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Narrative Review: Alternative Causes for Elevated Cardiac Troponin Levels when Acute Coronary Syndromes Are Excluded

Allen Jeremias, MD; and C. Michael Gibson, MS, MD
[+] Article and Author Information

From Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.


Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Allen Jeremias, MD, Division of Cardiology, Beth Israel Deaconess Medical Center, One Deaconess Road, Baker 4, Boston, MA 02215; e-mail, ajeremia@bidmc.harvard.edu.

Current Author Addresses: Drs. Jeremias and Gibson: Division of Cardiology, Beth Israel Deaconess Medical Center, One Deaconess Road, Baker 4, Boston, MA 02215.


Ann Intern Med. 2005;142(9):786-791. doi:10.7326/0003-4819-142-9-200505030-00015
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Current guidelines for the diagnosis of non-ST-segment elevation myocardial infarction are largely based on an elevated troponin level. While this rapid and sensitive blood test is certainly valuable in the appropriate setting, its widespread use in a variety of clinical scenarios may lead to the detection of troponin elevation in the absence of thrombotic acute coronary syndromes. Many diseases, such as sepsis, hypovolemia, atrial fibrillation, congestive heart failure, pulmonary embolism, myocarditis, myocardial contusion, and renal failure, can be associated with an increase in troponin level. These elevations may arise from various causes other than thrombotic coronary artery occlusion. Given the lack of any supportive data at present, patients with nonthrombotic troponin elevation should not be treated with antithrombotic and antiplatelet agents. Rather, the underlying cause of the troponin elevation should be targeted. However, troponin elevation in the absence of thrombotic acute coronary syndromes still retains prognostic value. Thus, cardiac troponin elevations are common in numerous disease states and do not necessarily indicate the presence of a thrombotic acute coronary syndrome. While troponin is a sensitive biomarker to “rule out” non-ST-segment elevation myocardial infarction, it is less useful to “rule in” this event because it may lack specificity for acute coronary syndromes.

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ALTERNATIVE CAUSES FOR ELEVATED CARDIAC TROPONIN LEVELS WHEN ACUTE CORONARY SYNDROMES ARE EXCLUDED
Posted on May 9, 2005
Robert T. Means, Jr.
Medical Service, VA Medical Center and University of Kentucky College of Medicine, Lexington KY
Conflict of Interest: None Declared

With their narrative review on causes of elevated cardiac troponin levels other than acute coronary syndromes (Ann Intern Med 2005;142:786- 92), Hayden, van Tulder, and Tomlinson make a valuable contribution to enhancing the correct interpretation of this common laboratory parameter in different clinical settings. However, their review does not discuss variations in cardiac troponin levels due to interference with the laboratory assay itself.

We have recently encountered a patient in whom hemoglobinemia and hyperbilirubinemia from acute intravascular hemolysis produced false elevation of troponin-I and ultimately led to coronary angiography. While free hemoglobin and or bilirubin shows negative interference (falsely low troponin levels) with cardiac troponin determinations using most assays studied [1-3], the Ortho-Clinical Diagnostics Vitros ECi cTnI assay system can show positive interference (falsely elevated troponin levels) [4]. In addition to considering the coexistence of conditions which may elevate troponin in a physiologic manner (as discussed by Hayden, van Tulder, and Tomlinson), it is also important to consider circumstances which affect the performance characteristics of laboratory assays in interpreting troponin results.

Nziavake Masimasi, M.D.

Robert T. Means, Jr., M.D.

1. Dasgupta A, Wells A, Biddle D.A. Negative interference of bilirubin and hemoglobin in the MEIA Troponin I assay but not in the MEIA CK-MB assay. J Clin Lab Anal 2001; 15:76-80

2. ver Elst KM, Chapelle JP, Boland P, et al. Analytic and clinical evaluation of the Abbott AxSYM cardiac troponin assay. Am J Clin Pathol 1999; 112:745-752.

3. Lyon ME, Hall CL, Krause RD, et al. Effect of hemolysis on cardiac troponin T determination by the Elecsys 2010 immunoanalyzer. Clin Biochem 2004;37:698-701.

