subject: Cardiac markers new and old [print this page] Cardiac markers new and old Cardiac markers new and old
Introduction
Cardiac markers or cardiac enzymes are proteins that leak out of injured myocardial cells through their damaged cell membranes into the bloodstream.
They are:
A: specific.
1. Cardiac troponin I and cardiac troponin T
2. Creatine kinase-MB isoenzyme (CK-MB).
B: Non specific.
Until the 1980s, the enzymes SGOT and LDH were used to assess cardiac injury.
1.C-reactive protein
2.B-type natriuretic peptide
3.Copeptin
4.lactate dehydrogenase
5.Aspartatetransferase
6.myoglobin
7.ischemia modified albumin.
8.Glycogen phosphorylase isoenzyme BB.
9.Adiponectin.
10.Adrenomedullin.
A: specific.
1.Cardiac troponin I and cardiac troponin T .
The troponins are part of the actomyosin contractile apparatus of muscle cells. Structurally unique forms of troponin T and troponin I are found in cardiac tissue, enabling the development of immunoassays, which recognise only the cardiac forms of these two proteins. In most clinicalsituations both cardiac troponin I (cTnI) and cardiac troponin T (cTnT) seem to offer similarly useful clinical information.
When a cardiac myocyte dies, CK-MB passes rapidly from the cytoplasm into the circulation and is cleared. In contrast, most of the troponin within the myocyte is found in the structural elements of the cell, so when necrosis occurs there is a steady leaching of troponin into the circulation. Consequently, troponin remains in the circulation for several days after a cardiac event.
Despite extended searching, there is currently no evidence that the cardiac troponins may be produced by tissues other than myocardium. However, the presence of cardiac troponin, while indicating that cardiac injury has occurred, provides no information as to the mechanism of injury. Cardiac troponin concentrations may rise in conditions unrelated to ischaemic damage such as pericarditis, trauma and sepsis. Such rises provide no information about the likelihood of future ischaemic cardiac disease.
When associated with coronary artery ischaemia even low concentrations of cardiac troponin predict an adverse outcome. This is regardless of whether the other WHO criteria for the formal diagnosis of myocardial infarction are met. The pathophysiological mechanism for these acute coronary syndromes is the presence of an unstable coronary plaque, with release of micro-emboli causing focal myocardial necrosis with release of cardiac troponin. The increased mortality is a reflection of a large thrombus separating from the unstable plaque.This improved understanding of the mechanism of the acute coronary syndrome, has led to a proposal to redefine myocardial infarction, using the presence of a cardiac biochemical marker, with some evidence of coronary artery ischaemia, as the central diagnostic criterion.
False positive troponin.
1.Cardiac troponins in patients with renal failure
A small proportion of patients with renal failure undergoing dialysis have detectable concentrations of cTnT. This finding was originally thought to be a false positive test, but careful analysis has shown that these patients do have a worse cardiac prognosis. When one considers that approximately 20% of patients on dialysis die each year and that cardiac disease is the commonest cause of mortality, this result is not unexpected. Although there is some increase in cTnI in dialysis patients, this appears to be one area where cTnT is more informative.
2.Problems with assays for cardiac troponin I
Cardiac troponin I is prone to modification in the circulation. It may be phosphorylated and oxidised and can exist as a complex with either cTnT or cardiac troponin C. This has some clinical relevance, because the different antibodies used in commercial assays may recognise these different molecular forms to varying extents. A major problem with cTnI assays is that the different assays are calibrated with different standards. The same blood sample may give quite different apparent concentrations in different assays. If it is accepted that the presence of any cardiac troponin in the presence of coronary artery ischaemia indicates a worse prognosis, then the absolute concentration is less important.
2.Creatine kinase-MB isoenzyme (CK-MB) .
Creatine kinase (CK) and more particularly its isoenzyme CK-MB still have a formal place in defining myocardial infarction. However the current definition is not a particularly useful one because studies have shown that, as currently defined, patients with myocardial infarction and unstable angina have similar outcomes.
Interpretation of CK-MB is problematic, with both false positives and false negatives occurring. While CK-MB is relatively cardiac-specific, even healthy people may have low concentrations of this isoenzyme in their blood. People with chronic myopathies may have high concentrations of CK-MB because it is produced by regenerating skeletal muscle. A high concentration of CK-MB may therefore be unrelated to cardiac disease (false positive).
