Collateral Connections Research Articles

The role of coronary artery collaterals in the preservation of left ventricular function: a study to address a long-standing controversy.

SummaryIntroduction:The functional significance of coronary artery collateral (CAC) vasculature in humans has been debated for decades and this has been compounded by the lack of a standard, systematic, objective method of grading and documenting CAC flow in man. CACs serve as alternative conduits for blood in obstructive coronary artery disease. This study aimed to evaluate the impact of CACs on left ventricular function in the presence of total coronary arterial occlusion.Methods:The study group included the coronary angiographic records of 97 patients (mean age: 59 ± 8 years). CACs were graded from 0–3 based on the collateral connection between the donor and recipient arteries. Left ventricular function was computed from the ventriculogram and expressed as ejection fraction (EF).Results:The mean EF of the patients with grades 0, 1, 2 and 3 CACs were calculated as 50.4, 47, 60.5 and 70%, respectively. A significant difference was recorded in the mean EF calculated for the different CAC grades (p = 0.001). There was a significant positive correlation (p < 0.001; r = 0.478) between the mean EF and the CAC grades.Conclusion:The patients with better coronary collateral grades had a higher mean EF. Therefore, as the grade of CACs increased, there was an improvement in their ability to preserve left ventricular function.

Dopaminergic treatment weakens medium spiny neuron collateral inhibition in the parkinsonian striatum.

The striatal medium spiny neurons (MSNs) are critical to both motor and cognitive functions. A potential regulator of MSN activity is the GABAergic collateral axonal input from neighboring MSNs. These collateral axon terminals are further under the regulation of presynaptic dopamine (DA) receptors that may become dysfunctional when the intense striatal DA innervation is lost in Parkinson's disease (PD). We show that DA D1 receptor-expressing MSNs (D1-MSNs) and D2 receptor-expressing MSNs (D2-MSNs) each formed high-rate, one-way collateral connections with a homotypic preference in both normal and DA-denervated mouse striatum. Furthermore, whereas the homotypic preference, one-way directionality and the basal inhibitory strength were preserved, DA inhibited GABA release at the D2-MSN→D2-MSN collateral synapse in a supersensitive manner in the DA-denervated striatum. In contrast, for D1-MSN-originated collateral connections, whereas D1 agonism facilitated D1-MSN→D1-MSN collateral inhibition in the normal striatum, this presynaptic D1R facilitation of GABA release was lost in the parkinsonian striatum. These results indicate that in the parkinsonian striatum, dopaminergic treatment can presynaptically weaken the D2-MSN→D2-MSN collateral inhibition and disinhibit the surrounding D2-MSNs, whereas the D1-MSN→D1-MSN collateral inhibition is weakened by the loss of the presynaptic D1 receptor facilitation, disinhibiting the surrounding D1-MSNs. Together, these newly discovered effects can disrupt the MSN circuits in the parkinsonian striatum and may contribute to dopaminergic treatment-induced aberrant motor and nonmotor behaviors in PD.NEW & NOTEWORTHY With the use of a large database, this study establishes that neighboring homotypic striatal spiny projection neurons have a 50% chance to form one-way collateral inhibitory connection, a substantially higher rate than previous estimates. This study also shows that dopamine denervation may alter presynaptic dopamine receptor function such that dopaminergic treatment of Parkinson's disease can weaken the surround inhibition and may reduce the contrast of the striatal outputs, potentially contributing to dopamine's profound motor and nonmotor behavioral effects.

Prevalence of ischaemia in patients with a chronic total occlusion and preserved left ventricular ejection fraction.