4. Hawkins R. Hemolysis interference in the Ortho-Clinical Diagnostics Vitros ECi cTnI assay. Clin Chem 2003; 49:1226.

Conflict of Interest:

None declared

ELEVATED CARDIAC TROPONIN AND MYOCARDIAL STRAIN
Posted on May 8, 2005
José Pedro L. Nunes
Faculdade de Medicina do Porto, Portugal
Conflict of Interest: None Declared

TO THE EDITOR:

A most interesting review paper on elevated cardiac troponin levels was recently published (1). A number of clinical conditions other than ischemic heart disease were presented that may be associated with elevated troponin levels, and possible mechanisms were discussed (1).

The authors state that the release of troponin could be due either to reversible or to irreversible cell damage (1). In a number of clinical situations, supply-demand oxygen mismatch (in supraventricular tachycardia, atrial fibrillation and sepsis) and subendocardial ischemia (in left ventricular hypertrophy) were presented as possible mechanisms, while myocardial strain was indicated as a possible mechanism for other clinical situations (in heart failure, pulmonary embolism, pulmonary hypertension or emphysema, strenuous exercise) (1).

It has previously been suggested that perhaps the link between myocardial strain and elevated troponin levels, initially suggested to occur in pulmonary embolism (2) and in heart failure (3), may be present in most non-ischemic, non-inflammatory and non-traumatic cases of elevated troponin (4). For instance, in the case of atrial fibrillation, it has been hypothesized that "a very rapid change in sarcomere length may produce some kind of damage in the myocardium" (5).

The concept has been presented according to which elevated troponin levels with and without concomitant elevations in creatine kinase levels may represent two different types of pathophysiology (4): cell necrosis when the two markers are abnormal; myocardial strain in the other case. Strain is a concept that, although having a relatively precise physical meaning, also has a broader patho-physiological significance. The presence of strain, taken in a broader sense, is not incompatible with a possible simultaneous presence of other patho-physiological mechanisms (e.g. sympathetic nervous system activation, supply-demand oxygen mismatch, subendocardial ischemia).

The main advantage of generalizing the use of the strain concept in the present context might be to clearly separate most non-ischemic from the ischemic causes of elevated troponin levels. A simple scheme such as this might lead, as a consequence, to the situation where a diagnosis of myocardial strain would be equal to stating that precise coronary artery studies are probably not necessary.

Also of note is the possibility of apoptosis (a type of cell death with preserved membrane integrity) being the cause of cell death in some cases of abnormal troponin release: "It remains to be known if myocardial strain could lead to the release of troponin I in viable cells with myofibrillary damage, in necrotic cells, or in apoptotic cells"(4).

References

1. Jeremias A, Gibson CM. Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med. 2005; 142: 786-91.

2. Nunes JPL, Macedo F. An analytical triad for the diagnosis of pulmonary embolism. Cardiology. 2000; 94: 264.

3. Logeart D, Beyne P, Cusson C, Tokmakova M, Leban M, Guiti C, et al. Evidence of cardiac myolysis in severe nonischemic heart failure and the potential role of increased wall strain. Am Heart J. 2001; 141: 247- 253.

4. Nunes JPL. Cardiac troponin I in systemic diseases. A possible role for myocardial strain. Rev Port Cardiol. 2001; 20: 785-788.

5. Nunes JPL, Silva JC, Maciel MJ. Troponin I in atrial fibrillation with no coronary atherosclerosis. Acta Cardiol. 2004; 59: 345-346.

Conflict of Interest:

None declared

To the Editor,
Posted on May 12, 2005
Said B. Iskandar
East Tennessee State University
Conflict of Interest: None Declared

We read with interest the informative article by Drs. Jeremias and Gibson entitled "Narrative review: Alternative causes for elevated cardiac tropin levels when acute coronary syndromes are excluded". (1) The authors did a superb job of presenting the nonthrombotic etiologies associated with an elevated cardiac troponin level. We would like to add another consideration for a nonoronary elevation of troponin to their excellent review.

