Collateral Flow Index Research Articles

Improvement of fractional flow reserve and collateral flow by treatment with external counterpulsation (Art.Net.‐2 Trial)

Arteriogenesis (collateral artery growth) is nature's most efficient rescue mechanism to overcome the fatal consequences of arterial occlusion or stenosis. The goal of this trial was to investigate the effect of external counterpulsation (ECP) on coronary collateral artery growth. A total of 23 patients (age 61 +/- 2.5 years) with stable coronary artery disease and at least one haemodynamic significant stenosis eligible for percutaneous coronary intervention were prospectively recruited into the two study groups in a 2 : 1 manner (ECP : control). One group (ECP group, n = 16) underwent 35 1-h sessions of ECP in 7 weeks. In the control group (n = 7), the natural course of collateral circulation over 7 weeks was evaluated. All patients underwent a cardiac catheterization at baseline and after 7 weeks, with invasive measurements of the pressure-derived collateral flow index (CFIp, primary endpoint) and fractional flow reserve (FFR). In the ECP group, the CFIp (from 0.08 +/- 0.01 to 0.15 +/- 0.02; P < 0.001) and FFR (from 0.68 +/- 0.03 to 0.79 +/- 0.03; P = 0.001) improved significantly, while in the control group no change was observed. Only the ECP group showed a reduction of the Canadian Cardiovascular Society (CCS, P = 0.008) and New York Heart Association (NYHA, P < 0.001) classification. In this study, we provide direct functional evidence for the stimulation of coronary arteriogenesis via ECP in patients with stable coronary artery disease. These data might open a novel noninvasive and preventive treatment avenue for patients with non-acute vascular stenotic disease.

Assessment of the effect of external counterpulsation on myocardial adaptive arteriogenesis by invasive functional measurements — design of the arteriogenesis network trial 2

Stimulation of collateral artery growth is a promising therapeutic option for patients with coronary artery disease. External counterpulsation is a non-invasive technique suggested to promote the growth of myocardial collateral arteries via increase of shear stress. The Art.Net.2 Trial tests invasively and functionally for the first time the hypothesis whether a treatment course with external counterpulsation (over 7 weeks) can induce the growth of myocardial collateral arteries. This study is designed as a prospective, controlled, proof-of-concept study. Inclusion criteria are (1) age 40 to 80 years, (2) stable coronary disease, (3) a residual significant stenosis of at least one epicardial artery and (4) a positive ischemic stress-test for the region of interest. As primary endpoint serves the pressure-derived collateral flow index (CFIp), the invasive gold-standard to assess myocardial collateral pathways. CFIp is determined by simultaneous measurement of mean aortic pressure (Pa, mm Hg), distal coronary occlusive (wedge) pressure (Pw, mm Hg) and central venous pressure (Pv, mm Hg). The index is calculated as CFIp=(Pw-Pv)/(Pa-Pv). The pressure derived fractional flow reserve (FFR) and the index of microcirculatory resistance (IMR) are assessed as secondary invasive endpoints to investigate the effect of ECP on the myocardial vasculature. The non-invasive secondary endpoints include symptoms (CCS and NYHA classification), treadmill-testing and analysis of shear-stress related soluble proteins. The Art.Net.-2 Trial will report within the next months whether direct evidence can be brought that ECP promotes coronary collateral growth in patients with stable angina pectoris.

Local Cytokine Concentrations and Oxygen Pressure Are Related to Maturation of the Collateral Circulation in Humans

