Serial Lesion FFR Made Simple

I am frequently asked questions about performing fractional flow reserve (FFR) in vessels with serial lesions. For example, one colleague asks, “You have a left anterior descending coronary artery (LAD) with several lesions separated by 10-20mm of irregular but nearly normal-appearing segments [Figure 1]. Each lesion is only of moderate severity. The stress test was abnormal for an anterior wall motion abnormality. The patient is scheduled for lung surgery and I want to put as little metal (stents) in the artery as possible. It seems serial lesion assessment is the way to go. If I measure a distal lesion FFR of 0.65 and the FFR between another lesion is 0.7, should I then treat both lesions, with the distal lesion first? I recall I need a pressure wire pullback to get the answer. What is the correct way to assess these lesions?”

The short answer to this question is: 1) You cannot use the FFR for individual lesions in series and 2) We need to measure the pressure gradients between lesions during pull back (with hyperemia) to determine which of the two lesions or whether both lesions need to be stented. Let’s look at the theory and practice of serial lesion assessment.

Why does FFR not apply for individual lesions in a series?

In order to calculate an accurate FFR, one must produce maximal (hyperemic) trans-stenotic flow. When there are two (or more) consecutive or serial stenoses, the first stenosis limits maximal flow across the downstream lesions, and all downstream stenoses limit the maximal flow across the more proximal lesion (Figure 2). Thus, the interaction between the stenoses prevents us from using the simple FFR ratio (Pd/Pa) for each stenosis individually. To say it another way, when there is more than one significant lesion in the same epicardial vessel, each lesion blunts maximal flow (i.e., produces submaximal flow) of the other and therefore results in an inaccurate individual lesion FFR. The extent to which both stenoses influence each other is somewhat unpredictable. However, the simple FFR can assess the summed result of any group of stenoses.

Experimental studies have demonstrated how to determine an individual lesion FFR in a series.^1,2 Pijls et al¹ have shown that the individual FFR of each stenosis separately can be predicted by a different FFR equation:

[FFR_predicted = (P_d-[(P_m/P_a)*P_w])/((P_a-P_m)+(P_d-P_w))

The equation uses arterial pressure (P_a), pressure between the two stenoses (P_m), distal pressure (P_d), and coronary occlusion wedge pressure (P_w) during maximum hyperemia. This special calculation requires the use of the P_w during balloon inflation, a highly impractical way to make these measurements for diagnosis alone. Pijls et al¹ and DeBruyne² nicely demonstrated the effect of increasing the severity of the distal lesion on the serial FFR measurements of a proximal lesion in series in an experimental animal model (Figure 3). As the distal lesion becomes more severe with a larger gradient, the hyperemic flow across the first lesion becomes less and the FFR of the proximal lesion goes up (i.e., becomes less severe). This experiment confirmed the adverse interaction between serial lesions when attempting to use simple FFR alone.

How should serial lesions be assessed?

The most practical way to assess serial lesions involves two steps:

Step 1. After passing the pressure wire beyond the last lesion, measure the FFR (total) across all lesions with IV adenosine in standard fashion. For example, if the FFR is 0.84, then none of the lesions would need treatment and nothing further needs to be done.

Step 2. If the summed FFR in step 1 is < 0.80, then perform a pressure pull back during IV adenosine hyperemia.

Treatment of the most severely narrowed lesion is then determined by which of the lesions produces the biggest pressure gradient (Figure 4a). Do NOT measure separate lesion FFR values; it is the pressure gradient (ΔP) (Figure 4b) that will be used to decide which lesion to treat first.

After stenting the lesion with the largest ΔP, reassess the remaining lesion(s), repeating either step 1 or step 2, depending on how many lesions remain. If there are more than two lesions and FFR remains abnormal, then stent the lesion with the next largest ΔP.

An example of serial lesion assessment and treatment is shown in Figure 5. As an aside, it is often practical to treat the distal lesion first. Alternatively, if the two lesions are longitudinally close together and can be covered by one drug-eluting stent that is not excessively long, then it is reasonable to treat both lesions with one stent. (In such a case, these are probably not serial lesions, but rather one long lesion).

Special case of serial lesions: The left main stenosis with LAD or CFX disease

FFR is often used to obtain the correct clinical assessment of a left main stenosis in the cath lab when evidence of ischemia is lacking. This decision is especially important for intermediately severe lesions where the result is critical to this patient’s future. Decisions for coronary artery bypass graft surgery (CABG), percutaneous coronary intervention or continued medical therapy based on angiography alone, especially in the absence of ischemia, cannot be made with certainty, and according to guidelines, should be supported by adjunctive lesion assessment modalities (either FFR or intravascular ultrasound [IVUS]).³

Clinical outcome support for use of FFR in the left main is strong. Non-ischemic FFR values (> 0.80) in left main lesions are associated with excellent long-term outcomes. In the largest multicenter trial, over the five-year follow-up period, Hamilos et al⁴ found a similar and low incidence of major adverse cardiac events (MACE), including cardiac death or myocardial infarction, when the group with FFR > 0.80 (treated medically) was compared to the group with FFR < 0.80 undergoing CABG. A recent review of left main assessment by Puri et al⁵ from The Cleveland Clinic summarizes the state of the art for optimally assessing left main stenoses and is very helpful in putting FFR and IVUS in perspective.