All of the currently available troponin measurement techniques employ two-site immunoassays. In immunoassay testing, there is a potential for antibody interference.(2) In an older population of patients at risk for coronary artery disease, the presence of rheumatoid factor has been documented to interfere with the troponin I (TnI) assay resulting in falsely elevated reports. In addition to patients with rheumatoid factor due to connective tissue disease or present as an acute phase reactant, approximately 5% of otherwise healthy individuals may have circulating rheumatoid factor. (3) Immunoassay interference is estimated to account for approximately 1% of all patients without acute coronary syndrome who have elevated cardiac TnI levels. While this number is low, we offer the observation to further the completeness of published review by Drs Jeremias and Gibson.(1)

Interestingly, if the clinician suspects rheumatoid factor interference, the test can be repeated using a rheumatoid factor-blocking agent for more accurate measurement. (4) No correlation has been found between the rheumatoid factor titer and the degree of interference in cardiac TnI measurement. In one study, most elevated TnI values occurred in individuals with rheumatoid factor values less than 1000 IU/ml. The lack of concordance between the measured rheumatoid factor level and degree of interference may be due to immunoglobulin heterogeneity of the rheumatoid factor or possibly the difference in monoclonal antibodies used in different manufactured assays.

Apparent elevation of TnI concentration should be evaluated with care in patients with seropositive rheumatoid arthritis. (5) The elevation of TnI may occasionally be significant and there have been reports of measured levels as high as 1267 ng/ml. (5,6)

Less common causes of a falsely elevated cardiac troponin measurement include the presence of heterophile antibodies (7), fibrin clots or microparticles (8) and analyzer malfunction. (9)

Thank you,

Said B. Iskandar, M.D. Bernard Abi-Saleh, M.D. Thomas M. Roy, M.D.

Department of Internal Medicine James H. Quillen College of Medicine East Tennessee State University Johnson City, TN 37604

Correspondence

Said B. Iskandar, M.D. 2 Professional Drive Suite 15 Johnson City, TN 37604 Phone: 423-232-4860 Fax: 423-232-4881

References 1. Jeremias A, Gibson CM. Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med. 2005 May 3;142(9):786-91 2. Ward G, McKinnon L, Badrick T, Hickman PE. Heterophilic antibodies remain a problem for the immunoassay laboratory. Am J Clin Pathol. 1997 Oct;108(4):417-21. 3. Krahn, J, Parry, DM, Leroux, M, et al High percentage of false positive cardiac troponin I results in patients with rheumatoid factor. Clin Biochem 1999;32,477-480 4. Dasgupta, A, Banjiree, SK, Datta, P False positive troponin I in the MEIA due to the presence of rheumatoid factors in serum. Am J Clin Pathol 1999;112,753-756 5. Krahn J, Parry DM, Leroux M, Dalton J.High percentage of false positive cardiac troponin I results in patients with rheumatoid factor.Clin Biochem. 1999 Aug;32(6):477-80 6. Katwa G, Komatireddy G, Walker SE. False positive elevation of cardiac troponin I in seropositive rheumatoid arthritis. J Rheumatol. 2001 Dec;28(12):2750-1. 7. Fitzmaurice, TF, Brown, C, Rifai, N, et al False increase of cardiac troponin I with heterophilic antibodies. Clin Chem 1998;44,2212-2214 8. Nosanchuk, JS False increases of troponin I attributable to incomplete separation of serum [letter]. Clin Chem 1999;45,714 9. Galambos, C, Brink, DS, Ritter, D, et al False-positive plasma troponin I with the AxSYM analyzer. Clin Chem 2000;46,1014-1015

Conflict of Interest:

None declared

Elevated Cardiac Troponin Levels in Thrombotic Thrombocytopenic Purpura
Posted on May 10, 2005
Kamran Darabi
Harvard University Joint Program in Transfusion Medicine
Conflict of Interest: None Declared

I read with interest the paper published by Drs. Jeremias and Gibson (1). The authors provide an informative update on conditions other than acute coronary syndromes (ACS) which result in elevations of serum troponin. However, their list omits a rare but important hematologic disorder, namely thrombotic thrombocytopenic purpura (TTP). In my clinical practice, I have encountered multiple cases of elevated troponin levels in patients who were hospitalized for severe acute TTP. Physicians are often unaware that TTP may also lead to micro-thrombi in the heart and therefore result in the release of troponin from damaged myocardial cells. Imaging studies will be negative for large vessel occlusions that would be amenable to interventional procedures. Therefore, clinicians should not embark upon an algorithm for diagnosis and treatment of ACS in such patients since it may interfere with appropriate treatment for the underlying disorder. Even in the presence of a significant "troponin leak", the first line of treatment treatment for TTP remains plasma exchange and oral corticosteroids. Aspirin and Heparin should not be given to patients with severe acute TTP since it may increase the risk of life- threatening bleeding due to severely depressed platelet counts.