Our aim was to determine cytokine and oxygen gradients over the collateral circulation in humans. The molecular background of the maturation of the collateral circulation in response to coronary narrowing is poorly understood in humans, partly because of difficulties in obtaining local samples from the human collateral circulation. Coronary collateral blood was sampled in 60 patients with nontotal (n = 25) or total coronary occlusions (n = 35) using a special wide-lumen catheter. Coronary collateral flow index (CFI) was assessed by intracoronary pressure measurements. Oxygenation and lactate content was measured as well as 30 cytokines potentially involved in collateral artery growth, using a custom-made multiplex assay. No rise in lactate or change in pH was found in collateral blood. Oxygen gradient between coronary and collateral arterial blood correlated inversely with CFI (r = -0.61, p < 0.001). Locally increased plasma levels were found for basic fibroblast growth factor, eotaxin, macrophage migration inflammatory factor, monocyte chemoattractant protein-1, and transforming growth factor-beta, while stem cell factor and stem cell growth factor-beta were significantly decreased. The highest cytokine gradients were found in patients with the least developed collateral circulation. The majority of cytokines correlated more strongly with the pO(2) gradient across the collateral bed than with CFI. Intravascular ischemia during brief balloon coronary occlusion is absent in human coronary collateral arteries. The oxygen gradient found over the collateral circulation is increased in patients with a less matured collateral circulation and relates to local levels of several known pro-arteriogenic cytokines. In case of a more developed collateral circulation, relatively low levels of cytokines are present, suggesting that growth factor therapy might be beneficial at this stage.

Appraising the pathophysiologic impact of coronary collaterals as measured by fractional flow reserve on symptoms and signs of myocardial ischemia

The purpose of coronary revascularization in stable patients is anginal relief, yet there is no linear relationship between stenosis severity and clinical significance. A major factor in this complex lesion-myocardium interaction is collateral flow. We aimed to define which collateral flow cut-offs separate asymptomatic from symptomatic patients during coronary occlusion. Patients undergoing percutaneous transluminal coronary angioplasty for a single stenotic lesion were selected, collaterals were appraised angiographically, and fractional flow reserve was used during prolonged balloon occlusion to measure collateral flow index (FFRcoll). Changes in anginal symptoms, ST-T segment, and left ventricular wall motion were appraised before and during/shortly after balloon dilation. Receiver-operating-characteristic curves and area under the curve were computed to identify the most appropriate FFRcoll cut-offs. Twenty consecutive patients were enrolled. At baseline, 10 patients had angiographic evidence of collaterals, whereas 10 had no angiographic evidence of collateral flow distal to the target lesion. FFRcoll had an excellent discriminatory performance for the presence of angiographic collaterals (area under the curve = 0.90, P = 0.003), a good discriminatory performance for the occurrence of angina (area under the curve = 0.80, P = 0.025), and a trend toward a good discriminatory performance for the occurrence of asynergy (area under the curve = 0.81, P = 0.06). On the basis of receiver-operating-characteristic curves, an FFRcoll cut-off greater than 0.26 could reliably distinguish patients with adequate collaterals (sensitivity = 0.90, specificity = 0.80), whereas a greater than 0.41 cut-off distinguished patients having angina or wall motion abnormalities from those remaining asymptomatic. This study shows that distal collateral pressure greater than 41% of proximal perfusion pressure protects from anginal symptoms or regional systolic dysfunction during coronary occlusion, whereas a greater than 26% cut-off is more appropriate to identify angiographically evident collaterals ensuring distal myocardial viability.

Abstract 3933: Local Cytokine Release is Increased in Less Mature Collateral Arteries and Reflects Collateral Arterial Oxygen Pressure in Man

Background: The molecular background of the maturation of the human collateral circulation in response to coronary narrowings is poorly understood, particularly because of the complexity to evaluate coronary collateral growth in-vivo. Local sampling of collateral blood in patients could provide valuable insights in this process. We sought to determine metabolic parameters and plasma cytokine profiles in the human coronary collateral circulation in relation to collateral maturation. Methods and Results: We used a Proxis® proximal embolic protection device (St. Jude Medical) to perform blood sampling directly from the coronary collateral circulation in 60 patients with non-total (n=25) or total coronary occlusions (n=35). Coronary collateral flow index (CFI) was assessed by intracoronary pressure measurements. Oxygenation and lactate content was measured as well as 30 cytokines potentially involved in collateral artery growth, using a custom-made multiplex assay. Oxygen gradient between systemic and collateral arterial correlated inversely with CFI (R=−0.63, p&lt;0.001). No rise in lactate or change in pH was found in collateral blood. Locally increased plasma levels were found for bFGF, Eotaxin, MIF, MCP-1, VEGF and TGFbeta, while SCF was significantly decreased. The highest cytokine gradients were found in patients with the least developed collateral circulation. The majority of cytokines correlated more strongly with pO2 extraction across the collateral bed than with CFI. Conclusion: Upregulation of cytokines at the site of coronary collateralization and in collateral vessels with enhanced oxygen gradient between systemic and collateral arterial blood demonstrate increased inflammatory activity in arteries where oxygen delivery is insufficient. Less pronounced cytokine gradients in collateral arteries in CTOs indicate reduced arteriogenic activity in these vessels. Determining oxygen gradient may be a more sensitive tool for the assessment of the functional capacity of the collateral circulation in patients than measurements of CFI.