Previous studies on invasive assessment of collateral function in patients with a chronic total occlusion (CTO) have displayed only a limited increase in collateral flow and high occurrence of coronary steal during pharmacological stress. This could question the necessity for ischaemia testing prior to revascularization of CTOs in the presence of myocardial viability. The purpose of the present study was to determine the prevalence of perfusion impairments in patients with a CTO as assessed by [15O]H2O positron emission tomography (PET). Seventy-six consecutive patients (60 men, 62 ± 10 years) with a documented CTO and preserved left ventricular ejection fraction (LVEF) were included. All patients underwent PET to assess (hyperaemic) myocardial blood flow (MBF) and coronary flow reserve (CFR). Collateral connection score was 0 in 7 (9%), 1 in 13 (17%), and 2 in 56 (74%) of the cases, with predominantly a high Rentrop grade (96% ≥2). MBF of the target area during hyperaemia was significantly lower when compared with the remote area (1.37 ± 0.37 vs. 2.63 ± 0.71 mL min-1 g-1, P < 0.001). Target to remote ratio during hyperaemia was on average 0.54 ± 0.13, and 73 (96%) patients demonstrated a significantly impaired target to remote ratio (≤0.75). Only 7 (9%) patients displayed a preserved CFR of ≥2.50, whereas coronary steal (CFR <1.0) was observed in 10 (13%) patients. Even in the presence of angiographically well-developed collateral arteries, the vast majority of CTO patients with a preserved LVEF showed significantly impaired perfusion. These results suggest that collateral function during increased blood flow demand in viable myocardium is predominantly insufficient.

Natural allelic variation of the IL-21 receptor modulates ischemic stroke infarct volume.

Risk for ischemic stroke has a strong genetic basis, but heritable factors also contribute to the extent of damage after a stroke has occurred. We previously identified a locus on distal mouse chromosome 7 that contributes over 50% of the variation in postischemic cerebral infarct volume observed between inbred strains. Here, we used ancestral haplotype analysis to fine-map this locus to 12 candidate genes. The gene encoding the IL-21 receptor (Il21r) showed a marked difference in strain-specific transcription levels and coding variants in neonatal and adult cortical tissue. Collateral vessel connections were moderately reduced in Il21r-deficient mice, and cerebral infarct volume increased 2.3-fold, suggesting that Il21r modulates both collateral vessel anatomy and innate neuroprotection. In brain slice explants, oxygen deprivation (OD) activated apoptotic pathways and increased neuronal cell death in IL-21 receptor-deficient (IL-21R-deficient) mice compared with control animals. We determined that the neuroprotective effects of IL-21R arose from signaling through JAK/STAT pathways and upregulation of caspase 3. Thus, natural genetic variation in murine Il21r influences neuronal cell viability after ischemia by modulating receptor function and downstream signal transduction. The identification of neuroprotective genes based on naturally occurring allelic variations has the potential to inform the development of drug targets for ischemic stroke treatment.

The collateral circulation of coronary chronic total occlusions.

Despite advances in understanding the physiological role of collaterals in coronary chronic total occlusions (CTOs), collateral anatomy remains poorly defined. Our aim was to define the anatomy and interventional utility of collaterals within a large population of patients with CTOs. We studied the coronary angiograms of 481 patients with 519 CTOs at six centres in the U.K. over four years. Detailed angiographic analysis was performed by interventional cardiologists specialising in CTO percutaneous coronary intervention (PCI). All visible collaterals with a collateral connection (CC) grade ≥1 were recorded. A subgroup of CTOs (n=277) was assessed for interventional capability, defined as whether the collateral supply was able to facilitate retrograde access. We described 45 different collateral patterns: 20 in right coronary artery (RCA), 13 in left anterior descending (LAD), and 12 in circumflex artery CTOs. Septal collaterals from the LAD to the right posterior descending artery (RPDA), and from the posterior descending artery to the LAD were most common, and most often considered as having "interventional capability". This is the largest analysis of collateral circulation anatomy in a population of patients with CTOs. We anticipate that these data will be of significant benefit in angiographic analysis and procedure planning for CTO PCI.

