This meta-analysis of seven studies shows that a 'good collateralization' is predictive for restenosis in patients undergoing PCI. This risk was found to be increased by 40% (95% CI 0% to 80%) compared to patients with poor collateralization. This association was found to be stronger in patients with stable coronary artery disease (risk increased by 64% (14% to 135%)) while it was weaker for patients with acute MI (risk increased by 23% (-11% to 69%)) and did not reach statistical significance in this subset. It has to be considered that the differences of the RR estimates between these subgroup analyses were not statistically significant. Moreover, all these values are estimates of the average effect across the different studies.
This data indicate that the degree of collateralization may be a useful and simple tool to inform individual clinical decision making, patients at high risk for restenosis may profit from the more expensive drug-eluting stents and from cilostazol, which both reduce the restenosis risk [27, 28].
Collaterals: good or bad?
Good coronary collateralization has been found to be associated with improved survival [3, 4, 29]. In this regard it may seem contradictory that good collateralization is a risk factor for restenosis after PCI. Similarly, accelerated disease progression of the native vessel after coronary artery bypass grafting (CABG) is a frequent phenomenon that does not affect the clinical benefit of CABG .
Coronary collaterals may be regarded as an analog to CABG in that both provide an alternative blood supply to the myocardium. Therefore, increased restenosis after PCI and improved survival benefit in patients with good collateralization are not mutually exclusive. Restenosis is usually a slow process and rarely results in a life-threatening event. This is demonstrated by the fact that most treatments that reduce the risk for restenosis, for example, drug eluting stents, do not result in improved survival.
One of the possible reasons for the increased risk of restenosis in case of a good collateralization is the flow via the collaterals, which competes with the antegrade blood flow through the native vessel [23, 31, 32]. As mentioned above, a similar phenomenon is frequently observed in native coronary arteries in proximity to a bypass graft, which also represents a collateral circulation, leading to decreased flow through the native vessel [31, 32]. This reduced flow subsequently results in a decreased shear stress on the endothelial cell layer. This shear stress is known to be atheroprotective . Monocytes and platelets are key players in the pathogenesis of intimal hyperplasia and atherosclerosis; low flow and low shear stress increases the chance of cell adhesion to the vessel walls . Low shear stress also modulates endothelial cell gene expression into a proinflammatory state . High shear stress, on the other hand, is suppressing the expression of these proinflammatory genes, specifically via the lung Kruppel-like factor (LKLF), an anti-inflammatory endothelial transcription factor [36, 37]. LKLF also reduces the expression of the substance monocyte chemoattractant protein 1 (MCP-1). As its name suggests, MCP-1 attracts monocytes and has a proatherogenic effect . However, the exact mechanism of this 'mechanotransduction', translating physical forces into changes at a molecular level, is not completely understood. Data suggest that G proteins may act as primary mechanosensors on endothelial cells; a further concept that has evolved are mechanosensitive ion channels that translate the physical force into a corresponding intracellular signal .
Coronary collaterals as a marker or as a causal risk factor for restenosis?
The major determinant of collateral function is the degree of vessel stenosis, which itself has been described to increase restenosis risk [40–42]. The studies included in this meta-analysis did not adjust for covariates such as vessel diameter stenosis or the extent of CAD. As an alternative explanation, coronary collaterals could simply represent markers for more severe underlying CAD with consecutive increased risk for restenosis after PCI. This interesting question remains to be resolved in future studies. Regardless of a causal or a casual association, the degree of coronary collateralization represents a valuable and simple marker to predict the risk for restenosis.
Future research should evaluate possible mechanisms of this increased restenosis risk in patients with good collateralization. This patient group may show different levels of cytokine activation, inflammation, levels of reactive oxygen species (ROS) or platelet activation after percutaneous transluminal coronary angioplasty (PTCA), which may be addressed by additional pharmacologic approaches. One hypothesis to be tested is that the oxygen level distal to the vessel occlusion during angioplasty varies with varying collateralization and may lead to different ROS levels. Higher ROS levels may damage endothelial cells downstream and thereby increase the risk for restenosis.
Limitations of this meta-analysis
Most studies used exclusively binary data for their analysis. The extent of variable of interest, collateralization, was dichotomized into 'good collateralization' and 'poor collateralization', while in fact the degree of collateralization is a continuous variable. Besides this variable of interest, the outcome was also dichotomized in most studies, using a restenosis threshold of 50%. One drawback of this approach is the impaired statistical power. Still, this meta-analysis was large enough to detect a significant influence of collaterals on restenosis risk. A related problem is the fact that all patients underwent routine angiographic follow-up. Some of the patients may have had a stable in-stent restenosis without symptoms, the routine angiographic follow-up may overrate the clinical importance of restenosis and it may overestimate the impact of collaterals on restenosis .
Further, the included studies did not adjust for potential confounding factors such as the severity of CAD, the diameter stenosis, and so on. Since this is a study-level and not a patient-level meta-analysis, we were not able to include these factors in our analyses. However, we think that significant confounding regarding our primary outcomes is rather unlikely. The main determinant of collaterals (our predictor) is the degree of the vessel diameter stenosis; the narrower the stenosis, the better the collaterals . However, the degree of stenosis is not known to be a risk factor for future restenosis (primary outcome of our study).
Moreover, this study does not capture the dynamic of the coronary collaterals. The coronary collateral function has been demonstrated to decrease over a 6-month period after PCI . This dynamic may explain the non-significant results in the setting of acute MI. During an acute vessel occlusion, the collaterals undergo rapid changes; a fact, that limits the value of a single timepoint measurement. Further, the increased left ventricular end diastolic pressure during acute MI impairs the accuracy of the collateral assessment .
Another important limitation is the heterogeneity among the studies included in this analysis. The extent of heterogeneity reduces the robustness of our results. We therefore performed several subset analyses and meta-regression analysis, and found several aspects that contribute to this heterogeneity. The most important one is the difference in study populations. Four studies included patients with stable CAD while three studies focused on patients with acute MI (Table 2). Further, the earliest two studies used plain balloon angioplasty while the newest studies used bare metal stents in all patients [5, 24]. Also, four studies used CFI-based collateral assessment while three studies used visual assessment of collaterals. Despite this heterogeneity between studies, the findings were very consistent in most of the subset and sensitivity analyses. Moreover, the accuracy of CFI measurements in the setting of acute MI has been questioned . However, this only applies to one study  and excluding this study only minimally influenced the overall results (see 'Sensitivity analyses').
A further drawback of this study is that early studies used plain balloon angioplasty and later studies used BMS. No drug-eluting stents (DES) were used in the present studies. Whether the results of this meta-analysis can be generalized to DES remains unanswered. DES have further reduced the risk for restenosis; it is highest for POBA (32% in average), around 22% for BMS and around 16% for first-generation DES [45, 46]. The predictive value of collaterals may be reduced in the context of DES. However, even with DES, restenosis is still a significant and unresolved problem. Our findings were consistent in the POBA and in the BMS group; they were not significantly influenced by the proportion of BMS use in the individual studies or by the average restenosis risk in the control groups (poor collaterals). We would therefore expect similar results for drug-eluting stents.
Another limitation of our study is that it does not provide further insights into possible causal mechanisms of our findings. Our considerations in the Discussion are thus rather hypothetical. This study, overall, is hypothesis generating rather than confirmatory.
With regard to the meta-regression analyses, it has to be considered that they have limited statistical power and a lack of statistical significance does not necessarily mean that there is no true effect.