Non-invasive gene-expression-based detection of well-developed collateral function in individuals with and without coronary artery disease

Background: In patients with coronary artery disease (CAD), a well grown collateral circulation has been shown to be important. The aim of this prospective study using peripheral blood monocytes was...

Interferon-β Signaling Is Enhanced in Patients With Insufficient Coronary Collateral Artery Development and Inhibits Arteriogenesis in Mice

Stimulation of collateral artery growth in patients has been hitherto unsuccessful, despite promising experimental approaches. Circulating monocytes are involved in the growth of collateral arteries, a process also referred to as arteriogenesis. Patients show a large heterogeneity in their natural arteriogenic response on arterial obstruction. We hypothesized that circulating cell transcriptomes would provide mechanistic insights and new therapeutic strategies to stimulate arteriogenesis. Collateral flow index was measured in 45 patients with single-vessel coronary artery disease, separating collateral responders (collateral flow index, >0.21) and nonresponders (collateral flow index, < or 1). Isolated monocytes were stimulated with lipopolysaccharide or taken into macrophage culture for 20 hours to mimic their phenotype during arteriogenesis. Genome-wide mRNA expression analysis revealed 244 differentially expressed genes (adjusted P, <0.05) in stimulated monocytes. Interferon (IFN)-beta and several IFN-related genes showed increased mRNA levels in 3 of 4 cellular phenotypes from nonresponders. Macrophage gene expression correlated with stimulated monocytes, whereas resting monocytes and progenitor cells did not display differential gene regulation. In vitro, IFN-beta dose-dependently inhibited smooth muscle cell proliferation. In a murine hindlimb model, perfusion measured 7 days after femoral artery ligation showed attenuated arteriogenesis in IFN-beta-treated mice compared with controls (treatment versus control: 31.5+/-1.2% versus 41.9+/-1.9% perfusion restoration, P<0.01). In conclusion, patients with differing arteriogenic response as measured with collateral flow index display differential transcriptomes of stimulated monocytes. Nonresponders show increased expression of IFN-beta and its downstream targets, and IFN-beta attenuates proliferation of smooth muscle cells in vitro and hampers arteriogenesis in mice. Inhibition of IFN-beta signaling may serve as a novel approach for the stimulation of collateral artery growth.

Intracoronary Autologous Bone Marrow−Derived Mononuclear Cell Transplantation Improves Coronary Collateral Vessel Formation and Recruitment Capacity in Patients With Ischemic Cardiomyopathy: A Combined Hemodynamic and Scintigraphic Approach

This study investigated the effects of intracoronary autologous bone marrow-derived mononuclear cell (BMC) transplantation on coronary microcirculation. Fifteen patients with ischemic cardiomyopathy were treated by intracoronary infusion of BMCs via the patent infarct-related artery. The thermodilution-derived coronary flow reserve, index of microvascular resistance, pressure-derived collateral flow index, and coronary wedge pressure were measured at baseline and at 6 months. Successive balloon inflations during BMC transplantation were performed to observe the recruitment in pressure-derived collateral flow index and coronary wedge pressure, and the percentage changes between baseline and 6 months were calculated. The mean (SD) coronary flow reserve increased from 1.3 (0.4) to 2.1 (0.5), and the mean (SD) index of microvascular resistance decreased from 44.9 (24.4) to 21.2 (14.1) (P = .001 for both). The mean (SD) improvement in pressure-derived collateral flow index (from 0.14 [0.05] to 0.22 [0.08]) was also statistically significant (P = .001). Similarly, the percentage improvements in pressure-derived collateral flow index and coronary wedge pressure were statistically significant (P = .01 for both). The percentage improvement in perfusion assessed by single-photon emission computed tomography strongly correlated with the percentage changes in pressure-derived collateral flow index (r = 0.88, P = .001) and coronary wedge pressure (r = 0.69, P = .01). These results demonstrate for the first time (to our knowledge) that intracoronary autologous BMC transplantation improves coronary collateral vessel formation and recruitment capacity in human subjects.