TCTAP C-076 Percutaneous Coronary Intervention for Stumpless Ostial Left Anterior Descending Artery Chronic Total Occlusion with Poor Developed Collateral Connection

### Patient initials or identifier number DT ### Relevant clinical history and physical exam A 45-year-old man with exertional dysnea of 2 months duration refractory to maximal medical therapy. The past cardiac history was significant for PCI 13 years previously, including a bare metal stent

Novel retrograde approach for percutaneous treatment of chronic total occlusions of the right coronary artery using ipsilateral collateral connections: a European centre experience

A systematic description of the percutaneous treatment of chronic total occlusions (CTOs) of the right coronary artery (RCA) using ipsilateral collateral connections (CCs) for the retrograde approach has never been carried out. Our aim was to investigate this issue systematically. Based on the experiences of a European high-volume CTO centre: 1) a generalised scheme of the varying anatomic courses of ipsilateral CCs bridging CTOs of the RCA was developed; 2) important stepwise technical advice for the ipsilateral retrograde approach was formulated; and 3) a supportive clinical case series was assessed. Of a total of 158 patients with CTOs of the RCA, 30% (n=47) revealed ipsilateral CCs of the RCA. Five different types (A-E) of ipsilateral CCs were assessed. The retrograde ipsilateral approach was attempted in nine patients, and was completed successfully in 89% (8/9 patients). Median left ventricular ejection fraction was 56% (interquartile range [IQR]: 50-60%) and mean J-CTO score was 2.9 (standard error of mean [SEM]: ±0.3). Median procedural duration time was 150 min (IQR 117-160 min), with a median applied amount of contrast of 360 ml (IQR 270-400 ml). No relevant complications, such as acute renal failure or severe bleedings, occurred. The percutaneous treatment of CTOs of the RCA using ipsilateral CCs for the retrograde approach might provide a novel treatment alternative for patients with CTOs of the RCA in specific clinical situations.

Long-term MACCE Rate after Retrograde Compared to Antegrade Recanalization of Chronic Total Coronary Occlusions

Background: The recanalization success rate of chronic total occlusion (CTO) percutaneous coronary interventions (PCI) can be increased by the retrograde approach. However, the long-term outcome of patients undergoing retrograde procedures is unknown. Aim: We aimed to evaluate the long-term MACCE (major adverse cardiac and cerebrovascular event) rate (death, myocardial infarction, coronary artery bypass surgery and stroke) in patients after retrograde versus antegrade CTO-PCI. Methods and results: In a prospective single center study from January 2008 to June 2012, 396 consecutive patients with CTO´s (≥ 3 months old) were enrolled. Mean age was 63.4 ± 10.3 years, 86.4% were male. The recanalization success rate of the total patient cohort was 88.6%. The retrograde PCI, only attempted after a failed antegrade intervention, was performed in 18% (n = 71) of patients. Long-term MACCE rate (mean follow up 2.3 ± 1.6 years) was significantly higher in the unsuccessful compared to the successful CTO-PCI group (23.1% versus 9.4%, p = 0.01) and this was also the case in the subgroup of antegrade CTO-PCI. In the retrograde subgroup, however, procedural success had no impact on outcome. As a possible explanation for this surprising finding, patients with unsuccessful retrograde CTO-PCI had a significantly better collateral connection compared to patients with an unsuccessful antegrade approach. Conclusions: Long-term MACCE rate after unsuccessful recanalization was significantly higher which was driven by a higher MACCE rate after unsuccessful versus successful antegrade approach. In contrast, procedural success in the retrograde group had no impact on outcome.

Combined analysis of myocardial function, viability, and stress perfusion in patients with chronic total occlusion in relation to collateral flow.

Indications for revascularisation in chronic total occlusion (CTO) of the coronary artery depend on the interplay between myocardial function, viability, and ischaemia. The technical feasibility of the procedure often relies on the collateral flow to the occluded artery. To assess the relation between the degree of collateral flow and characteristics of the myocardium supplied by the oc-cluded artery. The study included 54 patients (mean age 62 years, 85% males) with CTO referred for cardiovascular magnetic resonance (CMR) to assess indications for revascularisation. The presence of well-developed collateral flow was defined as a collateral connection grade = 2 and Rentrop score = 3. The presence of well-developed collaterals (n = 24, 44%) was less likely to be related to systolic dysfunction of the segments supplied by the occluded artery (mean wall motion score index 1.31 ± 0.44 vs. 1.64 ± 0.67, p = 0.04) in comparison to a lack of well-developed collaterals. Patients with well-developed collaterals had a lower frequency of previous myocar-dial infarction of the CTO territory (38% vs. 67%, p = 0.03) with similar frequency of transmural infarctions (21% vs. 23%, p = 0.83). They less frequently presented perfusion deficits of the CTO area during hyperaemia (42% vs. 70%, p = 0.03) and the size of deficits was smaller (median 0.0% [interquartile range 0-12%] vs. 7.5% [0-15%], p = 0.04). Myocardial segments supplied by CTO with well-developed collaterals are less prone to inducible ischaemia, have better systolic function, and are less likely to undergo myocardial infarction, in comparison to those supplied by CTO with poor collateral circulation. CMR is a non-invasive method that can be used for a comprehensive workup of patients be-ing considered for CTO revascularisation.

