Patients suspected of having epicardial coronary disease are often investigated with noninvasive
myocardial ischemia tests to establish a diagnosis and guide management. However, the relationship between
myocardial ischemia and coronary stenoses is affected by multiple factors, and there is marked biological variation between patients. The ischemic cascade represents the temporal sequence of pathophysiological events
that occur after interruption of myocardial oxygen delivery. The earliest part of the cascade is examined via perfusion imaging, and fractional flow reserve (FFR) is a corresponding index which is specific to the coronary artery.
Whereas FFR has come to be regarded a clinical reference standard against which other newer invasive and
noninvasive tests are validated, the diagnostic FFR threshold for detecting ischemia was established against a
combination of noninvasive ischemia tests that assessed different stages of the ischemic cascade. Moreover, the
validity of invasive pressure-derived indices of stenosis severity are contingent on the assumption that pressure is
proportional to flow if microvascular resistance is constant, a condition induced by pharmacological intervention
or by examining specific segments of the cardiac cycle. Furthermore, myocardial perfusion reserve depends on
dynamic modulation of microvascular resistance, and dysfunction of the microvasculature can lead to ischemia
even in the absence of epicardial coronary disease.
