Reduction of fluoroscopy dose for cardiac electrophysiology procedures: A feasibility and safety study.

BACKGROUND: Exposure to high doses of radiation during cardiac interventional procedures is associated with increased rates of cataract and cancer in patients and staff members. Thus, reduction of radiation is recommended by international medical societies. The aim of this study was to evaluate, if the lowest reasonable fluoroscopic acquisition setting for electrophysiological procedures using a novel X-ray detector operated at a minimum detector entrance dose per fluoroscopy pulse is feasible and safe. METHODS: 641 consecutive patients (407 m/234f) underwent ablation procedures at our institution between August 2015 and December 2017. All ablations were performed using an Artis Q.zen X-ray system (Siemens, Germany). The first 308 patients were treated using the conventional dose program ("fluoroscopy zen standard"), from October 2016 until December 2017 another 333 patients underwent ablations using the optimized X-ray dosing program "fluoroscopy zen ULD". For the standard program fluoroscopy dose was set to 18nGy/f, for the minimized dosing program the dose was set to 6nGy/pulse and could be increased to 10 or 15 nGy/pulse manually. RESULTS: A total of 213 AV-node reentry tachycardia (AVNRT), 73 accessory pathways (AP), 71 atrial flutter and 284 atrial fibrillation (AF) ablation procedures were performed. Pulmonary vein isolation was performed using an electroanatomic mapping system (CARTO, Biosense Webster, USA) in 117 or a cryoballoon (Cryocath Medtronic, USA) in 167 patients. Total area dose could be reduced in all groups by a mean of 74.7% (4201.4µGym² vs. 1063.7µGym²), with a relative reduction of 73.1% for left atrial and 78.0% for right sided ablations. Total fluoroscopy time, procedure duration, acute ablation success, recurrence rate and complications remained unchanged. CONCLUSION: Fluoroscopy dose could be significantly reduced using an optimized X-ray dosing program in a novel X-ray detector without increasing total fluoroscopy time and without alterations of the incidence of recurrences or complications.

Localizing the accessory pathway in ventricular preexcitation patients using a score based algorithm.

OBJECTIVES: Clinical data was analyzed to find an efficient way to localize the accessory pathway in patients with ventricular preexcitation. METHODS: The delta wave morphologies and ablation sites of 186 patients who underwent catheter ablation were analyzed and an algorithm ("locAP") to localize the accessory pathway was developed from the 84 data sets with a PQ interval ≤0.12s and a QRS width ≥0.12s. Fifty additional patients were included for a prospective validation. The locAP algorithm ranks 13 locations according to the likelihood that the accessory pathway is localized there. The algorithm is based on the locAP score which uses the standardized residuals of the available data sets. RESULTS: The locAP algorithm's accuracy is 0.54 for 13 locations, with a sensitivity of 0.84, a specificity of 0.97, and a positive likelihood ratio of 24.94. If the two most likely locations are regarded, the accuracy rises to 0.79, for the three most likely locations combined the accuracy is 0.82. This new algorithm performs better than Milstein's, Fitzpatrick's, and Arruda's algorithm both in the original study population as well as in a prospective study. CONCLUSIONS: The locAP algorithm is a valid and valuable tool for clinical practice in a cardiac electrophysiology laboratory. It could be shown that use of the locAP algorithm is favorable over the localizing algorithms that are in clinical use today.

High-density lipoprotein cholesterol, C-reactive protein, and prevalence and severity of coronary artery disease in 5641 consecutive patients undergoing coronary angiography.

