EDITORIAL COMMENT
Coronary collaterals, stenoses, and stents
Is a new era of physiologic-guided percutaneous revascularization emerging?*
Habib Samady, MB, ChB, FACC*,*,
Michael Ragosta, MD, FACC* and
George A. Beller, MD, MACC*
* Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia, USA
* Reprint requests and correspondence: Dr. Habib Samady, Cardiovascular Division, Department of Medicine, University of Virginia Health System, P.O. Box 800158, Charlottesville, Virginia 22908-0158, USA.
hsamady{at}virginia.edu
Experimental models of acute myocardial infarction (MI) have demonstrated that, for a given duration of vessel occlusion, the amount of collateral circulation together with the area of myocardium at risk are the two major determinants of final infarct size (1–3). The degree of recruitable collateral perfusion is highly variable but has been shown to provide as much as 60% to 80% of normal antegrade perfusion (4,5), well beyond the 25% required to maintain myocyte viability and minimize final infarct size (1–3). In the clinical setting, demonstration of spontaneous angiographic collaterals (6) after MI has been associated with limited infarct size (7), improved ventricular function (6), less ventricular aneurysm formation (8), and even improved survival (9) compared with those without collaterals.
In 1985, to evaluate the potential collateral reserve of a myocardial bed, Rentrop et al. (10) described a semiquantitative angiographic score of recruitable collaterals, by performing angiography of the contralateral coronary artery during balloon occlusion of the index lesion. This allowed evaluation of the potential collateral reserve in a jeopardized myocardial bed in the event of disease progression leading to occlusion of the index vessel. While this technique improved our understanding of recruitable collateral circulation in humans, it is semiquantitative and impractical to apply to widespread patient use (requiring dual arterial access). Furthermore, the limit of resolution of angiography is 100 µm, and many collaterals are smaller than this. Therefore, better techniques for practical quantitative assessment of recruitable collaterals were sought.
In the early 1990s, ultra-thin Doppler and pressure angioplasty guidewires were developed. This led to the measurement of velocity and pressure in distal vascular beds, allowing the physiologic assessment of coronary stenoses and recruitable collateral circulation in humans. On the premise that blood flow is proportional to velocity when vessel surface area is constant, in 1991 Ofili et al. (11) described the Doppler-derived collateral flow index (CFI) as the ratio of blood velocity in a vessel distal to an occluded balloon, to blood velocity in the same vessel during patency (after the reactive hyperemia has subsided) (Fig. 1). Subsequently, in 1993 Pijls et al. (12) described the use of coronary pressure to assess the contribution of antegrade epicardial and retrograde collateral flow to a given coronary bed. They defined myocardial fractional flow reserve (FFRmyo) as the maximal achievable flow in a myocardial bed in the presence of a stenosis divided by the maximal flow through the same bed in the theoretic absence of the stenosis; and fractional collateral flow (FFRcoll) as the maximum fraction of total myocardial blood flow contributed to a bed by the collateral circulation. They demonstrated that, by simultaneously measuring mean aortic pressure (Pa), mean coronary pressure distal to a stenosis (Pd), coronary wedge pressure (Pw), and central venous pressure (Pv) during maximal hyperemia (when resistance is minimal and constant), the following equations represent FFRmyo and FFRcoll:
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Figure 1 Schematic diagram of measurement of Doppler-derived collateral flow index (Doppler-CFI) and pressure-derived collateral flow index (Pressure-CFI), also known as FFRcoll, during balloon inflation of the index lesion during percutaneous revascularization. Pa = mean aortic pressure; Pv = central venous pressure; Pw = coronary wedge pressure; Voccl = blood velocity distal to balloon occlusion; Vpatent = blood velocity in patent vessel after reactive coronary hyperemia has subsided. See text for details. Reprinted with permission from the American College of Cardiology Foundation Journal of the American College of Cardiology, 1998;32:1272–9.
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Fractional collateral flow has also been termed pressure-derived CFI (Fig. 1).