A protective role of early collateral blood flow in patients with ST-segment elevation myocardial infarction

Conflict persists regarding whether the presence of early collateral blood flow to the infarct-related artery has an effective role in reducing infarct size and improving myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI). We sought to investigate the impact of the collateral circulation on myocardial salvage and infarct size in STEMI patients. In 306 patients who were diagnosed with STEMI and underwent cardiac magnetic resonance within 1 week after revascularization, initial collateral flow to the infarct-related artery was assessed by coronary angiography. Using cardiac magnetic resonance imaging, myocardial infarct size and salvage were measured. Among 247 patients with preprocedural Thrombolysis in Myocardial Infarction flow 0/1, 54 (22%) patients had good collaterals (Rentrop grade ≥ 2, Collateral Connection Score ≥ 2). Infarct size and area at risk were significantly smaller in patients with good collaterals than those with poor collaterals (infarct size: 17.1 ± 10.1 %LV vs 21.8 ± 10.5 %LV, P = .003, area at risk: 33.8 ± 16.8 %LV vs 38.8 ± 15.5 %LV, P = .039). There was a significant difference of myocardial salvage index between 2 groups (50.9% ± 15.0% vs 43.8% ± 18.5%, P = .005). Poor collateralization was an independent predictor for large infarct size (odd ratio 2.48 [1.28-4.80], P = .007). In patients with STEMI, the presence of well-developed collaterals to occluded coronary artery from the noninfarct vessel and its extent were independently associated with reduced infarct burden and improved myocardial salvage. Our results help explain why MI patients with well-developed collateralization have reduced mortality and morbidity.

Fatal derecruitment of occluded left anterior descending collaterals after left circumflex revascularization

Coronary arteries are not definitely functionally terminal arteries, as previously thought; indeed, they are linked and interconnected by a rich network of collaterals. Chronic total occlusions (CTOs) represent a subset of frequent lesions encountered in everyday catheterization laboratory practice, generally associated with a developed system of collateral connections. These latter have the capacity to prevent myocardial necrosis and may even uphold metabolic supply to the ischemic territory to maintain its contractile capacity. Authors have reported a rapid and progressive reduction of collateral function and their decline after antegrade flow restoration, resulting in higher myocardial susceptibility to ischemia in the CTO territory. Here, we report the case of a fatal derecruitment of collaterals for a left anterior descending CTO not reopened, after left circumflex subocclusion revascularization.

Physiologic significance of coronary collaterals in chronic total occlusions

Chronic total occlusions (CTOs) are commonly found in patients with coronary artery disease, and a system of collateral connections are found in almost all of these patients. These collateral vessels serve to prevent myocardial necrosis but are not sufficient to prevent myocardial ischemia during exercise. Unfortunately, the presence of well-developed collaterals has been used as argument against CTO revascularization. Many continue to falsely believe that these patients are "protected" by collaterals and, therefore, CTO recanalization is not indicated. Our knowledge of the physiologic significance of coronary collaterals has increased significantly over the past several years. Studies utilizing coronary pressure and flow velocity have answered a number of basic physiologic questions. We therefore sought to review the evidence for coronary collateral flow and their clinical significance in patients with CTOs.