BACKGROUND: Although high-density lipoprotein cholesterol (HDL-C) and C-reactive protein (CRP) are well-established predictors for future cardiovascular events, little information is available regarding their correlation with the prevalence and severity of angiographically evaluated coronary artery disease (CAD). MATERIAL AND METHODS: Five thousand six hundred forty-one consecutive patients undergoing coronary angiography for the evaluation of CAD were analysed. Cardiovascular risk factors were assessed by routine blood chemistry and questionnaire. CAD severity was graded by visual estimation of lumen diameter stenosis with significant stenoses defined as lumen diameter reduction of >or= 70%. Coronary angiograms were graded as one-, two- or three-vessel disease, as nonsignificant CAD (lumen irregularities < 70%) or non-CAD. RESULTS: HDL-C (60.3 +/- 18.5 vs. 51.9 +/- 15.3 mg dL(-1); P < 0.001) was higher and CRP was lower (0.65 +/- 1.68 vs. 1.02 +/- 2.38 mg dL(-1); P < 0.001) in non-CAD (n = 1517) compared to overall CAD patients (n = 4124). CAD patients were older (65.2 +/- 10.5 years vs. 59.9 +/- 11.4 years), more often diabetics (19.2% vs. 10.6%) and hypertensives (79.2% vs. 66.0%) and included more smokers (18.8% vs. 16.5%) (all P < 0.005). Low-density lipoprotein cholesterol (124.5 +/- 38.3 vs. 126.0 +/- 36.3 mg dL(-1); P = NS) was similar in overall CAD and non-CAD patients with more statin users (43.4% vs. 27.9%; P < 0.001) among CAD patients. Comparing non-CAD with different CAD severities using analysis of variance, results did not change substantially. In a multivariate analysis, HDL-C and CRP remained independently associated with the prevalence of CAD. In addition, HDL-C is also a potent predictor for the severity of CAD. CONCLUSIONS: In this large consecutive patient cohort, HDL-C and CRP are independently associated with the prevalence of CAD. In this analysis, HDL-C is an even stronger predictor for CAD than some other major classical risk factors.

Plasma tumour necrosis factor-alpha and early carotid atherosclerosis in healthy middle-aged men.

AIMS: Tumour necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine, which is implicated in some metabolic disorders and may play a role in the development of cardiovascular disease. We examined whether plasma TNF-alpha is related to established cardiovascular risk indicators, plasma levels of soluble cellular adhesion molecules and carotid artery intima-media thickness determined by ultrasound examination in a population-based cohort of 96 healthy 50-year-old men. METHODS AND RESULTS: TNF-alpha and cellular adhesion molecules were measured with enzyme-linked immunosorbent assays. Plasma TNF-alpha concentration was associated with systolic and diastolic blood pressure, degrees of alimentary lipaemia, plasma very low density lipoprotein triglyceride, low density lipoprotein (LDL) cholesterol concentrations and peak LDL particle size. Two indices of insulin resistance as well as all soluble cellular adhesion molecules correlated positively with TNF-alpha. The plasma TNF-alpha concentration was associated with common carotid intima-media thickness in univariate analysis. In contrast, soluble E-selectin and postprandial triglycerides, but not TNF-alpha, were independent determinants of common carotid intima--media thickness. CONCLUSION: The plasma TNF-alpha concentration is associated with degrees of early atherosclerosis and correlates with metabolic and cellular perturbations that are considered important for the vascular process.

Vascular endothelial growth factor synthesis in vascular smooth muscle cells is enhanced by 7-ketocholesterol and lysophosphatidylcholine independently of their effect on nitric oxide generation.

Nitric oxide (NO) generated by inducible NO synthase (iNOS) enhances vascular endothelial growth factor (VEGF) synthesis in vascular smooth muscle cells (VSMC) and both NO and modified low density lipoprotein (LDL) augment VEGF production in macrophages. Oxidized LDL (oxLDL) are known inhibitors of NO generation in the cells of vascular wall. As the relationship between VEGF, iNOS and oxLDL has not been well elucidated, we studied the effect of two main components of oxLDL, 7-ketocholesterol (7-Kchol) and lysophosphatidylcholine (LPC), on VEGF and NO synthesis in rat VSMC and on VEGF synthesis in human VSMC. Both LPC and 7-Kchol significantly augmented VEGF production in rat and human VSMC. Increase in VEGF generation was related to the activation of VEGF promoter by both 7-Kchol and LPC and enhancement of VEGF mRNA transcription. In rat, VSMC IL-1beta-induced NO generation and enhanced VEGF synthesis. 7-Kchol decreased rat iNOS promoter activity, iNOS expression and NO generation, but it did not impair IL-1beta-induced VEGF synthesis. LPC did not significantly influence IL-1beta-induced NO production in rat VSMC and VEGF synthesis was significantly enhanced by combined treatment with IL-1beta and LPC in comparison to the effect of either compound alone. The results indicate that VEGF and NO synthesis in VSMC can be modulated by oxLDL. Those interactions might have an effect on the plaque growth and might be of relevance for the physiology of vascular wall cells.

