Dr. William F. Fearon, Stanford University, 300 Pasteur Drive, Room H2103, Stanford, California 94035.
Coronary flow reserve (CFR) is defined as the ratio between the maximum achievable coronary flow and the resting coronary flow. CFR interrogates the entire coronary system, including the epicardial artery and coronary microcirculation. Noninvasive CFR measurements have shown prognostic value; however, use of invasively measured CFR in the catheterization laboratory to guide revascularization decisions has never gained traction (1). This is because CFR has no normal value (although a CFR <2 is considered abnormal); measurement with a Doppler wire can be technically challenging; CFR has poor reproducibility because resting flow is affected by changes in heart rate and blood pressure; and most importantly, CFR cannot distinguish microvascular dysfunction from epicardial stenosis-related flow limitation (2).
This led to the development of fractional flow reserve (FFR), which is advantageous because it quantifies the contribution of epicardial coronary disease to the degree of myocardial ischemia, independent of the influence of the microvasculature. Because FFR is measured during maximal hyperemia, microvascular resistance is minimized, and the effect of changing hemodynamics on resting flow is eliminated. Microvascular dysfunction can affect FFR in that a given stenosis may have less maximal flow across it, a lower pressure gradient, and a higher FFR than would occur in the setting of normal microvascular function; however, this does not invalidate FFR, and in fact, its accuracy in this setting has been extensively proven (3,4). In the presence of microvascular dysfunction, FFR still informs the operator about the expected gain in epicardial coronary flow should a stenosis be relieved by revascularization. This, of course, is the critical information we need when deciding to revascularize an epicardial stenosis.
Another advantage of FFR is that in a normal coronary artery, the distal coronary pressure is the same as the proximal pressure and FFR has a value of 1.0. In a diseased artery, the proximal coronary pressure is a reflection of what the distal pressure would be in the absence of epicardial disease, providing a normal reference for every patient and every vessel. On the other hand, coronary flow decreases from the proximal vessel to the distal vessel in a normal coronary artery. Measuring hyperemic coronary flow in isolation is not helpful because there is no normal reference to compare it within a given vessel or a given patient. For all of these reasons, it is expected and, in fact, is an advantage that FFR does not correlate well with hyperemic velocity of blood flow or with CFR.
Recently, multiple alternative pressure wire–based measures of coronary ischemia without the use of adenosine-induced hyperemia have been studied, including resting distal pressure/aortic pressure (Pd/Pa), contrast FFR, and the instantaneous wave free ratio (iFR), which measures Pd/Pa during diastole (5). Of these alternative measures, iFR has led the way, with 2 recently published outcome trials (DEFINE-FLAIR [Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation] and iFR SWEDEHEART [Evaluation of iFR vs FFR in Stable Angina or Acute Coronary Syndrome]) finding that iFR is statistically noninferior for guiding revascularization when compared with FFR (6,7). However, multiple other studies have found that iFR is only 80% accurate when compared with FFR (5,8).
With this background, we read with interest the article published by Cook et al. (9) in this issue of JACC: Cardiovascular Interventions and commend the authors on this latest addition to the coronary physiology published reports, which attempts to explain discordant FFR and iFR cases by examining differences in coronary flow. They conducted a retrospective analysis of iFR, FFR, and Doppler wire-derived CFR measurements in 366 vessels with intermediate stenoses in 291 patients, and in 201 unobstructed vessels in 153 patients, which served as a reference group. They found that iFR at a cutoff of ≤0.89 and FFR at a cutoff of ≤0.80 were discordant in 14% (55 of 366) of cases. In cases in which FFR was ≤0.80 (FFR+) and iFR was >0.89 (iFR−), the hyperemic flow velocity and CFR values were statistically similar to FFR−/iFR− cases and to reference cases with unobstructed coronary vessels. Likewise, in FFR−/iFR+ cases, the hyperemic flow velocity and CFR values were similar to the FFR+/iFR+ group, suggesting that CFR agrees with iFR over FFR. The authors conclude that because iFR was more congruent with CFR and hyperemic blood flow than FFR, iFR should be the preferred pressure-based index for the assessment of angiographic intermediate severity epicardial coronary lesions.
Another interpretation of the data is that in the FFR−/iFR+ cases, the abnormal iFR can be explained by the elevated resting flow compared with the FFR+/iFR− cases (19.3 vs. 15.1 cm/s). Of note, there were significantly more diabetic patients in the FFR−/iFR+ group (42% vs. 14%). This is relevant because diabetic patients may have impaired autoregulation and/or altered myocardial energy metabolism leading to increased resting flow, as was shown in previous studies (10,11). The higher prevalence of diabetes is also important because there was likely a greater degree of microvascular dysfunction in this group explaining the abnormal CFR in the presence of a nonischemic FFR. Unfortunately, the authors do not include the hyperemic distal coronary pressure measurements, because this would have allowed calculation of the minimal achievable microvascular resistance and confirmed the presence of microvascular dysfunction in the FFR−/iFR+ cases.
In the FFR+/iFR− cases, the authors have suggested that the FFR is likely a false positive because of supra-normal hyperemic coronary flow. However, it is important to note that the hyperemic flow was numerically lower than what was measured in unobstructed coronary vessels, and there was a strong statistical trend toward a lower CFR (2.36 vs. 2.5; p = 0.08). Likely, these patients have normal microvascular function and should have a CFR of 4, but have a depressed CFR due to the epicardial stenosis. The negative iFR in these cases may be related to the fact that these lesions had the lowest resting flow.
The FFR+/iFR− cases had a mean FFR value of 0.77. Multiple studies have demonstrated that stenoses with FFR values in the 0.75 to 0.80 range are associated with increased adverse cardiac events compared with narrowings with FFR values >0.80 when both are treated medically (12,13). Moreover, FFR+/iFR− discordance most commonly occurs across left main and proximal left anterior descending coronary artery lesions, as demonstrated in a study by Kobayashi et al. (14), because of the larger amount of myocardium supplied by these vessels and the greater hyperemic flow. The greater deferral of percutaneous coronary intervention on these important stenoses in the patients randomized to iFR guidance may explain why there was a strong trend toward a higher rate of death and myocardial infarction (relative risk: 1.3, 95% confidence interval: 0.96 to 1.77; p = 0.09) in the iFR-guided strategy as compared with the FFR-guided strategy in a recent meta-analysis of the DEFINE-FLAIR and iFR SWEDEHEART trials (15).
Dr. Fearon has received research grants from Edwards Lifesciences, Medtronic, ACIST Medical Systems, Abbott, and CathWorks; and holds minor stock options with HeartFlow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(2006) Fractional flow reserve of infarct-related arteries identifies reversible defects on noninvasive myocardial perfusion imaging early after myocardial infarction. J Am Coll Cardiol 47:2187–2193.
(2017) FFR/iFR discordance in angiographically intermediate coronary stenoses: an analysis using Doppler-derived coronary flow measurements. J Am Coll Cardiol Intv 10:2514–2524.
(2011) Increased basal coronary blood flow as a cause of reduced coronary flow reserve in diabetic patients. Am J Physiol Heart Circ Physiol 301:H2279–H2284.
(2016) Bimodal pattern of coronary microvascular involvement in diabetes mellitus. J Am Heart Assoc 5. e003995.
(2016) Significance of intermediate values of fractional flow reserve in patients with coronary artery disease. Circulation 133:502–508.
(2016) A prospective natural history study of coronary atherosclerosis using fractional flow reserve. J Am Coll Cardiol 68:2247–2255.
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