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Copper (Cu) deficiency plays an important role in the development of cardiovascular disorders. Resveratrol (RSV) possesses pleiotropic cardiovascular benefits; however, the mechanism(s) by which RSV exerts protective effects are not completely understood. Male Wistar rats at 6 weeks of age were fed for 8 weeks with a Cu deficient diet (no added Cu, Cu = 0). In addition, Cu deficient rats were supplemented with RSV (500 mg/kg of diet, n = 9). Blood and intestinal samples were taken for further analysis together with internal organs and thoracic arteries. RSV supplementation resulted in elevated blood plasma levels of Cu (x2.1) and Zn (x1.1), in an increased activity of superoxide dismutase (SOD, x1.5) and ferric reducing antioxidant power (FRAP, x1.2). Meanwhile, markers of lipid peroxidation expressed as malondialdehyde (MDA, x1.5) and lipid hydroperoxides (LOOH, x1.1) were also increased in a significant way. Food intake, body weight, blood glucose, catalase, ceruloplasmin, lipid profile and intestinal samples were not modified. RSV enhanced the vasoconstriction of isolated thoracic arteries to noradrenaline (x1.4), potentiated the vasodilation to acetylcholine (ACh, x1.4) and increased the sensitivity to sodium nitroprusside (SNP). In addition, preincubation with the cyclooxygenase (COX)-inhibitor, indomethacin, potentiated the ACh-induced vasodilation, which was more pronounced in animals not supplemented with RSV. The K ATP channel opener, pinacidil, induced a similar response in both studied groups. In conclusion, this study demonstrates that RSV supplementation influences oxidative stress and the antioxidant status, which may modify the vascular response in Cu deficiency., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

We aimed to study the physiological effects of diet supplemented with copper (Cu) nanoparticles (NPs). During the eight weeks of the experiment, young Wistar rats (at seven weeks of age, n = 9) were supplemented with 6.5 mg of Cu either as NPs or carbonate salt (Cu6.5). A diet that was not supplemented with Cu served as a negative control (Cu0). The impact of nano Cu supplementation on lipid (reflected as thiobarbituric acid reactive substances-TBARS) and protein peroxidation (thiol and carbonyl groups) in blood plasma as well as the influence on the vasodilatory mechanism(s) of isolated rat thoracic arteries were studied. Supplementation with Cu enhanced lipid peroxidation (TBARS) in NP6.5 (x2.4) and in Cu6.5 (x1.9) compared to the negative control. Significant increase in TBARS was also observed in NP6.5 (x1.3) compared to the Cu6.5 group. The level of thiol groups increased in NP6.5 (x1.6) compared to Cu6.5. Meanwhile, significant (x0.6) decrease was observed in the Cu6.5 group compared to the negative control. Another marker of protein oxidation, carbonyl groups increased in NP6.5 (x1.4) and Cu6.5 (x2.3) compared to the negative control. However significant difference (x0.6) was observed between NP6.5 and Cu6.5. Arteries from Cu supplemented rats exhibited an enhanced vasodilation to gasotransmitters: nitric oxide (NO) and carbon monoxide (CO). An enhanced vasodilation to NO was reflected in the increased response to acetylcholine (ACh) and calcium ionophore A23187. The observed responses to ACh and CO releasing molecule (CORM-2) were more pronounced in NP6.5. The activator of cGMP-dependent protein kinases (8-bromo-cGMP) induced similar vasodilation of thoracic arteries in NP6.5 and Cu0 groups, while an increased response was observed in the Cu6.5 group. Preincubation with the inducible nitric oxide (iNOS) synthase inhibitor- 1400W, decreased the ACh-induced vasodilation in NP6.5, exclusively. Meanwhile the eicosanoid metabolite of arachidonic acid (20-HETE) synthesis inhibitor-HET0016, enhanced vasodilation of arteries from Cu0 group. In conclusion, this study demonstrates that supplementation with nano Cu influences oxidative stress, which further has modified the vascular response., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose: Impaired endothelium-dependent relaxation (EDR) is a hallmark of endothelial dysfunction. A deficiency of tetrahydrobiopterin (BH 4 ) causes endothelial NOS to produce ROS rather than NO. PPARδ is an emerging target for pharmacological intervention of endothelial dysfunction. Thus, the present study examined the role of PPARδ in the regulation of dihydrofolate reductase (DHFR), a key enzyme in the BH 4 salvage pathway., Experimental Approach: Gene expression was measured by using qRT-PCR and western blotting. Biopterins and ROS were determined by using HPLC. NO was measured with fluorescent dye and electron paramagnetic resonance spectroscopy. Vasorelaxation was measured by Multi Myograph System., Key Results: The PPARδ agonist GW501516 increased DHFR and BH 4 levels in endothelial cells (ECs). The effect was blocked by PPARδ antagonist GSK0660. Chromatin immunoprecipitation identified PPAR-responsive elements within the 5'-flanking region of the human DHFR gene. The promoter activity was examined with luciferase assays using deletion reporters. Importantly, DHFR expression was suppressed by palmitic acid (PA, a saturated fatty acid) but increased by docosahexaenoic acid (DHA, a polyunsaturated fatty acid). GSK0660 prevented DHA-induced increased DHFR expression. Conversely, the suppressive effect of PA was mitigated by GW501516. In mouse aortae, GW501516 ameliorated the PA-impaired EDR. However, this vasoprotective effect was attenuated by DHFR siRNA or methotrexate. In EC-specific Ppard knockout mice, GW501516 failed to improve vasorelaxation., Conclusion and Implications: PPARδ prevented endothelial dysfunction by increasing DHFR and activating the BH 4 salvage pathway. These results provide a novel mechanism for the protective roles of PPARδ against vascular diseases., (© 2019 The British Pharmacological Society.)

In this study, we aimed at performing a histomorphometric analysis of human left internal thoracic artery (ITA) samples as well as at correlating the histomorphometric findings with the clinical profile, including risk factors and medication. Distal segments of ITA were obtained from 54 patients undergoing coronary artery bypass grafting. Histological observation was performed in paraffin-embedded transverse sections of ITA through four staining protocols: hematoxylin-eosin, van Gieson, Masson's trichrome and von Kossa. Morphometric analysis included the intimal width (IW), medial width (MW) and intima/media ratio (IMR). No overt atherosclerotic lesions were observed. Mild calcifications were observed across the vascular wall layers in almost all samples. Multivariable linear regression analysis showed associations between IW and IMR and the following clinical variables: age, gender, kidney function expressed as eGFR and myocardial infarction history. Age (odds ratio = 1.16, P = 0.004), female gender (odds ratio = 11.34, P = 0.011), eGFR (odds ratio = 1.03, P = 0.059) and myocardial infarction history (odds ratio = 4.81, P = 0.040) were identified as the main clinical predictors for intimal hyperplasia. Preatherosclerotic lesions in ITA samples from patients undergoing coronary revascularization were associated not only with classical cardiovascular risk factors such as age and gender, but also with other clinical variables, namely kidney function and myocardial infarction history., Competing Interests: The authors have declared that no competing interests exist.

Reported here are the results of an experimental study on the response to low-intensity cavitation induced by low-frequency (4-6 W/cm 2 , 20 kHz and 32.6 kHz) ultrasound of isolated human arterial samples taken during conventional myocardial revascularization operations. Studies have found that low-frequency ultrasound results in a significant (48%-54%) increase in isometric contraction force and does not depend on the number of exposures (10 or 20) or the time passed since the start of ultrasound (0, 10 and 20 min), but does depend on the frequency and location (internal or external) of the blood vessels for the application of ultrasound. Diltiazem (an inhibitor of slow calcium channels) and carbachol (an agonist of muscarinic receptors) used in a concentration-dependent manner did not modify the relaxation dynamics of smooth muscle affected by ultrasound. Thus, ultrasound conditioned to the augmentation of the isometric contraction force the smooth muscle of blood vessels and did not improve endothelial- and calcium channel blocker-dependent relaxation., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The body plan of arthropods and vertebrates involves the formation of repetitive segments, which subsequently diversify to give rise to different body parts along the antero-posterior/rostro-caudal body axis. Anatomical variations between body segments are crucial for organ function and organismal fitness. Pioneering work in Drosophila has established that Hox transcription factors play key roles both in endowing initially identical segments with distinct identities and organogenesis. The focus of this review is on Alary Muscles (AMs) and the newly discovered Thoracic Alary-Related Muscles (TARMs). AMs and TARMs are thin muscles which together connect the circulatory system and different midgut regions to the exoskeleton, while intertwining with the respiratory tubular network. They were hypothesized to represent a new type of muscles with spring-like properties, maintaining internal organs in proper anatomical positions during larval locomotion. Both the morphology of TARMs relative to AMs, and morphogenesis of connected tissues is under Hox control, emphasizing the key role of Hox proteins in coordinating the anatomical development of the larva., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the distribution of superparamagnetic iron oxide (SPIO)-labeled cells in a perfused segment of a porcine artery and to estimate the number of adherent cells by means of magnetic resonance (MR) imaging., Materials and Methods: Six vessel specimens (diameters between 0.8 and 1.2 cm) were placed in a bioreactor system, and 2 × 10(4) to 1 × 10(6) SPIO-labeled endothelial colony-forming cells were injected into the artery within the perfused reactor. The area of resulting signal extinctions at the inner wall of the vessels was quantified on MR images by using a high-resolution T2*-weighted sequence with a slice-by-slice approach. After imaging, the labeled cells were quantified histologically., Results: The total iron load of each cell was 56.5 pg ± 14.4. In the applied range of 2 × 10(4) to 1 × 10(6) cells per vessel, the area of iron-induced signal extinction at the vessel wall on T2*-weighted imaging corresponded to the histologically detected cell number (r = 0.98, P < .001)., Conclusions: A correlation between the area of signal extinction and the number of labeled cells at the vessel wall was found. This might help to evaluate dose rates in further clinical applications of intravascular cell-based therapies., (Copyright © 2015 SIR. Published by Elsevier Inc. All rights reserved.)

