Introduction
Coronary blood flow and pressure measurements across a stenotic coronary artery provide information on the ischemic potential of a specific lesion at the time of catheterization. Physiologic assessment of coronary artery stenosis by fractional flow reserve (FFR) has become the gold standard for invasive assessment of myocardial ischemia. Its integration into the catheterization procedure as an adjunct to coronary angiography has made a significant impact on clinical decision making and outcomes for patients with a variety of angiographic presentations including intermediately severe single-vessel disease, multivessel disease, left main stenosis, diffuse disease, and bifurcation or ostial branch stenoses. The clinical outcome validation of FFR from several large randomized trials has led to favorable recommendations in guidelines for coronary revascularization, making it part of the standard of care for patients with coronary artery disease (CAD). This chapter reviews the concepts behind coronary physiology and FFR for clinical applications.
Rationale for In-Lab Coronary Physiologic Measurements
The rationale for using coronary physiologic assessment arises from two sources: (1) that the coronary angiogram has significant limitations to demonstrating the clinical significance of lesions accurately, particularly in intermediately narrowed (between 30%-80% diameter stenosis), lesions and (2) that decisions for revascularization via percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery should be based on the presence of ischemia, information which may not be apparent from the angiogram or prior noninvasive testing.
Coronary angiography produces a two-dimensional silhouette image of the three-dimensional vascular lumen. The interpretation of this image as representing an ischemia-producing lesion is both difficult and unreliable as evidenced from the poor correlation between noninvasive testing with angiographic percent diameter stenosis. Angiography does not provide vascular wall detail sufficient to characterize plaque size, length, or eccentricity. Viewed from different radiographic projections, the eccentric lesion produces an image with an unknown lumen dimension and is associated with at least six additional morphologic features known to contribute to the resistance to flow. Almost all of these features cannot be measured accurately from the angiogram ( Figures 15-1 and 15-2 ). Other confounding artifacts of coronary angiography include contrast streaming, branch overlap, vessel foreshortening, calcifications, and ostial origins, which all contribute to uncertainty in gauging the ischemic potential of lesions.
The uncertainty of angiographic lesion assessment can be overcome with direct physiologic measurements in the catheterization laboratory (cath lab) using pressure and flow sensor guidewires.
Derivation of Fractional Flow Reserve from Coronary Pressure Measurements
Pijls and De Bruyne developed and validated an index for determining the physiologic impact of coronary stenoses, called the fractional flow reserve (FFR). In the cath lab, FFR is measured as the ratio of mean distal coronary pressure divided by the mean proximal aortic pressure during maximal hyperemia. The coronary pressure beyond the stenosis is measured with a 0.014-inch guidewire with a high-fidelity pressure transducer mounted 1.5 cm from the tip of the wire, at the junction of the radio-opaque and radiolucent segments ( Figure 15-3 ). The proximal coronary pressure is measured from the guide catheter and is equivalent to aortic pressure.
Using coronary pressure distal to a stenosis measured at constant and minimal myocardial resistances (i.e., maximal hyperemia), Pijls et al. derived an estimate of the percentage of normal coronary blood flow expected to go through a stenotic artery. A simplified derivation for FFR is shown in Figure 15-4 . FFR can be subdivided into three components describing the flow contributions by the coronary artery, the myocardium, and the collateral supply. FFR of the coronary artery (FFR cor ) is defined as the maximum coronary artery flow in the presence of a stenosis divided by the theoretic normal maximum flow of the same artery (i.e., the maximum flow in that artery if no stenosis were present). Similarly, FFR of the myocardium (FFR myo ) is defined as maximum myocardial (artery and bed) flow distal to an epicardial stenosis divided by its value if no epicardial stenosis were present. Stated another way, FFR represents that fraction of normal maximum flow that remains despite the presence of an epicardial lesion. Note that at maximal hyperemia FFR cor is about equal to FFR myo because myocardial bed resistance is minimal. The difference between FFR myo and FFR cor is FFR of the collateral flow.