Pharmacological options for inducing maximal hyperaemia during studies of coronary physiology

The coronary pressure wire is used for physiological assessment of the coronary vasculature increasingly frequently in clinical practice. Fractional flow reserve (FFR) can now be used to assess lesion severity in a variety of anatomical situations. Increasingly, the coronary pressure wire is being used to interrogate the coronary microvasculature. Coronary flow reserve (CFR) and Index of microcirculatory resistance (IMR) require hyperaemia to accurately assess thermodilution-derived mean transit times, and pressure derived collateral flow index (CFIp) is calculated from coronary wedge pressure and aortic pressure at hyperaemia. In addition, coronary flow velocity as assessed by a coronary Doppler flow wire needs appropriate induction of hyperaemia. However, the majority of this article will however focus on hyperaemia induction for pressure wire studies particularly FFR. Significant clinical decisions are made as a result of FFR readings, therefore it is imperative that they are carried out correctly. Maximal coronary hyperaemia is essential in producing accurate, reproducible measurements. This article focuses on the pharmacological agents that can be used for this purpose, discusses which agents can be used in specific situations, and briefly addresses the future of pharmacological stress in the catheter laboratory.

Abstract 3341: Human Coronary Collaterals Inversely Correlate with Indices of Ischemic Left Ventricular Diastolic Dysfunction during Coronary Balloon Occlusion.

Background: Coronary collaterals are thought to reduce myocardial ischemia during coronary artery occlusion. Coronary collaterals, defined angiographically, reduce end diastolic LV dilatation during coronary occlusion. However, counter to a role in reducing ischemia, they appear to be associated with an increase in LV end diastolic pressure. These changes may be explained if coronary collaterals act as an external LV scaffold. We aimed to re-evaluate this relationship by simultaneously measuring coronary collaterals and LV contractility quantitatively. Methods: Ten patients with normal LV function and single vessel coronary disease awaiting PCI were recruited. Collateral flow index, derived by pressure-wire measurement (CFI p = [P distal (occluded) − P venous ] / [P aorta − P venous ]) and change in LV end-diastolic pressure (LVEDP), volume (LVEDV) and Tau, measured by an LV cavity conductance catheter, were recorded simultaneously after 1 minute coronary balloon occlusion. A mean of 5 cardiac cycles was analyzed. Measurements were repeated after a recovery period of 30 minutes. Results: Percentage change in LVEDP and Tau inversely correlated with CFI p (ΔLVEDP vs. CFI p : y = −216.6x +63.4, r = 0.57, p=0.01; ΔTau vs. CFI p : y = −64.1x + 27.8, r = 0.47, p&lt;0.05) (Figure ). There was also an inverse relationship between ΔLVEDV vs. CFI p (y = −8.4x + 1.5, r = 0.35, p = 0.15). Conclusion: Coronary collaterals inversely correlate with LV end diastolic stiffness and dilatation after 1 minute of coronary artery occlusion. This reflects a role in reducing ischemic LV diastolic dysfunction, by providing an alternative blood supply to the LV myocardium, rather than acting as an LV scaffold.

