The non-cardiac use and significance of cardiac troponins

Introduction

Troponin I and its counterpart Troponin T are cardiac contractile structural proteins which bind to actin and tropomyosin, respectively. They are distinctive to cardiac tissue and their serum levels are elevated following cardiac damage. It is by virtue of this that their detection is such an important indicator for myocardial ischaemia and necrosis. Following 6 to 8 h after initial symptom onset, these cardiac-specific markers are highly effective in diagnosing myocardial infarction (MI). Their role in myocardial ischaemia has been well established in studies from around the world in all ethnic populations. However, there are many causes of false-positive Troponin levels. This article will describe the history of cardiac Troponins followed by the respective uses and pitfalls of these tests. It will focus on the various non-cardiac causes of elevated Troponin I levels and its significance in these conditions.

History of cardiac markers

In the 1950s, it was noted that certain transaminases were released from dying myocytes and that they could in turn be detected in the laboratory with potential clinical significance for the diagnosis of MI.^1–3 This initiated the contest to develop biochemical markers of myocardial damage and to determine their prognostic value. Early markers developed included AST, lactate dehydrogenase (LDH), and the improved creatine kinase (CK) assay in the 1960 s. ⁴ However, despite the advances, these tests were still limited by specificity to cardiac tissue and a stride forward was made with CK isoenzymes, particularly the MB fraction in 1966. ⁵ The MBCK assay could be utilised just 12–24 h after symptom onset and so the days of patients waiting three days in coronary care units for a biochemical verification were now succeeded.

These developments were predocessors for the appearance of the tissue plasminogren activator streptokinase which was cleared for use in patients in the 1980s. With it came a unique time pressure to accurately identify those patients suffering from MIs within the first few hours in order to qualify administering the drug. It was during this time that the relationship between cardiac biomarkers and clinical management began to rapidly evolve and provided the pressure for faster assays.

The 1980 s gave rise to the development of Troponin I. ⁶ The post-MI rise of Troponin I was comparable to CK-MB; however, elevated Troponin I levels remained present for more than twice as long as CK-MB which proved to be useful in late presentations of MI. Around a similar time, the development of the Troponin T test allowed greater differentiation between the skeletal and cardiac origins of elevated serum CK-MB with particular value in normal CK-MB chest pain. ⁷

Advantages and disadvantages

The generic advantage of Troponin tests over CK and CK-MB (which are also found in skeletal muscle) is the specificity of troponins for cardiac damage. They rise after 3–6 h and reach their peak at around 20 h. ⁸ They remain elevated for 7–10 days providing an advantage over CK and CK-MB in patients presenting late. ⁹ A summary of the comparative similarities and differences between Troponin I and T is illustrated in Figure 1. The chief initial value of cardiac markers was in the rapid and accurate diagnosis of MI. However, their role quickly evolved into the prognostic stratifications of these patients. By the 1990s, Troponin T had established itself as a prognostic marker for future events post-MI. ¹⁰ OPEN IN VIEWER

With all developing biochemical tests the question remains on where to set the threshold for normality. This is usually positioned depending on the normal distribution of the population being assessed and with Troponin I and T a positive result is considered once serum levels are ≥0.04 µg/l. With the development of more accurate assays and technology in recent years, great interest has been sparked regarding the diagnostic threshold for abnormal results. It has been demonstrated that by reducing the diagnostic threshold to the 99th centile (to detect those patients with serum levels of 0.012–0.049 µg/l who would otherwise be missed under current assays), it would increase the diagnosis of MI by 47% (accepting greater imprecision of the result). ¹¹ Whether this will improve outcome is the key question in the coming years.

The main disadvantage of both Troponin I and Troponin T is that although they are indicative of cardiac damage, this damage can occur through a number of ways outside acute coronary syndrome (ACS). The various pathophysiological mechanisms responsible are summarised in Figure 2. The non-cardiac causes of elevated Troponins are discussed below. Another possible problem is that reference ranges will slightly differ between hospital laboratories, depending upon the analysis methods or machines employed. However, this are rarely of significant consequence as regular calibration minimises this issue. OPEN IN VIEWER

ACS

After considering the above, it is important to establish that Troponin proteins are nevertheless both a specific and sensitive serum marker of myocardial necrosis and if raised, MI should of course be excluded before investigating other causes. ACSs can present in the medical setting as a myriad of ambiguous manifestations ranging from sudden onset confusion to simply ‘off legs’. Many acute medicine clinicians would consider requesting Troponin I investigations to aid in delineating the underlying pathology. Cardiac Troponins are important in assisting accurate diagnosis and allow prognostication following presentation.