The following equations are used to calculate the FFR of a coronary artery and its dependent myocardium:
FFR cor = ( P d − P w ) / ( P a − P w )
FFR myo = ( P d − P v ) / ( P a − P v )
FFR collateral = FFR myo − FFR cor
In most clinical circumstances P v is negligible relative to aortic pressure and omitted from the calculations. P v may be included when right atrial pressure is >10 mm Hg and may influence FFR ± 0.02 units in patients with elevated right atrial pressure. FFR reflects both antegrade and collateral (or bypass graft) myocardial perfusion rather than merely trans-stenotic pressure loss (i.e., a stenosis pressure gradient). Because it is calculated only at peak hyperemia and excludes the microcirculatory resistance from the computation, FFR, unlike the coronary velocity reserve (CVR), is largely independent of basal flow, heart rate, systemic blood pressure, or status of the microcirculation. Table 15-1 lists the calculations for FFR. Table 15-2 lists the thresholds for clinical applications of FFR.
| INDICATION | FFR |
|---|---|
| Ischemia detection | <0.75 |
| Deferred PCI | >0.80 |
| Endpoint of PCI * | >0.90 |
* Endpoint of stenting is anatomic apposition of stent struts best determined by IVUS. FFR can normalize despite malapposition of some stent struts.
Coronary Flow Reserve versus Fractional Flow Reserve
Coronary flow reserve (CFR) differs from FFR in several significant ways. CFR is defined as the ratio of peak hyperemic flow (or velocity) to basal flow ( Figure 15-5 ). CFR is altered by changing maximal and basal flow velocity values, which vary with heart rate, blood pressure, and contractility. FFR does not depend on basal flow levels since it is computed only at maximal flow and is unaffected by changing hemodynamics or the status of the microcirculation. CFR >2.0 represents a nonischemic value with an unknown normal value as CFR can change depending on existing conditions of the patient. In contrast, FFR has an absolute normal value of 1.0 for every artery, every patient, and every condition. FFR is specific for determining the ischemic potential of a specific epicardial coronary stenosis, whereas CFR provides the maximal flow across both the epicardial (R1) and microvascular (R2, R3) resistances ( Figure 15-6 ). If either one or both is abnormal, CFR is abnormal, with no way to distinguish the contribution of the stenosis to impaired flow reserve. For these reasons FFR is preferred over CFR for in lab lesion assessment.
Fractional Flow Reserve and Myocardial Bed Size
An important concept to understanding the visual-functional mismatch of angiographic lesion severity and FFR is the relationship of myocardial bed size to epicardial flow. The larger the myocardial mass subtended by a vessel, the larger the hyperemic flow, and in turn, the larger the gradient and the lower the FFR for a given stenosis ( Figure 15-7 ). This explains why a stenosis with a minimal cross-sectional area of 4 mm 2 has totally different hemodynamic significance in the proximal left anterior descending artery (LAD) versus a more distal location or region such as might be supplied by a second marginal branch in the lateral wall distribution. Proof of this concept was demonstrated by Iqbal et al., whereby an intermediately stenotic LAD supplying the anterior and inferior myocardial beds in a patient with an occluded right coronary artery (RCA) had an FFR of 0.72. After stenting and opening the RCA, reducing the LAD myocardial bed, the FFR across the LAD now rose to 0.84. In a similar manner the hemodynamic significance of a particular stenosis may change if the perfusion territory changes after myocardial infarction. It is for this reason that FFR in the ST-elevation myocardial infarction (STEMI) patient may not be valid until the dynamic changes of the acute injury are over. Regardless of the visual appearance, FFR accounts for the flow through the epicardial artery related to the bed supplied.
Techniques of Intracoronary Pressure Sensor Wire Measurement
FFR can be easily measured using a 5 Fr or 6 Fr guide catheter and either of two available pressure wire systems (St. Jude Medical, Minneapolis, Minnesota, or Volcano Therapeutics, Rancho Cordova, California). After diagnostic angiography with a catheter seated in the coronary ostium, the steps to measure FFR are as follows:
- 1.
Anticoagulation (intravenous [IV] heparin usually 40 U/kg or bivalirudin) and intracoronary (IC) nitroglycerin (100-200–mcg bolus) are administered before guidewire insertion.
- 2.
The pressure wire is connected to the system’s pressure analyzer and calibrated and zeroed to atmospheric pressure outside the body.
- 3.
