Question

Indicate the importance of measuring fractional flow reserve and the clinical significance of stenosis in clinical cardiology.

Answer 1

Coronary angiography still plays a pivotal role in invasive imaging of the coronary arteries. However, it is limited in its ability to determine the physiologic significance of coronary stenosis.[1,2] It is important to emphasize that in coronary artery disease, the most important factor related to outcome is the presence and extent of inducible ischemia.[3,4] A functionally significant stenosis should be revascularized if technically possible.[5,6,7] On the other hand, if a stenosis has no functional significance, medical treatment is excellent with an infarction and a mortality rate of <1% per year.[7,8] Intracoronary (IC) physiologic measurement of myocardial fractional flow reserve (FFR) was introduced and has proven to be a reliable method.[9] An FFR value of 0.80 or less identifies ischemia-causing coronary stenoses with an accuracy of more than 90%.[9,10,11] An incontrovertible proof of the benefit of FFR-guided multivessel percutaneous coronary intervention (PCI) compared with standard angiography was provided in the large randomized, multicenter FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study.[7,12] In that study, it was demonstrated that all types of adverse events were decreased by 30% in the 1^st year after PCI when guided by FFR. The information provided by FFR is similar to that obtained with myocardial perfusion studies, but it is more specific and has a better spatial resolution, because every artery or segment is analyzed separately, and masking of one ischemic area by another, more severely ischemic, zone is avoided.[13,14] Despite all the benefits, there are several pitfalls related to FFR measurement and a few clinical situations, in which it is not reliable and should not be applied.

Definition of Fractional Flow Reserve

Fractional flow reserve is defined as the ratio of maximum blood flow in a stenotic artery to maximum blood flow if the same artery is normal assuming that these measurements are obtained when the microvasculature resistance is minimal and constant (maximal hyperemia).[9,10,15,16,17] This ratio of the two flows is expressed as the ratio of two pressures, which can be easily measured by a pressure wire and the guiding catheter, respectively. Therefore, FFR equals Pd/Pa, where Pd is the distal coronary pressure across the stenosis, and Pa is the aortic pressure, both measured at maximum coronary hyperemia. FFR shows how far maximal myocardial blood flow is limited when epicardial stenosis is presence. FFR of 0.60 means that the maximum blood flow (and oxygen supply) to the myocardial distribution of the respective artery only reaches 60% of what it would be if that artery was completely normal. An increase to 0.90 after stenting indicates that maximum blood supply has now increased by 50%. Therefore, FFR is linearly related to maximum blood flow, and its normal value is 1.0, irrespective of the patient, artery, blood pressure, and so forth. The measurement of FFR is independent of changes in systemic blood pressure, heart rate, or myocardial contractility and is highly reproducible.[15,18] The concept of FFR is explained

Fractional Flow Reserve Practicalities

Catheters

In general, a 6F guiding catheter is used because the lumen of such catheter is large and smooth and easily accommodates advancement of a pressure guidewire. However, a recent study by Legalery et al.[19] has demonstrated that FFR measurement can also be safely performed through a conventional 4F diagnostic catheter. The use of diagnostic catheters is technically feasible. However, due to the higher levels of friction hampering wire manipulation, the smaller internal caliber prejudicing pressure measurements and the inability to perform ad hoc PCI using diagnostic catheters, the use of guiding catheters is recommended.[20]

Wires

At present, two Food and Drug Administration (FDA)-approved pressure wire systems are available: Pressure Analyzer (RADI Medical Systems, Uppsala, Sweden) and WaveMap (Volcano Therapeutics Inc., Rancho Cordova, USA). Both are 0.014-inch in diameter and, therefore, allow all possible coronary interventions without needing another guidewire. The sensor is located 30 mm from the tip, at the junction between the radiopaque and radiolucent portions. The last generations of these 0.014-inch wires have similar handling characteristics to most standard angioplasty guide wires. The PressureWireVR from St. Jude Medical (St Pauls, MN, USA)/Radi Medical Systems (Uppsala, Sweden) also offers a thermodilution capability that allows measurement of the index of myocardial resistance and absolute coronary blood flow. In addition, the later wire also exists in a “wireless” version: PressureWireVR Aeris in which the signals are transmitted by radiofrequency to a receiver directly connected to the conventional catheterization laboratory physiologic monitoring system, therefore eliminating the need for any dedicated interface.