In vivo stimulation of vascular plasminogen activator inhibitor-1 production by very low-density lipoprotein involves transcription factor binding to a VLDL-responsive element.

High plasma levels of plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of cardiovascular disease. There is also a close relation between high plasma levels of PAI-1 and hypertriglyceridemia. Cell culture studies have shown that very low density lipoprotein (VLDL) increases the production and secretion of PAI-1 in endothelial cells and hepatocytes, suggesting a possible mechanism for this association. To determine whether VLDL stimulates PAI-1 production in vascular cells also in vivo, Sprague-Dawley rats were injected intravenously with 6 mg/kg of VLDL (derived from human subjects with type IV hyperlipidemia). Previous studies have demonstrated that this results in an accumulation of human VLDL in the aorta and other arteries followed by increased nuclear factor-kappa B (NF-kappaB) activation. Endothelial, but not smooth muscle cells, showed a basal PAI-1 mRNA and protein expression as assessed by in situ hybridization and immunohistochemistry, respectively. Six to twenty-four hours after the VLDL injection, lipoprotein particle accumulation was seen in the aortic wall, which was accompanied by increasing PAI-1 mRNA and protein expression in endothelial and smooth muscle cells. Within the rat PAI-1 promoter we identified a sequence located at -589 to -571 with 74% homology with the recently described VLDL responsive element in the human PAI-1 promoter and located adjacent to a 4-guanosine motif presumably corresponding to the human 4G/5G polymorphism. Transient transfection studies showed that VLDL exerts its stimulatory effects on rat PAI-1 gene expression in vascular cells by interaction with promoter sequences located within bp -656 and -505. Electrophoretic mobility shift assays showed that VLDL increases the binding of as yet incompletely characterized factors to this response element. Taken together these observations support a direct influence of VLDL on vascular PAI-1 gene expression ill vivo. This stimulation is exerted on the level of PAI-1 gene transcription, and involves transcription factor binding to a VLDL responsive element adjacent to a 4G motif within the PAI-1 promoter.

Natriuretic peptides stimulate cyclic guanosine monophosphate production in human saphenous vein and internal mammary artery.

OBJECTIVE: It has been shown previously that the internal mammary artery releases more cyclic guanosine monophosphate after stimulation with atrial natriuretic peptide than the saphenous vein, and that C-type natriuretic peptide possesses a cyclic guanosine monophosphate stimulating potential on saphenous vein bypass grafts. The present study was undertaken to investigate intracellular content and extracellular release of cyclic guanosine monophosphate, by the internal mammary artery and saphenous vein, after challenge with further members of the natriuretic peptide family. METHODS: Specimens of human internal mammary artery and saphenous vein from 29 patients were cut into segments and stimulated with 10(-6) M concentrations of atrial natriuretic peptide (internal mammary artery n=8, saphenous vein n=10), brain natriuretic peptide (internal mammary artery n=9, saphenous vein n=13), C-type natriuretic peptide (internal mammary artery n=12, saphenous vein n=15), and urodilatin (internal mammary artery n=8, saphenous vein n=12). Intracellular content and extracellular release of cyclic guanosine monophosphate were determined using an (125)I radioimmunoassay. RESULTS: The following median stimulated intracellular cyclic guanosine monophosphate concentrations were measured in the internal mammary artery and saphenous vein: 35358 and 8672 fmol/cm(2) (P<0.001) after atrial natriuretic peptide, 45632 and 7830 fmol/cm(2) (P=0.003) after brain natriuretic peptide, 10144 and 13216 fmol/cm(2) (P=NS for intergraft comparison) after C-type natriuretic peptide, and 20949 and 6690 fmol/cm(2) (P=0.001) after urodilatin. Stimulation with atrial natriuretic peptide, brain natriuretic peptide and urodilation also led to a significant increase of extracellular cyclic guanosine monophosphate release by the internal mammary artery. CONCLUSIONS We conclude that brain natriuretic peptide and urodilatin exhibit a similarly effective cyclic guanosine monophosphate-stimulating potential on the internal mammary artery as atrial natriuretic peptide. In contrast, C-type natriuretic peptide shows comparable effects on the internal mammary artery and saphenous vein.

