Absence of histamine-induced nitric oxide release in the human radial artery: implications for vasospasm of coronary artery bypass vessels

Radial artery (RA) bypass grafts can develop severe vasospasm. As histamine is known to induce vasospasm, its effect on RA was assessed compared with the classic bypass vessels internal mammary artery (MA) and saphenous vein (SV). The vessels were examined in organ chambers for isometric tension recording. Histamine induced contractions on baseline; the sensitivity was higher in RA and SV than MA. After precontraction with norepinephrine, histamine did not evoke relaxations of RA but induced relaxations of MA and less of SV at lower concentrations; it induced contractions at higher concentrations, reaching similar levels in all three vessels. Indomethacin did not affect the response of MA and RA but potentiated relaxations and reduced contractions of SV. Endothelium removal, N(omega)-nitro-L-arginine methyl ester (L-NAME), or the H2-receptor blocker cimetidine did not affect the response of RA, but inhibited relaxations and enhanced contractions in MA and inhibited relaxations in SV; in the latter, only L-NAME enhanced contractions. Real-time PCR detected much lower expression of endothelial H2-receptor in RA than MA or SV. Western blots revealed similar endothelial nitric oxide (NO) synthase expression in all three vessels. Relaxations to acetylcholine were identical in RA and MA. Thus histamine releases NO by activating the endothelial H2-receptor, the expression of which is much lower in RA than MA or SV. H2-receptor activation also releases prostaglandins in SV, partially antagonizing NO. The lack of histamine-induced NO production represents a possible mechanism of RA vasospasm.

Internal iliac artery embolization before endovascular repair of aortoiliac aneurysms with a nitinol vascular occlusion plug

PURPOSE: To evaluate the acute and midterm effectiveness of a novel vascular occlusion device for embolization of the internal iliac artery (IIA) before endovascular repair of aortoiliac aneurysms. MATERIALS AND METHODS: Between March 2005 and April 2006, nine men (mean age, 75 years +/- 5; range, 66-83 y) with aortoiliac aneurysms underwent bifurcated endovascular stent-graft procedures. All these patients were referred specifically for embolization. Pre- and perioperatively, eight patients underwent unilateral embolization and one underwent bilateral embolization of the IIA to prevent type II endoleak. Via a contralateral femoral approach with a 6-F or 8-F sheath, the embolization procedure was performed with an Amplatzer Vascular Plug, a self-expandable cylindrical device consisting of a nitinol-based wire mesh. Technical success, clinical outcome, and complications were evaluated. Follow-up at 3, 6, and 12 months was performed with clinical and radiologic examinations. RESULTS: IIA embolization was technically successful in all cases and no procedure-related complications occurred. Imaging at discharge and at 3-, 6-, or 12-month follow-up was accomplished in all nine patients. Control computed tomography and magnetic resonance angiography did not reveal retrograde perfusion of the aneurysmal sac, ie, type II endoleak. Three of nine patients (33.3%) reported symptoms of buttock claudication that did not resolve completely. Clinical symptoms such as bowel ischemia or sexual dysfunction were not observed. CONCLUSIONS: The midterm results of this study suggest that preoperative IIA embolization with a nitinol vascular occlusion plug during endovascular treatment of aortoiliac aneurysms is safe and effective.

Recanalization and outcome after intra-arterial thrombolysis in middle cerebral artery and internal carotid artery occlusion: does sex matter?

BACKGROUND AND PURPOSE: Recent studies have reported sex differences in recanalization and outcome after intravenous thrombolysis (IVT) in acute ischemic stroke. METHODS: We analyzed sex differences in outcome in consecutive patients with middle cerebral artery (MCA) M1 or M2 and internal carotid artery (ICA) occlusion treated with intra-arterial thrombolysis (IAT). Recanalization immediately after thrombolysis and outcome after 3 months were assessed. RESULTS: Two hundred five patients (111 men) with MCA and 43 (22 men) with ICA occlusion were identified. Baseline variables did not differ between the sexes except for a higher prevalence of smokers among men in the MCA group (31% vs 12%; P=0.001). Partial or complete recanalization (TIMI flow 2 or 3) of the MCA was observed in 71 (75%) women and 80 (72%) men (P=0.488). In the ICA group, 14 (67%) women and 11 men (50%) showed TIMI 2 or 3 recanalization (P=0.425). Favorable outcome (modified Rankin Scale score 0 to 2) was seen in 57 women (61%) and 63 men (57%) with MCA occlusion (P=0.512) and in 6 women (28%) and 4 men (18%) with ICA occlusion (P=0.656). After multiple-regression analyses, there was still no association between sex and outcome (P=0.763 for MCA and P=0.813 for ICA occlusion) or recanalization (P=0.488 for MCA and P=0.104 for ICA occlusion). CONCLUSIONS: There was no association between sex and recanalization or outcome after IAT. These findings are in contrast to previous studies reporting better recanalization and outcome after IVT in women and might have implications in the selection of patients for IAT or IVT.

