CFR in Clinical Practice
Myocardial ischemia is the metabolic derangement that results when myocardial blood flow is insufficient to meet demand. Epicardial coronary artery disease that is moderate to severe, but not flow-limiting at rest, often produces a situation where ischemia occurs only when further increases in flow cannot meet increases in myocardial oxygen demand beyond resting conditions. The “unmasking” of this inadequacy of flow reserve in the clinical setting generally relies on exercise stress or inotropic drugs such as dobutamine that increase myocardial oxygen demand, or on the drugs that directly dilate the coronary resistance arterioles. These “stressors” are generally used in conjunction with methods that non-invasively image myocardial function (wall motion, strain) or regional perfusion.
Abnormal flow reserve caused by epicardial stenosis or by conditions that alter microvascular function can also be detected invasively by measurement of coronary “flow” reserve (CFR). This measurement has traditionally been made at the time of angiography with a steerable intracoronary Doppler flow wire and intracoronary administration of a vasodilator such as adenosine. The word flow is in quotations because conventionally only coronary flow velocity is measured and coronary arterial diameter is not. Because of improvements in ultrasound technology and the advent of ultrasound contrast agents that augment spectral Doppler signals, it has become possible to detect epicardial flow responses in coronary artery disease non-invasively with transthoracic echocardiography. This approach has been shown to be possible not only for the left anterior descending (LAD) vessel, which is easily identified in the anterior interventricular sulcus, but also for the right and left circumflex arteries. It is also worth noting that while the use of epicardial Doppler to measure CFR is relatively new, CFR was the first method applied to evaluate the physiologic significance of stenosis by Gould et al in 1974.
There are several common clinical scenarios that justify the evaluation of epicardial CFR, either invasively or non-invasively. The physiologic significance of a stenosis can be in question when intermediate-severity disease is discovered in patients referred for angiography without preceding stress imaging. CFR has also been used to assess “incidental” disease that is found in vessels other than those of primary concern in patients undergoing catheterization due to acute coronary syndrome or positive stress imaging. In these settings, rapid assessment of CFR can be used to make a decision on coronary intervention while the patient is still in the angiography suite. Assessment of CFR may also be useful when, despite high clinical suspicion for a significant obstructive disease, non-invasive imaging is equivocal or is negative. There are recognized limitations in detecting mild to moderate ischemia by using non-invasive imaging of either wall thickening response or regional uptake of radionuclide imaging probes. In other words, there is non-linearity, or a “leveling off” of the relation between flow reserve and either wall motion during inotropic stress or uptake of 99m Tc and 201 Tl imaging probes. As a result, only small differences that are difficult to discern may be present between normal myocardial regions and abnormal regions supplied by vessels with moderate stenosis. Finally, measurement of CFR may be of value in identifying individuals with multivessel disease in whom relative uptake of radionuclide tracers may not show regional heterogeneity, although data are scarce regarding this application.
Competing Techniques for Measuring CFR
In the study by Meimoun et al in this issue of JASE, transthoracic Doppler echocardiography was used to test the physiologic impact of intermediate severity stenosis in the LAD in patients referred for diagnostic angiography. The vast majority of these patients had one of the clinical scenarios described above where evaluation of the physiologic significance in the angiography suite may be helpful. Non-invasive CFR measurement by transthoracic Doppler during hyperemia produced by intravenous adenosine was compared to fractional flow reserve (FFR) after intracoronary bolus administration of adenosine. The latter is a technique also commonly employed in the angiography suite to evaluate the significance of coronary stenosis. The physiologic measurements made for each approach are shown schematically in Figure 1 . For CFR ( top panel ), the spectral pulsed-wave Doppler flow velocity in the LAD is recorded at rest ( dark gray waveform ) and during peak hyperemia ( light gray waveform ) produced by intravenous adenosine infusion. CFR is calculated simply as the ratio of the peak diastolic flow velocity during adenosine to that at rest. For FFR ( bottom panel ), measurements are made only during hyperemia, usually produced by intracoronary adenosine. FFR is calculated as the ratio of mean coronary pressure distal to stenosis to that measured in the aorta. The derivation of FFR was intended to provide an estimate of the ratio of flow during maximal hyperemia to that which can be achieved, in theory, in the absence of stenosis, and assumes that microvascular resistance during hyperemia is not different in these two circumstances.
One is tempted to criticize Meimoun et al ’s study design since FFR is used as a comparator rather than quantifying microvascular blood flow with positron emission tomography or myocardial contrast echocardiography. However, the authors clearly state that the purpose of the study was to evaluate concordance for two different practical approaches that can be used to evaluate the physiologic significance of stenosis in the catheterization lab. It is also worth noting that small studies comparing CFR to myocardial perfusion have already been performed. The current study was appropriately designed to exclude infarction which may affect one measurement more than the other, and to perform FFR and CFR at approximately the same vascular segment. Although the study was somewhat limited by the small number of patients with physiologically significant disease (n=13 with FFR <0.8), the authors found a good agreement between CFR and FFR.
Competing Techniques for Measuring CFR
In the study by Meimoun et al in this issue of JASE, transthoracic Doppler echocardiography was used to test the physiologic impact of intermediate severity stenosis in the LAD in patients referred for diagnostic angiography. The vast majority of these patients had one of the clinical scenarios described above where evaluation of the physiologic significance in the angiography suite may be helpful. Non-invasive CFR measurement by transthoracic Doppler during hyperemia produced by intravenous adenosine was compared to fractional flow reserve (FFR) after intracoronary bolus administration of adenosine. The latter is a technique also commonly employed in the angiography suite to evaluate the significance of coronary stenosis. The physiologic measurements made for each approach are shown schematically in Figure 1 . For CFR ( top panel ), the spectral pulsed-wave Doppler flow velocity in the LAD is recorded at rest ( dark gray waveform ) and during peak hyperemia ( light gray waveform ) produced by intravenous adenosine infusion. CFR is calculated simply as the ratio of the peak diastolic flow velocity during adenosine to that at rest. For FFR ( bottom panel ), measurements are made only during hyperemia, usually produced by intracoronary adenosine. FFR is calculated as the ratio of mean coronary pressure distal to stenosis to that measured in the aorta. The derivation of FFR was intended to provide an estimate of the ratio of flow during maximal hyperemia to that which can be achieved, in theory, in the absence of stenosis, and assumes that microvascular resistance during hyperemia is not different in these two circumstances.