Kamran Darabi MD, Harvard University Joint Program in Transfusion Medicine

References: 1. Jeremias A, Gibson M. Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med. 2005;142:786-91.

Conflict of Interest:

None declared

Letter to Editor
Posted on June 25, 2005
Nicola Mumoli
Department of Internal Medicine. Livorno Hospital. 57100 Livorno, Italy
Conflict of Interest: None Declared

The review of "Alternative Causes for Elevated Cardiac Troponin Levels when Acute Coronary Syndromes Are Excluded" by Allen Jeremias and C. Michael Gibson (May 17 issue)(1) raises some questions. First, before they states that "in the absence of any supportive data at present, in our practice, patients with nonthrombotic troponin elevation are generally not treated with antithrombotic and antiplatelet agents" and contraddice then asserting that "Unless aspirin is contraindicated, we frequently recommend the use of this drug, which appears to be relatively safe in most clinical circumstances". Although this is an interesting item from a speculative point of view, the use of aspirin remains to be ascertained. Second, the authors declares that myocardial troponin can be released as a consequence of tachycardia alone in the absence of myodepressive factors, inflammatory mediators, and coronary artery disease. It is unknown whether the elevated troponin I concentrations sometimes observed in patients with tachycardia and several tachyarrhythmias are reflective of this factors (2). Reference: (1)Jeremias A, Gibson CM. Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med. 2005 May 3;142(9):786-91 (2)Roongsritong C, Warraich I, Bradley C. Common causes of troponin elevations in the absence of acute myocardial infarction: incidence and clinical significance. Chest. 2004 May;125(5):1877-84

Conflict of Interest:

None declared

Cardiac Troponin is a specific biochemical marker of myocardial damage not of ischemic diseases
Posted on July 19, 2005
Mario Plebani
University-Hospital of Padova
Conflict of Interest: None Declared

We read with interest the paper by Allen Jeremias and Michael Gibson. The conclusions of the paper, however, may be confounding mainly because the Authors state that "while troponin is a sensitive biomarker to rule- out non-ST segment elevation myocardial infarction, it is less useful to rule-in this event because it is not specific for acute coronary syndromes" (1). Cardiac troponin measurement represents a major advance in the biochemical and laboratory approach to cardiac diseases being the marker of choice for its specificity and sensitivity (2). Available evidence demonstrates the high positive predictive value of cardiac troponin that allows to diagnose as "acute myocardial infarction" around 30% of ST-negative patients with chest pain and clinical evidence of ischemia (3). However, if troponin, as any other laboratory test is applied indiscriminately in broad populations that have a low pre-test probability of disease, the positive predictive value of the marker is greatly diminished despite its excellent specificity in test research (4). The supposed "poor specificity" of cardiac troponin refers to the evidence that many clinical situations may lead to myocardial injury and necrosis other than myocardial ischemia. The clinical context and eventually the kinetics of the marker, that is significantly different between acute coronary syndromes and other clinical conditions, allow an appropriate interpretation, diagnosis, risk-stratification and patient-management(5). In other words, the problem is the inappropriate request and interpretation of the results, not the marker itself. In fact, cardiac troponin is increasingly used by clinicians, in an appropriate clinical context, as a valuable tool to exclude or confirm significant myocardial injury after trauma, high-dose chemotherapy and viral disorders such as myocarditis and pericarditis. The supposed "poor specificity" translates into a diagnostic usefulness when the troponin measurement is appropriately requested and interpreted in the clinical context.