Late Coronary Stent Thrombosis

Introduced >20 years ago,1 coronary artery stents have improved the safety and particularly the efficacy of percutaneous coronary interventions (PCIs).2 Abrupt vessel closure, complicating 6% to 8% of balloon angioplasty procedures, was associated with a 5% mortality, 40% rate of myocardial infarction (MI), and 40% rate of emergency coronary artery bypass grafting.3 Stents significantly reduced these adverse events (Figure 1).4,5 The reduction of restenosis afforded by bare metal stents (BMS) was modest (30% to 40%). Repeat revascularization still occurred in 15% to 20% of cases.6 Drug-eluting stents (DES) with antiproliferative drugs attached via polymers on the stent surface to minimize smooth muscle proliferation have reduced restenosis and rates of target lesion revascularization by 50% to 70% compared with BMS across nearly all lesion and patient subsets.7 Initially8 and again more recently,9–16 safety concerns were raised about DES, particularly about late stent thrombosis (ST). Figure 1. Outcome of 112 patients with abrupt vessel closure in the prestent balloon angioplasty experience of a registry (1985 to 1986; total, 1801 patients)3 and 339 patients with abrupt vessel closure during balloon angioplasty treated with BMS (Palmaz-Schatz) (total, 4596 patients).5 CABG indicates coronary artery bypass grafting. ST was a bane of stent implantation from the beginning. The initial experience with Wallstents in the late 1980s was overshadowed by ST rates approaching 24%.17 Subsequent series with Palmaz-Schatz and Gianturco-Roubin stents (still predominantly bailout stenting) observed ST in 6% to 12% of cases.4,18 The postprocedural antithrombotic regimen at the time consisted of aspirin, often in conjunction with oral anticoagulation. Dual antiplatelet therapy of aspirin and the thienopyridine ticlopidine in conjunction with a shift from bailout to elective stenting resulted in a significant reduction of ST to <2%.5,19 Earlier oral antiplatelet drug loading and …

Six simultaneously employed methods to gauge the coronary collateral flow of the decade

A 59-year-old woman with bronchial asthmaand obesity underwent coronary angiographybecause of exertional dyspnea and atypicalchest pain both at rest and sometimes duringexertion. Coronary angiography revealed achronic total occlusion (CTO) of the proximalleft anterior descending (LAD) artery (fig. 1A).Systolic left ventricular (LV) function was nor-mal (fig. 1B, 1C). Angiography of the right coro-nary artery showed a large collateral artery tothe LAD and some smaller septal collateralvessels (fig. 2A). The very well developed coro-nary collateral circulation protected the pa-tient entirely from a large anterior myocardialinfarction. Moreover, it was likely sufficient toprevent angina pectoris even under physicalexertion. There are more than half a dozenmethods for collateral assessment, six of themperformed in this particular patient. The pres-ence of normal LV anterior wall motion in thepresence of a CTO of the LAD qualifies collat-erals as relevant enough to prevent myocar-dial infarction (fig. 1B, 1C). The coronary an-giographic assessment, first described by Ren-trop et al., qualifies naturally or artificially(fig. 2B) occluded coronary arteries accordingto the degree (0–3) of retrograde filling by col-lateral vessels (grade 3 as in the present casewith entire filling of the balloon-occluded LAD)[1]. Two further methods for the characterisa-tion of well developed collaterals during a briefcoronary balloon occlusion are the absence ofST-segment changes in the intracoronary ECG(fig. 3), and the lack of angina pectoris. Meas-urement of invasively derived collateral flowindex (CFI) or contrast-echocardiography-ob-tained collateral perfusion index (CPI) provide

Relationship between Microvascular Resistance and Perfusion in Patients with Reperfused Acute Myocardial Infarction

Despite its prognostic importance, accurate assessment of microvascular perfusion in patients with ST elevation acute myocardial infarction (STEMI) is difficult. As a new tool, the index of microvascular resistance (IMR) measurement provides us a new opportunity for interrogating microvascular condition after STEMI. In this study, we measured IMR in infarct-related artery (IRA) and explored its relation with other indices which have been suggested to evaluate microvascular perfusion in patients with reperfused STEMI. Forty-two patients with STEMI treated successfully with primary percutaneous coronary intervention (pPCI) were prospectively included. After 48 hours following pPCI, patients were recatheterized and IMR, coronary flow reserve (CFR), systolic and mean coronary wedge pressures (CWPs and CWPm) pressure-derived collateral flow index (CFIp) were measured in IRA by using intracoronary pressure-temperature sensor tipped guide wire. Myocardial blush grade was assessed from the second angiogram. Coronary flow velocity pattern (diastolic deceleration time: DDT) was examined with transthoracic echocardiography 48 hours after pPCI. Percentage of ST-segment recovery was calculated from surface ECG (STR%). IMR well correlated with CWPs (r = 0.70, P < 0.001), CWPm (r = 0.59, P < 0.001), CFIp (r = 0.65, P < 0.001), CFR (r =-0.50, P = 0.001), and DDT (r =-0.59, P = 0.001). Correlations of IMR to non/semiinvasive indices like myocardial blush grades (MBG) (r =-0.42, P = 0.007) and STR (r =-0.37, P = 0.024) are somewhat weaker. Given its simplicity of measurement, independence from the presence of an epicardial stenosis, and good correlation with all measures of microvascular obstruction used in this study, IMR may prove to be a valuable modality for evaluating the microcirculation.