Introduction: Indications for flow-through latissimus dorsi (LD) flaps have been limited for reconstructing distal extremities. In addition, there has been little discussion in regard to the question of which branch is most suitable as a distal runoff of the flow-through anastomosis. The aims of this study were to investigate the feasibility of flow-through LD flaps in various areas in the body and the rationale for branch selection for the distal runoff vessel., Methods: This retrospective study included 33 patients who underwent reconstruction of an oncology-related defect with a free flow-through LD flap. Defect locations, branches used for the distal runoff, and postoperative complications were investigated., Results: The defect location was in the lower extremity in 13 patients, the scalp in seven, the upper extremity in six, the pelvis in six, and the chest in one. In 19 of the 33 patients, the defects were located in areas other than the distal extremities. The circumflex scapular artery (CSA) was most frequently used as the distal runoff vessel (24 patients) followed by the serratus anterior branch (SAB) (five patients). All flaps were transferred successfully without anastomotic failure., Conclusions: The flow-through LD flap is a reliable option for reconstruction in many areas of the body. It can provide high success rates not only for extremity reconstruction but also for scalp and pelvic reconstruction. The CSA matches well with the workhorse recipient vessels. The SAB is suitable when there is a vascular defect of the recipient artery., (Copyright © 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

In systemic atherosclerosis develops the abnormal vascular tone which is associated with elevated calcium influx into smooth muscle cells and their calcification that may be proportional to the extent and severity of atherosclerotic disease. The goal of the present study was to investigate the responses of isolated human arterial samples to Ca²⁺-channel agonists and antagonists by varying the external Ca²⁺ concentration. Two dihydropyridine type calcium-channel blockers, amlodipine and cerebrocrast, were used in this study. The benzodiazepine-type calcium-channel blocker diltiazem, the benzimidazole derivative 1-acetyl-5,6-dimethoxy-2-methylthiobenzimidazole and 3,4'-bipyridine derivative milrinone were also used. Experiments were carried out on isolated human thoracic artery samples obtained from 74 patients, aged 38-88 years, during conventional myocardial revascularisation operations. The contraction of artery samples was recorded using an iFOT10 force transducer. Cumulative concentration-contraction curves of the tested agents (10⁻⁷ to 10⁻⁴ M) were established by varying the external Ca²⁺ concentration from 0.9 mM to 2.7 mM. Cerebrocrast, regardless of the Ca²⁺ concentration significantly increased arterial contraction, particularly at the lower Ca²⁺ (≈77%). Diltiazem, the benzimidazole derivative and milrinone caused the artery samples to relax at 10⁻⁴ M concentrations by 55%, 55% and 44%, respectively, when the external Ca²⁺ corresponded to the physiological standard. Shifting to lower or higher Ca²⁺ concentrations significantly altered the response of vessel samples by increasing their contraction. In conclusion, the present study shows that the response of isolated human thoracic artery samples to both the slow calcium channel suppressant diltiazem and to agonists of that channel (milrinone and the benzimidazole derivative) is regulated by the amount of calcium present in the physiological solution. Treatment with a slow calcium channel inhibitor, the 1,4-dihydropyridine derivative cerebrocrast, resulted in a response that was independent of the external Ca²⁺ concentration.

The aim of this study was to assess intraoperatively the hemodynamic changes in the donor vessel of free latissimus dorsi (LD) flap before and after denervation and to analyze flow changes after flap transfer. Twenty-seven patients underwent LD muscle microvascular reconstruction for lower-limb soft tissue defects. Measurements of blood flow were performed intraoperatively by using a 2- to 5-mm probe ultrasonic transit-time flowmeter around the dissected vessels. Registrations were made in the thoracodorsal artery before and after harvesting the flap, after compressing and cutting the motor nerve, and after anastomosis. Mean blood flow of in situ harvested thoracodorsal artery as measured intraoperatively by transit-time flowmeter was (mean ± standard deviation) 16.6 ± 11 mL/min and was significantly increased after raising the flap to 24.0 ± 22 mL/min (p <0.05); it was 25.6 ± 23 mL/min after compressing the motor nerve and was significantly increased after cutting the motor nerve to 32.5 ± 26 mL/min (p <0.05). A significant increase of blood flow to 28.1 ± 19 mL/min was also detected in the thoracodorsal artery after flap transplantation with end-to-side anastomosis (p <0.05). Vascular resistance in the thoracodorsal artery significantly decreased after flap raising and anastomosis (from 7.5 ± 3.4 to 4.0 ± 1.9 and to 4.5 ± 2.4, respectively, p <0.05). LD flap harvesting increases blood flow and decreases resistance in the thoracodorsal artery, especially after denervation., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Strength training is a recommended measure against loss of strength and muscle mass because of age- or illness-induced inactivity. Strength exercises may impose heavy cardiovascular load by increasing heart rate and blood pressure. To increase strength efficiently, a heavy load has to be applied; this, however, leads to a spontaneous Valsalva manoeuvre, which additionally raises blood pressure. Avoidance of this manoeuvre is recommended. If the additional rise in arterial blood pressure caused by Valsalva manoeuvre is smaller than intrathoracic or intracranial pressures during this manoeuvre, Valsalva manoeuvre may actually protect arteries located in the thorax and in the brain by diminishing transmural pressure acting across these vessels. Effect of controlled breathing or brief Valsalva manoeuvre on arterial pressure at rest and during knee extension against 15-repetition maximum resistance was evaluated. In 12 healthy young men blood pressure was measured continuously and non-invasively, knee angle, speed of respiratory air or mouth pressure (MP) were continuously registered. Each combination of respiratory and exercise manoeuvres was repeated six times, for every of last three repetitions peak and trough systolic and diastolic pressure were determined. Strength exercises elevated peak pressures more than trough pressures, systolic more than diastolic. Valsalva manoeuvre increased only peak systolic and peak diastolic pressure. This increase was in average lesser than MP, thus rendering an argument in favour of protective role of brief Valsalva manoeuvre because of decline in transmural pressure acting on thoracic and possibly cerebral arteries. However, there was strong individual variability, and in few instances, arterial pressure increased because of brief Valsalva manoeuvre more than MP; thus in some subjects, the manoeuvre might enhance transmural pressure acting on thorax arteries., (© 2011 The Authors. Clinical Physiology and Functional Imaging © 2011 Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Objectives: The internal thoracic artery (ITA) is the preferred conduit for coronary artery bypass graft (CABG) surgery. The authors investigated whether thoracic epidural anesthesia (TEA) as an adjunct to general anesthesia (GA) can increase the blood flow of the ITA., Design: A prospective randomized study., Setting: A university hospital., Participants: Patients with ischemic heart disease., Interventions: Thirty patients scheduled for elective CABG surgery were randomized to receive either GA (n = 15) or GA + TEA (n = 15) after receiving institutional review board approval. Demographics showed similarity between the groups. The epidural catheter was inserted in the thoracic region between T1 and T5 levels. In the GA + TEA group, the patients received a 20-mg bolus of 0.25% bupivacaine through epidural catheters 1 hour before surgery, and this was followed by the infusion (20 mg/h) of 0.25% bupivacaine. In all patients, ITA free blood flow was measured before cardiopulmonary bypass and without the administration of any vasodilatory agent. A short segment of ITA was excised for histologic examination; immunocytochemistry analysis was performed using antirabbit polyclonal VEGF antibody, rabbit polyclonal inducible nitric oxide synthase (i-NOS) antibody, and adenosine anti-A2B receptor antibody. The immunoreactivity rates then were evaluated., Main Results: The mean ITA free flow in the GA + TEA group was significantly higher than in the GA group (56.0 ± 9.0 mL/min v 39.6 ± 14 mL/min, p = 0.001). Immunostaining intensity in the sections after incubation with each primary antibody increased in the GA + TEA group compared with the GA group., Conclusions: The results of this study indicated that TEA increased ITA free blood flow significantly via increased VEGF, i-NOS, and adenosine-A2B receptor expressions. Therefore, the use of TEA as an adjunct to GA might be considered as an alternative to vasoactive agents for increasing ITA flow in CABG surgery., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Although bradykinin is known to play a major role in the pathophysiology of hereditary and angiotensin-converting enzyme inhibitor (ACEi)-induced angioedema, other factors acting as triggers or enhancers are likely important as well., Objective: We hypothesized that fibrinogen might contribute to ACEi-induced angioedema (eg, through direct actions on vascular tone)., Methods: Plasma levels of fibrinogen were determined in 59 patients with acute angioedema. Vascular activity of human and bovine fibrinogen and its effects on bradykinin-induced vasodilation and phosphorylation of vasodilator-stimulated phosphoprotein were investigated in small (0.8-1.4 mm in diameter) porcine coronary artery and human internal thoracic artery (ITA) segments., Results: In patients with ACEi-induced angioedema, fibrinogen levels (481 +/- 22 mg/dL, n = 39) were significantly higher than in patients with idiopathic angioedema (302 +/- 15 mg/dL, P < .001). Fibrinogen (1-15 mumol/L) induced a concentration-dependent vasodilation in preconstricted small porcine coronary arteries (n = 13), reaching a maximum vasodilator effect of 70% +/- 4.7%. Likewise, fibrinogen induced a 52.1% +/- 9.1% (n = 7) vasodilation in ITA rings. Fibrinogen vasorelaxations were completely inhibited by abciximab and diminished by endothelial denudation and treatment with the nitric oxide synthase inhibitor L-nitroargininemethylester and glibenclamide (P < .01). Importantly, fibrinogen increased the vasodilator potency of bradykinin by 10-fold (P < .0001) and increased bradykinin-induced vasodilator-stimulated phosphoprotein phosphorylation (P < .01)., Conclusion: The increase of plasma fibrinogen levels, its vasodilator activity in human ITAs, and the potentiation of bradykinin-induced vasodilation suggest that fibrinogen might contribute to the pathophysiology of ACEi-induced angioedema. Thus acute-phase proteins, such as fibrinogen, might be viewed as risk factors for bradykinin-induced angioedema.