Different migration of vascular smooth muscle cells from human coronary artery bypass vessels. Role of Rho/ROCK pathway

BACKGROUND: We examined whether vascular smooth muscle (VSMC) or endothelial cell (EC) migration from internal mammary artery (MA) differed from VSMC or EC migration from saphenous vein (SV). METHODS AND RESULTS: Migration to PDGF-BB (1-10 ng/ml) was lower in VSMC from MA than SV; however, attachment, movement without chemokine, and chemokinesis were identical. Unlike VSMC, migration of EC was similar in response to several mediators. Expression of PDGF receptor-beta was lower in VSMC from MA than SV, while alpha-receptor expression was higher. PDGF-BB-induced RhoA activity was lower in MA than SV, while basal activity was identical. Rosuvastatin and hydroxyfasudil impaired PDGF-BB-induced migration of VSMC from MA and SV. Mevalonate and geranylgeranylpyrophosphate rescued inhibition by rosuvastatin. PDGF-BB induced less stress fiber formation in VSMC from MA than SV. A dominant negative RhoA mutant inhibited stress fiber formation to PDGF-BB, while a constitutively active mutant resulted in maximal stress fiber formation in MA and SV. Rosuvastatin and hydroxyfasudil impaired PDGF-BB-induced stress fiber formation in MA and SV. CONCLUSIONS: VSMC migration to PDGF-BB is lower in MA than SV, which is at least in part related to lower activity of the Rho/ROCK pathway.

Inactivity of nitric oxide synthase gene in the atherosclerotic human carotid artery

OBJECTIVE: Nitric oxide (NO) inhibits thrombus formation, vascular contraction, and smooth muscle cell proliferation. We investigated whether NO release is enhanced after endothelial NO synthase (eNOS) gene transfer in atherosclerotic human carotid artery ex vivo. METHODS AND RESULTS: Western blotting and immunohistochemistry revealed that transduction enhanced eNOS expression; however, neither nitrite production nor NO release measured by porphyrinic microsensor was altered. In contrast, transduction enhanced NO production in non-atherosclerotic rat aorta and human internal mammary artery. In transduced carotid artery, calcium-dependent eNOS activity was minimal and did not differ from control conditions. Vascular tetrahydrobiopterin concentrations did not differ between the experimental groups.Treatment of transduced carotid artery with FAD, FMN, NADPH, L-arginine, and either sepiapterin or tetrahydrobiopterin did not alter NO release. Superoxide formation was similar in transduced carotid artery and control. Treatment of transduced carotid artery with superoxide dismutase (SOD), PEG-SOD, PEG-catalase did not affect NO release. CONCLUSIONS: eNOS transduction in atherosclerotic human carotid artery results in high expression without any measurable activity of the recombinant protein. The defect in the atherosclerotic vessels is neither caused by cofactor deficiency nor enhanced NO breakdown. Since angioplasty is performed in atherosclerotic arteries,eNOS gene therapy is unlikely to provide clinical benefit.

Vascular adaptation of the internal thoracic artery graft early and late after bypass surgery

OBJECTIVE: Flow mismatch between the supplying artery and the myocardial perfusion region has been observed in patients with internal thoracic artery grafts. Thus coronary flow changes of arterial (internal thoracic artery grafts) and saphenous (saphenous vein grafts) bypass grafts were studied early and late after coronary artery bypass grafting. METHODS: Thirty patients undergoing elective bypass surgery (internal thoracic artery and saphenous vein grafts) were studied intraoperatively and (17 patients) 3 to 10 months postoperatively. Coronary flow was measured intraoperatively with the transit-time Doppler scanning technique. Postoperatively, flow velocity and coronary flow reserve were determined with the Doppler flow wire technique. Quantitative angiographic analysis was used to determine vessel size for calculation of absolute flow. RESULTS: Intraoperatively, internal thoracic artery graft flow was significantly lower than saphenous vein graft flow (31 +/- 8 vs 58 +/- 29 mL/min, P < .01). Postoperatively, internal thoracic artery graft flow increased significantly to 42 +/- 24 mL/min at 3 months and to 56 +/- 30 mL/min (P < .02 vs intraoperative value) at 10 months, respectively. However, saphenous vein graft flow remained unchanged over time (58 +/- 29 to 50 +/- 27 mL/min at 3 months and 46 +/- 27 mL/min at 10 months). Coronary flow reserve was abnormally low intraoperatively in the internal thoracic artery (1.3 +/- 0.3) and saphenous vein (1.6 +/- 0.5) grafts but increased significantly to normal values in both types of graft at follow-up. CONCLUSIONS: Bypass flow of the internal thoracic artery graft is significantly reduced intraoperatively when compared with that of the saphenous vein graft. However, 3 and 10 months after the operation, flow of the internal thoracic artery graft increases significantly and is similar to saphenous vein graft flow. This finding can be explained by an early flow mismatch of the native internal thoracic artery in the presence of a large perfusion territory. During follow-up, there is vascular remodeling of the internal thoracic artery, probably because of endothelium-mediated mechanisms.