Beneficial Effect of Recruitable Collaterals

The prognostic relevance of the collateral circulation is still controversial. The goal of this study was to assess the impact on survival of quantitatively obtained, recruitable coronary collateral flow in patients with stable coronary artery disease during 10 years of follow-up. Eight-hundred forty-five individuals (age, 62+/-11 years), 106 patients without coronary artery disease and 739 patients with chronic stable coronary artery disease, underwent a total of 1053 quantitative, coronary pressure-derived collateral measurements between March 1996 and April 2006. All patients were prospectively included in a collateral flow index (CFI) database containing information on recruitable collateral flow parameters obtained during a 1-minute coronary balloon occlusion. CFI was calculated as follows: CFI = (P(occl) - CVP)/(P(ao) - CVP) where P(occl) is mean coronary occlusive pressure, P(ao) is mean aortic pressure, and CVP is central venous pressure. Patients were divided into groups with poorly developed (CFI < 0.25) or well-grown collateral vessels (CFI > or = 0.25). Follow-up information on the occurrence of all-cause mortality and major adverse cardiac events after study inclusion was collected. Cumulative 10-year survival rates in relation to all-cause deaths and cardiac deaths were 71% and 88%, respectively, in patients with low CFI and 89% and 97% in the group with high CFI (P=0.0395, P=0.0109). Through the use of Cox proportional hazards analysis, the following variables independently predicted elevated cardiac mortality: age, low CFI (as a continuous variable), and current smoking. A well-functioning coronary collateral circulation saves lives in patients with chronic stable coronary artery disease. Depending on the exact amount of collateral flow recruitable during a brief coronary occlusion, long-term cardiac mortality is reduced to one fourth compared with the situation without collateral supply.

Recruitable collateral blood flow index predicts coronary instent restenosis after percutaneous coronary intervention

Collateral flow may influence long-term results after percutaneous coronary intervention (PCI) because of haemodynamic forces compete with the antegrade flow through the dilated lesion. The aim of the study was to assess the influence of recruitable collateral blood flow on restenosis in patients undergoing PCI with bare metal stents and using optimal antithrombotic treatment. In 95 patients, 95 de novo lesions were treated with PCI and a bare metal stent. Fractional flow reserve (FFR) at maximum hyperaemia induced by intravenous adenosine was determined. The pressure-derived collateral flow index (CFI) was determined as (P(w)-P(cvp))/(P(a)-P(cvp)), where P(w) represents coronary wedge pressure, P(cvp) central venous pressure, and P(a) mean aortic blood pressure. Both were measured during transient coronary occlusion by a balloon inflation of 30 s. Pre-interventional FFR (0.65 +/- 0.20) correlated inversely with the CFI (0.18 +/- 0.11), r =- 0.356, P < 0.001. After 9 months, binary angiographic restenosis (>/=50% diameter stenosis) was seen in 29.1%. Compared to patients with poorly developed collaterals (CFI < 0.25), patients with well-developed collaterals (CFI >/= 0.25) had a lower pre-interventional FFR (0.50 +/- 0.14 vs. 0.72 +/- 0.18, P < 0.001), a higher CFI (0.33 +/- 0.08 vs. 0.13 +/- 0.07, P < 0.001), and a higher binary restenosis rate (54.2% vs. 19.4, P = 0.003). CFI*100 was an independent predictor of restenosis after 9 months (odds ratio 1.07, 95% CI 1.02-1.12, P = 0.016). Recruitable collateral blood flow measured during balloon inflation predicts angiographic instent restenosis in PCI patients treated with bare metal stents.