Background: We have previously demonstrated differences in the gene expression of voltage-gated K v1.X channel alpha-subunits in arteries from Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs). The purpose of this study was to test the hypothesis that these differences are also present at the protein level., Methods: Proteins were isolated from the aorta, mesenteric (MAs) and tail arteries (TAs) of 12- to 15-week-old male WKY and SHR, and analyzed by immunoblotting. K(v) currents were recorded from MA myocytes by patch clamp methods., Results: Expression of Kv1.2, Kv1.5, and Kv2.1 was higher in MAs but was not different in aortas of SHRs as compared to WKYs. In the TA, expression of Kv1.2 and Kv1.5 was higher while that of Kv2.1 was lower in SHR compared to WKY. In the MA, the larger expression of an 80 kDa species of Kv1.2 in SHRs was associated with a lower expression of a 60 kDa species. Kv2.1 gene expression was larger in MAs from SHRs but not different in TAs. K(v) currents associated with Kv1.X and Kv2.1 channels were both larger in MA myocytes from SHRs but less than expected based upon differences in K(v) alpha-subunit protein expression., Conclusions: For the MA, K(v) protein expression and current components between WKYs and SHRs were qualitatively consistent, but differences in gene and protein expression were not closely correlated. The higher expression of K(v) subunits in small mesenteric arteries (SMAs) of SHR would tend to maintain normal myogenic activity and vasoconstrictor reserve, and could be viewed as a form of homeostatic remodeling.

The mechanical behavior of blood vessels is known to be viscoelastic rather than elastic. The functional role of viscoelasticity, however, has remained largely unclear. The hypothesis of this study is that viscoelasticity reduces the stresses and strains in the vessel wall, which may have a significant impact on the fatigue life of the blood vessel wall. To verify the hypothesis, the pulsatile stress in rabbit thoracic artery at physiological loading condition was investigated with a quasi-linear viscoelastic model, where the normalized stress relaxation function is assumed to be isotropic, while the stress-strain relationship is anisotropic and nonlinear. The artery was subjected to the same boundary condition, and the mechanical equilibrium equation was solved for both the viscoelastic and an elastic (which has a constant relaxation function) model. Numerical results show that, compared with purely elastic response, the viscoelastic property of arteries reduces the magnitudes and temporal variations of circumferential stress and strain. The radial wall movement is also reduced due to viscoelasticity. These findings imply that viscoelasticity may be beneficial for the fatigue life of blood vessels, which undergo millions of cyclic mechanical loadings each year of life.

Ablation of the fibulin-5 gene (fbln5) in mice results in loose skin, emphysematous lungs and tortuous vessels. Additionally, fbln5(-/-) animals display an apparent increase in vascular sprouting from systemic and cutaneous vessels. From these observations, we hypothesized that a de-regulation of vascular sprouting occurs in the absence of endogenous fibulin-5. To test this hypothesis, vascular sprouts from the long thoracic artery were quantified and polyvinyl alcohol sponges were implanted subcutaneously in wild-type and fbln5(-/-) mice to assess fibrovascular invasion. Results showed a significant increase in in situ sprouting from vessels in fbln5(-/-) mice and a significant increase in vascular invasion, with no increase in fibroblast migration, into sponges removed from fbln5(-/-) mice compared with wild-type mice. Localization of fibulin-5 in wild-type mice showed the protein to be present subjacent to endothelial cells (ECs) in established vessels at the periphery of the sponge, and as a component of the newly formed, loose connective tissue within the sponge. These results suggest that fibulin-5 could function as an inhibitor molecule in initial sprouting and/or migration of ECs. To elucidate the molecular mechanism that drives the increased angiogenesis in the absence of fibulin-5, expression of vascular endothelial growth factor (VEGF) and the angiopoietins (Angs) was determined in sponges implanted for 12 days in wild-type and fbln5(-/-) mice. Quantitative RT-PCR showed message levels for VEGF and all three Angs to be elevated by several fold in the area of invasion of sponges from fbln5(-/-) mice compared with wild-type mice. Expression of Ang-1 was also shown to be elevated (30-fold) in vitro in aortic smooth muscle cells isolated from fbln5(-/-) mice when compared with wild-type cells, with no change in the expression of the Ang-1 mediating transcription factor, ESE-1. Taken together, these results suggest that the normal angiogenic process is enhanced in the absence of fibulin-5.

The biometry and the histology of coronary, radial, ulnar, epigastric and internal thoracic arteries were studied in order to investigate the cause of their occlusions in coronary bypass grafts and to improve the results of these bypass grafts. These various arteries were removed from 40 anatomical specimens (27 males and 13 females). We found a correlation between the internal calibers of the ulnar and coronary arteries in males. Intimal changes and the presence of atheromatous plaque were observed in coronary, radial and ulnar arteries, but never in the internal thoracic artery. Like coronary arteries and their branches, radial, ulnar and epigastric arteries are muscular arteries and ageing results in thickening of the intima, which becomes fibrotic with migration of myocytes from the media and duplication of the internal elastic lamina. The media becomes fibrous, hypertrophic or atrophic. In contrast, the internal thoracic artery is an elastic artery, like the aorta. Ageing is characterized by loss, over a variable extent, of one or several elastic laminae of the media and more marked intimal thickening. Although anatomically, the caliber of radial, ulnar, and epigastric arteries remains adapted to that of coronary arteries, the long-term patency of radial, ulnar and epigastric arteries used as grafts is related to their histological characteristics.

Physically useful measures in current clinical practice refer often to the blood flow rate, that is related to the mean velocity. However, the direct measurement of the latter is currently not possible using a Doppler velocimetry technique. Therefore, the usual approach to calculate the flow rate with this technique consists in measuring the maximum velocity and in estimating the mean velocity, making the hypothesis of parabolic profile that in realistic situations results in strongly inaccurate estimates. In this paper, we propose a different way for estimating the flow rate regarded as a function of maximum velocity and Womersley number. This relation is obtained by fixing a parametrised representation and by evaluating the parameters by means of a least-square approach working on the numerical results of CFD simulations (about 200). Numerical simulations are carried out by prescribing the flow rate, not the velocity profile. In this way, no bias is implicitly induced in prescribing boundary conditions. Validation tests based on numerical simulations show that the proposed relation improves the flow rate estimation.

Here, we report the existence of endothelial precursor (EPC) and stem cells in a distinct zone of the vascular wall that are capable to differentiate into mature endothelial cells, hematopoietic and local immune cells, such as macrophages. This zone has been identified to be localized between smooth muscle and adventitial layer of human adult vascular wall. It predominantly contains CD34-positive (+) but CD31-negative (-) cells, which also express VEGFR2 and TIE2. Only few cells in this zone of the vascular wall are positive for CD45. In a ring assay using the fragments of human internal thoracic artery (HITA), we show here that the CD34+ cells of the HITA-wall form capillary sprouts ex vivo and are apparently recruited for capillary formation by tumor cells. New vessels formed by these vascular wall resident EPCs express markers for angiogenically activated endothelial cells, such as CEACAM1, and also for mature endothelial cells, such as VE-cadherin or occludin. Vascular wall areas containing EPCs are found in large and middle sized arteries and veins of all organs studied here. These data suggest the existence of a ;vasculogenic zone' in the wall of adult human blood vessels, which may serve as a source for progenitor cells for postnatal vasculogenesis, contributing to tumor vascularization and local immune response.

