High incidence of acute sub-clinical circumflex artery 'injury' following mitral isthmus ablation.

AIMS: Mitral isthmus (MI) ablation is technically challenging, requiring long endocardial ablation times and frequently coronary sinus (CS) ablation. The circumflex artery lies in the epicardium in close proximity to the CS and the mitral annulus and may potentially be injured during radiofrequency ablation. METHODS AND RESULTS: Fifty-four patients underwent catheter ablation procedures that included MI ablation for treatment of atrial fibrillation. Irrigated ablation catheters were used with the following settings: endocardial surface (max power: 40/50 W at the annular end; max temperature: 48°C); CS (max power: 25/30 W; max temperature: 48°C). Coronary angiography was performed pre- and post-ablation and analysed by two cardiologists with quantitative coronary angiography. Mitral isthmus block was achieved in 89% of patients (60% required CS ablation). Fifteen patients (28%) had angiographic changes following ablation: eight had mid-circumflex narrowing only, one had circumflex and obtuse marginal (OM) artery narrowing, one had OM narrowing only, and five had distal circumflex occlusion/narrowing. Five patients had significant narrowing (50-84%), which resolved with intracoronary glycerine trinitrate. Fourteen (93%) of the patients with circumflex 'injury' had CS ablation and a longer mean CS ablation time (5.0 ± 3.0 vs. 2.6 ± 3.3 min, P = 0.03). Patients with distal circumflex occlusion had significantly smaller vessel diameter (1.0 ± 0.1 vs. 2.1 ± 0.2 mm, P = 0.03). A shorter distance between the circumflex and the CS was also associated with circumflex 'injury' (3.2 ± 1.9 vs. 5.6 ± 3.2 mm, P = 0.04). There were no electrocardiographic or echocardiographic abnormalities and no angina symptoms during follow-up. CONCLUSION: Acute sub-clinical circumflex 'injury' following MI ablation is not uncommon. Ablation within the CS, proximity of the circumflex and the CS, and a small distal circumflex were risk factors for 'injury'.

Local activation times at the high posterior wall of the left atrium during left atrial appendage pacing predict roof line block with high specificity and sensitivity.

AIMS: Ensuring complete block after left atrial (LA) linear lesions is important as partial block may be pro-arrhythmic. Techniques to confirm roof line block may be time consuming and challenging and have not been well described. This study investigates whether local activation times (LAT) during left atrial appendage (LAA) pacing help in the assessment of roof line block. METHODS AND RESULTS: Forty-five patients underwent ablation for atrial fibrillation (AF) including circumferential pulmonary vein isolation, roof, and mitral isthmus lines. Local activation times were measured at pre-defined points on the posterior wall and high anterior wall during LAA pacing at the following stages: (i) baseline; (ii) incomplete roof line; (iii) roof block; and (iv) roof and mitral isthmus block. Time from pacing at high posterior wall to LAA was also recorded at each stage. Receiver operator curve analyses were performed on different parameters to assess if they could confirm roof line block. There was a stepwise increase in mean high posterior wall LAT: 83 ± 16 ms (baseline); 105 ± 20 ms (incomplete roof block); 133 ± 26 ms (roof block), and 152 ± 35 ms (roof and MI block; one way analysis of variance, P< 0.0001). Increased LA diameter, amiodarone use, and adjunctive complex fractionated atrial electrogram ablation were associated with longer LATs. For patients with persistent AF, LAA to high posterior wall times of >133 ms, high posterior wall to LAA times of >125 ms and double potential >77 ms predict roof line block with high specificity and sensitivity especially if there was also mitral isthmus block. CONCLUSION: Parameters derived from the measurement of LAT of the high posterior and anterior LA wall help guide the assessment of roof line block.

Larger coronary sinus diameter predicts the need for epicardial delivery during mitral isthmus ablation.