The carboxyl-terminal fragment of alpha1-antitrypsin is present in atherosclerotic plaques and regulates inflammatory transcription factors in primary human monocytes.

alpha1-Antitrypsin (AAT) serine proteinase inhibitor is found in most biological fluids, diffuses into most tissues, and is an important factor in controlling tissue damage by proteases in inflammatory diseases such as atherosclerosis. We have previously reported that the C-terminal fragment (C-36) generated during the cleavage of AAT by proteinases forms amyloid fibrils which have biological effects unrelated to precursor functions. Here we show that the C-36 fragment is present in atherosclerotic plaques, particularly within the fibrous cap at the base of the lipid core. We also found that human monocyte stimulation with C-36 fibrils led to a strong activation of both peroxisome proliferator-activated receptors alpha and gamma (PPARalpha and PPARgamma) at 1, 2, and 18 h of cell culture. A parallel increase in the intracellular lipid accumulation was also observed. Furthermore, stimulation of monocytes with C-36 for 18 h led to activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) activation. These data for the first time demonstrate the peptide of AAT as a component of atherosclerotic plaques and as a novel activator of PPARalpha, PPARgamma, NF-kappaB, and AP-1 in cultured monocytes. Taken together, the effects of the peptide represent a new mechanism of monocyte activation that may be of importance not only in atherogenesis, but also in other inflammatory processes.

Oxidized LDL and lysophosphatidylcholine stimulate plasminogen activator inhibitor-1 expression in vascular smooth muscle cells.

Plasminogen activator inhibitor-1 (PAI-1) functions as an important regulator of fibrinolysis by inhibiting both tissue-type and urokinase-type plasminogen activator. PAI-1 is produced by smooth muscle cells (SMCs) in atherosclerotic arteries, but the mechanisms responsible for induction of PAI-1 in SMCs are less well understood. In cultured human aortic SMCs, PAI-1 mRNA expression and protein secretion were increased after incubation with oxidized low-density lipoprotein (LDL) and the lipid peroxidation product lysophosphatidylcholine, whereas the effects of native LDL on PAI-1 production and release were more variable and did not reach statistical significance. The effect of LDL on arterial expression of PAI-1 in vivo was also studied in an animal model. Intravenous injection of human LDL in Sprague-Dawley rats resulted in accumulation of apolipoprotein B in the aorta within 12 hours as assessed by immunohistochemical testing. Epitopes specific for oxidized LDL began to develop in the aorta 12 hours after injection of LDL and peaked at 24 hours; this peak was accompanied by intense expression of PAI-1 immunoreactivity in the media. Also, increased aortic expression of PAI-1 mRNA after LDL injection was detected by using in situ hybridization. The transcription factor activator protein-1, which is known to bind to the promoter of the PAI-1 gene, was activated in the aortic wall 24 hours after LDL injection as assessed by electrophoretic mobility shift assay. Pretreatment of LDL with the antioxidant probucol decreased expression of oxidized LDL and PAI-1 immunoreactivity and activator protein-1 induction in the aorta but did not affect expression of apolipoprotein B immunoreactivity. These findings demonstrate that LDL oxidation enhances secretion of PAI-1 from cultured SMCs and that a similar mechanism may be involved in vascular expression of PAI-1.

Very low-density lipoprotein activates nuclear factor-kappaB in endothelial cells.

