Association of right atrial structure with incident atrial fibrillation: a longitudinal cohort cardiovascular magnetic resonance study from the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: While studies of the left atrium (LA) have demonstrated associations between volumes and emptying fraction with atrial fibrillation (AF), the contribution of right atrial (RA) abnormalities to incident AF remains poorly understood. OBJECTIVES: Assess the association between RA structure and function with incident AF using feature-tracking cardiovascular magnetic resonance (CMR). METHODS: This is a prospective cohort study of all participants in the Multi-Ethnic Study of Atherosclerosis with baseline CMR, sinus rhythm, and free of clinical cardiovascular disease at study initiation. RA volume, strain, and emptying fraction in participants with incident AF (n = 368) were compared against AF-free (n = 2779). Cox proportional-hazards models assessed association between variables. RESULTS: Participants were aged 60 ± 10 yrs., 55% female, and followed an average 11.2 years. Individuals developing AF had higher baseline RA maximum volume index (mean ± standard deviation [SD]: 24 ± 9 vs 22 ± 8 mL/m2, p = 0.002) and minimum volume index (13 ± 7 vs 12 ± 6 mL/m2, p < 0.001), and lower baseline RA emptying fraction (45 ± 15% vs 47 ± 15%, p = 0.02), peak global strain (34 ± 17% vs 36 ± 19%, p < 0.001), and peak free-wall strain (40 ± 23% vs 42 ± 26%, p = 0.049) compared with the AF-free population. After adjusting for traditional cardiovascular risk factors and LA volume and function, we found RA maximum volume index (hazards ratio [HR]: 1.13 per SD, p = 0.041) and minimum volume index (HR: 1.12 per SD, p = 0.037) were independently associated with incident AF. CONCLUSIONS: In a large multiethnic population, higher RA volume indices were independently associated with incident AF after adjustment for conventional cardiovascular risk factors and LA parameters. It is unclear if this predictive value persists when additional adjustment is made for ventricular parameters.

Ventricular Tachycardia Ablation in the Presence of Left Ventricular Thrombus: Safety and Efficacy.

INTRODUCTION: The safety of ventricular tachycardia (VT) ablation in patients with laminated left ventricular (LV) thrombus has not been examined. METHODS: Patients with laminated LV thrombus on transthoracic echocardiogram who underwent scar-mediated VT ablation at two centers from 2010 to 2013 were retrospectively analyzed. All patients had failed medical therapy. Acute procedural outcomes, complications, and clinical outcomes at 1 year were assessed. RESULTS: Eight patients (four ischemic, four nonischemic cardiomyopathy) underwent VT ablation in the presence of laminated intracavitary thrombus. Six out of eight (75%) had electrical storm (ES). The mapping and ablation approach was LV endocardial-only in three patients, epicardial-only in two, combined epicardial-RV endocardial in two, and combined epicardial-LV endocardial in one. Major complication (ischemic stroke) occurred in one patient 9 days post-procedure. There was no procedural mortality. Complete acute procedural success (noninducibility of any VT after ablation) was achieved in five (63%), and partial success (ablation of only clinical VT) in an additional three (37%). At 1 year, freedom from VT and survival were achieved in six (75%) and seven (88%) patients, respectively. CONCLUSION: Initial data suggest that ablation of VT in the presence of intracavitary thrombus is feasible, is associated with a similar success rate to historical studies in patients without thrombus, and has an acceptable risk of complications given the high-risk nature of patients with ES. Further data are needed; however, the presence of a laminated thrombus should not necessarily preclude ablation in patients who have failed medical therapy for VT in whom ablation is otherwise indicated.

Biophysical parameters during radiofrequency catheter ablation of scar-mediated ventricular tachycardia: epicardial and endocardial applications via manual and magnetic navigation.

