Cardiac Troponins in Critical Care

Introduction
Combining targeted biochemical assays to conventional clinical acumen including a thorough history and examination is common to all medical specialties. The accuracy and yield of such tests vary depending on the assay’s sensitivity, specificity and positive and negative predictive values. Cardiac troponin specific assays are not immune to these issues.

This article will discuss the interpretation of increased levels of cardiac troponin in the critical care environment.

Troponin physiology
Troponin complexes occur in both skeletal and myocardial muscle. However, the expression of the cardiac isoform of troponin is exclusive to myocardial tissue. Troponins are the regulatory complex of the myofibrillar actin or thin filament that plays a crucial role in regulating excitation-contraction coupling in the heart.

Troponin complex is composed of three distinct single-copy genes in the human genome, each of which is expressed in a unique cardiac-restricted developmentally regulated fashion:

Troponin C (cTnC)
the 18-kD Ca2+-binding subunit
Troponin I (cTnI)
the 23-kD inhibitory subunit that prevents contraction in the absence of Ca2+ binding to cTnC by inhibiting actomyosin ATPase
Troponin T (cTnT)
the 35-kD subunit that attaches troponin to tropomyosin and to the myofibrillar thin filament

Over the past 5 decades, extensive bio-chemical, physical and structural studies have provided incisive knowledge into the molecular basis of troponin function and thin filament activation in the heart. These can be summarised as:
Onset of systole
Ca2+ binds to the N-terminal Ca2+ binding site of cTnC
cTnC undergoes a structural conformational change
cTnC then catalyzes protein-protein associations activating the myofibrillar thin filament

Myofibrillar thin filament activation facilitates cross-bridge cycling and contraction of the heart thus determining both the intrinsic length-tension properties of cardiac myocytes and the Frank-Starling properties of the intact heart.

Troponin assay

The majority of the cardiac troponin is bound to the contractile complex but upto 5% cTnI and 7% cTnT can exist freely in the myocardial cytosol. The specificity of both cTnI and cTnT is ≥ 95% as early as 2 hrs post onset of symptoms or an event, and remains so up to 22 hrs. The sensitivity of cTnI and cTnT at 10 hrs are 92% and 88% respectively, and peak between 10 to 22 hrs. The serum level for a previously positive cardiac troponin may remain elevated above the 99th percentile for up to 10 to 14 days post initial event, providing no further myocardial injury is sustained in the interim.

Unexpectedly high or low cardiac troponin levels may be generated due to false positive or negative results. The human anti-mouse antibody (HAMA) is an immunoglobulin IgG directed against the common fragment of the mouse antibody heavy chain. HAMAs can mimic circulating cardiac troponin by cross-linking the capture and detection antibodies in the assay. This leads to a positive result in the absence of cardiac troponin. Chimeric (part mouse, part human) monoclonal antibodies are used in the treatment of following conditions and can potentially lead to false positive result:
Rheumatoid arthritis (infliximab)
Crohn’s disease (infliximab)
Non-Hodgkin’s lymphoma (rituximab)
Prevention of renal transplant rejection (basiliximab)
Prevention of coagulation in percutaneous coronary interventions (abciximab)
The newer humanized versions contain a lower murine contribution. However, if a false positive result is supected, advice from the clinical chemistry may be useful in order to refine the assay.

Troponins and Acute Coronary Syndromes
The term acute coronary syndrome (ACS) was an all encompassing term for the syndromes caused by the root disease of atherosclerosis and associated plaque rupture driven myocardial ischaemia. The syndromes included in this definition were:

unstable angina
non-ST segment elevation MI (NSTEMI)
ST segment elevation MI (STEMI)
However, the broad ACS terminology 'greyed' the accurate diagnosis of a given patient to either the unstable angina or NSTEMI group. This ultimately disadvantages further risk stratification of the patient. Clinical evidence highlighted that cardiac troponins could provide a potential mechanism of further risk stratification:

patients with barely above the 99th percentile reference range rise of cardiac troponin have up to a three fold increase risk of death
a positive cardiac troponin result post PCI is associated with a worsened outcome, with a sequential increase in the level predicting a corresponding increase in the risk of death
nearly half of NYHA class III and IV heart failure patients show baseline cardiac troponin levels above normal and have higher subgroup mortality
In 2000 the European Society of Cardiology and the American College of Cardiology re-defined the existent WHO diagnostic criteria of myocardial infarction (MI). This revision was partly due to strong and compelling evidence of the benefit of incorporating cardiac troponin as the bio-marker of choice over the more traditional CK-MB assay. Indeed, nearly half of patients presenting with symptoms consistent with acute myocardial ischaemia and an elevated cardiac troponin level above the 99th percentile did not meet the WHO criteria for an MI.


Troponins and Acute Coronary Syndromes on the ICU
It can be argued that routine cardiac troponin testing in sedated ICU patients (who therefore lack the ability to complain of any symptoms) with an absence of an ischaemic ECG, is an inefficient use of both clinical acumen and medical resources. However, targeted troponin testing in ICU patients based on other associated factors such as prolonged hypotension, hypoxaemia or decompensating arrhythmias may further help in their risk-stratification and in-patient management. In the ICU setting, bedside echocardiography is a strong non-invasive tool in the diagnosis and directed management of myocardial ischaemia, and may be combined with troponin assays to enhance patient care.