Hyperemia

To measure FFR, it is absolutely essential to achieve maximal vasodilatation of the two vascular compartments of the coronary circulation, namely the epicardial (conductance arteries) and the microvascular arteries (resistance arteries). If maximal vasodilatation is not achieved, the pressure gradient across a lesion will be smaller than expected, and FFR will be overestimated. Consequently, the severity of the lesion will be underestimated. Practically speaking, a desirable hyperemic stimulant should fulfill the following criteria: Rapid onset and short duration of action, low cost, lack of significant side effects, and stable steady state. Several hyperemic stimulants, delivered either through IC injection or as a continuous intravenous (IV) infusion, have been used for this purpose, including adenosine,[21] adenosine 5’-triphosphate (ATP),[22,23,24] and papaverine.[25] IC papaverine is cheap and creates maximum hyperemia for approximately 30–60s, but has the disadvantage of inducing arrhythmias in some patients. IC adenosine or ATP creates hyperemia for a few seconds only and can be used in patients with 1-vessel disease and no other abnormalities. It does not allow for performance of a pressure pullback recording. IV administration of adenosine (particularly by the central venous route) is the gold standard for creating hyperemia, acts within 1 min, creates a steady state level of maximum hyperemia and is safe. The disadvantage is an unpleasant feeling in the chest or the throat of the patient (which is harmless, and that should be emphasized). IV adenosine is contraindicated in cases of severe asthma. ATP can be used as an equivalent to adenosine (similar dosage). In the experience of the Catharina Hospital in more than 11,000 patients undergoing FFR measurements, IV adenosine was used in 98%, and only two serious adverse events were observed (0.02%).[26] The different hyperemic drugs and their actions are summarized in

Clinical Relevance of Fractional Flow Reserve

Intermediate coronary lesion

The potential of angiography to evaluate the hemodynamic severity of an intermediate lesion is limited. Moreover, angiographic assessment is often the only decision-making modality for performance of angioplasty, especially in the absence of any sort of functional evaluation.[29] In patients with angiographically dubious stenoses, it has been shown that FFR is more accurate than exercise electrocardiography, myocardial perfusion scintigraphy, and stress echocardiography for assessing hemodynamic significance.[10] These results strongly supported the use of FFR measurements as a guide for decision-making about the need for revascularization in “intermediate” lesions.

Left main coronary artery

The presence of a significant stenosis in the left main coronary artery (LMCA) is a critical prognostic importance, and it determines the type of treatment.[18] The evaluation of hemodynamic severity is essential, and noninvasive testing is often noncontributive.[30] There are significant interobserver variations in the assessment of LMCA lesions.[31] the LMCA is generally short, and when present, atherosclerosis is often distributed diffusely, so that a normal segment is lacking, which leads to an underestimation of the “reference” segment and thus to an underestimation of LMCA stenoses by both visual estimation and quantitative coronary angiography; the myocardial mass that depends on the LMCA is large, so the amount of blood that flows through it is great, and substantial trans-stenotic flow, in turn, induces large pressure gradients, especially during hyperemia.[32] FFR can identify LMCA stenosis responsible for ischemia. Several studies showed that an FFR-guided strategy for equivocal LMCA lesions is safe and related to a favorable clinical outcome.[32,33,34,35,36] Left main disease is rarely isolated. When tight stenoses are present in the left anterior descending (LAD) or the left circumflex coronary artery (LCx), the presence of these lesions will tend to increase the FFR measured across the left main. The influence of a LAD/LCx lesion on the FFR value of the left main will depend on the severity of this distal stenosis but, even more, on the vascular territory supplied by this distal stenosis. For example, if the distal stenosis is in the proximal LAD, its presence will markedly affect the stenosis in the left main. If the distal stenosis is located in a small second marginal branch, its influence on the left main stenosis will be minimal. Nevertheless, even in the presence of other stenoses in addition to LMCA stenosis, the distal FFR value indicates to what degree maximum perfusion of the different left coronary artery territories is decreased. In a recent prospective study by Hamilos et al.,[32] an excellent outcome of FFR-guided revascularization was found in 213 consecutive patients with equivocal LMCA disease, whether or not in conjunction with LAD or LCx stenosis.