BACKGROUND: There is a paucity of data on biophysical parameters during radiofrequency ablation of scar-mediated ventricular tachycardia (VT). METHODS AND RESULTS: Data were collected from consecutive patients undergoing VT ablation with open-irrigation. Complete data were available for 372 lesions in 21 patients. The frequency of biophysical parameter changes were: >10Ω reduction (80%), bipolar EGM reduction (69%), while loss of capture was uncommon (32%). Unipolar injury current was seen in 72% of radiofrequency applications. Both EGM reduction and impedance drop were seen in 57% and a change in all 3 parameters was seen in only 20% of lesions. Late potentials were eliminated in 33%, reduced/modified in 56%, and remained after ablation in 11%. Epicardial lesions exhibited an impedance drop (90% vs. 76%, P = 0.002) and loss of capture (46% vs. 27%, P < 0.001) more frequently than endocardial lesions. Lesions delivered manually exhibited a >10Ω impedance drop (83% vs. 71%, P = 0.02) and an EGM reduction (71% vs. 40%, P < 0.001) more frequently than lesions applied using magnetic navigation, although loss of capture, elimination of LPs, and a change in all 3 parameters were similarly observed. CONCLUSIONS: VT ablation is inefficient as the majority of radiofrequency lesions do not achieve more than one targeted biophysical parameter. Only one-third of RF applications targeted at LPs result in complete elimination. Epicardial ablation within scar may be more effective than endocardial lesions, and lesions applied manually may be more effective than lesions applied using magnetic navigation. New technologies directed at identifying and optimizing ablation effectiveness in scar are clinically warranted.

Outcomes of Catheter Ablation of Ventricular Tachycardia Based on Etiology in Nonischemic Heart Disease: An International Ventricular Tachycardia Ablation Center Collaborative Study.

OBJECTIVES: This study sought to characterize ventricular tachycardia (VT) ablation outcomes across nonischemic cardiomyopathy (NICM) etiologies and adjust these outcomes by patient-related comorbidities that could explain differences in arrhythmia recurrence rates. BACKGROUND: Outcomes of catheter ablation of VT in patients with NICM could be related to etiology of NICM. METHODS: Data from 2,075 patients with structural heart disease referred for catheter ablation of VT from 12 international centers was retrospectively analyzed. Patient characteristics and outcomes were noted for the 6 most common NICM etiologies. Multivariable Cox proportional hazards modeling was used to adjust for potential confounders. RESULTS: Of 780 NICM patients (57 ± 14 years of age, 18% women, left ventricular ejection fraction 37 ± 13%), underlying prevalence was 66% for dilated idiopathic cardiomyopathy (DICM), 13% for arrhythmogenic right ventricular cardiomyopathy (ARVC), 6% for valvular cardiomyopathy, 6% for myocarditis, 4% for hypertrophic cardiomyopathy, and 3% for sarcoidosis. One-year freedom from VT was 69%, and freedom from VT, heart transplantation, and death was 62%. On unadjusted competing risk analysis, VT ablation in ARVC demonstrated superior VT-free survival (82%) versus DICM (p ≤ 0.01). Valvular cardiomyopathy had the poorest unadjusted VT-free survival, at 47% (p < 0.01). After adjusting for comorbidities, including age, heart failure severity, ejection fraction, prior ablation, and antiarrhythmic medication use, myocarditis, ARVC, and DICM demonstrated similar outcomes, whereas hypertrophic cardiomyopathy, valvular cardiomyopathy, and sarcoidosis had the highest risk of VT recurrence. CONCLUSIONS: Catheter ablation of VT in NICM is effective. Etiology of NICM is a significant predictor of outcomes, with ARVC, myocarditis, and DICM having similar but superior outcomes to hypertrophic cardiomyopathy, valvular cardiomyopathy, and sarcoidosis, after adjusting for potential covariates.

Identification of a novel cell cycle regulated gene, HURP, overexpressed in human hepatocellular carcinoma.

An analytic strategy was followed to identify putative regulatory genes during the development of human hepatocellular carcinoma (HCC). This strategy employed a bioinformatics analysis that used a database search to identify genes, which are differentially expressed in human HCC and are also under cell cycle regulation. A novel cell cycle regulated gene (HURP) that is overexpressed in HCC was identified. Full-length cDNAs encoding the human and mouse HURP genes were isolated. They share 72 and 61% identity at the nucleotide level and amino-acid level, respectively. Endogenous levels of HURP mRNA were found to be tightly regulated during cell cycle progression as illustrated by its elevated expression in the G(2)/M phase of synchronized HeLa cells and in regenerating mouse liver after partial hepatectomy. Immunofluorescence studies revealed that hepatoma up-regulated protein (HURP) localizes to the spindle poles during mitosis. Overexpression of HURP in 293T cells resulted in an enhanced cell growth at low serum levels and at polyhema-based, anchorage-independent growth assay. Taken together, these results strongly suggest that HURP is a potential novel cell cycle regulator that may play a role in the carcinogenesis of human cancer cells.

