Introduction
The ischaemic cascade was initially described over 20 years previously,1 based on experiments in animals2–9 and humans,10–20 and refers to a temporal sequence of pathophysiological events that occur with increasing myocardial oxygen supply–demand imbalance. The ischaemic cascade has been described as occurring in the following sequence: metabolic alterations, inducible changes of perfusion, diastolic dysfunction, regional systolic wall motion dysfunction, ischaemic ECG changes and finally angina.1
A cascade is a sequence of events, each of which triggers the next. Since causation is difficult to demonstrate directly, instead progression is demonstrated and causation inferred. To create progressively more intense ischaemia within an individual animal, so that the sequence of emergence of elements of the cascade can be identified, three broad approaches are possible (figure 1):
Progressively tighter stenosis, with workload kept constant and measured at steady state.
Progressive passage of time after a fixed acute occlusion, with workload kept constant.
Progressively increasing workload, with stenosis kept constant and measured at steady state.
Three different ‘x axes’ along which to rank states for ischaemia. The underlying hypothesis behind the ischaemic cascade is that the order of development of the various manifestations of ischaemia is the same for all three main ways of producing the ischaemia phenomenon. One approach is to ligate a coronary artery and monitor carefully in the ensuing seconds, with the temporal sequence of events showing the cascade sequence. A second is to progressively increase stenosis. A third is to progressively increase workload. If these three methods of inducing progressively more severe ischaemia produce manifestations in conflicting sequences, the ischaemic cascade concept is imperilled.
Assembling data from experiments that use different possibilities from the three ways of spreading ischaemia intensity on a spectrum relies on the assumption that the three different meanings of increasing ischaemia are equivalent. If the ischaemic cascade model is accurate, the order of events should be the same in all three. For example, it might be metabolic alterations first, followed sequentially by myocardial perfusion abnormalities, wall motion abnormalities, ECG changes and angina. If this assumption is not correct then we should be much more thoughtful when displaying illustrations of the process of ischaemia.
Metabolic alterations consist of the conversion from aerobic to anaerobic myocardial cell metabolism, thus producing biochemical changes of lactate, and cellular polarity. At a single-cell level a cascade is feasible, however cellular events will not occur synchronously in all cells beyond a stenosis. It is the later stages of the ischaemic cascade concept that are of clinical interest, but these can be subject to confounding effects of concomitant medications and varying degrees of coronary disease.
If the ischaemic cascade is not as solid a sequence as is often portrayed, this article discusses how the process of ischaemia could be conceptualised, the implications this has on the development of new tests of ischaemia and the implications for clinical practice.
Some clinicians and scientists may have already rejected the ischaemic cascade for not being true; for them, our paper is attacking a ‘straw man’. Unfortunately however, figures and slides are commonly shown21–24 and clinical studies (that use a single ‘gold standard’ for ischaemia) continue to assume that the cascade is true. This implies that rejection of the ischaemic cascade is not yet universal, and therefore our paper may be a useful enumeration of information.