PACAP and VIP signaling in chondrogenesis and osteogenesis

Skeletal development is a complex process regulated by multifactorial signaling cascades that govern proper tissue specific cell differentiation and matrix production. The influence of certain regulatory peptides on cartilage or bone development can be predicted but are not widely studied. In this review, we aimed to assemble and overview those signaling pathways which are modulated by PACAP and VIP neuropeptides and are involved in cartilage and bone formation. We discuss recent experimental data suggesting broad spectrum functions of these neuropeptides in osteogenic and chondrogenic differentiation, including the canonical downstream targets of PACAP and VIP receptors, PKA or MAPK pathways, which are key regulators of chondro- and osteogenesis. Recent experimental data support the hypothesis that PACAP is a positive regulator of chondrogenesis, while VIP has been reported playing an important role in the inflammatory reactions of surrounding joint tissues. Regulatory function of PACAP and VIP in bone development has also been proved, although the source of the peptides is not obvious. Crosstalk and collateral connections of the discussed signaling mechanisms make the system complicated and may obscure the pure effects of VIP and PACAP. Chondro-protective properties of PACAP during oxidative stress observed in our experiments indicate a possible therapeutic application of this neuropeptide.

Coronary competitive reverse flow: Imaging findings at CT angiography and correlation with invasive coronary angiography

ObjectiveTo study the imaging features of coronary competitive reverse flow and incidence of a “reverse attenuation gradient” in coronary CT angiography (CTA) with correlation to invasive coronary angiography (ICA). MethodsPatients who had undergone coronary CTA and ICA within 2 weeks were retrospectively identified in our database and reviewed. All cases with ICA-confirmed competitive reverse flow or chronic total occlusions (CTOs) were included for further analysis. The “reverse attenuation gradient sign” was defined as a reverse intraluminal opacification gradient of vessels which showed higher opacification in more distal compared with proximal segments. ICA findings were recorded and served as the reference to identify the clinical implications of this sign. ResultsIn total, 134 patients (mean age, 68.1 ± 11.3 years; range, 38–90 years; 104 men) were included in our study. ICA revealed 11 cases of coronary competitive reverse flow and 123 cases of CTO. A reverse attenuation gradient sign was present in 9 of 11 patients (82%) with coronary competitive reverse flow and 72 of 123 (59%) chronically occluded coronary arteries. Myocardial bridges, distal collateral filling, as well as direct visualization of collateral connection were all more frequent in cases with coronary competitive reverse flow group compared with cases with a CTO. ConclusionsThe reverse attenuation gradient sign distal to an upstream coronary severe stenosis indicates the presence of competitive collateral flow. Coronary CTA is able to correctly detect coronary competitive collateral flow and differentiate it from CTOs.

Architectural constraints are a major factor reducing path integration accuracy in the rat head direction cell system.

Head direction cells fire to signal the direction in which an animal's head is pointing. They are able to track head direction using only internally-derived information (path integration)In this simulation study we investigate the factors that affect path integration accuracy. Specifically, two major limiting factors are identified: rise time, the time after stimulation it takes for a neuron to start firing, and the presence of symmetric non-offset within-layer recurrent collateral connectivity. On the basis of the latter, the important prediction is made that head direction cell regions directly involved in path integration will not contain this type of connectivity; giving a theoretical explanation for architectural observations. Increased neuronal rise time is found to slow path integration, and the slowing effect for a given rise time is found to be more severe in the context of short conduction delays. Further work is suggested on the basis of our findings, which represent a valuable contribution to understanding of the head direction cell system.

The CA3 region of the hippocampus: how is it? What is it for? How does it do it?

The CA3 region of the hippocampus: how is it? What is it for? How does it do it?

TCT-52 The impact of collateral connection between chronic total occlusion and infarct related artery on early clinical outcomes in acute ST elevation myocardial infarction

TCT-52 The impact of collateral connection between chronic total occlusion and infarct related artery on early clinical outcomes in acute ST elevation myocardial infarction

Detection and quantification methods of monocyte homing in coronary vasculature with an imaging cryomicrotome

