Pathophysiology is the combination of disease effects influencing both the epicardial conduit and the microvascular structure of the myocardium. The conduits are connected through collateral channels, which can be detected, quantitated and influenced by pressure and flow variables. The microcirculation is affected to varying degrees by different pathologic conditions. Now the influence of a stenosis on coronary flow as detected in the post-stenotic region can be precisely quantitated using both pressure and flow techniques.

Measuring the physiology of a coronary stenosis is based on the basic concepts of lesion resistance, as determined by the curvilinear relation between flow increases and different degrees of pressure loss (Fig. 1). The concept of fractional flow reserve (FFR) advances the traditional concept of determining the pressure gradient, the change of pressure between proximal and distal portions within the vessel, determining a greater degree of pressure loss for any stenosis more severe than another. In FFR the absolute distal perfusion pressure is a measure of stenosis severity and the threshold at which that stenosis can induce myocardial ischemia.

Excellent tools for invasive and intracoronary assessment of pathophysiology are now available. The angiogram and intravascular ultrasound (IVUS) imaging provide precise anatomic detail, and can measure translesional pressure gradient and the absolute pressure at maximal hyperemia (Fig. 2). FFR is the difference between the aortic and distal pressure at high hyperemia. The FFR has a well-defined threshold below which myocardial ischemia in stable patients is associated.

Coronary flow velocity is measurable and can provide a graphic demonstration of the changes in coronary flow over time and in response to different stimuli (drug, exercise, intrinsic stimuli that alter the coronary circulation). The influence of different interventions over time on flow patterns can be observed by using the measurement of flow trending. Combining the two measures of change in pressure and change in flow, results in an absolute precise determination of the entire coronary circulation, both the response at the epicardial level and at the microvascular level.

Pressure guide wires have been developed to measure distal pressure and proximal aortic pressure. FFR has become critically important to the complete understanding of when a stenosis is significant enough to cause myocardial ischemia and warrant coronary intervention. As coronary flow increases through a coronary stenosis, the distal pressure loss increases in proportion to the resistance in an exponential fashion (Fig. 3). That pressure loss can be caused by friction, turbulence, separation, or the energy of flow being taken out as heat, thus the pressure loss is distal to that stenosis.

FFR and myocardial ischemia

FFR is the ratio of absolute distal pressure to proximal pressure at maximal hyperemia. FFR is defined as a percentage of the normal flow going through an artery in the absence of the stenosis. (FFR = the ratio of flow through the stenotic vessel (QS) over the ratio of flow in the theoretic normal value (QN) (FFR= QSmax/ QN max.) When resistance is minimal, the simple equation of distal pressure over aortic pressure measured at maximal hyperemia (Pa/Pd) can be used. When this percentage is less than 75%, it has a very strong association with inducible myocardial ischemia in stable patients.

FFR is based on a fixed resistance and is specific for the stenosis resistance, thus it is independent of variables that influence coronary flow reserve, such as heart rate, blood pressure, and contractility that can influence basal and hyperemic flow. Work by Pijls has shown that the reproducibility of CFR under different hemodynamic conditions is not as strong as is the reproducibility with FFR.

CFR measures both the stenosis and the effect of the myocardial bed, and is thus a composite measure. Measuring relative coronary flow reserve (rCFR), the ratio of CFR in a reference vessel to that in a target vessel, eliminates the influence of the myocardial bed and increases specificity. FFR or concepts using pressure-derived FFR can begin to inform about the influence of collateral circulation on myocardial ischemia.

The relation between absolute CFR and FFR is not very strong, as CFR measures both the microvascular bed and the conduit. There is a stronger relation between the rCFR and FFR, by eliminating the microvascular bed. In some conditions, rCFR is thought to be a more lesion-specific measure. More work in this area is forthcoming to determine the relation of rCFR to myocardial ischemic stress testing.

Comparison of FFR and CFR

Hemodynamic and microvascular independence are both related to rCFR and FFR. The normal value for FFR is 1.0, and for rCFR it is a range greater than 0.8. A CFR value greater than 2 is associated with normal ischemic stress testing. FFR and CFR, but not rCFR, can be employed in multiple vessel disease. The collateral circulation can be assessed using CFR measured during balloon angioplasty and FFR measured with a pressure wire during balloon occlusion.

The relation between CFR in the post-stenotic region and positive stress testing has been examined. Values less that 2 are associated with positive ischemic stress testing, ranging from adenosine, sestamibi, exercise thallium, dipyridamole echo, and exercise ECG. This is based on a number of studies during the past five years that have relatively high sensitivity (ranging from 82-100%), specificity (71-100%) and predictive accuracy (86-96%).