MI is subdivided into non-ST-elevation MI and ST-elevation MI based on the results of electrocardiograph investigations. Both of these sub-types are clumped along with unstable angina under the ambiguous title of ACS. The exact management of ACS will depend on the exact condition being treated.

Nonetheless, the majority patients would be started on Aspirin and Clopidogrel as studies have shown these drugs to be of prognostic value in these patients and hence have been incorporated in all mainstream international guidelines.^12–14 This will be followed by lifestyle and risk factor modification after any immediate cardiological intervention. The detailed review of assessment and management of ACS is beyond the scope of this article. This paper will now focus on non-cardiac causes of raised Troponin I which a physician may wish to consider once excluding ACS. The mechanisms for elevated Troponins in these cases are complex and some of the underlying processes are illustrated in Figure 2.

Renal disease and Troponin I

Renal failure is a particularly important cause of a raised Troponin I assay since patients with myocardial disease or heart failure can have concomitant renal disease. Raised Troponin I in these patients may be prognostic for the development of further cardiovascular disease. ¹⁵ The cardiovascular processes resulting from renal disease are complex but two specific changes have been noted, namely left ventricular structure change and myocardial ischaemia. ¹⁶ These processes in themselves concomitantly raise Troponin I from myocardial damage.

Although Troponin T has poor specificity in end-stage renal disease, Troponin I consistently maintains a higher sensitivity and specificity for cardiac damage in end-stage renal failure patients. ¹⁷ However, the accuracy in these patients is still diminished. A study on African Americans showed that Troponin I has a sensitivity of 60% and specificity of 71% in ACS patients with renal insufficiency. ¹⁸ Interpreting acute rises in Troponin I in these cases is difficult but can be considered a dynamic marker of myocardial damage by an experienced physician. Although what is clear from meta-analyses is that raised serum Troponin T (>0.1 ng/ml) suggests a heightened risk of cardiac death and reduced survival rates in asymptomatic patients with end-stage renal disease. ¹⁹ Heterogenous standardisation techniques of assays prevented Troponin I being accurately assessed in this context but another meta-analysis showed that raised Troponin T and I in these patients show a two- to five-fold increase in mortality. ²⁰

Interpretation of Troponin I assays in patients on dialysis is even more complicated but studies show the Troponin I levels either remain the same or decrease in these patients after correcting for haemoconcentration. ²¹ It is difficult to state the accuracy of Troponin assays beyond certain estimated glomerular filtration rates, and many authors suggest the measurement of ‘baseline’ Troponin levels for later comparison. What is certainly true is that an acute rise in Troponin above baseline is linked with a poorer prognosis.^15,16,21

Heart failure

The presence of chronic heart failure results in raised serum Troponin levels. Additionally, raised Troponin I levels may even suggest a considerably increased risk of the condition in patients not clinically in heart failure. Elevated Troponin I level is an independent and useful prognostic predictor in patients with systolic heart failure. Troponin I elevations and brain natriuretic peptide elevations are linked with increased mortality and readmission rates. ²²

Heart failure likely results from a process of cardiac fibrosis and subsequent ventricular dysfunction. Research has gone into the autoimmune elements of Troponin I release as a mechanism to potentiate this process of progressive ventricular dysfunction. Studies in mice have shown that Troponin I-specific T cells can induce inflammation and fibrosis, which results in a deterioration of contractile function. ²³ The severity of inflammation correlates with the expression of chemokines in the myocardium. An immuno-dominant epitope of Troponin I has been identified in these experiments. ²⁴ These anti-troponin autoantibodies are also found in patients with dilated cardiomyopathy as well as ischaemic cardiomyopathy. ²⁵

Heart failure can raise Troponin I levels indirectly as a pathophysiological response from concomitant renal failure as mentioned previously. In renal failure as described above ventricular remodelling can occur which will raise brain natriuretic peptide and result in abnormal ventricular function. The myocardial ischaemia in this case may be secondary to the cardiovascular complications of end-stage renal disease. ¹⁶

Sepsis

Troponin can be elevated in as many as 85% of patients with sepsis in the absence of ACS. ²⁶ It is thought the origin of raised Troponin levels in these patients is once again from myocardial cell injury, likely from the positive inotropic and chronotropic effects of sepsis. The mainstay of this process is on left ventricular function during septic shock where Troponin I could be used to review this process. However, it has been suggested that transient loss in membrane integrity with subsequent troponin leakage or microvascular thrombotic injury may be possible aetiologies. ²⁷

There may be a direct process by a cardiac myocytotoxic effect of reactive oxygen radicals, cytokines or endotoxins by the infectious process itself. ²⁸ In severe sepsis, elevated cardiac Troponin I is an independent prognosticator of mortality. ²⁶ However, controversy exists over the significance of pre-existing cardiac disease on serum Troponin level alone. A number of small studies demonstrate raised Troponin I levels predict increased severity of sepsis and higher mortality without mention of pre-existing risk factors.