Both pressure-derived and Doppler-derived CFIs have been clinically validated. Pressure-derived CFI (FFRcoll) was shown to have an excellent correlation with extent and severity of 99mTc-sestamibi defect in the territory of an occluded artery during balloon angioplasty in the catheterization laboratory (13). Doppler-derived CFI has been shown to have an excellent correlation with pressure-derived CFI, and low values for both indexes were found to be highly predictive of ischemic ST-segment changes on electrocardiography during balloon occlusion (14).
These simple quantitative physiologic indexes of recruitable collateral flow in humans have heralded the investigation of the protective value of recruitable collaterals in nonocclusive stenotic vessels undergoing percutaneous coronary intervention (PCI). To assess the clinical utility of recruitable collaterals during PCI, Pijls et al. (15) compared FFRcoll in 120 patients with single-vessel disease undergoing PCI to ischemic ST-segment changes on electrocardiography during balloon occlusion, and evaluated the predictive value of FFRcoll on cardiac outcomes. They found that when the FFRcoll was high ( 24%), patients were very unlikely to develop electrocardiographic evidence of ischemia during balloon inflation, and had an almost eightfold lower risk of developing a subsequent acute cardiac event (unstable angina or MI), compared with patients with low (<24%) FFRcoll. In contrast, Wahl et al. (16) found that patients undergoing PCI of lesions with high recruitable collateral flow had higher restenosis rates than those with low recruitable collateral flow.
Given these apparently conflicting studies regarding the association of recruitable collaterals during PCI and recurrent cardiac events, the study by Billinger et al. (17) published in this issue of the Journal is timely and sheds important light on the matter. They report on the long-term ischemic cardiac event rate of a large series of patients with stable angina who underwent quantitative assessment of recruitable CFI at the time of PCI, measured either by the Doppler-derived or pressure-derived CFI. Among 403 patients studied, 134 (33%) had high CFI (25%) and 269 (67%) had low CFI (<25%). There were no significant differences in cardiac risk factors, medications, or left ventricular ejection fraction between the two groups. Patients with high CFI were found to have higher grade stenoses, greater extent of coronary disease, and less angina and ST-segment changes during balloon inflation. The incidence of all subsequent cardiac events (death, MI, unstable angina, and stable angina) was similar in the two groups at a mean of two year follow-up (23% in high collateral group vs. 20% in low collateral group, p = NS). Consistent with the Pijls et al. study (15), the authors observed significantly fewer unstable cardiac events (death, MI, or unstable angina) in patients with high compared with low CFI (2.2% vs. 9%, respectively; p < 0.01). However, they observed a higher incidence of stable angina in patients with high CFI compared with the low collateral group (21% vs. 12%; p < 0.01). Interestingly, angiographically assessed collaterals had no prognostic value in predicting either stable or unstable ischemic cardiac events in this patient population.
At first glance, the association of higher recruitable collateral flow during PCI with lower subsequent incidence of unstable cardiac events, yet higher stable angina, may appear somewhat discordant. Indeed, it is difficult to have a definitive explanation for these findings without angiographic follow-up to help determine which cardiac events were related to restenosis of the index PCI lesions versus new lesions in other areas within the coronary vasculature. Nevertheless, it is clear that patients who are capable of recruiting brisk collaterals in the event of progression of coronary obstruction are protected from acute ischemic events. The higher incidence of stable angina in the patients with high CFI may be related to a greater extent of coronary artery disease (CAD) observed in these patients compared with those with low CFI (2.0 ± 0.8 vessel CAD vs. 1.8 ± 0.7 vessel CAD, respectively, p < 0.05). This is consistent with our previous observation of a greater prevalence and extent of exercise-induced ischemia on 201Tl scintigraphy in patients with angiographically visible collaterals versus those without visible collaterals (18). An alternative explanation for the higher incidence of stable angina in patients with high recruitable collaterals is that such patients may develop restenosis more commonly, as previously reported by Wahl et al. (16), albeit with a more gradual clinical presentation. The mechanism by which recruitable collateral distal to an angioplastied lesion might influence restenosis is not known and difficult to explain. One potential pathophysiologic explanation might be that, as the restenotic process begins limiting antegrade blood flow, abundant collateral flow is recruited and competes with antegrade flow, somehow accelerating the process of restenosis. While these collaterals would provide enough myocardial blood flow to avoid an unstable coronary syndrome, they may not provide adequate flow during exercise, resulting in a stable anginal pattern.
