Prior to the era of coronary angiography and revascularization, AMI had been predominantly a clinical diagnosis based on symptoms and classic electrocardiographic changes. The pathology in non survivors showed evidence of coagulation necrosis of the myocardium corresponding to the detection of occlusive coronary thrombosis of an epicardial coronary artery, with the degree of necrosis or reparative changes correlating to the time between onset of AMI and death [2]. Clinically, chemical biomarkers were introduced and added to the accuracy of diagnosis. Initially, serum glutamic oxaloacetic transaminase (also known as aspartate transaminase) was used as a biomarker of myocardial injury [3]. However, this was neither sensitive nor specific for myocardial injury, only to be replaced by lactate dehydrogenase (LDH) or creatine kinase, both of which also lacked specificity for the myocardium [3]. The search for a more specific marker for myocardial injury lead to discovery of the creatinine kinase myocardial band (CKMB) isoenzyme and then the troponin proteins [3, 4]. Troponins have essentially replaced all other biomarkers and they have now become the standard laboratory screening test for cardiac disease. The troponin assays have improved over time and now the current fourth generation troponin assays have excellent sensitivity.

With such a sensitive test, the troponin assay has become a ubiquitous test for myocardial disease. Yet, the clinical picture of many patients with elevated serum troponin levels was not consistent with AMI. Over the years, the definition of a true AMI has been redefined to incorporate the use of these more sensitive biomarkers and reflect not simply just an elevated troponin level. The first Global MI Task Force convened in 2000 to reach a consensus on the definition of a myocardial infarction. The most recent iteration of this was the third Universal Definition of myocardial infarction, a consensus expert statement in 2012, endorsed by the ACC, ESC, AHA, and the WHF [5].

While it is understood that myocardial infarctions involved myocardial necrosis due to myocardial ischemia, the Universal Definition of myocardial infarction delineated the spectrum of etiologies. It has become apparent that elevated cardiac biomarkers were present in disease states other than classical acute coronary syndromes. This definition, as mentioned above, categorized MI into five subtypes in order to sort out all the known clinical presentations. A type I MI was a spontaneous myocardial infarction due to an acute disturbance within the coronary arterial tree [5]. This can be due to atherosclerotic plaque rupture, erosion or a calcified nodule with superimposed thrombosis. This is the usual scenario in a patient with obstructive coronary artery disease but occasionally a type 1 MI was seen with no apparent significant atherosclerotic disease on angiography as will be discussed later.

With its superior sensitivity, the preferred biomarker for diagnosing AMI, as already alluded to, is now troponin. Both troponin I and T are used and the commonly utilized assays are very sensitive for even minute quantities of myocardial necrosis. However, the more sensitive the test, the less specific they have become. While assays for CKMB have not changed appreciably over the years, the new era of troponin assays has advanced with improved detection of myocardial necrosis. Troponin assays are ever evolving in precision and biochemical research is steering to even more sophisticated laboratory testing. At our institution, the assay for troponin T was changed about 7 years ago. The new assay for high sensitivity troponin I (TnI-Ultra assay on the ADVIA Centaur XP immunoanalyzer, Siemens Healthcare Diagnostics) was about 25 times more sensitive than the prior assay with an upper reference level for the new assay of .04 ngs/ml. The ever changing spectrum of biochemical analysis of cardiac biomarkers created a need for standardization of nomenclature and interpretation of results. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) task force on clinical applications of cardiac biomarkers standardized the nomenclature so various assays can be considered a ‘high-sensitivity’ troponin assay if the total imprecision (coefficient of variance) was <10 % at the 99th percentile value in the population of interest [4]. Furthermore, the assay should attain measureable concentrations for samples below the 99th percentile, above the assays limit of detection in at least 50 % of healthy individuals [4].

As such, elevated troponin I levels are sensitive to detect myocardial necrosis, but there remains controversy whether small rises in troponin signify myocyte infarction versus reversible ischemia or other mechanisms. It has been shown that troponin levels may rise above the 99th percentile in patients undergoing rigorous exercise [6]. Complimenting this idea was data that perhaps measurable troponin levels can be induced during routine stress testing. The TIMI 35 group published data demonstrating detectable levels of troponin I in patients undergoing exercise stress testing who had positive ischemic responses [7]. The proposed theory for these small elevations in troponin include changes in cell membrane permeability with release of free troponin from the cytosol, which accounts for about 5 % of the total myocyte troponin [8]. Other proposed mechanisms of troponin release in patients who do not meet clinical criteria for myocardial infarction included apoptosis, cellular release of proteolytic products, increased cell wall permeability with stress or stretch and the production of membranous blebs containing troponin [9, 10]. However, the counter argument is that this small troponin elevation still reflects minute levels of myocyte necrosis [11].

Regardless of the sensitivity of the assay, no biochemical test alone will help the clinician determine the diagnosis. While the primary concern is that of an acute coronary syndrome, there are multiple other conditions associated with (or causing) elevated troponin values (Table 10.2). Some patients will meet criteria for AMI that are not related to an acute disturbance within the epicardial coronary arterial tree, but rather due to another cause for a supply demand mismatch. This has been designated as a type 2 MI by the Universal Definition [5]. Common causes include severe anemia, a hypertensive crisis, severe aortic valve disease, tachyarrhythmias and sepsis. Still there are other causes of troponin elevation that appear in low levels and do not clinically meet the current definition of AMI (a rise and /or fall in troponin and clinical evidence of ischemia related to symptoms, ECG changes or new wall motion abnormalities). Several conditions including pulmonary embolism, congestive heart failure, acute neurological disease and renal failure can elevate troponin levels but do not meet diagnostic criteria.