The wire is advanced through the guide to the coronary artery. The pressure wire and guide pressures are matched (i.e., equalized, also called normalized) before crossing the stenosis, usually at the tip of the guide.
- 4.
The wire is then advanced across the stenosis about 2 centimeters distal to the coronary lesion.
- 5.
Maximal hyperemia is induced with IV adenosine (140 mcg/kg/min) or IC bolus adenosine (20-30 mcg for the right coronary artery, 60 mcg or 100 mcg for the left coronary artery [LCA]). In some cases where borderline FFR values generate uncertainty, 180 mcg/kg/min can be tested. For IV adenosine, FFR is typically measured at 2 min. For IC adenosine, FFR is measured at 15-20 seconds.
- 6.
The ratio of the mean distal pressure to mean proximal pressure during maximal hyperemia is calculated as the FFR. An FFR of ≤0.80 is correlated to abnormal ischemic testing and is useful as an indication to proceed with PCI.
- 7.
PCI can be performed using the pressure wire as the working angioplasty guidewire. After the procedure, FFR can be remeasured to assess the adequacy of the intervention and any residual or new angiographic narrowings.
- 8.
Finally, at the end of the procedure, the pressure wire is pulled back into the guide to confirm equal pressure readings, indicating signal stability.
Pitfalls and practice of measuring FFR are described in more detail elsewhere.
Pharmacologic Coronary Hyperemia
Stenosis severity should always be assessed using measurements obtained during maximal hyperemia. At maximal hyperemia, autoregulation is abolished and microvascular resistance fixed and minimal. Under these conditions, coronary blood flow is directly related to the driving pressure. Therefore, maximal hyperemic coronary blood flow is closely related to the coronary arterial pressure and is part of the derivation of pressure-derived FFR of the myocardium.
Hyperemia is most commonly achieved with IV or IC adenosine ( Table 15-3 ). Alternative intravenous hyperemic agents include IV adenosine triphosphate (ATP) (140 mcg/kg/min), regadenoson 400 mcg IV bolus, and IV dopamine (10-40 mcg/min × 2 min increments). Less commonly used agents include IC ATP (50-100 mcg), and rarely used agents are IC papaverine (10-15 mg) and IC nitroprusside (50-100 mcg).
| ADENOSINE | ADENOSINE | REGADENOSON | NTP | PAPAVERINE | |
|---|---|---|---|---|---|
| Route | IV | IC | IV | IC | IC |
| Dosage | 140 mcg/kg/min | 60-100 mcg LCA 20-30 mcg RCA | 0.4 mg | 50-100 mcg | 15 mg LCA 10 mg RCA |
| Half-life | 1-2 min | 30-60 sec | 2-4 min (up to 30 min) | 1-2 min | 2 min |
| Time to max hyperemia | <1-2 min | 5-10 sec | 1-4 min | 10-20 sec | 20-60 sec |
| Advantage | Gold standard | Short action | IV bolus | Short action | Short action |
| Disadvantage | ↓ BP, chest burning | AV Block, ↓ BP | ↑ HR, long action, ?redose | ↓ BP | Torsades, ↓ BP |
Adenosine
IV adenosine is the preferred method of inducing hyperemia because it achieves a steady state and produces prolonged hyperemia and is weight based and operator independent. The onset of action of adenosine is rapid, its duration very brief with a half-life of <10 seconds. By providing prolonged hyperemia, IV adenosine infusion allows for a slow pullback of the pressure wire, useful to identify the exact location of the pressure drop-off for both simple and serial lesions or the presence of diffuse disease. IV adenosine also permits maximal coronary flow for assessment of aorto-ostial narrowings without guide catheter obstruction that may potentially occur with administration of IC adenosine.
While hyperemia of IC adenosine is equivalent to IV infusion in a large majority of patients, in a small percentage of cases, coronary hyperemia may be suboptimal with IC adenosine. Jeremias et al. compared IC (15-20 mcg in the right and 18-24 mcg in the left coronary artery) to IV adenosine (140 mcg/kg/min) in 52 patients with 60 lesions. There was a strong linear relationship between IC and IV adenosine (r = 0.978 and p < 0.001). The mean measurement difference for FFR was 0.004 ± 0.03. In 8.3% of stenoses, FFR with IC adenosine differed by 0.05 or more compared with IV adenosine, suggesting an inadequate hyperemic response with IC adenosine. Subsequent studies have confirmed the correlation between IC and IV adenosine; however, it has been suggested that higher doses of IC adenosine (>60 mcg) may improve hyperemia and generate lower FFR values.