Tandem lesions

Tandem lesions [Figure 2] are defined as two separate lesions with >50% stenosis each (with visual assessment on conventional angiography) in the same coronary artery, separated by an angiographically normal segment.[37,38] Theoretically, the FFR can be calculated for each stenosis individually.[39] However, it is important to realize in such cases that each of several stenoses will influence hyperemic blood flow and therefore FFR across the other one. De Bruyne et al.[37] have developed equations for predicting the FFR of each individual lesion separately in the case of tandem lesions, and these equations have been validated successfully in animals and humans.[39] Practically, as for diffuse disease, a pull-back maneuver under maximal hyperemia is the best way to appreciate the exact location and physiologic significance of sequential stenoses and to guide the interventional procedure step-by-step. After the most severe stenosis (i.e., the stenosis with the largest gradient) has been stented, the pull-back recording can be repeated, and it can be decided whether and where a second stent should be placed.

Fractional flow reserve in bifurcation lesions

Overlapping of vessel segments and radiographic artifacts make bifurcation stenoses particularly difficult to evaluate on angiography, whereas PCI of bifurcations is often more challenging than for regular stenoses. The principle of FFR-guided PCI applies in bifurcation lesions, two studies by Koo et al.,[40,41] used FFR in the setting of bifurcation stenting. The results of these studies can be summarized as follows: (1) After stenting the main branch, the ostium of the side branch (SB) often looks pinched. Yet such stenoses are grossly overestimated by angiography: Few of these ostial lesions with a stenosis diameter <75% were found to have FFR < 0.75; and (2) When kissing balloon dilation was performed only in ostial stenoses with FFR < 0.75, the FFR at 6 months was >0.75 in 95% of cases. These studies favor an approach in bifurcation lesions of stenting the main branch and kissing balloon dilation thereafter only if FFR of the SB is < 0.75. If FFR of the SB is >0.75, the outcome is excellent without further intervention.

Multivessel coronary disease

For patients with multivessel coronary disease, it is important to know which particular lesion is physiologically significant and responsible for reversible ischemia. FFR can help to identify one or more culprit lesions in this type of patients so that catheter-based treatment of culprit lesions can be performed. Studies conducted by Chamuleau et al.[42] showed that FFR was more useful than single-photon emission computed tomography for clinical decision-making and risk stratification in patients with multivessel disease. Recent study by Botman et al.[43] also demonstrated that in patients with multivessel disease, intervention undertaken in those patients with one or two physiologically-significant lesions identified by FFR < 0.75 yielded a favorable outcome similar to that of patients with three or more culprit lesions who undergo surgical treatment.

Diffuse and long lesions

De Bruyne et al.[44] suggested that in diffusely atherosclerotic coronary arteries at angiography, coronary pressure measurement is useful in quantifying the severity of the lesion. A pressure pull-back curve is needed in a diffusely affected coronary vessel. This can be done by withdrawing the pressure-sensing guidewire from a distal to a proximal position very slowly during a steady-state maximum hyperemia induced by IV ATP or adenosine.[44] This curve represents the pressure gradient over the entire length of the vessel, and clearly demonstrates the exact location and severity of the lesion. This so-called pull-back curve is extremely useful in guiding spot-stenting in a vessel with long and diffuse lesions.

Transplant vasculopathy

Cardiac allograft vasculopathy (CAV) is the major cause of mortality and morbidity after the 1^st year of heart transplantation.[45] Techniques that can be used as tools for decision-making to either justify intervention procedures on unstable CAV patients or to avoid unnecessary intervention would clearly benefit interventional cardiologists. Casella et al.[46] reported a case in which FFR measurement was used to guide and monitor the results of coronary balloon angioplasty on a CAV patient and the results seem very promising. In addition, a recent study by Fearon et al.[47] on 53 cardiac transplant patients further suggested that the use of physiologic assessment techniques was feasible for screening asymptomatic cardiac transplant recipients for angiographically unapparent transplant arteriopathy.

