Invited critical review
Cardiac troponin may be released by ischemia alone, without necrosis

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Abstract

Whilst it is formally stated that cardiac troponin is only released when cardiac myocytes undergo necrosis, there are a number of clinical situations where troponin is present in the circulation, without any apparent cardiac injury. In these cases, troponin half-life in the circulation is usually substantially shorter than that seen when troponin is released following myocardial infarction with frank necrosis.

A mechanism has been described in liver, where large cytoplasmic molecules can pass from the intra- to extra-cellular space without cellular necrosis occurring. This occurs by the formation of membranous blebs which bud off from the plasma membrane of the cell. Blebs develop during cellular ischemia. If the ischemia is limited and re-oxygenation occurs, the blebs may be released into the circulation without rupture of the plasma membrane, resulting in a one-off release of cytoplasmic contents including macromolecules.

Evidence from cardiac studies is presented supporting the presence of membranous blebs in cardiac myocytes, enabling troponin to be released from cardiac cells due to ischemia alone, without necrosis.

Introduction

The introduction of cardiac troponin measurement to the clinical laboratory has been a signal advance in laboratory support for physicians investigating patients with possible myocardial disease. The presence of cardiac troponin was quickly included in the formal definition of myocardial infarction [1] and it is now recommended that troponin should be the only marker used for investigation of the acute coronary syndrome [2].

Although the possibility of troponin release due to ischemia without necrosis has been raised [3], [4], more recently it has been stated unequivocally that troponin release only occurs in the presence of necrosis [5], [6]. However, a recurring theme in the clinical literature, has been the presence of troponin in the circulation, without any subsequent evidence of coronary artery disease or of cardiac myocyte necrosis. Whilst many of these conditions are related to major systemic disease and the precise causes are difficult to assess [7], there have been a number relating specifically to conditions affecting the myocardium and in particular, causing transient myocardial ischemia. This has been particularly noted with supraventricular tachycardia (SVT), where patients presented with SVT and detectable troponin, which settled quickly to undetectable after treatment, and there was no evidence of coronary artery disease on angiography [8], [9].

In this paper, we review the available evidence and propose a mechanism whereby cardiac troponin can be released from myocardial cells by ischemia alone, without necrosis, and discuss the potential significance of this information.

Section snippets

The cellular location of cardiac troponin

The cardiac troponins are predominantly myofibril bound with only approximately 5–8% of both troponin I and troponin T being unbound in the cytosol [10]. In any cardiac myocyte injury it will be this unbound pool of troponin which is released first.

Cardiac troponin release during the acute coronary syndrome

During the acute coronary syndrome, there is an interruption of blood flow in the coronary circulation – most commonly involving thrombus formation on a ruptured plaque associated with transitory or prolonged occlusion of a coronary vessel, or distal embolization – leading to myocyte necrosis. The number of myocytes affected may vary from small through very large and the amount of damage caused is reflected by the rise in troponin concentration in the peripheral blood.

Although the true

Clinical situations associated with a short half-life of troponin in the circulation

We describe 4 clinical cases from our own experience.

  • 1.

    A 76 year old woman presented to her family practitioner with tiredness and anorexia. She developed marked tachycardia and hypotension whilst with the doctor and was admitted directly to hospital. At admission, an ECG showed atrial fibrillation with a rapid ventricular response and myocardial ischemia. The hypotension lasted for approximately 2 h. Troponin I at admission (Immulite 2000) was undetectable but rose rapidly to a peak of 5.6 μg/L,

Clinical

Ischemic hepatitis (an incorrect but clinical established terminology) describes the condition whereby the liver is rendered ischemic, usually due to a decrease in cardiac output, which in turn is often caused by myocardial infarction. The condition is characterized by a rapid and often very large increase in plasma concentration of hepatocyte intracellular enzymes. If cardiac output does not improve, patients die in a short timeframe, but if they recover their cardiac output, they survive and

Is there any evidence for reversible enzyme or troponin release and/or bleb development in cardiac myocytes?

There is evidence available that shows that cardiac myocytes both develop blebs and release cytoplasmic contents, without undergoing necrosis. Spieckerman and colleagues [21], [22], [23], [24] (see Fig. 2) showed that cultured cardiac myocytes developed blebs during the development of anoxia, with the release of cytosolic enzymes without cell necrosis occurring.

Katus and colleagues showed in perfused rat hearts that short duration ischemia followed by re-oxygenation led to a very short burst of

Could bleb development be artifactual and related to preparation of single cells?

Whilst cell culture is an excellent way of viewing individual cells in detail, there is a concern that how cells behave in tissue culture may not reflect cell behaviour in an intact organ. The process of separating cells might cause membrane damage and the blebs that are seen may be artefacts of this process. However, even though cells in intact organs have less free membrane surface from which blebs may develop, bleb formation in intact perfused organs has been well documented, in both liver

How cardiac troponin is released during ischemia without necrosis

During ischemia, blebs develop on the surface of cardiac myocytes. If the ischemia is prolonged the blebs rupture and cellular necrosis with prolonged troponin release follows.

However, if the ischemia is corrected before any blebs rupture, then the blebs are either resorbed or shed into the circulation. If shed they will release cytoplasmic contents as a “one-off” event and this will be cleared with a short half-life (see Fig. 3).

During coronary artery occlusion, downstream myocytes will

What is the significance of troponin being released by ischemia alone?

One important outcome from this model is that it explains a frequent puzzling clinical finding, namely the presence of cardiac troponin in the circulation, with either no necrosis, or insufficient cellular necrosis to explain the amount of troponin present. An ischemic mechanism for troponin release will correct the often incorrect interpretation that any troponin elevation is due to an acute coronary syndrome, which may lead to inappropriate clinical management. The arrival of the new high

Linkage of bleb formation and release of cardiac troponin with integrin stimulation

The mechanism by which troponin may be released in reversible injury through bleb formation appears to be linked to integrin stimulation. The integrins are a family of adhesion molecules that have been implicated in the pathophysiology of atherosclerosis. Along with other adhesion molecules such as the selectins, the immunoglobulin superfamily, and the cadherins, the integrins participate in the extravasation of leukocytes and monocytes into the shoulder regions of coronary artery plaques [39].

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