It is common practice in the arterial wall modeling to assume material incompressibility. This assumption is driven by the observation of the global volume preservation of the artery specimens in some mechanical loading experiments. The global volume preservation, however, does not necessarily imply the local volume preservation - incompressibility. In this work, we suggest to use the arterial ring- cutting experiments for the assessment of the local incompressibility assumption. The idea is to track the local stretches of the marked segments of the arterial ring after the stress-relieving cut. In the particular case of the rabbit thoracic artery, considered in this work, the following criteria for radial stretches come from preliminary analysis. If after the radial cut the marked segments shorten at the inner surface of the wall and lengthen at the outer surface while remaining unchanged in the middle of the wall then material is locally incompressible. If, however, the marked segments remain unchanged at the surfaces while lengthening in the middle of the wall then the material is locally compressible. Any other scenario would be an indication of the improper modeling assumptions, i.e. residual stresses are not relieved or material constants are inaccurate etc. It is believed that the proposed approach can be successfully implemented in experiments shedding new light on the arterial incompressibility issue.

Objective: In patients with coronary artery disease, the concomitant presence of renal function impairment is associated with decreased survival. We aimed to assess whether in coronary artery diseased patients renal function impairment is associated with systemic vascular function, functional parameters of the renin-angiotensin system, or inflammation as potential mediators for cardiovascular risk., Methods and Results: We studied 125 patients, 87% male, with a mean age of 62.2+/-8.2 years; 72% had 3-vessel disease, and mean renal function was 74+/-13 mL/min per 1.73 m2. Internal thoracic artery rings were sampled during coronary bypass surgery and used for in vitro vascular measurements. We could not establish an association between endothelium-dependent vasorelaxation (response to methacholine) and renal function. In addition, vascular response to potassium chloride, phenylephrine, and angiotensin II were not associated with renal function. Finally, serum angiotensin-converting enzyme (ACE) activity, usage of ACE inhibitors, C-reactive protein, and soluble intercellular adhesion molecule 1 were not related to renal function., Conclusions: In coronary artery disease patients, mild renal function impairment is not associated with systemic vasomotor responsiveness, inflammation, or functional systemic parameters of the renin-angiotensin system. The relation between systemic endothelial dysfunction and mild renal insufficiency might be more complicated than previously thought.

Objective: Recent studies have shown that perivascular adipose tissue from the rat aorta secretes a substance that can dilate the aorta. The purpose of the present study was to examine whether this vasodilator is also present in human internal thoracic arteries., Methods: Vascular function of human internal thoracic arteries with and without perivascular adipose tissue was assessed with wire myography, and morphology was examined with light microscopy., Results: The presence of perivascular adipose tissue attenuated the maximal contraction to U 46619 and the contraction to phenylephrine (1 micromol/L) by 37% and 24%, respectively. Transfer of the solution incubated with a perivascular adipose tissue-intact vessel (donor) to a vessel without perivascular adipose tissue (recipient) induced a significant relaxation (36%) in the recipient artery precontracted with phenylephrine. Transfer of incubation solution with perivascular adipose tissue alone also induced a relaxation response in the recipient vessel (37%). The relaxation of the recipient artery induced by the transfer of incubation solution from the donor (artery with intact perivascular adipose tissue or perivascular adipose tissue alone) was absent in vessels precontracted by KCl (60 mmol/L) and was prevented by calcium-dependent potassium channel blockers (tetraethylammonium chloride, 1 mmol/L; iberiotoxin, 100 nmol/L), but not by the voltage-dependent potassium channel blocker 4-aminopyridine (1 mmol/L) and the adenosine triphosphate-dependent potassium channel blocker glibenclamide (10 micromol/L)., Conclusions: Perivascular adipose tissue in human internal thoracic arteries releases a transferable relaxation factor that acts through the activation of calcium-dependent potassium channels. Because perivascular adipose tissue is often removed in coronary artery bypass grafting, retaining perivascular adipose tissue might be helpful in reducing the occurrence of vasospasm of the graft vessels.

Vascular endothelial cells (EC) are exposed to a complex biomechanical environment in vivo and are responsible for relaying important messages to the underlying tissue. EC and smooth muscle cells (SMC) communicate to regulate vascular development and function. In this work, a vascular perfusion bioreactor is used to grow tubular constructs seeded with EC and SMC under pulsatile shear stress in long-term co-culture to study the effects of EC on SMC function. SMC seeded into porous poly(glycolic acid) tubular scaffolds are cultured in the bioreactor for 25 days. Constructs are seeded with EC on day 10 or day 23 creating 2-day (short-term) or 15-day (long-term) EC and SMC co-cultures. Long-term EC-SMC co-culture significantly increases cell proliferation and downregulates collagen and proteoglycan deposition compared to short-term co-culture. After 25 days of culture, 15-day co-culture constructs have a more uniform cell distribution across the construct thickness and SMC express a more contractile phenotype compared to 2-day co-culture constructs. These data demonstrate strong interactions between SMC and EC in the bioreactor under physiologically relevant conditions. Thus, the vascular construct perfusion bioreactor is an important tool to investigate cell-cell and cell-extracellular matrix interactions in vascular cell biology and tissue engineering.

The present study was designed to study the difference effects between nicardipine and its two enantiomers on thoracic artery of rabbit. A high-performance liquid chromatographic method was used to prepare the two enantiomers of nicardipine. The thoracic artery of rabbit was removed. The vessels were cut into 3 mm in width and 15 mm in length spiral strips and immersed into tissue baths. The concentration-response curves of nicardipine and its enantiomers were obtained by cumulative administration of the vasoconstrictors. Nicardipine and the enantiomers could shift the dose-response curves of NE, KCl or CaCl2 to right in a nonparallel manner and decrease the maximum effective in a concentration-depended manner, respectively. The pD2' value of R-(-)-nicardipine showed significantly effective than that of nicardipine and S-(+)-nicardipine (P<0.01). There was not obviouse difference between the pD2' value of nicardipine and S-(+)-nicardipine (P>0.05). The results demonstrate that the stereoselective interaction between R-(-)-nicardipine and L-calcium channel receptor is more stronger than that of S-(+)-nicardipine.

The main sources of blood supply to the breast are described in textbooks as the internal thoracic, lateral thoracic, and posterior intercostal arteries. Textbooks, however, do not describe the contribution of each to the nippie-areoia complex (NAC), nor do they describe the pattern of supply. To investigate this issue, 15 female cadavers were injected intraarterially with latex, and dissections were performed on 27 breasts. The results were as follows: In all the dissected breasts (27/27), the NAC received at least one or more vessels from the internal thoracic artery. In 20 of 27 dissected breasts, the NAC received vessels from the anterior intercostal arteries, In 19 of the 27 dissected breasts, the NAC received vessels from the lateral thoracic artery. Direct branches from the axillary artery supplied the NAC in 2 of the 27 breasts. The posterior intercostal arteries supplied the NAC in only 1 of the 27 dissected breasts. An underlying segmental pattern could be detected that can be explained by the embryological development. According to this study, the internal thoracic arteries are to be considered the main and constantly reliable source of blood supply to the NAC.

Background: Complex use of arterial conduits has resurrected concerns about the adequacy of conduit flow. The T-graft is the extreme example of this trend. Our purpose was to identify the limitation of single source inflow and to compare flow capacity with completion coronary flow., Methods: Between February 1999 and November 2001, 372 patients underwent total arterial revascularization with the T-graft alone. Intraoperative flows were recorded for each limb of the T-graft before and after distal anastomoses in 204 patients. Independent predictors of T-graft flow were identified by multivariate analysis., Results: Free flow for the radial arterial (RA) limb was 161 +/- 81 mL/min, the internal thoracic artery (ITA) limb 137 +/- 57 mL/min (combined 298 +/- 101 mL/min) versus simultaneous limb flow of 226 +/- 84 mL/min giving a flow restriction of 24% +/- 14%. Completion coronary flow was 88 +/- 49 mL/min for the RA, 60 +/- 45 mL/min for the ITA, and 140 +/- 70 mL/min for both limbs simultaneously to give a flow reserve (vs simultaneous free flow) of 160% or 1.6. Independent predictors of completion RA limb flow are RA proximal diameter (p = 0.005), number of anastomoses (p = 0.018), and target stenosis (p = 0.005)., Conclusions: A flow reserve of 1.6 compares favorably with an ITA flow reserve of 1.8 at 1-month postoperatively and 1.8 for both the ITA T-graft and the ITA/RA T-graft at 1-week postoperatively as reported by others. Proximal RA diameter and competitive coronary flow influence completion T-graft flow. These data quantitate the limitation of single source inflow of the T-graft configuration and support its continued use.