AIMS: Mitral isthmus ablation is technically challenging, often requiring both endocardial and epicardial coronary sinus (CS) ablation. Blood flow in the CS and circumflex artery may act as a 'heat sink' and reduce the efficacy of radiofrequency ablation. This study investigates how the CS and circumflex artery diameters affect mitral isthmus ablation. METHODS AND RESULTS: Thirty-five patients underwent ablation for atrial fibrillation. Irrigated-tip catheters were used during mitral isthmus ablation with the following settings: endocardial surface (maximum power: 40-50 W at the annular end of line; maximum temperature: 48°C); CS (maximum power: 25-30 W; maximum temperature: 48°C). The absence of block after 10 min of endocardial ablation led to CS ablation for up to 5 min. If there was still no block, further ablation was at the discretion of the physician. Coronary angiography and CS venography were performed and analysed with quantitative coronary angiography. Mitral isthmus block was achieved in 31 patients (89%). Twenty-three patients (74%) required CS ablation to achieve block. These patients were found to have significantly larger CS diameters (6.5 ± 1.2 vs. 5.4 ± 0.5 mm, P< 0.02). Coronary sinus diameter >59 mm predicted the need for CS ablation (specificity: 100%; sensitivity: 78%). Coronary sinus diameter correlated significantly with total mitral isthmus ablation time (r = 0.52, P < 0.003) and CS ablation time (r = 0.59, P < 0.0005), whereas circumflex diameter did not. CONCLUSION: Larger-diameter CS is associated with a need for CS ablation during mitral isthmus ablation. Coronary sinus but not circumflex diameter was significantly correlated with total and CS ablation time, supporting the hypothesis that the CS but not the circumflex artery acts as a heat sink.

Balloon occlusion of the distal coronary sinus facilitates mitral isthmus ablation.

BACKGROUND: Mitral isthmus ablation is challenging. Blood flow in the coronary sinus (CS) may act as a heat sink and reduce the efficacy of radiofrequency ablation. OBJECTIVE: This study investigates whether balloon occlusion of CS facilitates mitral isthmus ablation. METHODS: This single-center, prospective, randomized controlled trial included patients undergoing ablation for atrial fibrillation. After circumferential pulmonary vein isolation and roof line ablation, mitral isthmus ablation was performed during left atrial appendage pacing using an irrigated ablation catheter (endocardium: maximum power: 40/50 W, maximum temperature: 48°C; CS: maximum power: 25/30 W, maximum temperature: 48°C). An air-filled 40 × 10-mm percutaneous transluminal angioplasty balloon (Opta Pro, Cordis Europa, LJ Roden, The Netherlands) was used to occlude the CS on the epicardial aspect of the ablation line. Left coronary and CS angiography were performed before and after the procedure. RESULTS: Forty-six patients were studied. The balloon was successfully positioned in the distal CS in 20 of 23 patients (87%). Mitral isthmus block was achieved in 41 of 46 patients (91%). According to intention-to-treat analysis, there was significant reduction in the need for epicardial CS ablation (48% vs. 83%, P = .01) in the CS occlusion group but no difference in acute success rate. Secondary analysis showed reduction in mean total ablation time (9.4 ± 5.5 vs. 13.3 ± 4.6 minutes, P <.02) and mean CS ablation time (1.5 ± 2.8 vs. 3.4 ± 2.7 minutes, P <.05) in patients who had CS occlusion. CONCLUSION: Balloon occlusion of the CS during mitral isthmus ablation is feasible and safe. It significantly reduces ablation time and the need for CS ablation to achieve mitral isthmus block. The results support the hypothesis that heat sink is one of the obstacles to successful mitral isthmus ablation.

Cardiac phenotype of mitochondrial creatine kinase knockout mice is modified on a pure C57BL/6 genetic background.

UNLABELLED: Discrepant results for the phenotype of mitochondrial creatine kinase knockout mice (Mt-CK(-/-)) could be due to mixed genetic background and use of non-littermate controls. We therefore backcrossed with C57BL/6J for >8 generations, followed by extensive in vivo cardiac phenotyping. Echocardiography and in vivo LV haemodynamics were performed in independent cohorts at 20-40 weeks and 1 year. No significant differences were observed for ECG, LV volumes, pressures, and systolic or diastolic function compared to littermate controls. Furthermore, responses to dobutamine were not different, indicating preserved contractile reserve. Contrary to published reports using Mt-CK(-/-) on a mixed background, we observed normal LV weights even in year old mice, and gene expression of common hypertrophic markers were not elevated. However, previously undetected adaptations were observed: an increase in activity of the cytosolic MM-CK isoenzyme (+20% vs WT, P=0.0009), and of citrate synthase (+18% vs WT, P=0.0007), a marker for mitochondrial volume. In a 3-week voluntary wheel running protocol, Mt-CK(-/-) ran significantly less per day (P=0.009) and attained lower maximum speed compared to controls (P=0.0003), suggesting impaired skeletal muscle function. MM-CK isoenzyme activity was significantly elevated in soleus but not gastrocnemius muscle of KO mice, and citrate synthase activities were normal in both, suggesting compensatory mechanisms are incomplete in skeletal muscle. CONCLUSIONS: in contrast to previous reports using a mixed genetic background, Mt-CK(-/-) on a C57BL/6 background do not develop LV hypertrophy or dysfunction even up to 1 year, and this may be explained by a compensatory increase in MM-CK activity and mitochondrial volume.