High plasma levels of VLDL are associated with increased risk for atherosclerosis. Here we show that VLDL (75 to 150 microg/mL) activates nuclear factor-kappaB (NF-kappaB), a transcription factor known to play a key role in regulation of inflammation. Oxidation of VLDL reduced its capacity to activate NF-kappaB in vitro, whereas free fatty acids such as linoleic and oleic acid activated NF-kappaB to the same extent as did VLDL. Intravenous injection of human VLDL (6 mg protein per kg) into rats resulted in arterial activation of NF-kappaB as assessed by electrophoretic mobility shift assay. Aortic endothelial cells showed positive nuclear staining for the activated RelA (p65) subunit of NF-kappaB at 6 to 24 hours after injection. There was also a parallel expression of the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, as well as the cytokine tumor necrosis factor-alpha. Pretreatment of the rats with diet containing 1% of the antioxidant probucol for 8 weeks did not inhibit arterial activation of NF-kappaB in response to injection of VLDL. Moreover, injection of triglycerides (10% Intralipid, 5 mL/kg) activated arterial expression of NF-kappaB to the same extent as VLDL. Our results suggest that VLDL may promote the development of atherosclerotic lesions by activation of the proinflammatory transcription factor NF-kappaB. The effect appears to be mediated by a release of VLDL fatty acids but not to involve VLDL oxidation.

Atrial natriuretic peptide-induced release of cyclic guanosine monophosphate by coronary bypass grafts.

BACKGROUND: Superior long-term patency rates of the internal mammary artery (IMA) versus saphenous vein (SV) after coronary artery bypass grafting are well documented. Higher production rates of vasodilating and platelet-inhibiting mediators (prostacyclin and nitric oxide) by the IMA seem to have a major impact on its long-term durability and resistance to coronary artery graft disease. For the right gastroepiploic artery (RGEA) marked release of protective mediators is reported as well. The vasodilating effect of cyclic guanosine monophosphate (cGMP) released after stimulation by atrial natriuretic peptide might serve as another graft protective system. The aim of the present study was to determine cGMP release by IMA, RGEA, and SV after atrial natriuretic peptide challenge. METHODS: Samples of human IMA (n = 19), RGEA (n = 7), and SV (n = 18) discarded during coronary artery bypass grafting were stimulated with 10(-6) mol/L atrial natriuretic peptide after a resting phase in nutrient medium. Release of cGMP was determined by 125-iodide radioimmunoassay. RESULTS: Basal cGMP production rates of the IMA (759.9 +/- 277.0 fmol/cm2) and RGEA (739.9 +/- 186.0 fmol/cm2) were higher than production rates of SV (281.2 +/- 64.0 fmol/cm2). Application of atrial natriuretic peptide led to a statistically significant increase of cGMP release in IMA grafts (1,939.3 +/- 778.0 fmol/cm2), whereas RGEA (618.4 +/- 141.3 fmol/cm2) and SV (221.7 +/- 64.5 fmol/cm2) remained at basal levels (p < 0.05). CONCLUSIONS: From these data we conclude that the IMA in comparison with the RGEA and SV produces more extracellular cGMP when stimulated by atrial natriuretic peptide. This effect might support the cGMP-mediated protective properties of nitric oxide and could underline the extraordinary suitability of the IMA as a bypass conduit.

Stimulated prostacyclin release by conduits used for coronary artery bypass grafting.

A direct comparison of the three coronary artery bypass conduits internal mammary artery (IMA), right gastroepiploic artery (RGEA), and saphenous vein (SV) concerning arachidonic acid (AA) stimulated release of the vasodilating and platelet inhibiting mediator prostacyclin was the aim of the present study. Pieces of saphenous vein (n = 16), right gastroepiploic artery (n = 8), and internal mammary artery (n = 19) were obtained from patients undergoing coronary artery bypass grafting. After a resting phase of 30 min in HEPES medium arachidonic acid (AA) was added in order to stimulate prostacyclin release. Time-dependent production of the stable prostacyclin metabolite 6-keto-prostaglandin F1 alpha was determined following stimulation. Under basal conditions the IMA (12.4 ng/cm2) and RGEA (12.0 ng/cm2) released more prostacyclin than saphenous vein (4.0 ng/cm2). After AA stimulation 6-keto-prostaglandin F1 alpha release at 30 min was as follows: IMA 806.0 ng/cm2, RGEA 35.9 ng/cm2, SV 82.3 ng/cm2 (p < 0.0001 within grafts, p < 0.0001 between grafts, ANOVA for repeated measures). The internal mammary artery in comparison with the right gastroepiploic artery and saphenous vein seems to be better protected against local thrombotic events and development of coronary artery graft disease with the aid of the vasodilating and platelet inhibiting mediator prostacyclin.