In acute septic shock, acute cardiovascular and renal deterioration are well recognised and collectively referred to as the septic cardiorenal syndrome. ²⁹ This syndrome via a mixture of the cardiovascular impact of renal disease mentioned above and the direct septic influence on myocardium can result in a raised Troponin. ²⁹ Levels of troponin also correspond with the intensity of vasopressor support in patients with septic shock and their duration of hypotension.

Critically ill patients

Although sepsis results in raised Troponin I levels, generally critically ill patients without sepsis or septic shock can have elevated Troponin levels. It is a reasonably common occurrence in these patients with as many as 40 to 50% of critically ill medical and surgical patients having raised serum Troponin levels. ³⁰ This is likely due to the increased burden on the myocardium and should not be rapidly treated for ischaemic heart disease.

The exact basis of raised Troponin in these patients largely results from decreased left ventricular function with higher levels of TNF-alpha and IL-6 also being recorded in this subgroup. ³¹ These patients are at a higher incidence of new failure of two or more organs and elevated levels of Troponin I act as a mortality risk factor alongside the (APACHE) II score. ³² However, suggestions that serial measurements of Troponin alone may help predict prognostic changes have not been convincing. MI has a high incidence in the intensive care setting is an independent determinant of prognosis.

Pericarditis and myocarditis

Elevated levels of Troponin I are seen in both pericarditis and myocarditis and particularly so in younger patients and those with a recent infection. A raised Troponin in patient with pericarditis suggests involvement of the myocardium; an entity known as myopericarditis has been mentioned in the literature and has a worse prognosis than pericarditis. ³³ Due to the clinical similarity with symptoms of MI, these patients are unfortunately often managed incorrectly under the ACS protocol. ³⁴

A normal or slightly raised Troponin-I in addition to a low left ventricular ejection fraction on admission in patients presenting with fulminant acute myocarditis collaborate to result in worse in-hospital and mid-term prognosis. ³⁵ In the short-term cardiac troponins levels can predict the prognosis and the severity of myocarditis. ³⁶

Pulmonary embolism

A raised Troponin I in pulmonary embolus likely originates from the heightened right ventricular load. The value of raised Troponin I is not sufficient to steer towards thrombolysis. ³⁷ Raised cardiac Troponin levels in these patients may again help identify those with a poor prognosis, especially in normotensive patients. ³⁸ Elevated Troponin I can indicate a higher risk for in hospital mortality and a complicated clinical course. It should be mentioned that the sole long-term prognostic benefits of Troponin I alone have been questioned and not yet confirmed. ³⁹

Meta-analysis supports the contribution of Troponin levels towards short-term mortality in these patients. ⁴⁰ Nonetheless, it can be argued that the delay in diagnosis could influence the usefulness of Troponin I. ³⁹ Troponins have been considered in establishing or rejecting the diagnosis of pulmonary embolism but not convincingly. ⁴¹

Biochemically related spurious results

A summary of the most common of causes of non-cardiac elevated Troponin levels are summarised in Figure 3. However, it is important to not overlook biochemical causes of positive Troponin assays. Potential causes of biochemically related raised Troponin I and T levels include machine error or surplus fibrin from unclotted samples. Troponin assays from patients with circulating rheumatoid factor result in potentially inaccurate results. ⁴² Heterophilic Antibodies ⁴³ from cancer therapy or monoclonal antibodies in diagnostic imaging can raise this serum marker. In these cases, the use of other cardiac markers such as the traditional CK-MB and total CK can aid in making a diagnosis. OPEN IN VIEWER

Conclusion

This article has reviewed some of the common causes of raised Troponin I levels. Troponin I is a vitally important component of a physician’s investigative toolbox. A thorough understanding of the strengths and weaknesses of this blood test can provide an invaluable support in establishing an accurate diagnosis and instigating effective management. This is especially pertinent these days in light of our patient cohort now living longer, with increasing comorbidities and with numerous factors which could confound this assay. The old physicians adage is particularly true in this case; ‘one must always remember to treat the patient as a whole and not the abnormal blood result in isolation’.