Myocardial infarction

In the case of prior myocardial infarction (MI), the mass of viable myocardium is smaller, and impairment of resistance vessels might blunt pharmacologically induced maximal hyperemia. However, as both the decrease of viable myocardium and impairment of coronary resistance vessels are matched in the infarcted area, FFR is still a reliable indicator. Claeys et al.[48] provided data that FFR is minimally affected (+5%) in patients with severely impaired microvascular function and may still be applied to patients with recent MI. De Bruyne et al.[11] have demonstrated that FFR assessment criteria are also valid in detecting reversible ischemia in patients at least 6 days after MI. Another study conducted by Usui et al.[49] comparing FFR and thallium-201 myocardial imaging also showed that pressure-derived FFR is reliable in assessing coronary artery stenosis in patients with previous MI, with a sensitivity of 79% and specificity of 79%.

Unstable angina

In patients with unstable angina, it is commonly believed that maximal hyperemic flow can be lower than in patients with stable angina. Consequently, the 0.75 cut-off value of FFR might not be valid in these patients, and the appropriate value needs to be determined. However, a recent study by Leesar et al.[50] for patients with unstable angina or non-ST-segment elevation MI further demonstrated that the FFR assessment criteria were also valid in these patient groups. A decision-making strategy based on the 0.75 cut-off is superior to a more conservative approach based on stress perfusion scintigraphy.

Coronary artery bypass graft lesions

In theory, the assessment of stenosis severity in coronary artery bypass graft lesions (CABGs) by FFR should not be different from FFR assessment of native vessels. At present, there are no clinical outcome data available regarding the use of FFR in graft stenosis. Therefore, FFR should be used with caution in bypass graft stenosis. Nevertheless, in patients requiring CABG for multivessel revascularization, angiographic lesions of uncertain significance would benefit from FFR, providing prognostic information regarding potential of future bypass graft patency. Botman et al.[51] showed that the rate of occlusion was approximately three times higher when the bypass was placed on a native artery with a hemodynamically nonsignificant stenosis. This study suggested that FFR could have serious implications for best long-term CABG outcomes.

Diabetes mellitus:

In patients with diabetes mellitus (DM), structural abnormalities in the microvascular system may blunt the maximal hyperemic response to potent hyperemic agents, and as a result, the FFR may not reliably reflect the degree of ischemia in this patient group. However, recently, a research team in Japan provided data that the cut-off value of 0.75 for FFR can also reliably detect myocardial ischemia in patients with DM. Yanagisawa et al.[52] compared the pressure-derived FFR for detecting inducible ischemia with SPECT imaging in diabetic patients with a mean hemoglobin A1c of 7.3%. The FFR cut-off value of 0.75 was still applicable and reliable in patients with DM, with a sensitivity of 83% and a specificity of 75%.

Special Features of Fractional Flow Reserve:

Fractional flow reserve has a theoretical normal value of 1 for every patient, artery, and myocardial bed

In a normal epicardial coronary artery, there is virtually no decrease in pressure, not even during maximal hyperemia.[44] This means that normal epicardial arteries do not contribute to the total resistance to coronary blood flow, it is obvious that Pd/Pa will equal or be very close to unity.

Fractional flow reserve has a well-defined cut-off value with a narrow gray zone between 0.75 and 0.80

Stenoses with FFR < 0.75 are almost invariably able to induce myocardial ischemia, whereas stenoses with FFR >0.80 are almost never associated with exercise-induced ischemia. The gray zone for FFR (between 0.75 and 0.80) spans <10% of the entire range of FFR values.

Fractional flow reserve is not influenced by systemic hemodynamic

In the catheterization laboratory, systemic pressure, heart rate, and left ventricular contractility are prone to change. These indices do not influence the value of FFR in a given coronary stenosis.[18,53]

Fractional flow reserve takes into account the contribution of collaterals

Distal coronary pressure during maximal hyperemia reflects both antegrade and retrograde flows according to their respective contribution.[8,9] This holds true for the stenoses supplied by collaterals but also for stenosed arteries providing collaterals to another more critically diseased vessel.

Fractional flow reserve specifically relates the severity of the stenosis to the mass of tissue to be perfused

The larger the myocardial mass traverse by a vessel is the larger the hyperemic flow, and in turn, the larger the gradient and the lower the FFR for a given stenosis.[54] It also means that the hemodynamic significance of a particular stenosis may change if the perfusion territory changes (as is the case after MI).