Almost 40 years ago, K. Lance Gould proposed the concept of coronary flow reserve (CFR) to quantify the effect of epicardial narrowings on myocardial blood flow (1). CFR represents the extent to which hyperemic coronary flow can increase above resting flow. These animal experiments still constitute the basis for our understanding of coronary physiology. The development of flow velocity catheters ((2),3), progress in positron emission tomography–derived absolute flow measurements (4), and, more recently, transthoracic Doppler flow velocity measurements (5) extended Gould's findings into patients with coronary artery disease. Until the description of fractional flow reserve became available ((6),7), CFR was the only index commonly used in the clinical field. Yet, the main problem with CFR in clinical practice resides in its lack of specificity for the epicardial vessel: a too-low CFR value does not determine whether this abnormal flow velocity relates to the epicardial stenosis, to microvascular disease, or to a combination of both. In addition, the cutoff value for separating normal from abnormal is actually a moving target and is influenced by a large variety of factors such as blood pressure, heart rate, resting flow (which is difficult to obtain in a patient in a catheterization or echocardiography laboratory), myocardial mass, and age.

Despite these limitations for individual clinical decision making, Cortigiani et al. (8) report in this issue of iJACC an impressive relationship between transthoracic Doppler velocity-derived coronary flow in the left anterior descending artery (LAD) and mortality. Grouches will observe that obtaining reliable flow velocity tracings in the LAD is not always possible, especially during maximal hyperemia. And, indeed, the authors do not report on the feasibility of the method. Raising 1 eyebrow, others will wonder what colleagues would think of a LAD-only angiogram or of a chest radiograph displaying only the left hemithorax.

The take-home message of this paper (8) is not a pragmatic one about individual clinical decision making and treatment strategies on the basis of transthoracic Doppler flow velocity measurement in the LAD. The findings of Cortigiani et al. (8) illustrate a more conceptual finding: when the adaptation of flow to hyperemic stimuli is normal—be it only in the LAD—patients' prognosis is excellent and much better than when CFR is abnormal. This is not new information, but it is an important confirmation using a noninvasive, cheap, and radiation-free methodology.

The first conclusion of the authors (8) (i.e., abnormal CFR or ischemia is associated with a worse prognosis) is only scarcely supported by their data. A number of important issues remain, including a surprisingly high annual death rate of 10%. No details are provided on the type of revascularization or the extent of the coronary lesions or their left ventricular function. Only 61% of patients who had ischemia underwent revascularization. Were the other 39% considered too high-risk for revascularization? This would explain the high mortality. Is it not surprising that revascularization did not seem to influence prognosis since functional information was present in all patients? Recent data indicate that, when properly selected, patients do indeed benefit from revascularization (9).

The second conclusion (i.e., normal CFR goes along with a good prognosis) is well supported by the present data. A normal noninvasive test result has been shown repeatedly to be associated with a very favorable prognosis, regardless of the coronary anatomy (10). More recently, Muller et al. (11) reported that in patients with an isolated, angiographically defined stenosis in the proximal LAD but a fractional flow reserve >0.80, patients' survival was similar to that of an age- and gender-matched control population. In the current study (8), only 9% of patients with CFR >2 had to undergo revascularization. Thus, the survival rate can be considered to reflect, to some extent, the natural history of this group of patients.

There are many hypotheses regarding the link between ischemia and mortality. Repeated episodes of ischemia may alter left ventricular function and trigger arrhythmias. Alternatively, stress-induced ischemia might well be an (almost) innocent bystander rather than the direct cause. In this hypothesis, ischemia would only be indicative of abnormal resistance in the epicardial arteries, much like smoke behind a car is not the cause of the problem but indicates an issue with the engine. A stenosis with a low CFR may induce stress-related ischemia because the autoregulatory mechanisms cannot compensate for the abnormal epicardial resistance. Myocardial autoregulatory mechanisms maintain blood flow at the cost of a pressure gradient. This pressure gradient is the trigger for a number of physical forces that may contribute to plaque destabilization: turbulences, abnormal shear stress, high and localized plaque stress, slicing forces and torsions, intraplaque gradients, and Venturi effects. In contrast, in case of nonsignificant stenosis, CFR will be (near) normal, the gradient will be small or absent, and these physical forces will remain absent. These physical phenomena do not appear when there is no gradient. This may help explain why the absence of stress-induced ischemia and the presence of a normal CFR are associated with a good prognosis, as described by Cortigiani et al. (8). No gradient, no worries.

⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.