Outcome of patients with occlusions of the internal carotid artery or the main stem of the middle cerebral artery with NIHSS score of less than 5: comparison between thrombolysed and non-thrombolysed patients

BACKGROUND AND PURPOSE The use of thrombolysis in patients with minor neurological deficits and large vessel occlusion is controversial. METHODS We compared the outcome of patients with low National Institutes of Health Stroke Scale (NIHSS) scores and large vessel occlusions between thrombolysed and non-thrombolysed patients. RESULTS 88 (1.7%) of 5312 consecutive patients with acute (within 24 h) ischaemic stroke had occlusions of the internal carotid or the main stem of the middle cerebral artery and baseline NIHSS scores ≤5.47 (53.4%) were treated without thrombolysis, and 41 (46.6%) received intravenous thrombolysis, endovascular therapy or both. Successful recanalisation on MR or CT angiography at 24 h was more often observed in thrombolysed than in non-thrombolysed patients (78.9% versus 10.5%; p<0.001). Neurological deterioration (increase of NIHSS score ≥1 compared to baseline) was observed in 22.7% of non-thrombolysed versus 10.3% of thrombolysed after 24 h (p=0.002), in 33.3% versus 12.5% at hospital discharge (p=0.015) and in 41.4% versus 15% at 3 months (p<0.001). Symptomatic intracerebral haemorrhage occurred in two (asymptomatic in five) thrombolysed and in none (asymptomatic in three) non-thrombolysed. Thrombolysis was an independent predictor of favourable outcome (p=0.030) but not survival (p=0.606) at 3 months. CONCLUSIONS Non-thrombolysed patients with mild deficits and large vessel occlusion deteriorated significantly more often within 3 months than thrombolysed patients. Symptomatic intracerebral haemorrhages occurred in less than 5% of patients in both groups. These data suggest that thrombolysis is safe and effective in these patients. Therefore, randomised trials in patients with large vessel occlusions and mild or rapidly improving symptoms are needed.

Congenital aural atresia associated with agenesis of internal carotid artery in a girl with a FOXI3 deletion.

We report on the molecular characterization of a microdeletion of approximately 2.5 Mb at 2p11.2 in a female baby with left congenital aural atresia, microtia, and ipsilateral internal carotid artery agenesis. The deletion was characterized by fluorescence in situ hybridization, array comparative genomic hybridization, and whole genome re-sequencing. Among the genes present in the deleted region, we focused our attention on the FOXI3 gene. Foxi3 is a member of the Foxi class of Forkhead transcription factors. In mouse, chicken and zebrafish Foxi3 homologues are expressed in the ectoderm and endoderm giving rise to elements of the jaw as well as external, middle and inner ear. Homozygous Foxi3-/- mice have recently been generated and show a complete absence of the inner, middle, and external ears as well as severe defects in the jaw and palate. Recently, a 7-bp duplication within exon 1 of FOXI3 that produces a frameshift and a premature stop codon was found in hairless dogs. Mild malformations of the outer auditory canal (closed ear canal) and ear lobe have also been noted in a fraction of FOXI3 heterozygote Peruvian hairless dogs. Based on the phenotypes of Foxi3 mutant animals, we propose that FOXI3 may be responsible for the phenotypic features of our patient. Further characterization of the genomic region and the analysis of similar patients may help to demonstrate this point. © 2015 Wiley Periodicals, Inc.

MR Angiography at 3 Tesla to Assess Proximal Internal Carotid Artery Stenoses: Contrast-Enhanced or 3D Time-of-Flight MR Angiography?