Catheter ablation of scar-based ventricular tachycardia: Relationship of procedure duration to outcomes and hospital mortality.

BACKGROUND: Ablation has become an important option for treatment of ventricular tachycardia (VT). The influence of procedure duration on outcomes remains unexamined. OBJECTIVE: The purpose of this study was to determine the influence of procedure duration on outcomes and complications over an 8-year period METHODS: Patients referred for scar-mediated VT ablation from 2004 to 2011 were retrospectively analyzed. Procedure duration was defined as the time from the insertion of catheters through the femoral vein to the time of their withdrawal. Procedure duration was analyzed in relationship with baseline and intraoperative covariates, acute procedural outcomes, complications, and 6-month clinical outcomes. RESULTS: One hundred forty-eight patients underwent VT ablation with mean procedure duration of 5.7 ± 1.8 hours. VT recurrence and survival at 6 months were 46% and 82%, respectively, and were not associated with procedure duration. Hospital mortality increased with intraoperative intraaortic balloon pump insertion (adjusted odds ratio [OR] 13.7, 95% confidence interval [CI] 2.35-79.94, P = .004) and was improved with successful ablation of the clinical VT as a procedural end-point (adjusted OR 0.13, 95% Cl 0.03-0.54, P = .005). The association between procedure duration and hospital mortality remained after adjusting for significant baseline variables (adjusted OR 1.75, 95% CI 1.14-2.68, P = .0098) and intraoperative variables (adjusted OR 1.6, 95% CI 1.12-2.29, P = .0104). CONCLUSION: Hospital mortality was significantly increased by unsuccessful clinical VT ablation as a procedural end-point and intraoperative intraaortic balloon pump insertion. However, after adjusting for significant baseline and intraoperative covariates, procedure duration still was associated with increased hospital mortality. Procedure duration had no impact on VT recurrence and survival at 6 months.

Relationship between sinus rhythm late activation zones and critical sites for scar-related ventricular tachycardia: systematic analysis of isochronal late activation mapping.

BACKGROUND: It is not known whether the most delayed late potentials are functionally most specific for scar-related ventricular tachycardia (VT) circuits. METHODS AND RESULTS: Isochronal late activation maps were constructed to display ventricular activation during sinus rhythm over 8 isochrones. Analysis was performed at successful VT termination sites and prospectively tested. Thirty-three patients with 47 scar-related VTs where a critical site was demonstrated by termination of VT during ablation were retrospectively analyzed. In those who underwent mapping of multiple surfaces, 90% of critical sites were on the surface that contained the latest late potential. However, only 11% of critical sites were localized to the latest isochrone (87.5%-100%) of ventricular activation. The median percentage of latest activation at critical sites was 78% at a distance from the latest isochrone of 18 mm. Sites critical to reentry were harbored in regions with slow conduction velocity, where 3 isochrones were present within a 1-cm radius. Ten consecutive patients underwent ablation prospectively guided by isochronal late activation maps, targeting concentric isochrones outside of the latest isochrone. Elimination of the targeted VT was achieved in 90%. Termination of VT was achieved in 6 patients at a mean ventricular activation percentage of 78%, with only 1 requiring ablation in the latest isochrone. CONCLUSIONS: Late potentials identified in the latest isochrone of activation during sinus rhythm are infrequently correlated with successful ablation sites for VT. The targeting of slow conduction regions propagating into the latest zone of activation may be a novel and promising strategy for substrate modification.

Multicenter Outcomes for Catheter Ablation of Idiopathic Premature Ventricular Complexes.