A raised cardiac troponin level indicates myocardial injury versus ischaemia with a level corresponding to the degree of injury. Hence, whilst ischaemia may be the most predominant cause of myocardial injury in the Western World, other causes that may cause such injury can give raised cardiac troponin assays. For example, myocarditis and pericarditis are both associated with minor myocardial injury and hence may be associated with a rise in cardiac troponin in up to a third of patients. Deciphering between myocarditis/pericarditis and ischaemia may be difficult due to the co-existence of common ECG signs and localised regional wall motion abnormalities on bedside echocardiography. However, serial cardiac troponin testing may have 'diagnostic value' - myocarditis/percarditis are typically characterised by persistent, stable and mildly raised troponin levels; ischaemia by the typical acute peak rise and subsequent protracted decline. Brandt and colleagues demonstrated that in a cohort of patients with 'myopericarditis, a positive cardiac troponin was not associated with an increased moratality rate. Myocardial contusion due to trauma or cardio-pulmonary resuscitation, CPR, is not always associated with a rise in cardiac troponin. However, when CPR related cardiac troponin elevation is present, the level of cardiac troponin is related to the duration of CPR. DC defibrillation or cardioversion is not associated with a rise in serum troponin. Drug induced cardiotoxicity (e.g. use of the chemotherapeutic agent doxorubicin) may give positive troponin results due to direct myocardial injury and this will need to be assessed in its relevant individual context.


Troponins and Non-cardiac disease
Chronic or end stage renal failure (ESRF)
Whilst there appears to be a generally accepted understanding that clearance of cardiac troponin is mediated renally, the primary cardiac troponins are large macromolecules that are mainly cleared via non-renal mechanisms yet to be elucidated. However, smaller cardiac troponin fragments, especially of cTnT may be cleared via the kidney and could accumulate in ESRF in the absence of clinically overt myocardial ischaemia. Hence the positive predictive value of cTnI over cTnT in ESRF is better. This is also true in the setting of renal replacement therapy or an in-situ viable renal transplant.

Up to 3 in 4 people with ESRF have co-existent coronary artery disease and more frequently die as a result of their coronary artery disease than due to ESRF. Chronic silent myocardial injury and 'micro-MI' may be possible explanations for the elevated cardiac troponin levels, and is corroborated by post mortem evidence. A raised cardiac troponin level predicts a worsened short- and long-term outcome in ESRF.

Sepsis
Myocardial systolic and diastolic dysfunction may be present in sepsis and is thought to be cytokine mediated. In the presence of vasodilatory shock, such cardiac dysfunction may significantly impair cellular oxygen delivery. Troponin level is elevated above 99th percentile in 2 out of 3 septic patients, and is associated with a doubling of the risk of death. The rise in cardiac troponins in septic patients is likely to be multifactorial and mechanisms would include:

underlying state of coronary artery patency
myocardial ability to withstand increased stress and demand
baseline state of lung parenchyma and vasculature
any acute lung injury
degree of cellular mediated myocardial injury
Pulmonary embolism (PE)
Elevated cardiac troponins in non-decompensating (i.e systemic arterial blood pressure preserved) PE is a strong predictor of adverse hospital outcome including death. Both massive and submassive PE are associated with increased right ventricular wall stress, myocardial injury and dysfunction that leads to cardiac troponin release. The relative absence of myocardial muscle mass in the right ventricle as compared to the left, results in a much lower rise in the cardiac troponin level. The combination of bedside echocardiography with serum cardiac troponin analysis may provide incremental data for prognostication in this high risk sub-group as an elevated troponin level alone is associated with a poor outcome.

Stroke
Elevated cardiac troponin levels have been reported in thrombotic and haemorrhagic CVAs including in subarachnoid haemorrhage. The myocardial injury is thought to be neurally mediated via a process of uncontrolled autonomic activation. In one study, elevated cardiac troponin was present in 1 in 6 acute CVAs and was associated with a three-fold increase in mortality. Current evidence shows that the clinical severity, CT findings or GCS score are all poorly predictive of CVA related mortality but CVA related cardiac troponin levels may have a role.

Other
Myocardial dysfunction is frequently present in ICU patients with multi-organ dysfunction syndrome (MODS). Kollef and colleagues showed that although an elevated cardiac troponin level in a mixed heterogeneous ICU population does not predict hospital mortality, it is associated with an increased risk of MODS and longer hospital length of stay. Atherosclerosis is the primary disease of many vascular syndromes including cerebrovascular and peripheral vascular disease. Higham et al demonstareted that a post-operative elevated cardiac troponin level after aortic aneurysmal surgery is associated with an increased 12-month risk of cardiovascular complications and cardiac death. Similar findings have been reported after major orthopaedic joint surgery.


The future

Current third generation troponin assays are highly sensitive and specific. It is conceivable that future assays may provide even further improvement in diagnostic accuracy. These assays could even be combined with newer biochemical markers (such as 'ischaemia modified albumin' and 'NT-pro BNP') to provide further insight into both the diagnosis and the management of suspected of cardiac ischaemia on the ICU.

Conclusion

The incorporation of a targeted troponin assay to the clinical management of ICU patients could be beneficial as it may identifying a sub-group of patients with a high risk of mortality, and informs both risk-stratification and prognostication. This novel approach would facilitate further multi-disciplinary involvement and may ultimately improve the outcome of ICU patients with cardiac ischaemia.