Because the left main physiology is different than the single artery/single myocardial bed of the LAD, circumflex (CFX) or right coronary artery (RCA), the simple FFR assessment of the left main is more complicated by the presence of downstream disease, which may or may not influence the true left main FFR (Figure 6). The left main and additional disease in the LAD act like two lesions in a series.

The left main transmits flow to the majority of the left ventricle through the LAD and CFX. The myocardial bed subtended by the left main is the combined area of the LAD and CFX (Figure 7). Thus, the left main has a larger flow than either the LAD or CFX flow alone. An accurate left main FFR reflects maximal flow through both the LAD and CFX (Figure 7, top left). The left main bed can be even larger if the RCA is occluded and collateral supplied from the left coronary system (Figure 7, bottom left). In this case, the flow through the left main would involve supply to the inferior left ventricle as well as the anterior left ventricle.

An isolated left main narrowing with no LAD, CFX, or RCA stenoses reflects the physiologic significance of just the left main narrowing. However, when there is a significant lesion in either the LAD or the CFX, the apparent FFR of the left main would be higher than otherwise in the absence of a downstream lesion, because the myocardial flow bed is now smaller, flow is less, and FFR higher.

A new situation exists when there is left main narrowing plus LAD stenosis (Figure 7, top right). The presence of the LAD lesion could produce a higher left main FFR (from 0.78 to 0.82, hypothetically) because the left main bed is now decreased due to the LAD stenosis. The same considerations would apply in the setting of a CFX narrowing. The left main FFR alone cannot be accurately measured when there are significant downstream serial lesions. If the LAD and CFX are hemodynamically insignificant, the left main FFR will be accurate. Preliminary reports⁶ suggest if the summed FFR of left main + LAD is > 0.60, then the left main FFR will not be affected and will be accurately identified individually (by putting the pressure wire across the left main into the non-diseased CFX).

In the setting of left main narrowing plus totally occluded RCA with collaterals from the left coronary artery (LCA), and no LAD or CFX disease (Figure 7, bottom left), the left main FFR would reflect the flow through the entire left and right ventricular myocardium. After recanalization of the RCA with restoration of flow to the inferior wall, the left main FFR would increase (from 0.78 to 0.82, hypothetically) since left main myocardial bed size is now smaller (Figure 7, bottom right). The phenomenon of a reduced myocardial bed raising the FFR has been well illustrated by Iqbal et al.⁷

In summary, for serial stenoses not in the left main, first measure the summed FFR, then pull back and use the pressure gradient to guide you. For the left main stenoses with downstream additional disease, the left main FFR will be accurate if the summed FFR (left main + LAD) is > 0.60 and you can measure the left main FFR with the wire in the unobstructed CFX (and vice versa). I hope this review of the theory and methods of assessing serial lesions will help you in the lab when confronted with the more complex anatomy many of our patients will have.

References

1. Pijls NHJ, de Bruyne B, G. Bech GJ, et al. Pressure measurement to assess the hemodynamic significance of serial stenoses within one coronary artery validation in humans. Circulation 2000; 102: 2371.
2. De Bruyne B, Pijls NHJ, Heyndrickx GR, Hodeige D, Kirkeeide R, Gould KL. Pressure-derived fractional flow reserve to assess serial epicardial stenoses; theoretical basis and animal validation. Circulation 2000; 101: 1840.
3. ACCF/SCAI/STS/AATS/AHA/ASNC/HFSA/SCCT 2012 Appropriate Use Criteria for Coronary Revascularization Focused Update A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, American Society of Nuclear Cardiology, and the Society of Cardiovascular Computed Tomography Endorsed by the American Society of Echocardiography and the Heart Rhythm Society. Coronary Revascularization Writing Group. Manesh R. Patel, MD, FACC, Chair, J Am Coll Cardiol 59; 2012, in press.
4. Hamilos M, Muller O, Cuisset T, et al. Long-term clinical outcome after fractional flow reserve-guided treatment in patients with angiographically equivocal left main coronary artery stenosis. Circulation 2009; 120: 1505-1512.
5. Puri R, Kapadia SR, Nicholls SJ, Harvey JE, Kataoka Y, Tuzcu EM. Optimizing outcomes during left main percutaneous coronary intervention with intravascular ultrasound and fractional flow reserve. The current state of evidence. J Am Coll Cardiol Intv 2012; 5: 697–707.
6. Daniels D, Yong A, van’t Veer M, van der Horst A, Pijls N, Fearon W. Assessment of the Left Main with Fractional Flow Reserve: The Influence of Concomitant Proximal Epicardial Coronary Disease. TCT presentation, San Francisco, CA, October 2011.
7. Iqbal MB, Shah N, Khan M, et al. Reduction in myocardial perfusion territory and its effect on the physiological severity of a coronary stenosis. Circ Cardiovasc Interv 2010; 3: 89-90.