FFR values less than 0.75 are associated with myocardial ischemia, based on data in patients with stable angina. Such values for AMI or UA have not been developed and are the subject of future testing.

Angiograms are not always reliable in assessing diffuse CAD. For example, when CFR is measured in the right coronary artery (RCA) a value of 2.8 can be generated, whereas a value of 1.6 can be generated through the diseased left coronary artery (LCA). In this case, it is likely that benefit will be obtained by dilating the LCA region, rather than by dilating the RCA region.

Deferring treatment of intermediate stenoses with normal physiology results in good clinical outcomes. The safety of the technique and the long-term events in these patients are low, equivalent to those patients with CAD that is inactive and treated. Multiple studies using FFR or CFR indicate a 10% or less event rate for progression of disease in intermediate lesions having undergone physiologic evaluation with sensor guidewires.

Serial stenoses

Determining whether FFR can be useful in identifying which stenosis of serial stenoses may be important to dilate has been an area of recent investigation. The concept and the mathematics used to derive the equations can be somewhat complex. To consider the FFR between lesions requires knowing the relation between the pressure between lesion A and lesion B (Fig. 4). The FFR for lesion A is derived as a distal pressure of the middle section versus the aortic pressure. Lesion B is the distal pressure divided by the middle pressure. The classic FFR is the sum of the two stenoses. Changing the resistance across one lesion will change the flow, and thus will impact the re-calculation of the second lesion. This use is forthcoming.

Use of physiology during interventions

A case study illustrated employing physiology during interventions. A severe stenosis in a circumflex artery is associated with an abnormal and very low FFR of 0.38, a CFR of 1.1, and rCFR of 0.5 when the unaffected left anterior descending (LAD) has an FFR of 2.0. Angioplasty alters the pathophysiology. Although the anatomic result may be acceptable, the physiologic result, at least based on a CFR of 1.5, is unacceptable. In most cases this is due to material remaining in the artery that can be pushed aside with stenting, and in many cases this normalizes the FFR to 2.0 and creates an rCFR of 1.0. This is a classic example. CFR may not normalize in about 20% of patients and microcirculatory abnormalities may persist, despite having a normal FFR or rCFR. The FFR grading criteria for interventions is shown in Figure 5.

Physiologically-guided PTCA and stent

Provisional stenting is no longer practiced. However, three studies (DEBATE-II, DESTINE-CFR, FROST) indicate that about 50% of the time stent-like results can be achieved with balloon-angioplasty guided by a physiologic endpoint. A study by Bech et al found about a 15% 2-year target lesion revascularization rate when a good anatomic angioplastic endpoint was achieved with an FFR greater than 0.90.

Physiologic criteria in ischemic stress testing

The criteria for CFR and FFR in ischemic stress testing were summarized (Fig. 6). For each test, there is small gray zone, larger for CFR than for FFR. Thus, not every 0.75 stenosis requires dilation and clinical judgment must be employed. The estimated rCFR threshold value is greater than 0.8. But, no definitive studies have been published to support this value, and there is a little broader gray zone. Angioplasty endpoints in the DEBATE trial show that CFR values greater than 2.5 with good anatomy were associated with low event rates. FFR values greater than 0.90 were also associated with very satisfactory if not superior endpoints, based on data from Pijls. An FFR greater than 0.94 indicates the stent is fully deployed, when validated by IVUS. A multicenter trial is underway in the United States to evaluate whether FFR can be used to define the endpoint in stenting.

Assessment of diffuse CAD after stenting

What is the best way to assess if flow has been well restored in the setting of a severe LAD lesion with a well-stented segment, but a diffusely diseased distal vessel? When measuring FFR, initially there is a loss of distal pressure across the stenosis but no further pressure loss with adenosine. Despite achieving good anatomic results with stenting, CFR was impaired. The use of pressure and flow measures can help to determine whether the angioplasty in the proximal LAD is not as good as it looks (hidden material or an unappreciated segment), or if there is microvascular impairment, or abnormal conductance of the LAD segment, or a combination of these factors.

In this case, the FFR was normal when measured distal to the stent and in the proximal portion of the artery. The stent was perfectly expanded, placed well, and conductance up to that point in the arterial segment was normal. Measuring distally to the segment showed there was a mass of material in the vessel (the diffuse CAD) that was producing a gradual but continual pressure loss. When the FFR was measured in the distal region it was very abnormal. A hyperemic pull-back performed from the distal to the proximal vessel during infusion of intravenous adenosine showed there was a gradual, subtle decrement in the pressure gradient and improvement in pressure as it went up to the stent, indicating a long, diffuse segment of disease. Regardless of how well the epicardial conduit is treated, perfusion down the distal vessel is not possible due to the plaque accumulation. Treating focal stenoses along the vessel will not result in improvement.