The half-life of CK-MB in the circulation is relatively short (approximately 12 hours). Samples collected many hours after an infarction may have both a low absolute concentration of CK-MB and a low ratio of CK-MB to total CK (due to the longer half-life of the major isoenzyme, CK-MM). This can give a false negative result.
Some specialists believe that it is no longer appropriate to use CK-MB in the diagnosis of myocardial infarction. It may be more helpful for investigating possible reinfarction, where its short half-life may be useful compared to the longer time that cardiac troponins spend in the circulation.
B:non specific.
1.C-reactive protein
C-reactive protein (CRP) is an acute phase reactant produced by the liver in response to cytokine release during inflammation. It has long been used in clinical practice to follow systemic inflammation, especially bacterial infection. More recently, epidemiological evidence has shown that basal levels of CRP, in the absence of apparent inflammatory disease (so-called hs-CRP) may be informative in predicting future myocardial or cerebrovascular events.
The value of hs-CRP appears to relate to activity in the atherosclerotic plaque. Amongst the cellular elements of the atherosclerotic plaque are inflammatory cells, which, by releasing interleukin-6, cause secretion of CRP into the circulation. In the Physicians' Health Study, when people in the highest quartile of CRP values were compared to people with the lowest quartile of CRP values, they had a relative risk of future myocardial infarction of 1.9. In the Women's Health Study the relative risk was 4.4.
There are a number of problems in using CRP measurements to predict the likelihood of future cardiovascular events. These are both biological and analytical.
Biological variability in basal CRP concentration is considerable. Even mild, subclinical infections can cause significant increases in CRP concentration that are unrelated to cardiovascular disease. For this reason, no measurements should be made within two weeks of any infection. Even with this precaution, CRP concentrations may vary markedly. Several studies have investigated the variability of the CRP concentration in blood collected repeatedly from individuals over periods of weeks to months. The standard deviation for each individual varies from 30% to 63% of the mean value.Thus it might be highly misleading to contemplate using a single measurement to guide possible therapy. It has been proposed that two separate measurements should be made on each individual, while they are quite well, and at intervals of more than a week apart. The lowest value is then used to determine which quartile the person is in. Even this approach may be insufficient to correct for the variability.
There are outstanding laboratory problems with use of hs-CRP. Not all assays produce identical results. No laboratory has the resources to determine its own reference ranges, so transportability of results between assays is obviously of great importance in defining the concentrations that relate to the different quartiles of basal CRP concentration. At the present time it appears undesirable to attempt to use hs-CRP in individual risk stratification.
2 .B-type natriuretic peptide
The cardiac natriuretic peptide family of neuro-endocrine hormones has a complex physiological role in modulating blood volume and pressure. This involves natriuresis and diuresis as well as antagonism to the angiotensin-renin system. These peptides are also antimitotic and may modulate cardiac hypertrophy. In the presence of left ventricular dysfunction, with worsening cardiac failure, the concentration of plasma B-type natriuretic peptide (BNP) increases in proportion to the New York Heart Association's (NYHA) classification of severity. However, there are a number of other pathophysiological states in which BNP may be elevated, such as hypertension and cardiac hypertrophy, pulmonary hypertension and renal disease. The most appropriate use of this marker remains to be defined.
As with cTnI, several different assays for BNP or its associated peptides (e.g. NT-proBNP) have been used in the published studies. As these assays are not yet standardised, numerical values from one assay cannot be compared quantitatively with those from another.
B-Type Natriuretic Peptide: Prognostic in Heart Failure?
Many patients hospitalized with acute exacerbations of heartfailure are cared for by primary care physicians after discharge.Although some patients avoid rehospitalization within the next6 months, others are prone to multiple hospital admissions.Recently, BNP determinations have shown the potential to bea good prognostic marker for morbidity and mortality in patientswith heart failure, including predicting future cardiac eventin patients with acute exacerbations
One prospective study found that an initial BNP concentrationof 480 pg/mL had a sensitivity of 68%, specificity of 88%, andan accuracy of 85% of predicting a congestive heart failureendpoint (death, hospital admissions, and repeated emergencydepartment visits) after a 6-month follow-up period after hospitaldischarge. Patients with BNP levels greater than 480 pg/mLhad a 51%, 6-month cumulative probability of a heart failureevent (35% of these patients had death from heart failure astheir event), whereas BNP levels of less than 250 pg/mL hada much better prognosis, with only a 2.5% cumulative probabilityof a heart failure event. The authors reported that increasedBNP levels were associated with progressively worse prognosis.