There are a several limitations to the Billinger et al. study (17) that deserve mention. First, for accurate assessment of pressure-derived CFI, Pv should be measured and not estimated as done in this study. Second, Pw should be measured during maximal hyperemia induced by intravenous vasodilators (12). Although balloon occlusion itself is a vasodilatory stimulus, it is possible that some of patients who did not achieve a high pressure-derived CFI would have done so if hyperemia were induced with a vasodilator. Third, given the fact that the results of this study critically depend on the distinction between stable and unstable coronary syndromes, the exact definition of these syndromes is not made clear enough in the Billinger et al. study (17). Finally, almost 10% of the initial study population were lost to follow-up, and, in 19% of patients, follow-up information was obtained from the patients’ physicians who may not have had sufficiently detailed information on the patients’ status to distinguish stable from unstable angina.
Despite these limitations the study by Billinger et al. (17) is an important, large clinical study providing evidence for the association between physiologically assessed robust recruitable collaterals in patients with CAD undergoing PCI and a low rate of subsequent unstable ischemic cardiac events.
While the value of spontaneous coronary collateral flow after MI has been established, the present study by Billinger et al. (17) provides evidence of the protective value of recruitable collaterals at the time of PCI on subsequent acute cardiac events. Furthermore, it highlights the practical utility of physiologic assessment, as an adjunct to angiography, in the catheterization laboratory. With up to 60% of patients arriving to the catheterization laboratory without prior noninvasive evaluation (19), physiologic assessment of coronary lesions can provide valuable complementary information to angiography for directing revascularization. Indeed, several recent studies have examined the outcomes of patients undergoing physiologic-guided revascularization. A study by Bech et al. (20) suggests favorable outcomes in deferring PCI compared with performing PCI in patients with angiographically intermediate single-vessel disease who have physiologically nonsignificant flow limitation (FFR > 0.75). Likewise, in patients with multivessel CAD referred for coronary artery bypass surgery, those undergoing fractional flow reserve-guided percutaneous revascularization instead of coronary artery bypass surgery appear to have comparable two-year outcomes to patients undergoing coronary artery bypass surgery (21). Even in the difficult setting of intermediate left main stenosis, preliminary data suggest that physiologic assessment with fractional flow reserve can be used to safely defer coronary artery bypass surgery (22).
This study also contributes to the growing body of evidence regarding the prognostic value of physiologic assessment in the catheterization laboratory. For instance, while fractional flow reserve assessment had previously been shown to correlate well with intravascular ultrasound for evaluation of optimal stent deployment (23), only recently has its prognostic value been demonstrated in this setting (24). Indeed, a large multicenter registry of patients undergoing fractional flow reserve assessment after coronary stenting demonstrated post-stent fractional flow reserve to be the most powerful predictor of future major adverse cardiac events compared with other clinical, angiographic, and hemodynamic variables assessed (24). Patients with a post-stent fractional flow reserve of 0.90 had an eight times lower risk of subsequent major adverse cardiac event (death, MI, or revascularization) in the first year after PCI. Collateral flow index was not measured in that study, so the comparative prognostic value of CFI and post-stent fractional flow reserve is not known. Also, it is currently not known whether the prognostic value of these physiologic tools relates to predicting restenosis, progression of atherosclerosis, or the occurrence of de novo lesions. Only large-scale outcome studies of patients undergoing physiologic-guided PCI, with angiographic follow-up, can answer these important questions.
These powerful physiologic predictors of major adverse cardiac events after PCI, measured during the index intervention in the catheterization laboratory, are likely to remain valuable tools even in the era of drug-eluting stents. The estimated incremental cost of unrestricted use of drug-eluting stents may be prohibitive. Therefore, physiologic-based selection of patients in whom PCI with conventional "bare" stents may result in excellent long-term outcomes may avert the need for ubiquitous use of drug-eluting stents. Clearly, prospective randomized trials of physiologic- versus angiographic-guided percutaneous revascularization are warranted to contain the cost and improve long-term outcomes. Perhaps a new era of physiologic-guided percutaneous revascularization is emerging!
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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