Background: This study was conceived to evaluate the effect of carbon dioxide insufflation on free internal thoracic artery flows., Methods: We studied 56 consecutive patients who underwent coronary artery bypass grafting in which the left internal thoracic artery was anastomosed to the left anterior descending artery. The first 26 consecutive internal thoracic arteries were harvested as a pedicled graft (group 1), and the next 30 consecutive internal thoracic arteries were dissected by using the carbon dioxide insufflation technique (group 2). The internal thoracic artery harvesting was performed by 2 experienced surgeons by using the same instrumentation and technique. First, free flows of the internal thoracic arteries were registered after distal cutting of the vessel in both groups. After the first measurements, diluted papaverine was sprayed on the internal thoracic artery pedicle only in group 1, and then second measurements were registered after 15 minutes in both groups. Hemodynamic parameters were recorded with each measurement., Results: The first free flow measurement was significantly higher in the carbon dioxide-insufflated internal thoracic arteries (group 2, 60 +/- 32 mL/min; group 1, 28 +/- 19 mL/min; P <.05). Although the second free flow measurement of the carbon dioxide-insufflated group was higher than in group 1, the difference was not statistically significant (68 +/- 46 mL/min vs 53 +/- 32 mL/min; P =.53)., Conclusions: Carbon dioxide insufflation of the internal thoracic artery is an efficient technique to increase the flow and seems to be safe, simple, and reliable. When the internal thoracic artery is harvested in a carbon dioxide-insufflated fashion, arterial spasm and reduced early flow may be avoided, even without vasodilator agents such as papaverine.

Paraplegia remains one of the most serious complications after thoracoabdominal aortic aneurysm surgery. Spinal cord ischemia during the operation is thought to be the most important contributor to the development of this neurological deficit. So, it is important to preserve or reconstruct the critical segmental arteries for spinal cord protection. In order to identify the critical segmental arteries, we evaluate the segmental arteries by measuring the flow velocities using Doppler ultrasonography. The flow velocities are different among segmental arteries and some segmental arteries have no flow even though they are patent. Because we think that the segmental arteries with high flow velocities have much contribution to the spinal cord perfusion, we reconstruct or preserve such segmental arteries during the operation. We hope that this method would be clinically useful for spinal cord protection during thoracoabdominal aortic aneurysm surgery.

Objectives: To investigate the elastic properties of medium-size extracardiac arteries and veins between patients with and without left main stem coronary artery disease., Methods: The compliance, distensibility, and incremental elastic modulus (iEmod) of the internal thoracic arteries (n=53), long saphenous veins (n=38), and radial arteries (n=35) from 74 patients undergoing coronary surgery were studied in organ baths. Twenty-four patients had left main stem (LMS) disease and 50 non-LMS coronary disease., Results: Internal thoracic arteries from patients with LMS presented significantly lower compliance (-17%) and distensibility (-18%) and significantly higher iEmod (19%) than internal thoracic arteries from patients with non-LMS disease. Radial arteries from patients with LMS presented higher iEmod (50%) than radial arteries from patients with non-LMS disease. Furthermore, long saphenous veins from patients with LMS had reduced compliance (-45%), reduced distensibility (-40%) and increased iEmod (34%) compared to those from patients with non-LMS disease., Conclusions: LMS coronary disease is associated with a significantly reduced elasticity of extracardiac arteries and veins compared to non-LMS coronary disease. This finding suggests that widespread vascular elasticity defects may play a role in the development of LMS disease and be responsible for the higher incidence of early and late cardiovascular morbidity observed in this condition.

Background: Use of arterial grafts in coronary surgery is based on the excellent patency of the left internal thoracic artery (LITA) and an expectation that other arterial grafts-right internal thoracic artery (RITA) and radial artery (RA)-will give similar patencies, superior to saphenous vein. We examined patencies of arterial grafts in a practice with extensive use for more than 15 years., Methods: Consecutive postoperative angiograms of 2,127 arterial/coronary conduits were evaluated. Angiograms were performed for cardiac symptoms. Assessment was by two observers. String signs were considered as occlusions., Results: There were 2127 arterial conduits. Overall patencies were as follows: LITA, 96.4% (1296 of 1345); RITA, 88.3% (534 of 605); aortocoronary RA, 89.3% (158 of 177). The LITA patency to the left anterior descending artery was 97.1% (1131 of 1165); to the obtuse marginal artery it was 91.7% (165 of 180; p 0.01). The RITA pedicled graft patency was 86% (275 of 321) compared with free RITA, 91% (259 of 284; p = not significant). For RITA there was a hierarchy of patency for coronary territory grafted (left anterior descending artery best, right coronary/posterior descending artery worst) and for degree of coronary stenosis: if stenosis was less than 60%, patency was 65% (47 of 72); if stenosis was more than 60%, patency was 90.9% (485 of 533; p = 0.0001). Similarly for the radial artery there was higher patency with greater coronary stenosis. The LITA patency at 5 years was 98%, at 10 years it was 95%, and at 15 years it was 88%. The RITA patency at 5 years was 96%, at 10 years it was 81%, and at 15 years it was 65%. The radial artery patency at 1 year was 96% and at 4 years it was 89%. For 3,714 vein grafts also studied overall patency was 61% (2266 of 3214) with patencies of 95% at 5 years, 71% at 10 years, and 32% at 15 years., Conclusions: Excellent long-term patencies of arterial grafts are noted, superior to those of vein grafts. Patencies were influenced by conduit, by distribution, and by coronary artery stenosis.

Objective: We investigated the mechanism of the protamine action and the effects of free hemoglobin on protamine-induced responses in endothelium-denuded and-intact human internal thoracic artery (ITA) rings precontracted with phenylephrine (PE) or high KCl., Methods: Samples of redundant ITA obtained from patients undergoing a coronary artery bypass graft surgery were cut into 3 mm wide rings and suspended in 20 ml organ baths. Isometric tension was continuously measured with an isometric force transducer connected to a computer-based data acquisition system., Results: Acetylcholine (Ach, 10(-8)-10(-5) M) caused a concentration-dependent relaxation of PE-precontracted ITA rings. Free hemoglobin (0.1 and 0.5 microM) produced a concentration-dependent and significant decrease in sensitivity (pD(2)) and maximal contractility (E(max)) in response to Ach in PE-precontracted ITA rings (P<0.0001). Protamine (50-800 microg/ml), free hemoglobin (0.1 and 0.5 microM), nitric oxide (NO) blocker N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM) or soluble guanylate cyclase inhibitor methylene blue (10 microM) administration did not cause a significant alteration on basal tonus of endothelium-intact or -denuded ITA rings. Protamine (50-800 microg/ml) induced concentration-dependent relaxation responses in ITA rings precontracted by either PE or high KCl. There was no difference in sensitivity or maximal response to protamine between the endothelium-intact and -denuded rings. Incubation of endothelium-intact or -denuded ITA rings with L-NAME or free hemoglobin or methylene blue did not cause a significant inhibition on relaxation responses to protamine. ITA ring contractions induced by stepwise addition of calcium to high KCl solution with no calcium were almost completely inhibited by protamine (P<0.0001)., Conclusions: It was suggested that protamine induced relaxation responses in human ITA rings is not NO- or endothelium-dependent but seems to depend on the interactions of protamine with calcium influxes and/or calcium release from intracellular stores in this tissue.

Objective: Internal thoracic artery (ITA) flow competition is a diversion of graft flow through intact ITA branches with a net decrease in perfusion to the grafted coronary. Although a widely acknowledged phenomenon, the conditions under which flow competition occurs have not been established. This is examined in a canine H-graft model., Methods: Eight dogs had a right ITA segment interposed (H-graft) between their in situ left ITA (LITA) and the snared left anterior descending (LAD) coronary artery. Proximal LITA and H-graft flows were measured at baseline and during pacing-induced tachycardia, phenylephrine-induced hypertension, and nitroprusside-induced hypotension. Flows were measured with the distal LITA open and occluded. Two additional animals were subjected to eight separate 2-min periods of LAD ischemia, after which post-ischemic H-graft flow measurements were obtained with and without distal LIMA occlusion., Results: During baseline conditions, proximal LITA flow was greater when the distal LITA was open rather than occluded (46+/-15 versus 35+/-12 ml/min, respectively; P=0.002), but H-graft flow did not change significantly (32+/-18 versus 35+/-18 ml/min, respectively; P=0.21). Similarly, occlusion of the distal LITA had no impact on H-graft flow during tachycardia, hypertension, or hypotension. Only in animals subjected to transient LAD ischemia did H-graft flow increase with distal LITA occlusion, albeit marginally (65+/-7-70+/-9 ml/min, occluded versus open, respectively; P=0.04)., Conclusions: Mild diversion of flow from the LAD was demonstrated during immediate post-ischemic coronary reperfusion only, and could not be elicited under any other physiologic condition. These data suggest that flow competition is unlikely to constitute a clinically significant limitation to the use of H-grafts or other modalities that leave ITA branches patent.

