membrane to the mitochondria for oxidation. Due to their small size, they are easily diffused through the interstitial space and appear in 1 to 3 hours after onset, peak levels are achieved in 6 hours, and return to normal in 24 hours. Use of H-FABP may improve diagnostic ability, but the presence of easily available specific markers such as troponins has made it of an additive value only.

Natriuretic peptides are a group of structurally similar but genetically distinct molecules that are involved in the sodium and water excretion, thus lowering of blood pressure. Different biomarkers and their concentrations with relation to time after an AMI. Furthermore, it modulates diuresis, natriuresis, vasodilation, inhibition of renin and aldosterone, and helps reduce the blood pressure.

An acute phase protein synthesized by the liver, C-reactive protein CRP is mostly stimulated by the cytokine, interleukin IL CRP levels are thought to differ by sex and ethnicity and increase in acute illness. An intermediary amino acid, homocysteine is an independent risk factor for the development of atherosclerosis.

Hyperhomocysteinemia causes intimal thickening, disruption of the elastic lamina, smooth muscle hypertrophy, and platelet aggregation, and hence is directly implicated in vascular injury. It is therefore useful marker for risk assessment, and regular assays are available for the same.

It is another inflammatory marker, a signaling protein that reflects both inflammation and platelet interaction with the plaque and is found increased in ACS. Also, assays are cumbersome and not adaptable for diagnosis. Several biomarkers that are used currently and in the past decade are listed as follows. Also called platelet-activating factor, is synthesized by lymphocytes and monocytes and produces highly atherogenic lipid fragments that cause endothelial adhesion.

It is mostly used as a research tool and in risk stratification. It is a degranulation product of the white blood cells WBCs and is elevated in the blood vessels where a plaque is present and found to be increased in coronary artery disease and ACS.

Commercial assays are available for myeloperoxidase, but types of specimen collected have shown variation. This protein is a metalloproteinase and a member of the insulin-like growth factor family of proteins.

Elevated levels are indicative of an ongoing neovascularization process in the coronary arteries and an incipient plaque rupture. However, there is no established correlation with available markers; rather, it is an indicator of adverse CV events and not used routinely. It is released from phospholipids on cleavage and is suggested to indicate necrosis and ischemia. Again, it has been considered to be of value in prognostication.

It is member of IL-1 family and is believed to play a role in the cardiac remodeling and signal inflammation by its interaction with IL The gene is induced strongly by the stretch of a cardiomyocyte or cardiac fibroblast. In AHF patients, regardless of left ventricular ejection fraction, ST2 was found to be an independent and additive predictor of bad prognosis. In chronic HF, its ability to predict adverse events was similar to NT-proBNP, but it is advised to use a multimarker strategy to improve predictive ability.

For over a decade, galectin 3 has been implicated in fibrogenesis, myofibroblast proliferation, ventricular remodeling, and inflammation. Though it is elevated in acute or chronic HF, when adjusted for renal function or other markers, it loses its prognostic meaning. These are the long noncoding RNAs that inhibit gene expression by binding to sites in the untranslated regions of targeted messenger RNAs and are known to be involved in every biological process.

Four groups of miRNAs are identified, which are involved in regulation of the CV system of which nearly 18 seem specific for AMI, for example miR, miRa, miR, miRa, miRb, and a few others show much promise as specific and accurate markers of dysfunction.

In response to the cardiac dysfunction, which is a precursor of adrenomedullin, a vasodilator, synthesized from the adrenal medulla, is released. It is elevated in HF both acute and chronic and is useful in prediction of hospitalization and mortality. This is a marker in sepsis, which has been tried as an early biomarker for AMI with cardiac troponin, but much validation needs to be done. Copeptin is a stable C-terminal pro-peptide fragment of arginine vasopressin AVP and regulates the free water clearance and plasma osmolality by regulating absorption of water from the kidneys.

A multimarker approach, consisting of two or more pathologically diverse markers, which necessarily includes cardiac troponins, enhances risk stratification in patients of ACS. National Center for Biotechnology Information , U. Author manuscript; available in PMC Jan Rachel Jacob 1 and Mahmood Khan 2.

Author information Copyright and License information Disclaimer. Copyright notice. See other articles in PMC that cite the published article. Abstract Cardiac biomarkers are of great importance in the timely, accurate diagnosis and management of acute coronary syndrome as well as the prognosis. Keywords: cardiac biomarkers, cardiovascular disease, microRNA. Introduction Cardiac biomarkers are central to the new definition of acute myocardial infarction AMI as defined by the American College of Cardiology and the European society of Cardiology.

Cardiac Troponins Troponins are the contractile proteins in muscle cells, which present very early in the bloodstream, 3 to 9 hours post infarct. Myoglobin The small heme protein that assists in oxygen transport in all muscle tissues, is released within 1 hour and rises more rapidly than cTn or CK-MB, peaks in nearly 8 to 10 hours, and returns to normal within 24 hours.

Table 1 Different biomarkers and their concentrations with relation to time after an AMI6. Open in a separate window. Markers of Myocardial Ischemia Ischemia-Modified Albumin When the circulating serum albumin comes into contact with the ischemic heart tissue, a novel marker of ischemia is produced by the structural modification of albumin at the N-terminal end, which is used for the estimation.