The Coronary Collateral Circulation in Man

Well developed coronary collateral arteries in patients with coronary artery disease (CAD) mitigate myocardial infarcts with less ventricular aneurysm formation and improved ventricular function, they reduce future cardiovascular events, and improve survival. Myocardial infarct size is a product of coronary artery occlusion time, area at risk for infarction and the inverse of collateral supply. Collateral arteries preventing myocardial ischemia during brief vascular occlusion are present in 1/3 of patients with CAD. Collateral flow sufficient to prevent myocardial ischemia during coronary occlusion amounts to ≥25% of the normal flow through the open vessel. Among individuals without relevant coronary stenoses, there are preformed collateral arteries preventing myocardial ischemia in 20-25%. Coronary collateral flow can be assessed only during vascular occlusion of the collateral-receiving artery. Presently, the gold standard for clinical coronary collateral assessment is the measurement of intracoronary occlusive pressure- or velocity- derived collateral flow index which expresses collateral as a fraction of flow during vessel patency. Clinical variables predicting the development of collateral arteries are the hemodynamic severity of coronary stenoses and the duration of myocardial ischemic symptoms. One fifth to one third of patients with CAD cannot be revascularized by percutaneous coronary intervention or coronary artery bypass grafting; therapeutic promotion of collateral growth appears to be a valuable treatment strategy in those patients. Promotion of collateral growth should aim at inducing the development of large conductive collateral arteries (i.e. arteriogenesis) and not so much the sprouting of capillary like vessels (i.e. angiogenesis). So far, the largest, controlled clinical angiogenesis trials on the efficacy of VEGF and basic FGF have been negative with regard to treadmill exercise time and myocardial scintigraphic data. Large conductive collateral arteries (i.e. arteriogenesis) appear to be effectively promoted via the activation of monocytes / macrophages, which release VEGF, FGF, tumor necrosis factor alpha, granulocyte colony stimulating factors and other growth and remodelling-associated factors. Keywords: Coronary circulation, collateral circulation, arteriogenesis, angiogenesis

Coronary Collaterals Remain Recruitable After Percutaneous Intervention

Rapid loss of collateral support has been reported after percutaneous coronary intervention (PCI), leaving the myocardium susceptible to subsequent infarction. However, well-developed collaterals have been found in normal hearts, suggesting that collaterals exist even in the absence of an ischemic stimulus. We assessed the plasticity and determinants of collateral supply after PCI. Collateral flow index (CFI) was calculated in 60 patients as (P(w)-P(v))/(P(a)-P(v)) by measurement of aortic (P(a)), central venous (P(v)), and coronary wedge (P(w)) pressures. CFI was reassessed during transient balloon occlusion 5 minutes and 24 hours after PCI in the first 29 patients and at 6 months in the subsequent 25 patients. We also evaluated the relationship between collateral supply, lesion characteristics, and circulating hemopoietic cells numbers before and after successful PCI. CFI at baseline was 0.23+/-0.10, with no change 5 minutes and 1 day later (0.21+/-0.12, P=0.62; and 0.22+/-0.11, P=0.96, respectively). At 6 months, CFI was 0.14+/-0.07 or 63+/-27% of the baseline value (P<0.001). CFI was proportional to severity of the coronary lesion at baseline (r=0.63, P<0.0001) but not 6 months after PCI (r=-0.04, P=0.87). The number of circulating CD133+ and CD34+ cells was associated with CFI 6 months after PCI (CD133, r=0.59, P=0.035; CD34, r=0.63, P=0.037). Coronary collateral flow remains undiminished for at least 24 hours after successful PCI. Functional collateral support subsequently declines but does not regress completely.