OBJECTIVES: This study reports multicenter outcomes and complications for catheter ablation of premature ventricular complexes (PVCs) and investigates predictors of procedural success, as well as development of PVC-induced cardiomyopathy. BACKGROUND: Catheter ablation of frequent idiopathic PVCs is used to eliminate symptoms and treat PVC-induced cardiomyopathy. Large-scale multicenter outcomes and complication rates have not been reported. METHODS: This retrospective cohort study included 1,185 patients (55% female; mean age 52 ± 15 years; mean ejection fraction 55 ± 10%; mean PVC burden 20 ± 13%) who underwent catheter ablation for idiopathic PVCs at 8 centers between 2004 and 2013. The following factors were evaluated: patient demographics, procedural characteristics, complication rates, and clinical outcomes. RESULTS: Acute procedural success was achieved in 84% of patients. In centers at which patients were followed up routinely with post-ablation Holter monitoring, continued success at clinical follow-up without use of antiarrhythmic drugs was 71%. Including the use of antiarrhythmic medications, the success rate at a mean of 1.9 years of follow-up was 85%. In a multivariate analysis, the significant predictors of acute success were PVC location and number of distinct PVC configurations (p < 0.03). The only significant predictor of continued success at clinical follow-up was a right ventricular outflow tract PVC location (p < 0.01). In 245 patients (21%) with PVC-induced cardiomyopathy, the mean ejection fraction improved from 38% to 50% (p < 0.01) after ablation. Independent predictors for development of PVC-induced cardiomyopathy were male gender, PVC burden, lack of symptoms, and epicardial PVC origin (p < 0.05). The overall complication rate was 5.2% (2.4% major complications and 2.8% minor complications), and complications were most commonly related to vascular access (2.8%). There was no procedure-related mortality. CONCLUSIONS: Catheter ablation of frequent PVCs is a low-risk and often effective treatment strategy to eliminate PVCs and associated symptoms. In patients with PVC-induced cardiomyopathy, cardiac function is frequently restored after successful ablation.

Freedom from recurrent ventricular tachycardia after catheter ablation is associated with improved survival in patients with structural heart disease: An International VT Ablation Center Collaborative Group study.

BACKGROUND: The impact of catheter ablation of ventricular tachycardia (VT) on all-cause mortality remains unknown. OBJECTIVE: The purpose of this study was to examine the association between VT recurrence after ablation and survival in patients with scar-related VT. METHODS: Analysis of 2061 patients with structural heart disease referred for catheter ablation of scar-related VT from 12 international centers was performed. Data on clinical and procedural variables, VT recurrence, and mortality were analyzed. Kaplan-Meier analysis was used to estimate freedom from recurrent VT, transplant, and death. Cox proportional hazards frailty models were used to analyze the effect of risk factors on VT recurrence and mortality. RESULTS: One-year freedom from VT recurrence was 70% (72% in ischemic and 68% in nonischemic cardiomyopathy). Fifty-seven patients (3%) underwent cardiac transplantation, and 216 (10%) died during follow-up. At 1 year, the estimated rate of transplant and/or mortality was 15% (same for ischemic and nonischemic cardiomyopathy). Transplant-free survival was significantly higher in patients without VT recurrence than in those with recurrence (90% vs 71%, P<.001). In multivariable analysis, recurrence of VT after ablation showed the highest risk for transplant and/or mortality [hazard ratio 6.9 (95% CI 5.3-9.0), P<.001]. In patients with ejection fraction <30% and across all New York Heart Association functional classes, improved transplant-free survival was seen in those without VT recurrence. CONCLUSION: Catheter ablation of VT in patients with structural heart disease results in 70% freedom from VT recurrence, with an overall transplant and/or mortality rate of 15% at 1 year. Freedom from VT recurrence is associated with improved transplant-free survival, independent of heart failure severity.

Epicardial ablation of ventricular tachycardia: an institutional experience of safety and efficacy.

BACKGROUND: Epicardial ablation has been shown to be a useful adjunct for treatment of ventricular tachycardia (VT). OBJECTIVE: To report the trends, safety, and efficacy of epicardial mapping and ablation at a single center over an 8-year period. METHODS: Patients referred for VT ablation (June 2004 to July 2011) were divided into 3 groups: ischemic cardiomyopathy (ICM), nonischemic cardiomyopathy (NICM), and idiopathic ventricular arrhythmias (VA). Patients with scar-mediated VT who underwent combined epicardial and endocardial (epi-endo) mapping and ablation were compared with those who underwent endocardial-only (endo-only) ablation with regard to patient characteristics, acute procedural success, 6- and 12-month clinical outcomes. RESULTS: Among 144 patients referred for VT ablation, 95 patients underwent 109 epicardial procedures (94% access rate). Major complications were seen in 8 patients (8.8%) with pericardial bleeding (>80 cm(3)) in 6 cases (6.7%), although no tamponade, surgical intervention, or procedural mortality was seen. Patients with ICM who underwent a combined epi-endo ablation had improved freedom from VT compared with those who underwent endo-only ablation at 12 months (85% vs 56%; P = .03). In patients with NICM, no differences were seen between those who underwent epi-endo ablation and those who underwent endo-only ablation at 12 months (36% vs 33%; P = 1.0). In idiopathic VA, only 2 of 17 patients were successfully ablated from the epicardium. CONCLUSIONS: In this large tertiary single-center experience, complication rates are acceptably low and improved clinical outcomes were associated with epi-endo ablation in patients with ICM. Patients with NICM represent a growing referred population, although clinical recurrence remains high despite epicardial ablation. Epicardial ablation has a low yield in idiopathic VA.

