Stephan Zbinden

Beneficial Effect of Recruitable Collaterals A 10-Year Follow-Up Study in Patients With Stable Coronary Artery Disease Undergoing Quantitative Collateral Measurements

Background— 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. Methods and Results— 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: where Poccl is mean coronary occlusive pressure, Pao 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 ≥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. Conclusions— 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.

Is There Functional Collateral Flow During Vascular Occlusion in Angiographically Normal Coronary Arteries

Background—Thus far, it is unknown whether there is functional collateral flow through preexisting anastomoses in patients with angiographically normal coronary arteries. Such preformed coronary collateral vessels could form the basis for subsequently developing protective natural bypasses in the presence of coronary artery disease. Methods and Results—Among 100 patients, the collateral flow index (CFI) was measured in coronary arteries without stenotic lesions. The CFI was determined by simultaneous measurement of mean aortic pressure, central venous pressure, and coronary wedge pressure via a sensor-tipped guidewire at the end of a 1-minute balloon occlusion. Patients were divided in 2 groups according to complete angiographic absence (51 patients) or partial presence (49 patients) of stenotic lesions in coronary arteries other than that undergoing collateral measurement. CFI in all patients (61±10 years; men/women, 69/31) amounted to 0.18±0.08 (range, 0.04 to 0.36). It showed a normal Gaussian frequency distribution; 22 individuals had a CFI ≥0.25, a value that was empirically found to represent well-developed collaterals protective against myocardial ischemia during coronary occlusion. Accordingly, 17 patients did not reveal signs of myocardial ischemia during coronary balloon occlusion, as assessed from an intracoronary ECG, and 26 patients did not experience angina pectoris during occlusion. Conclusion—In humans with angiographically normal coronary arteries, there are functional collateral vessels to the extent that one fifth to one quarter of them do not show signs of myocardial ischemia during brief vascular occlusions.

CD8+ T Lymphocytes Regulate the Arteriogenic Response to Ischemia by Infiltrating the Site of Collateral Vessel Development and Recruiting CD4+ Mononuclear Cells Through the Expression of Interleukin-16

Background— Previous studies have demonstrated that macrophages and CD4+ T lymphocytes play pivotal roles in collateral development. Indirect evidence suggests that CD8+ T cells also play a role. Thus, after acute cerebral ischemia, CD8+ T cells infiltrate the perivascular space and secrete interleukin-16 (IL-16), a potent chemoattractant for monocytes and CD4+ T cells. We tested whether CD8+ T lymphocytes contribute to collateral vessel development and whether the lack of circulating CD8+ T cells prevents IL-16 expression, impairs CD4+ mononuclear cell recruitment, and reduces collateral vessel growth after femoral artery ligation in CD8−/− mice. Methods and Results— After surgical excision of the femoral artery, laser Doppler perfusion imaging demonstrated reduced blood flow recovery in CD8−/− mice compared with C57/BL6 mice (ischemic/nonischemic limb at day 28, 0.66±0.04 versus 0.87±0.04, respectively; P<0.01). This resulted in greater calf muscle atrophy (mean fiber area, 785±68 versus 1067±69 &mgr;m2, respectively; P<0.01) and increased fibrotic tissue content (10.8±1.2% versus 7±1%, respectively; P<0.01). Moreover, CD8−/− mice displayed reduced IL-16 expression and decreased CD4+ T-cell recruitment at the site of collateral vessel development. Exogenous CD8+ T cells, infused into CD8−/− mice immediately after femoral artery ligation, selectively homed to the ischemic hind limb and expressed IL-16. The restoration of IL-16 expression resulted in significant CD4+ mononuclear cell infiltration of the ischemic limb, faster blood flow recovery, and reduced hindlimb muscle atrophy/fibrosis. When exogenous CD8+ T cells deficient in IL-16 (IL-16−/−) were infused into CD8−/− mice immediately after femoral artery ligation, they selectively homed to the ischemic hind limb but were unable to recruit CD4+ mononuclear cells and did not improve blood flow recovery. Conclusions— These results demonstrate that CD8+ T cells importantly contribute to the early phase of collateral development. After femoral artery ligation, CD8+ T cells infiltrate the site of collateral vessel growth and recruit CD4+ mononuclear cells through the expression of IL-16. Our study provides further evidence of the significant role of the immune system in modulating collateral development in response to peripheral ischemia.

Coronary collateral flow in response to endurance exercise training.