Background: Statins may enhance vascular function independently of effects on cholesterol. This study investigated the ability of statins to modulate the vascular recovery of arteries used as coronary bypass grafts., Methods: Specimens of radial artery and left internal thoracic artery were obtained during coronary artery bypass grafting. The specimens were divided into vascular rings, which were incubated in the absence or presence of cerivastatin (10(-6) mol/L) for either 2 or 24 hours. Using an organ bath technique, endothelial function was examined using acetylcholine (10(-9) to 10(-5) mol/L) after contraction by 3x10(-8) mol/L of endothelin-1., Results: Time-related endothelial dysfunction was shown in the control group of radial artery but not in the cerivastatin group: maximal endothelium-dependent vasodilation in the control and cerivastatin groups were 56.8% +/- 10.2% and 65.9% +/- 10.1% at 2 hours and 39.4% +/- 4.7% and 68.4% +/- 5.0% (p < 0.01, vs control) at 24 hours, respectively. On the other hand, in the left internal thoracic artery, those in the control and cerivastatin groups were 38.3% +/- 8.2% and 45.0% +/- 5.5% at 2 hours and 38.1% +/- 8.2% and 56.5% +/- 8.8% at 24 hours, respectively (NS)., Conclusions: In radial artery, cerivastatin significantly preserved endothelium-dependent vasodilation, which diminished with time in the control group. This could have very important implications in the clinical practice of coronary artery bypass grafting.

In rats, injection of monocrotaline (MCT) causes pulmonary hypertension that leads to right ventricular failure. The aim of the present study was to characterize the responses of various vessels (the pulmonary artery, the thoracic aorta and small mesenteric arteries) to noradrenaline (NA; 10(-10)-10(-5) M) and carbachol (10 microM) in MCT-treated rats. For this purpose 6-week-old male Wistar rats ( n=13) were treated with 60 mg/kg MCT i.p. After 4-6 weeks the rats were killed and the heart, lungs and vessels removed and compared with those from age-matched saline-treated control rats ( n=47). First, the alpha(1)-adrenoceptor subtype(s) involved in the vascular NA-responses were characterized in normal rats using the alpha(1)-adrenoceptor subtype-selective antagonists 5-methylurapidil (5-MU; competitive alpha(1A)-adrenoceptor antagonist; 10(-8)-10(-6) M), BMY 7378 (competitive alpha(1D)-adrenoceptor antagonist; 10(-7)-10(-6) M) and chloroethylclonidine (CEC; irreversible alpha(1B)-adrenoceptor antagonist; 30 microM). In the pulmonary artery the pA(2) for BMY 7378 was 7.93, while that for 5-MU could not be calculated. CEC suppressed the NA-induced contraction significantly. In the thoracic aorta, the pA(2) for BMY 7378 was 8.06, while 5-MU was less effective (pA(2) 7.31). CEC again suppressed the NA-induced contraction significantly. In mesenteric arteries, CEC was ineffective whereas 5-MU induced a significant, rightwards shift of the concentration/response curve for NA (pA(2) 8.05). BMY 7378 had a lower pA(2) (6.6). MCT-treated rats developed an increased right ventricular pressure, obliteration of pulmonary vessels and inflammatory lung infiltration. In the pulmonary artery, but not in the thoracic aorta or mesenteric artery of MCT-treated rats NA-induced contraction was attenuated. In addition, carbachol-induced relaxation was reduced in the pulmonary and mesenteric arteries. In conclusion, NA-induced contraction is mediated predominantly by alpha(1A)-adrenoceptors in small mesenteric arteries, by alpha(1D)-adrenoceptors in the thoracic aorta (with a contribution from alpha(1A)- and alpha(1B)-adrenoceptors) and by alpha(1D)- and alpha(1B)-adrenoceptors in pulmonary arteries. MCT leads to reduced NA-responsiveness exclusively in the pulmonary artery that does not, however, account for the development of pulmonary hypertension, and to a more generalized endothelial dysfunction which may contribute to the pathogenesis of pulmonary hypertension in this model.

Background: This study was designed to compare internal thoracic artery (ITA) flow in different settings of supplemental vein grafting for ITA hypoperfusion., Methods: Fourteen dogs each received two coronary bypass grafts to the circumflex artery (CFX), using left ITA and vein grafts, and then the proximal CFX was ligated. The animals were divided into two groups. G-I dogs receiving the vein graft proximally to the ITA graft and G-II receiving the vein distally. ITA flow was evaluated regarding 1) effects of competition from the vein graft, and 2) pharmacological or physiological effects on the ITA's contribution to distal perfusion. Flow is expressed as a mean (ml/min)., Results: ITA flow was 44.2+/-5.9 in G-I, and 45.7+/-6.5 in G-II (p=ns), when the vein graft was occluded. With a vein graft open, ITA flow decreased to 7.5+/-1.6 in G-I, and 6.8+/-1.8 in G-II (p=ns), and ITA's contribution to total perfusion requirements was 18% in G-I and 16% in G-II. Adenosine (0.2 mg/min/kg) increased the ITA flow in both groups, 18.4+/-3.2, and 16.3+/-3.8, respectively (p=ns), and ITA's contribution to distal perfusion was increased to 32% in G-I and 27% in G-II. In contrast, phenylephrine (0.003 mg/min/kg) decreased ITA flow and ITA's contribution to distal flow in both groups (6.1+/-1.1, 11% vs 6.2+/-1.4, 11%, p=ns), but increased vein flow significantly. Cardiac pacing (150 bpm) increased the ITA flow and ITA's contribution to distal perfusion equally in both groups (8.4+/-1.5, 16% vs 7.6+/-2.6, 15%, p=ns)., Conclusions: Supplemental vein grafting, whether it is placed distally or proximally, limits ITA flow and ITA's contribution to distal perfusion both in the resting heart and during the increased myocardial oxygen demand.

Background: Cigarette smoking is known to promote endothelial dysfunction, thus it can be responsible for an impaired endothelium-dependent vasomotility in arterial grafts late after coronary surgery., Methods: Twenty consecutive patients (mean age 64.5 years), previously submitted to coronary bypass surgery with the internal thoracic artery, underwent quantitative angiography of the implanted graft at long-term follow-up (mean time 2.5 years). To assess both endothelium-dependent and independent vasomotility, angiograms were acquired before and after selective infusions of acetylcholine (10(-6) mmol/ml) and nitroglycerine (500 microg). The predictive value of risk factors, including previous and continued smoking, for an impairment in endothelium-dependent vasomotility was assessed., Results: Continued smoking (p = 0.038), but not a previous history of smoking (p = 0.55) was the only predictor of a reduced endothelium-dependent vasodilation. While previous smokers and non-smokers showed a similar response to acetylcholine, current smokers showed a reduced endothelium-dependent vasodilation vs non-smokers (94.8 +/- 2.6 vs 99.6 +/- 2.3% of the maximal vasodilative capacity, p = 0.001)., Conclusions: Although maintained, the vasodilative response to acetylcholine appears reduced in internal thoracic artery grafts of patients who continued smoking long term after coronary bypass surgery. Whether this could affect the long-term outcome of these patients has to be further investigated.

Background: A reduction in compliance of the large-sized cardiothoracic (central) arteries is an independent risk factor for the development of cardiovascular disease with advancing age., Methods and Results: We determined the role of habitual exercise on the age-related decrease in central arterial compliance by using both cross-sectional and interventional approaches. First, we studied 151 healthy men aged 18 to 77 years: 54 were sedentary, 45 were recreationally active, and 53 were endurance exercise-trained. Central arterial compliance (simultaneous B-mode ultrasound and arterial applanation tonometry on the common carotid artery) was lower (P:<0.05) in middle-aged and older men than in young men in all 3 groups. There were no significant differences between sedentary and recreationally active men at any age. However, arterial compliance in the endurance-trained middle-aged and older men was 20% to 35% higher than in the 2 less active groups (P:<0.01). As such, age-related differences in central arterial compliance were smaller in the endurance-trained men than in the sedentary and recreationally active men. Second, we studied 20 middle-aged and older (53+/-2 years) sedentary healthy men before and after a 3-month aerobic exercise intervention (primarily walking). Regular exercise increased central arterial compliance (P:<0.01) to levels similar to those of the middle-aged and older endurance-trained men. These effects were independent of changes in body mass, adiposity, arterial blood pressure, or maximal oxygen consumption., Conclusions: Regular aerobic-endurance exercise attenuates age-related reductions in central arterial compliance and restores levels in previously sedentary healthy middle-aged and older men. This may be one mechanism by which habitual exercise lowers the risk of cardiovascular disease in this population.