Coronary collateral flow in response to endurance exercise training

In humans, it is not known whether physical endurance exercise training promotes coronary collateral growth. The following hypotheses were tested: the expected collateral flow reduction after percutaneous coronary intervention of a stenotic lesion is prevented by endurance exercise training; collateral flow supplied to an angiographically normal coronary artery improves in response to exercise training; there is a direct relationship between the change of fitness after training and the coronary collateral flow change. Forty patients (age 61+/-8 years) underwent a 3-month endurance exercise training program with baseline and follow-up assessments of coronary collateral flow. Patients were divided into an exercise training group (n=24) and a sedentary group (n=16) according to the fact whether they adhered or not to the prescribed exercise program, and whether or not they showed increased endurance (VO2max in ml/min per kg) and performance (W/kg) during follow-up versus baseline bicycle spiroergometry. Collateral flow index (no unit) was obtained using pressure sensor guidewires positioned in the coronary artery undergoing percutaneous coronary intervention and in a normal vessel. In the vessel initially undergoing percutaneous coronary intervention, there was an increase in collateral flow index among exercising but not sedentary patients from 0.155+/-0.081 to 0.204+/-0.056 (P=0.03) and from 0.189+/-0.084 to 0.212+/-0.077 (NS), respectively. In the normal vessel, collateral flow index changes were from 0.176+/-0.075 to 0.227+/-0.070 in the exercise group (P=0.0002), and from 0.219+/-0.103 to 0.238+/-0.086 in the sedentary group (NS). A direct correlation existed between the change in collateral flow index from baseline to follow-up and the respective alteration of VO2max (P=0.007) and Watt (P=0.03). A 3-month endurance exercise training program augments coronary collateral supply to normal vessels, and even to previously stenotic arteries having undergone percutaneous coronary intervention before initiating the program. There appears to be a dose-response relation between coronary collateral flow augmentation and exercise capacity gained.

Does the β-Blocker Nebivolol Increase Coronary Flow Reserve?

Nebivolol, a highly selective beta1-adrenergic receptor-blocker, increases basal and stimulated endothelial nitric oxide (NO)-release. It is unknown, whether coronary perfusion is improved by the increase in NO availability. Therefore, we sought to evaluate the effect of nebivolol on coronary flow reserve (CFR) and collateral flow. Doppler-flow wire derived coronary flow velocity measurements were obtained in ten controls and eight patients with coronary artery disease (CAD) at rest and after intracoronary nebivolol. CFR was defined as maximal flow during adenosine-induced hyperemia divided by resting flow. In the CAD group, collateral flow was determined after dilatation of a flow-limiting coronary stenosis. Collateral flow index (CFI) was defined as the ratio of flow velocity during balloon inflation divided by resting flow. CFR at rest was 3.0+/-0.6 in controls and 2.1+/-0.4 in CAD patients. After intracoronary doses of 0.1, 0.25, and 0.5 mg nebivolol, CFR increased to 3.4+/-0.7, 3.9+/-0.9, and 4.0+/-0.1 (p<0.01) in controls, and to 2.3+/-0.7, 2.6+/-0.9, and 2.6+/-0.5 (p<0.05) in CAD patients. CFI decreased significantly with intracoronary nebivolol and correlated to changes in heart rate (r=0.75, p<0.001) and rate-pressure product (r=0.59, p=0.001). Intracoronary nebivolol is associated with a significant increase in CFR due to reduction in resting flow (controls), or due to an increase in maximal coronary flow (CAD patients). CFI decreased with nebivolol parallel to the reduction in myocardial oxygen consumption.

Importance of collateral circulation in coronary heart disease

Collateral arteries are a common but inconsistent finding in coronary heart disease (CHD). We endeavoured to review the methods for coronary artery collateral assessment, the predictors and clinical importance of collateral blood flow, and the potential for therapeutic augmentation of collateral anastomoses. While many methods have been used to assess collateral blood flow only a few have been formally validated. Collateral flow index, as determined by measurement of intra-coronary pressure or flow velocity, is the most robust measure of collateral flow. These techniques have led to important advances in our understanding of collateral artery function. Coronary collateral arteries may prevent myocardial ischaemia in healthy subjects and in patients with CHD. A functional collateral circulation may lead to reduced ischaemia, preservation of ventricular function, and an improved prognosis. Recent trials have demonstrated that vascular progenitor cell therapies may improve ventricular function following acute myocardial infarction, raising the possibility of effective biological treatments to improve myocardial blood flow and prognosis in CHD. Coronary collateral anastomoses represent a prognostically important adaptive response in patients with CHD. Therapeutic augmentation of collaterals with emerging biological therapies represents a desirable goal for treating CHD patients.