Background 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. Methods and results 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 (V o 2max 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 V o 2max (P=0.007) and Watt (P=0.03). Conclusion 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.

CARDIOVASCULAR RISK FACTORS IMPAIR NATIVE COLLATERAL DEVELOPMENT AND MAY IMPAIR EFFICACY OF THERAPEUTIC INTERVENTIONS

Animal and early clinical studies of gene therapy for tissue ischaemia suggested that this approach might provide benefit to patients with coronary artery disease not amenable to traditional revascularization. This enthusiasm was then tempered by the subsequent disappointing results of randomized clinical trials and led researchers to develop strategies using progenitor cells as an alternative to improve collateral function. However, the recent publication of several randomized clinical trials reporting either negative or weakly positive results using this approach have led to questions regarding its effectiveness. There are several factors that need to be considered in explaining the discordance between the positive studies of such treatments in animals and the disappointing results seen in randomized patient trials. Aside from the practical issues of arteriogenic therapies, such as effective delivery, vascular remodelling is an extraordinarily complex process, and the administration of a single agent or cell in the hope that it would lead to lasting physiological effects may be far too simplistic an approach. In addition, however, evidence now suggests that many of the traditional cardiovascular risk factors-such as age and hypercholesterolemia-may impair the host response not only to ischaemia but, critically, also to treatment as well. This review discusses the evidence and mechanisms for these observations and highlights future directions that might be taken in an effort to provide more effective therapies.

Clinical outcome of high-risk patients with severe aortic stenosis and reduced left ventricular ejection fraction undergoing medical treatment or TAVI

Introduction Reduced left ventricular function in patients with severe symptomatic valvular aortic stenosis is associated with impaired clinical outcome in patients undergoing surgical aortic valve replacement (SAVR). Transcatheter Aortic Valve Implantation (TAVI) has been shown non-inferior to SAVR in high-risk patients with respect to mortality and may result in faster left ventricular recovery. Methods We investigated clinical outcomes of high-risk patients with severe aortic stenosis undergoing medical treatment (n = 71) or TAVI (n = 256) stratified by left ventricular ejection fraction (LVEF) in a prospective single center registry. Results Twenty-five patients (35%) among the medical cohort were found to have an LVEF≤30% (mean 26.7±4.1%) and 37 patients (14%) among the TAVI patients (mean 25.2±4.4%). Estimated peri-interventional risk as assessed by logistic EuroSCORE was significantly higher in patients with severely impaired LVEF as compared to patients with LVEF>30% (medical/TAVI 38.5±13.8%/40.6±16.4% versus medical/TAVI 22.5±10.8%/22.1±12.8%, p <0.001). In patients undergoing TAVI, there was no significant difference in the combined endpoint of death, myocardial infarction, major stroke, life-threatening bleeding, major access-site complications, valvular re-intervention, or renal failure at 30 days between the two groups (21.0% versus 27.0%, p = 0.40). After TAVI, patients with LVEF≤30% experienced a rapid improvement in LVEF (from 25±4% to 34±10% at discharge, p = 0.002) associated with improved NYHA functional class at 30 days (decrease ≥1 NYHA class in 95%). During long-term follow-up no difference in survival was observed in patients undergoing TAVI irrespective of baseline LVEF (p = 0.29), whereas there was a significantly higher mortality in medically treated patients with severely reduced LVEF (log rank p = 0.001). Conclusion TAVI in patients with severely reduced left ventricular function may be performed safely and is associated with rapid recovery of systolic left ventricular function and heart failure symptoms.

Influence of diabetes mellitus on coronary collateral flow: an answer to an old controversy

Objectives: To determine the influence of diabetes mellitus on coronary collateral flow by accurate means of collateral flow measurement in a large population with variable degrees of coronary artery disease. Methods: 200 patients (mean (SD) age 64 (9) years; 100 diabetic and 100 non-diabetic) were enrolled in the study. Coronary collateral flow was assessed in 174 stenotic and in 26 angiographically normal vessels with a pressure guidewire (n  =  131), Doppler guidewire (n  =  36), or both (n  =  33) to calculate pressure or flow velocity derived collateral flow index (CFI). Diabetic patients were perfectly matched with a non-diabetic control group for clinical, haemodynamic, and angiographic parameters. Results: CFI did not differ between the diabetic and the non-diabetic patients (0.21 (0.12) v 0.19 (0.13), not significant). Likewise, CFI did not differ when only angiographically normal vessels (0.20 (0.09) v 0.15 (0.08), not significant) or chronic total coronary occlusions (0.30 (0.14) v 0.30 (0.17), not significant) were compared. Fewer patients in the diabetic group tended to have angina pectoris during the one minute vessel occlusion (60 diabetic v 69 non-diabetic patients, p  =  0.15). Conclusion: Quantitatively measured coronary CFI did not differ between diabetic and non-diabetic patients with stable coronary artery disease.