Another well-designed study compared BNP levels with the patient'sheart failure survival score (HFSS), a recognized and acceptedtool in determining a patient's prognosis. Patientswere classified into three different prognostic groups basedon the HFSS score: low risk, medium risk, or high risk. Therewere significant differences in each group. The mean BNP concentrationfor the low-risk group was 95.7 11.2 pg/mL, for themedium-risk group was 244.4 33.4 pg/mL, and for thehigh-risk group was 419.9 55.5 pg/mL. More importantly,the authors were able to show that higher BNP levels were associatedwith a change in cardiovascular functional class with time.The initial BNP level in patients who improved during the ensuing12 months had a BNP concentration of 42.4 8.6 pg/mL,those who remained stable had a BNP level of 102.2 16.1 pg/mL, and those who deteriorated during the ensuing 12months had a BNP level of 256.9 28.5 pg/mL.
B-Type Natriuretic Peptide and Therapeutic Monitoring of Heart Failure
Primary care physicians have the task of managing patients withcongestive heart failure. An important aspect of patient managementis the ability to monitor the therapeutic efficacy of the patient'spharmacological regimen. BNP levels have been found to followventricular function in response to medical management.
One study evaluated left ventricular volume and mass, includingneurohormone levels, in patients with mild to moderate nonischemiccongestive heart failure before and after 4 months of treatmentwith spironolactone or placebo. Patients who received a fixed25-mg dose of spironolactone had a change in their mean BNPconcentration from 200 66 pg/mL at baseline to 89.7 27 pg/mL at 4 months (P< .01), whereas the controlgroup showed no significant change.
Another study managed to show that BNP-guided treatment of heartfailure reduced total cardiovascular events and delayed timeto first event compared with intensive clinically guided treatment.The BNP concentration decreased 79 pmol/L in the BNP-guidedgroup compared with 3 pmol/L in the clinically-guided group.More importantly, the primary combined clinical endpoint (cardiovasculardeath, hospital admission, and outpatient heart failure) wassignificantly reduced in the BNP-guided group (P< .02).This significance increased when covariates were accounted for(baseline left ventricular ejection fraction, baseline BNP,and medication dosages, New York Heart Association heart failureclass, and systolic blood pressure) in the regression model(P< .001). The authors suggested that BNP-guided treatmentrepresents a preventive strategy targeting more intensive pharmacotherapyand follow-up for patients with elevated circulating BNP levelswho are at high risk of cardiovascular events.
Although both studies describe an important use of BNP, thesmall study sizes should raise caution when applying these findingsto clinical practice
3.Copeptin
Approximately 15 million patients present to the Emergency Department (ED) with symptoms suggestive of Acute Myocardial Infarction (AMI) every year. The vast majority (70 to 80%) of them finally prove not to have AMI. However, due to a delayed increase of circulating levels of Troponin it takes up to six hours before it can be measured. Therefore serial blood sampling is recommended by the European Guidelines. Study results indicate that by testing for both markers, along with an Electrocardiogram (ECG) and the clinical findings, approximately two-thirds of the patients would not need to wait those six hours in the ED for the second Troponin test. This may obviate the need for prolonged monitoring and serial blood sampling in the majority of patients.
"In the very situation of a patient presenting to the Emergency Department (ED) with symptoms suggestive of Acute Myocardial Infarction (AMI) the clinician quickly needs to know whether the person is in real danger or not. Ruling out AMI in this setting is an urgent and unmet need. The use of Copeptin together with Troponin can accelerate the rule out of AMI and thus improves patient management in the ED immensely. Two thirds of these patients may be ruled out with the first blood draw and most of them probably could leave the ED very soon," explained Dr. Tobias Reichlin from the Department of Internal Medicine at the University Hospital, Basel, Switzerland. While the concentration of Troponin rises four to six hours after the event of an AMI, concentrations of the new Copeptin biomarker are highest right after the onset of symptoms and then begin to drop. This difference makes the use of the combination of the two extremely promising.
The study was conducted in the University Hospital of Basel, Switzerland. In 487 consecutive patients presenting to the Emergency Department (ED) with symptoms suggestive of Acute Myocardial Infarction (AMI), the research team measured levels of copeptin at presentation, using a novel sandwich immunoluminetric assay in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists using all available data.
The adjudicated final diagnosis was Acute Myocardial Infarction (AMI) in 81 patients (17%). Copeptin levels were significantly higher in AMI patients compared with those in patients having other diagnoses (median 20,8pmol/l vs. 6,0 pmol/l, p