Cellular imaging modalities are important for revealing the behavior and role of monocytes in response to neovascularization progression in coronary artery disease. In this study we aimed to develop methods for high-resolution three-dimensional (3D) imaging and quantification of monocytes relative to the entire coronary artery network using a novel episcopic imaging modality.In a series of ex vivo experiments, human umbilical vein endothelial cells and CD14+ monocytes were labeled with fluorescent live cell tracker probes and infused into the coronary artery network of excised rat hearts by a Langendorff perfusion method. Coronary arteries were subsequently infused with fluorescent vascular cast material and processed with an imaging cryomicrotome, whereby each heart was consecutively cut (5μm slice thickness) and block face imaged at appropriate excitation and emission wavelengths. The resulting image stacks yielded 3D reconstructions of the vascular network and the location of cells administered. Successful detection and quantification of single cells and cell clusters were achieved relative to the coronary network using customized particle detection software. These methods were then applied to an in vivo rabbit model of chronic myocardial ischemia in which autologous monocytes were isolated from peripheral blood, labeled with a fluorescent live cell tracker probe and re-infused into the host animal. The processed 3D image stacks revealed homing of monocytes to the ischemic myocardial tissue. Monocytes detected in the ischemic tissue were predominantly concentrated in the mid-myocardium. Vessel segmentation identified coronary collateral connections relative to monocyte localization.This study established a novel imaging platform to efficiently determine the localization of monocytes in relation to the coronary microvascular network. These techniques are invaluable for investigating the role of monocyte populations in the progression of coronary neovascularization in animal models of chronic and sub-acute myocardial ischemia.

Noninvasive Evaluation of Coronary Collateral Arterial Flow by Coronary Computed Tomographic Angiography

Coronary collateral flow is an alternative source of myocardial perfusion in patients with totally occluded coronary arteries. Clinical evaluation of collateral flow has been limited by the need of invasive measurements. We investigated whether noninvasive coronary computed tomographic angiography can evaluate the angiographic extent of coronary collateral flow. We enrolled 325 coronary computed tomographic angiography cases with angiographically confirmed chronic total occlusion (median age, 63 years; men 83%). Transluminal attenuation gradient (TAG), which reflects the kinetics of contrast media in coronary artery, of an entire artery as well as of a distal vessel was assessed to evaluate the flow in entire vessel and distal vessel. TAGs were validated against visually assessed angiographic collateral connection and Rentrop grading. TAG of an entire artery increased consistently according to the angiographic extent of collateral flow (P<0.001). Well-developed collaterals, defined by highest collateral connection and Rentrop grades (n=103), could be predicted by TAG of an entire artery (cutoff, ≥-7.6 Hounsfield units/10 mm; c-statistics, 0.72; sensitivity, 65%; specificity, 73%; positive predictive value, 52%; negative predictive value, 82%). TAG of a distal vessel could discriminate the antegrade (n=143) and retrograde (n=182) flows in distal artery (cutoff, 0.0 Hounsfield unit/10 mm; c-statistics, 0.88; sensitivity, 78%; specificity, 85%; positive predictive value, 87%; negative predictive value, 75%). TAG, an intracoronary attenuation-based analysis of coronary computed tomographic angiography, moderately reflected the functional extent and direction of collateral flow.

Innate collateral vessels in the absence of ischemia undergo shear stress similar to normal arterial segments of the same diameter (1079.12)

Some species, including humans, have structural collateral vessels, CV, that can further develop in the presence of coronary stenosis by increasing pressure difference across them. Question is how CV's are maintained in the absence of ischemia.The coronary network of 6 healthy canine hearts was reconstructed in 3D from images obtained with an imaging cryomicrotome after filling with fluorescent replica material (resolution 0.020 mm). CV's were automatically detected. The full coronary network was reconstructed. For all segments, including CV's, diameter and perfused tissue mass, PTM, was derived and shear stress, SS, calculated.Innate collateral connections ranged from 286 to 1015 µm in diameter and were distributed over the myocardial wall with some higher density at the subendocardium: density 2.5 ‐ 5.0 per gram tissue. Highly correlating fractal relations were found between PTM and diameter for normal tree segments and for CV's which fully overlapped. SS in the CV's was equal to neighboring tree segments of similar diameter.Results indicate that collateral segments have the same function in distributing blood, and do so at the same SS, as normal tree segments. Hence, functionally CV's are not different from normal vascular segments and are therefore maintained. CV's form substrate for collateral growth in ischemia.Grant Funding Source: FP7‐ICT‐2007‐224495: euHeart