Vasodilation that occurs during normal pregnancy is associated with enhanced relaxation and decreased contractile response to agonists, which are in part due to increased stimulated and basal nitric oxide (NO). In preeclampsia and/or pregnancies carried at high altitude (HA), this normal vascular adjustment is reversed or diminished. We previously reported that HA exposure did not inhibit the pregnancy-associated decrease in contractile response to agonist or basal NO in guinea pig uterine arteries (UA). We therefore sought to determine whether altitude interfered with effects of pregnancy on endothelium-dependent relaxation through a reduction in stimulated NO. We examined the relaxation response to ACh in UA and bradykinin in thoracic arteries (TA) and effects of NO inhibition with 200 microM N(G)-nitro-L-arginine (L-NNA) in arterial rings isolated from nonpregnant and pregnant guinea pigs exposed throughout gestation to low altitude (LA, 1,600 m, n = 26) or HA (3,962 m, n = 22). In pregnant UA, relaxation to ACh was enhanced (P < 0.05) at both altitudes and NO inhibition diminished, but did not reverse, ACh relaxation. The effect of L-NNA on the relaxation response to ACh was less in HA than in LA animals (P = 0.0021). In nonpregnant UA, relaxation to ACh was similar in LA and HA animals. L-NNA reversed the relaxation response to ACh at HA but not at LA. In TA, relaxation to bradykinin was unaltered by pregnancy or altitude and was completely reversed by NO inhibition. These data suggest that effects of NO inhibition are diminished in UA during pregnancy at HA. Additional studies are needed to confirm whether these effects are mediated through inhibition of stimulated NO. HA exposure did not inhibit relaxation to ACh, perhaps because of stimulation of other vasodilators.

Objective: Total arterial myocardial revascularization may be achieved by using the 'Y-graft' techniques with different free arterial conduits anastomosed off the side of an in situ internal thoracic artery to reach distal coronary segments. This study was assessed to measure intraoperative graft flow, resistance and clinical outcomes., Methods: Seventy-six patients who underwent coronary artery bypass grafting during a time period of 27 months were enrolled in this prospective study. All patients received sequential grafting by using both internal thoracic arteries, inferior epigastric and right gastroepiploic artery joined as a composite Y graft. Intraoperative graft flow, resistance and derived variables were measured., Results: All patients except one showed good flow (ml/min and waveform) in either branch of composite graft. In one case, a low-flow situation through the graft was registered requiring surgical correction. Temporary occlusion of either branch did not significantly affect flow in the other side of the arterial Y. Mid-term follow-up (3 and 15 months) and angiographic studies showed a high graft patency rate., Conclusion: Composite arterial grafts provide excellent early and mid-term clinical results. Flow reserve of the left internal thoracic artery did not affect blood flow and resistance on either branch of the Y graft when temporary occlusion on the other side of the arterial Y was performed.

The free flow of skeletonized ITA grafts was compared with that of pedicled ITA grafts. One hundred patients with coronary artery diseases underwent elective CABG. In the group I (n = 50), the left ITA was dissected using the skeletonization technique. In the group II (n = 50), the ITA was harvested as a pedicled graft. Free flow of the ITA was recorded before and 15 min after intraluminal application of diluted papaverine. Mean arterial pressure was maintained at 9.31 kPa (70 mmHg). The results showed that before the application of papaverine, free flow of skeletonized and pedicled ITA grafts was identical between the two groups. After treatment with papaverine, the maximum free flow was significantly higher in the skeletonized ITA's in the group I (199.3 +/- 69.6 ml/min) than in the group II (145.7 +/- 70.3 ml/min, P < 0.05). There was on significant difference between the free flow after dilatation of the left and right ITA in the group I (left 199.3 +/- 69.6 ml/min, right 198.9 +/- 61.8 ml/min, respectively). It was concluded that preparation of the ITA with the skeletonization technique resulted in significantly higher free flow capacity than in pedicled grafts and would improve the results of arterial revascularization. The complication rate seems to be lower than with the conventional method.

The usefulness of the left internal thoracic artery (LITA) for aortocoronary bypass grafting is now established. Reports of variation in LITA graft function are rare. Graft flow was measured using a Doppler flow wire to estimate graft function in 27 patients (24 males, 3 females) who underwent LITA grafting to the left anterior descending artery. Patients were classified into the following 3 groups: Group A consisted of 9 patients with normal left ventricular function and no native flow; Group B consisted of 11 patients with normal ventricular function and good native flow; Group C consisted of 7 patients with abnormal left ventricular function and no native flow. LITA graft function was also estimated 1 year after operation in 12 of these 27 patients (4 in each group). Diastolic/systolic velocity ratio (DSVR) and flow reserve were determined in the proximal, middle, and distal portions of the LITA graft and native left anterior descending artery before and after papaverine administration (8-10 mg). DSVR was significantly higher in the distal portion than in the proximal portion (p < 0.01), but this value did not change after papaverine administration. After 1 year, DSVR in the proximal portion was significantly higher in Group C than in Groups A or B (p < 0.05 for both). Four weeks after operation, the flow reserve of the distal portion was significantly higher in Group A than in Group C (p < 0.001). After 1 year, this value was significantly higher in Group A than in either Groups B or C (p < 0.01, p < 0.001, respectively). The rate of increase in flow reserve in the distal portion was significantly greater in Group A (23.4%) than in groups B (2.53%) or C (1.94%; p < 0.05 for both). The distal portion of the LITA was the best measurement site, since the flow pattern in the LITA graft varied throughout all portions. Diastolic flow velocity in the LITA graft was dominant in patients with myocardial damage. The results indicate that flow reserve of the LITA graft depends on antegrade native coronary flow and distal myocardial damage.

Opening of potassium channels can cause hyperpolarization and relaxation of vascular smooth muscle cells. The aim of this work was to investigate the contribution of potassium channel activation to vasorelaxation in internal thoracic artery taken from patients undergoing coronary artery bypass graft surgery. Relaxations to carbachol and sodium nitroprusside were studied in isolated rings of internal thoracic artery in the absence and presence of nitric oxide synthase inhibitors and potassium channel blockers. The nitric oxide synthase inhibitors Nomega-nitro-L-arginine methyl ester and NG-monomethyl-L-arginine abolished relaxations to carbachol. Relaxations to both carbachol and sodium nitroprusside were attenuated in the presence of raised extracellular potassium and the potassium channel blockers charybdotoxin, iberiotoxin and tetraethylammonium. Neither apamin nor glibenclamide modified relaxation. ODQ (1H-[1,2,4]oxadiazolol-[4,3a] quinoxalin-1-one), an inhibitor of soluble guanylate cyclase, abolished relaxation to carbachol in rings from some but not all subjects. These results suggest that potassium channel opening may make a small contribution to endothelium-dependent vasorelaxation in internal thoracic artery. The potassium channels had characteristics consistent with those of large-conductance calcium-dependent potassium channels.

Objective: The internal thoracic artery (ITA) is the ideal conduit for coronary artery bypass grafting (CABG). The skeletonization technique of this arterial conduit has been proposed to reduce chest wall trauma, increase graft length and facilitate construction of sequential anastomoses. Nevertheless, some surgeons decline this technique because of potentially increased trauma to the ITA with impairment of flow. In this investigation we compared the free flow of skeletonized with that of pedicled ITA grafts., Methods: Two surgeons operated on 80 consecutive patients with coronary artery disease for elective CABG. In group I (n = 40), the left ITA was dissected using the skeletonization technique. In group II (n = 40), it was harvested as a pedicled graft. In 23 patients of group I both ITA's were dissected in skeletonized fashion for complete arterial revascularization. Diluted papaverine was instilled into the lumen of the ITA after distal transection of the vessel in both groups. Free flow of the ITA was registered before and 15 min after intraluminal application of diluted papaverine. Mean arterial pressure was maintained at 70 mmHg., Results: Before the application of papaverine, free flow of skeletonized and pedicled ITA grafts was identical between the two groups. After treatment with papaverine maximum free flow was significantly higher in the skeletonized ITA's (group I 197.2 (+/-66.6) ml/min; group II 147.1 (+/-70.5) ml/min; P < 0.05). There was no significant difference between free flow after dilatation of the left and right ITA in group I (left 197.2 (+/-66.6) ml/min; right 198.9 (+/-61.8) ml/min)., Conclusions: Preparation of the ITA with the skeletonization technique results in significantly, higher free flow capacity than in pedicled grafts. This may increase the safety of arterial revascularization by reducing the risk of ITA hypoperfusion syndrome.

We examined internal thoracic artery by transcutaneous duplex ultrasound in 26 patients on four occasions: 4 (+/-2) days before the operation, and 61 (+/-8) minutes, 5 days and 53 (+/-3) days postoperatively. There was dominant systolic flow in preoperative scans. After the operation a characteristic biphasic flow with increased peak diastolic velocity and a decrease in peak systolic/peak diastolic velocity ratio was detected in all patients. The pulsed Doppler spectrum was used to measure peak velocity, time averaged mean velocity and time averaged maximum velocity. Resting internal thoracic artery flows calculated using time averaged mean velocity were 30.9+/-5.4 ml/min preoperatively, 40.7+/-6.3 ml/min immediately after surgery, 41.1+/-8.2 ml/min at 5 days and 40.1+/-4.9 ml/min at 53 days. There were no significant changes in resting internal thoracic artery flow between early and late postoperative studies. Flow estimates calculated using 0.5 x time averaged maximum velocity or time averaged mean velocity showed good agreement. Early postoperative measurements appear to be a good predictor of later resting graft flow.