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 to identify marker genes for an extensively grown coronary collateral circulation. Methods: Collateral flow index (CFI) was obtained invasively by angioplasty pressure sensor guidewire in 160 individuals (110 patients with CAD, and 50 individuals without CAD). RNA was extracted from monocytes followed by microarray-based gene-expression analysis. 76 selected genes were analysed by real-time polymerase chain reaction (PCR). A receiver operating characteristics analysis based on differential gene expression was then performed to separate individuals with poor (CFI<0.21) and well-developed collaterals (CFI⩾0.21) Thereafter, the influence of the chemokine MCP-1 on the expression of six selected genes was tested by PCR. Results: The expression of 203 genes significantly correlated with CFI (p = 0.000002–0.00267) in patients with CAD and 56 genes in individuals without CAD (p = 00079–0.0430). Biological pathway analysis revealed 76 of those genes belonging to four different pathways: angiogenesis, integrin-, platelet-derived growth factor-, and transforming growth factor β-signalling. Three genes in each subgroup differentiated with high specificity among individuals with low and high CFI (⩾0.21). Two out of these genes showed pronounced differential expression between the two groups after cell stimulation with MCP-1. Conclusions: Genetic factors play a role in the formation and the preformation of the coronary collateral circulation. Gene expression analysis in peripheral blood monocytes can be used for non-invasive differentiation between individuals with poorly and with well grown collaterals. MCP-1 can influence the arteriogenic potential of monocytes.

Metallothionein Enhances Angiogenesis and Arteriogenesis by Modulating Smooth Muscle Cell and Macrophage Function

Objective—In a previous study we identified metallothionein (MT) as a candidate gene potentially influencing collaterogenesis. In this investigation, we determined the effect of MT on collaterogenesis and examined the mechanisms contributing to the effects we found. Methods and Results—Collateral blood flow recovery was assessed using laser Doppler perfusion imaging, and angiogenesis was measured using a Matrigel plug assay. Smooth muscle cells were isolated from MT knockout (KO) mice for functional assays. Gene expression of matrix metalloproteinase-9, platelet-derived growth factor, vascular endothelial growth factor, and Fat cadherin in smooth muscle cells was measured by real-time polymerase chain reaction, and protein levels of vascular endothelial growth factor and matrix metalloproteinase-9 were determined using enzyme-linked immunosorbent assay and Western blot. CD11b+ macrophages were tested for invasiveness using a real-time impedance assay. Both flow recovery and angiogenesis were impaired in MT KO mice. Proliferation, migration, and invasion were decreased in MT KO smooth muscle cells, and matrix metalloproteinase-9, platelet-derived growth factor, and vascular endothelial growth factor expression were also decreased, whereas FAT-1 cadherin expression was elevated. MT KO CD11b+ cells were more invasive than wild-type cells. Conclusion—MT plays an important role in collateral flow recovery and angiogenesis, an activity that appears to be mediated, in part, by the effects of MT on the functionality of 3 cell types essential for these processes: endothelial cells, smooth muscle cells, and macrophages.

Effect of statin treatment on coronary collateral flow in patients with coronary artery disease

Recent work has suggested an angiogenic,1 and conversely, an angiostatic2 or biphasic effect of statins.3 However, such hypotheses have been tested only in vitro or in animal models. The influence of statins on human arteriogenesis, the formation of collateral arteries, nowadays thought to be necessary to save myocardium from ischaemia, has not been previously investigated. Five hundred patients with stable one to three vessel coronary artery disease (CAD) and without Q wave myocardial infarction underwent quantitative assessment of the coronary collateral circulation during coronary angioplasty. The patients were divided into two different groups according to the use of statins (termed “statin group”, n  =  186) or the absence of statin treatment (termed “no statin group”, n  =  314). All patients underwent left heart catheterisation, including biplane left ventricular angiography and coronary angiography for diagnostic purposes. Aortic pressure was recorded using the angioplasty catheter. Coronary artery stenoses were assessed quantitatively as per cent lumen diameter reduction, using the guiding catheter for calibration. Collateral vessel assessment was performed by three …