The feasibility and efficacy of peripheral compared with central IV infusion of adenosine for FFR measurement were tested by Seo et al. They measured FFR in 71 patients using IC bolus injection and continuous IV infusion (140 µg/min/kg) of adenosine via the femoral and the forearm vein ( Figure 15-8AB ). In 20 patients, hyperemic mean transit time and index of microcirculatory resistance were also measured. After bolus IC adenosine FFR (mean) was 0.81 ± 0.10; after femoral vein infusion (FFR, 0.80 ± 0.10); after forearm vein infusion of adenosine (FFR, 0.80 ± 0.11; p for noninferiority = 0.01). There was no difference in the number of functionally significant stenoses (FFR, <0.75; femoral vein vs. forearm vein, 17 (25.0%) vs. 17 (25.0%); p = 1.0) nor values of hyperemic mean transit time and index of microcirculatory resistance. This study suggests that continuous intravenous infusion of adenosine via the forearm vein is a convenient and effective way to induce steady-state hyperemia for FFR and other physiologic measurements.
Regadenoson
Adenosine activates several adenosine receptor subtypes, which may result in undesirable effects including nausea, flushing, shortness of breath, chest pain, and atrioventricular block.
To reduce the incidence of side effects without affecting hyperemia, selective adenosine A 2A receptor agonist agents such as regadenoson have been developed. Regadenoson is a low-affinity A 2A adenosine receptor agonist that induces coronary vasodilatation and increased myocardial blood flow in a manner reportedly equivalent to adenosine. By selectively targeting the A 2A receptor in coronary arteries, it has fewer adverse effects compared with adenosine. Regadenoson has a longer half-life of 2-3 minutes in the initial phase, 30 minutes in the intermediate phase, and 2 hours in the terminal phase and may prove to be easier to use than short-acting adenosine. With a single infusion bolus of regadenoson, coronary hyperemia may be achieved and maintained equivalent to that achieved with a constant infusion of adenosine. Because of these properties, regadenoson may be a promising coronary vasodilator for the measurement of FFR.
Alternative Hyperemic Agents
Other agents that produce maximal coronary hyperemia include ATP, nitroprusside, and dobutamine. Coronary flow reserve was equivalent with ATP and papaverine with IC ATP doses >15 µg. IV dobutamine (10 to 40 µg/kg per minute) has also been used to assess lesion severity with FFR. Compared with IV adenosine, peak dobutamine infusion produced similar distal coronary pressure and pressure ratios (Pd/Pa 60 ± 18 vs. 59 ± 18 mm Hg; FFR, 0.68 ± 0.18 and 0.68 ± 0.17, respectively; all p = NS). High-dose IV dobutamine did not modify the angiographic area of the epicardial stenosis, and much like adenosine, fully exhausted myocardial resistance regardless of inducible left ventricular dysfunction. Intracoronary nitroprusside (50, 100 mcg bolus) produces nearly identical results to IV and IC adenosine.
The influence of caffeine (an adenosine receptor antagonist) on FFR remains controversial as it is unknown whether the concentration of caffeine after a cup of coffee prior to induction of hyperemia interferes with FFR measurement. A review of the literature suggests that a serum caffeine level of 3 to 4 mg/L at the time of an adenosine-hyperemia study does not affect the diagnostic ability of myocardial perfusion imaging to detect coronary artery disease. While this likely holds true for patients undergoing intravenous adenosine-induced hyperemia, if there is any concern the operator can increase the adenosine dose administered to overcome any receptor inhibition.
Precautions and Pitfalls of Fractional Flow Reserve
Consideration should be given to several possible reasons for a nonischemic FFR (>0.80) measurement despite apparently severe stenosis. Errors in the performance of FFR include hemodynamic artifacts and failure to induce maximal hyperemia. Table 15-4 lists factors that may lead to inaccurate FFR measurements.
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