Background: Intraoperative ultrasonography has the potential to provide anatomic and functional information about internal thoracic artery (ITA) graft, but this potential has been hindered by the relatively large standard probe. In this study, we used a color Doppler microprobe to evaluate ITA grafts., Methods: The subjects were 15 consecutive patients who underwent elective coronary artery bypass grafting either with cardiopulmonary bypass (n = 14) or without (n = 1). All patients underwent anastomosis of the left ITA to the left anterior descending artery. The ITA graft was assessed before the chest was closed, with the microprobe placed directly on the graft., Results: A good-quality color Doppler image of the ITA graft was easily obtained in all 15 patients within a few minutes. The ITA graft function was assessed by analyzing the shape of the pulsed Doppler wave. All ITA grafts were patent, and the mean graft diameter was 1.8 +/- 0.04 mm. The peak systolic velocity, peak diastolic velocity, and mean velocity were 52.0 +/- 14.9 cm/s, 58.3 +/- 22.4 cm/s, and 36.5 +/- 10.9 cm/s, respectively. The ratio of peak diastolic velocity to peak systolic velocity was 1.24 +/- 0.66. The ITA graft seemed to function well when the biphasic diastolic predominant flow appeared. The mean blood flow was 55.1 +/- 22.0 mL/min., Conclusions: Intraoperative ultrasonography using the microprobe provides adequate anatomic and hemodynamic information regarding ITA grafts. As the Doppler flow evaluation has high sensitivity and specificity, we suggest that intraoperative ultrasonography is useful for the assessment of these grafts.

The interaction between primary afferent neurons containing neuropeptides and the vascular smooth muscle is incompletely understood. To explore the function of perivascular afferent neurons and to determine whether they produce local effects on vascular smooth muscle cells, we investigated the effects of acute capsaicin and substance P administration in vitro on human internal thoracic arteries (ITA). Vessels were obtained from patients undergoing coronary bypass or from multiorgan transplant donors. Fourteen ITA segments (5 mm wide) were suspended as rings between two stainless-steel stirrups in water-jacketed (37 degrees C) tissue baths under 2.5 to 3 g of basal tension. The tissue baths contained 10 mL physiological salt solution (PSS) of the following composition (mM): NaCl, 119; KCl, 4.7; NaH2PO4, 1.0; MgCl2, 0.5; CaCl2, 2.5; NaHCO3, 25; and glucose, 11; aerated continuously with 95% O2 and 5% CO2. Peptidase inhibitors (phosphoramidon and captopril) were added to PSS to decrease peptide degradation. Mechanical responses were measured isometrically and recorded on a polygraph via isotonic force transducers. Vessels were preconstricted with submaximal concentrations of norepinephrine. After the tension had stabilized, substance P or capsaicin was added cumulatively to the tissue bath. At the end of the experiments, the viability of ITA was verified by its responses to endothelial-dependent (acetylcholine) and endothelial-independent (sodium nitroprusside) vasodilators. In the endothelium-intact ITA segments, substance P produced relaxation of ITA smooth muscle while it induced slight contraction when the ITA was devoid of its endothelium (P = 0.0585). The addition of capsaicin to human ITA primarily produced contractile effects on the developed smooth muscle force. The capsaicin-induced contraction of the ITA smooth muscle was independent of endothelial cell integrity, although contraction was greater in the endothelium-intact ITA segments (P = 0.0165). The acute capsaicin exposure of human ITA revealed that primary afferent neurons containing neuropeptides innervate human ITAs. There is a real potential for perivascular afferent neurons and sensory peptides to influence the ITA smooth muscle function.

Unlabelled: Surgeons have traditionally relied on ring preparations to predict how arterial bypass conduits will behave in the postoperative circulation., Objective: This study compared pharmacologic [norepinephrine (NE) challenge] and physiologic [arterial preload] responses of gastroepiploic (GEA) and internal thoracic (ITA) arteries in a standard static ring preparation and a dynamic perfusion system., Methods: Six GEAs (1.0-1.5 mm dia.) and six ITAs (1.5-2.0 mm dia.) 11 cm long were harvested from adult pigs and mounted on a computer controlled perfusion system. Inflow pressure was set at 80 mmHg and outflow resistance was adjusted to simulate high (80-90 ml/min) and low (15-20 ml/min) flow demands. NE response (10(-9)-10(-5) M) was measured under low flow conditions and at high flow conditions when distal arterial pressure (load) was reduced. NE response (10(-9)-10(-5) M) was also evaluated in arterial rings (ITA N = 6, GEA N = 6) with tensions adjusted to simulate the loads occurring at low flow (80 mmHg) and high flow (60 mmHg) situations., Results: In the static ring preparation, NE response [ED50] was similar for both GEA and ITA and was not affected by load. The dynamic preparation demonstrated that the GEAs were significantly more responsive to NE than the ITAs [ED50 high flow ITA 6.1 +/- 0.3**, GEA 7.2 +/- 0.3***; *P < 0.05 versus baseline, **P < 0.05 versus low flow values, ***P < 0.05 versus ITA]. Furthermore, in the dynamic preparation, NE response was profoundly affected by reduced load which occurs under high flow conditions [7.18 +/- 0.3 versus 6.1 +/- 0.3 under high flow and 5.8 +/- 0.1 versus no response under low flow conditions]., Conclusion: Static ring preparations do not discern differences between ITA and GEA susceptibility to spasm and fail to detect the effect of load. The dynamic preparation demonstrated significant differences between the GEA and ITA potential to spasm which is consistent with widespread clinical experience. Furthermore a dynamic preparation is highly sensitive to reduced load which occurs under high flow conditions. Although it is more demanding, the dynamic preparation provides superior information to the surgeon in predicting the behavior of arterial bypass grafts.

Objective: Competitive flow from patent native coronary vessels is implicated in the failure of internal thoracic artery (ITA) grafts, but it is not thought to affect saphenous vein graft (SVG) patency. This study examines instantaneous pressure and flow dynamics in left ITA and SVG grafts in competition with a patent left anterior descending (LAD) artery., Methods: SVG (3.0-4.0 mm) and ITA (1.5-2.0 mm) to proximal LAD (2.5-3.0 mm) coronary bypass was performed in 10 mongrel dogs. Flow and pressure were measured in the occluded (No Competition) and opened (Competition) ITA, SVG and LAD., Results: The ITA and SVG, when each was the sole inflow to the LAD, provided similar flow as the native LAD. During competitive flow, total LAD flow was preserved and flow in the ITA and SVG were reduced (8.20 +/- 1.25 and 10.00 +/- 1.73 ml/min; P < 0.005). SVG diastolic flow was reduced to 11.52 +/- 2.17 ml min (55.5%); P < 0.003. Flow in the SVG remained predominantly antegrade. In contrast, ITA diastolic flow was reduced more drastically, to 5.37 +/- 1.25 ml/min (80.7%); P < 0.0001. When the ITA was the only inflow to the LAD, there was delay in the LAD pressure wave. This delay disappears during competition due to the large, systolic retrograde flow up the ITA., Conclusion: The ITA, compared to the SVG, is a longer and narrower conduit with lower levels of flow during competition. Due to a delay in the pressure wave, the ITA flow is retrograde during early systole. Low levels of flow, with a markedly decreased diastolic phase, and the oscillating pattern in systole (retrograde/antegrade) may be poorly tolerated by the ITA endothelium and lead to graft deterioration.

Background: This study examines whether the measurement of internal thoracic artery (ITA) graft flow can determine the adequacy of the ITA-left anterior descending coronary artery (LAD) anastomosis., Methods: To study a wide range of clinical problems, we used a computer simulation of the cardiovascular system. The model included a time-varying elastance model of the heart, a systemic circulation represented by a multielement nonlinear model of the aorta and its major branches, a nonlinear model of the LAD circulation, and a model of the ITA bypass graft., Results: With a mild LAD stenosis, ITA graft flow was low and flow reversal occurred. As the percent stenosis increased, ITA flow and the percentage of ITA-to-total LAD flow increased. The ITA graft helped to maintain resting LAD blood flow. A partial obstruction (40%) at the ITA-LAD anastomosis reduced ITA graft flow at similar levels of LAD stenosis. However, overlap in flow values comparing a normal with a partially obstructed anastomosis occurred., Conclusions: Flow patterns in the ITA are highly dependent on the degree of stenosis of the LAD as well as the integrity of the anastomosis. The predictive power of ITA flow measurement increases with severe stenosis or total occlusion of the proximal LAD and with high coronary blood flow demands.