PURPOSE The aim of this study was to compare the diagnostic accuracy of 3D time-of-flight (TOF-MRA) and contrast-enhanced (CE-MRA) magnetic resonance angiography at 3 T for detection and quantification of proximal high-grade stenosis using multidetector computed tomography angiography (MDCTA) as reference standard. METHODS The institutional ethics committee approved this prospective study. A total of 41 patients suspected of having internal carotid artery (ICA) stenosis underwent both MDCTA and MRA. CE-MRA and TOF-MRA were performed using a 3.0-T imager with a dedicated eight-element cervical coil. ICA stenoses were measured according to the North American Symptomatic Carotid Endarterectomy Trial criteria and categorized as 0-25 % (minimal), 25-50 % (mild), 50-69 % (moderate), 70-99 % (high grade), and 100 % (occlusion). Sensitivity and specificity for the detection of high-grade ICA stenoses (70-99 %) and ICA occlusions were determined. In addition, intermodality agreement was assessed with κ-statistics for detection of high-grade ICA stenoses (70-99 %) and ICA occlusions. RESULTS A total of 80 carotid arteries of 41 patients were reviewed. Two previously stented ICAs were excluded from analysis. On MDCTA, 7 ICAs were occluded, 12 ICAs presented with and 63 without a high-grade ICA stenosis (70-99 %). For detecting 70-99 % stenosis, both 3D TOF-MRA and CE-MRA were 91.7 % sensitive and 98.5 % specific, respectively. Both MRA techniques were highly sensitive (100 %), and specific (CE-MRA, 100 %; TOF-MRA, 98.7 %) for the detection of ICA occlusion. However, TOF-MRA misclassified one high-grade stenosis as occlusion. Intermodality agreement for detection of 70-99 % ICA stenoses was excellent between TOF-MRA and CE-MRA [κ = 0.902, 95 % confidence interval (CI) = 0.769-1.000], TOF-MRA and MDCTA (κ = 0.902, 95 % CI = 0.769-1.000), and CE-MRA and MDCTA (κ = 0.902, 95 % CI = 0.769-1.000). CONCLUSION Both 3D TOF-MRA and CE-MRA at 3 T are reliable tools for detecting high-grade proximal ICA stenoses (70-99 %). 3D TOF-MRA might misclassify pseudo-occlusions as complete occlusions. If there are no contraindications for CE-MRA, CE-MRA is recommended as primary MR imaging modality.

Dynamic changes of intramural hematoma in patients with acute spontaneous internal carotid artery dissection.

BACKGROUND We prospectively investigated temporal and spatial evolution of intramural hematomas in patients with acute spontaneous internal carotid artery dissection using repeated magnetic resonance imaging over six-months. AIM The aim of the present study was to assess dynamic changes of intramural hematoma in patients with acute spontaneous internal carotid artery dissection at multiple follow-up time-points with T1w, PD/T2w, and magnetic resonance angiography. METHODS We performed serial multiparametric magnetic resonance imaging in 10 patients with spontaneous internal carotid artery dissection on admission, at days 1, 3, 7-14 and at months 1·5, 3, and 6. We calculated the volume and extension of the hyperintense intramural hematoma using T1w and PD/T2w fat suppressed sequences and assessed the degree of stenosis due to the hematoma using magnetic resonance angiography. RESULTS Mean interval from symptom onset to first magnetic resonance imaging was two-days (SD 2·7). Two patients presented with ischemic stroke, three with transient ischemic attacks, and five with pain and local symptoms only. Nine patients had a transient increase of the intramural hematoma volume, mainly up to day 10 after symptom onset. Fifty percent had a transient increase in the degree of the internal carotid artery stenosis on MRA, one resulting in a temporary occlusion. Lesions older than one-week were predominantly characterized by a shift from iso- to hyperintese signal on T2w images. At three-month follow-up, intramural hematoma was no longer detectable in 80% of patients and had completely resolved in all patients after six-months. CONCLUSIONS Spatial and temporal dynamics of intramural hematomas after spontaneous internal carotid artery dissection showed an early volume increase with concomitant progression of the internal carotid artery stenosis in 5 of 10 patients. Although spontaneous internal carotid artery dissection overall carries a good prognosis with spontaneous hematoma resorption in all our patients, early follow-up imaging may be considered, especially in case of new clinical symptoms.

A Case of Internal Carotid Artery Thrombosis associated with Thalidomide Administration in Multiple Myeloma

Thalidomide is an effective chemotherapeutic agent used to achieve remission in multiple myeloma. However, its administration is associated with several adverse effects including venous thromboembolism, while arterial thrombosis has also, although rarely, been described in the literature. We report a case of internal carotid artery occlusion within 1 week of starting thalidomide with prophylactic low molecular weight heparin in a patient who had no other prothrombotic risk factors. It is not known why this complication occurs despite the administration of anticoagulant prophylaxis. The role of factor VIII, von Willebrand factor antigen levels and fibrinogen in multiple myeloma patients should be studied in order to determine if these factors should be targeted in future prophylactic treatment.