Galectin-3 is an amplifier of inflammation in atherosclerotic plaque progression through macrophage activation and monocyte chemoattraction.

OBJECTIVE: Galectin-3 (Gal-3) is a 26-kDa lectin known to regulate many aspects of inflammatory cell behavior. We assessed the hypothesis that increased levels of Gal-3 contribute to atherosclerotic plaque progression by enhancing monocyte chemoattraction through macrophage activation. METHODS AND RESULTS: Gal-3 was found to be upregulated in unstable plaque regions of carotid endarterectomy (CEA) specimens compared with stable regions from the same patient (3.2-fold, P<0.05) at the mRNA (n=12) and (2.3-fold, P<0.01) at the protein level (n=9). Analysis of aortic tissue from ApoE-/- mice on a high fat diet (n=14) and wild-type controls (n=9) showed that Gal-3 mRNA and protein levels are elevated by 16.3-fold (P<0.001) and 12.2-fold (P<0.01) and that Gal-3 staining colocalizes with macrophages. In vitro, conditioned media from Gal-3-treated human macrophages induced an up to 6-fold increase in human monocyte chemotaxis (P<0.01, ANOVA), an effect that was reduced by 66 and 60% by Pertussis Toxin (PTX) and the Vaccinia virus protein 35K, respectively. Microarray analysis of human macrophages and subsequent qPCR validation confirmed the upregulation of CC chemokines in response to Gal-3 treatment. CONCLUSIONS: Our data suggest that Gal-3 is both a marker of atherosclerotic plaque progression and a central contributor to the pathology by amplification of key proinflammatory molecules.

Endothelial Nox2 overexpression potentiates vascular oxidative stress and hemodynamic response to angiotensin II: studies in endothelial-targeted Nox2 transgenic mice.

Vascular disease states are associated with endothelial dysfunction and increased production of reactive oxygen species (ROS) derived from vascular NADPH oxidases in both vascular smooth muscle cells (VSMCs) and endothelial cells. Recent evidence suggests an important role for VSMC NADPH oxidases in vascular ROS production. However, it is unclear whether increased NADPH oxidase activity in endothelial cells alone is sufficient to alter overall vascular ROS production and hemodynamics. We sought to address these questions using transgenic mice with endothelial-targeted overexpression of the catalytic subunit of NADPH oxidase, Nox2. Aortas of Nox2 transgenic (Nox2-Tg) mice had increased total Nox2 mRNA and protein levels compared with wild-type littermates. Both p22phox mRNA and protein levels were also significantly elevated in Nox2-Tg aortas. Aortic superoxide production was significantly increased in Nox2-Tg mice compared with wild-type, but this difference was abolished by endothelial removal. Superoxide dismutase inhibition increased superoxide release and levels of Mn superoxide dismutase protein were significantly elevated in aortas from Nox2-Tg mice compared with wild type. Increased ROS production from endothelial Nox2 overexpression led to increased endothelial nitric oxide synthase protein and extracellular signal-regulated kinase 1/2 phosphorylation in transgenic aortas. Basal blood pressure was similar, however the pressor responses to both acute and chronic angiotensin II administration were significantly increased in Nox2-Tg mice compared with wild type. These results demonstrate that endothelial-targeted Nox2 overexpression is sufficient to increase vascular NADPH oxidase activity, activate downstream signaling pathways, and potentiate the hemodynamic response to angiotensin II, despite compensatory increases in vascular antioxidant enzymes. Endothelial cell Nox2-containing NADPH oxidase plays an important functional role in vascular redox signaling.