Functional pace-mapping responses for identification of targets for catheter ablation of scar-mediated ventricular tachycardia.

BACKGROUND: Myocardial scars harbor areas of slow conduction and display abnormal electrograms. Pace-mapping at these sites can generate a 12-lead ECG morphological match to a targeted ventricular tachycardia (VT), and in some instances, multiple exit morphologies can result. At times, this can also result in the initiation of VT, termed pace-mapped induction (PMI). We hypothesized that in patients undergoing catheter ablation of VT, scar substrates with multiple exit sites (MES) identified during pace-mapping have improved freedom from recurrent VT, and PMI of VT predicts successful sites of termination during ablation. METHODS AND RESULTS: High-density mapping was performed in all subjects to delineate scar (0.5-1.5 mV). Sites with abnormal electrograms were tagged, stimulated (bipolar 10 mA at 2 ms), and targeted for ablation. MES was defined as >1 QRS morphology from a single pacing site. PMI was defined as initiation of VT during pace-mapping (400-600 ms). In a 2-year period, 44 consecutive patients with scar-mediated VT underwent mapping and ablation. MES were observed during pace-mapping in 25 patients (57%). At 9 months, 74% of patients who exhibited MES during pace-mapping had no recurrence of VT compared with 42% of those without MES observed (P=0.024), with an overall freedom from VT of 61%. Thirteen patients (30%) demonstrated PMI, and termination of VT was seen in 95% (18/19) of sites where ablation was performed. CONCLUSIONS: During pace-mapping, electrograms that exhibit MES and PMI may be specific for sites critical to reentry. These functional responses hold promise for identifying important sites for catheter ablation of VT.

Binding and "pKa" modulation of a polycyclic substrate analogue in a type II polyketide acyl carrier protein.

Type II polyketide synthases are biosynthetic enzymatic pathways responsible for the production of complex aromatic natural products with important biological activities. In these systems, biosynthetic intermediates are covalently bound to a small acyl carrier protein that associates with the synthase enzymes and delivers the bound intermediate to each active site. In the closely related fatty acid synthases of bacteria and plants, the acyl carrier protein acts to sequester and protect attached intermediates within its helices. Here we investigate the type II polyketide synthase acyl carrier protein from the actinorhodin biosynthetic pathway and demonstrate its ability to internalize the tricyclic, polar molecule emodic acid. Elucidating the interaction of acyl carrier proteins with bound analogues resembling late-stage intermediates in the actinorhodin pathway could prove valuable in efforts to engineer these systems toward rational design and biosynthesis of novel compounds.

hNinein is required for targeting spindle-associated protein Astrin to the centrosome during the S and G2 phases.

Human Ninein (hNinein) is implicated in centrosomal microtubule nucleation and microtubule anchoring in interphase cells and may act as a scaffold protein, but its direct interaction partners remain unexplored in the centrosome. In this report, we show clearly that a spindle-associated protein, Astrin, interacts and co-localizes with hNinein at the centrosome during the S and G2 phases, and this complex may dissociate in the M phase. We also demonstrate that the truncated forms of hNinein, which could interfere with gamma-tubulin and function as dominant-negative mutants, are able to affect Astrin localization to the centrosome. Moreover, siRNA-mediated knockdown of hNinein in HeLa cells causes Astrin to fail to target to the centrosome, whereas hNinein can localize at the centrosome in the absence of Astrin. In addition, reduction in hNinein protein levels causes mislocalization of Astrin with the spindle apparatus and results in the formation of an aberrant mitotic spindle. Collectively, these data suggest that hNinein is required for targeting Astrin to the centrosome during the S and G2 phases. We therefore propose a model wherein hNinein regulates the dynamic movement of Astrin throughout the cell cycle and this interaction, in turn, is required for maintenance of centrosome/spindle pole integrity.