References 1) Jeremias A, Gibson CM. Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Int Med 2005; 142: 786-91 2)Jaffe AS, Ravkilde J, Roberts R, Naslund U, Apple FS, Galvani M, Katus H. It's time for a change to a troponin standard. Circulation 200; 102: 1216-20 3) Kontos MC, Fritz LM, Anderson FP, Tatum JL, Ornato JP, Jesse RL. Impact of the troponin standard on the prevalence of acute myocardial infarction. Am Heart J 2003; 146:446-52 4) Moons KGM, Biesheuvel CJ, Grobbee DE. Test research versus diagnostic research. Clin Chem 2004; 50:473-6 5)Cardinale D, Sandri MT, Colombo A, Colombo N, Boeri M. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 2004; 109:2749-54.

Conflict of Interest:

None declared

Alternative causes for elevated cardiac troponin levels: the apical ballooning syndrome.
Posted on November 2, 2005
Francesco Dentali
Department of Clinical Medicine, University of Insubria, Varese, Italy
Conflict of Interest: None Declared

In their narrative review, Jeremias and colleagues (1) evaluated a variety of clinical scenarios that could lead to the detection of troponin elevation in the absence of thrombotic acute coronary syndrome. They provide a complete list of diseases, such as sepsis, hypovolemia, atrial fibrillation, congestive heart failure, pulmonary embolism, myocarditis, myocardial contusion, and renal failure, that could be associated with an increase in troponin levels. However, in their review the authors did not assess another important cause for elevated cardiac troponin levels without acute coronary syndrome: the transient left ventricular (LV) apical ballooning syndrome or Takotsubo cardiomyopathy. This newly discovered cardiac syndrome is relatively common in postmenopausal women and is characterized by transient LV dysfunction, electrocardiographic changes in the absence of obstructive coronary artery disease. A previous emotional or physical stressor episode is frequent in the personal history of these patients. Due to its clinical and radiological characteristics this syndrome is frequently interpreted as an acute coronary syndrome. Recent Japanese and non- Japanese series reported that apical ballooning syndrome accounted for approximately 2.2% of patients presenting with ST- segment elevation or other electrocardiographic abnormalities mimicking acute coronary syndromes (2, 3). Coronary angiography is often normal and none of the patients showed a coronary stenosis greater than 50% of the luminal coronary artery diameter. Furthermore, despite a frequent dramatic clinical presentation, almost all patients recover completely and the LV function, heavily compromised at the presentation, improved rapidly in a period of days to weeks.

In these patients cardiac biomarkers levels, and in particular troponin, are usually elevated. For instance in a recent Japanese study, Tsuchihashi et al (4) found elevated plasma levels of troponin in 72% (31/43) of patients with apical ballooning syndrome. This finding has been confirmed by a study of Bybee et al (3) that reported elevated levels of troponin in all patients (16/16) with apical ballooning syndrome. Although these data are based on a limited number of patients, publication of several series, case reports and of a recent systematic review (5) have confirmed that apical ballooning syndrome is not so uncommon as it was believed in the past and that in this particular disease troponin levels are frequently elevated.

Therefore, we suggest that in patients admitted to the hospital for suspected acute coronary syndrome and with subsequent detection of elevated troponin levels, apical ballooning syndrome should be considered in the list of potential differential diagnoses.

REFERENCES

1. Jeremias A, Gibson CM. Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med. 2005;142(9):786-91.

2. Matsuoka K, Okubo S, Fujii E, Uchida F, Kasai A, Aoki T, et al. Evaluation of the arrhythmogenecity of stress-induced "Takotsubo cardiomyopathy" from the time course of the 12-lead surface electrocardiogram. Am J Cardiol. 2003; 92(2):230-3.

3. Bybee KA, Prasad A, Barsness GW, Lerman A, Jaffe AS, Murphy JG, et al. Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical ballooning syndrome. Am J Cardiol. 2004;94(3):343-6. 4. Tsuchihashi K, Ueshima K, Uchida T, Oh-mura N, Kimura K, Owa M, et al. Angina Pectoris-Myocardial Infarction Investigations in Japan. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina Pectoris-Myocardial Infarction Investigations in Japan. J Am Coll Cardiol. 2001;38(1):11-8.

5. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright RS, et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med. 2004;141(11):858-65.

Conflict of Interest:

None declared

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