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Radiofrequency (RF) ablation for the treatment of atrial fibrillation has gained widespread acceptance since the concept was introduced by Haissaguerre et al a quarter of a century ago. High power short duration ablation has been widely adopted in the management of atrial fibrillation. Evidence for combining lesion size index and high power short duration ablation is lacking. In this issue of the journal, Cai et al evaluated the combination of HPSD with LSI with a focus on long-term efficacy.

Background There are limited data on the comparative analyses of TightRailTM rotating dilator sheath (Philips) and laser sheath for lead extraction. Objective To evaluate the effectiveness and safety of the TightRailTM sheath as a primary or secondary tool for TLE. Methods Retrospective cohort analysis of 202 consecutive patients who underwent TLE using either TightRailTM sheath and/or GlideLightTM laser sheath (Philips) in our hospital. The study population was divided into three groups: Group A underwent TLE with laser sheath only (N = 157), Group B with TightRailTM sheath only (N = 22), and Group C with both sheaths (N = 23). Results During this period, 375 leads in 202 patients were extracted, including 297 leads extracted by laser sheath alone, 45 leads by TightRailTM sheath alone, and 33 by both TightRailTM sheath and laser sheaths. The most common indications included device infection (44.6%) and lead-related complications (44.1%). The median age of leads was 8.9 years. TightRailTM sheath (Group B) achieved similar efficacy as a primary extraction tool compared with laser sheath (Group A), with complete procedure success rate of 93.3% (vs. 96.6%, P = 0.263) and clinical success rate of 100.0% (vs. 98.1%, P = 0.513). Among 32 leads in which TightrailTM was used after laser had failed (Group C), the complete procedure success rate was 75.8%. No significant difference in procedural adverse events were observed. Conclusion Our single-center experience confirms that the TightRailTM system is an effective first-line and second-line method for TLE. Further investigation is required to guide the selection of mechanical and laser sheaths in lead extraction cases. This article is protected by copyright. All rights reserved.

Background Interrupted inferior vena cava (IVC) is a rare venous anomaly that complicates the treatment of patients who require electrophysiology (EP) procedures. Methods We describe five consecutive cases of patients with interrupted IVC who presented to the EP laboratory requiring interventional procedures including catheter ablation for atrial fibrillation and supraventricular tachycardia and left atrial appendage closure. All cases were successfully completed utilizing a variety of approaches to vascular access including transseptal puncture via transhepatic and internal jugular approaches. Conclusion Procedures in the EP lab can be performed successfully in patients with interrupted IVC.

Atrial fibrillation (AF) is an all-too-common and often challenging reality of clinical care. AF leads to significant morbidity and mortality; however, currently available treatments for AF have modest efficacy and high recurrence rates. In recent years, genetic therapy approaches have been explored in preclinical models of AF, and offer potential as a treatment modality with targeted delivery, tissue specificity, and therapy tailored to address mechanisms underlying the arrhythmia. However, many challenges remain before gene therapy can advance to a clinically relevant AF treatment. In this review, we summarize the available published data on gene therapy and discuss the challenges, opportunities, and limitations of this approach.

Several clinical trials have established the role of cardiac resynchronization therapy in patients with heart failure, impaired left ventricular function and dyssynchrony. Challenges to traditional therapy include coronary sinus anatomy and failure to respond. Left ventricular endocardial pacing could overcome anatomic constraints, provide more flexibility, and allow for more physiologic activation. Cases and case series have demonstrated the promise of the approach. Preclinical studies support the superior hemodynamic effects of left ventricular endocardial pacing. Leadless left ventricular endocardial pacing is a recent innovation that is undergoing prospective testing. Successful delivery may be associated with clinical response and positive cardiac structural remodeling.

Background Atrial fibrillation (AF) is the most common clinical arrhythmia, although the pathophysiology remains poorly understood. Population-based genetic studies have identified a susceptibility locus for AF at the gene ZFHX3. Hypothesis We hypothesized that a cardiac-restricted knockout of the transcription factor ZFHX3 in a mammalian model organism would perturb normal cardiac development and function, and illuminate the role of ZFHX3 in AF. Methods and results We generated a murine cardiac-restricted knockdown of ZFHX3 using cre-lox recombination. Knockdown was confirmed by organ specific genotyping. Among knockdown mice, increased inducibility of atrial arrhythmias was observed at in vivo electrophysiology testing at 3 months of age (% arrhythmia induction maneuvers 10 vs 0, p Conclusion We have uncovered a role for ZFHX3 in the left-right patterning of cardiac atria. Disruption of this developmental process predisposes to atrial cardiomyopathy, affects atrial electrophysiology properties, changes which may increase the susceptibility to AF.

Stress is associated with increased susceptibility to infection. We investigated if the mechanism involves immunomodulation of dendritic cells and whether this can be inhibited by a polyphenol-rich diet. Blood samples were taken from a total of 100 male endurance athletes at 5 time points around a marathon run: 4 weeks before; 1 week before; and immediately, 24 h, and 72 h after. Participants were randomized into 2 double-blinded groups. One group received a polyphenol-rich beverage during a 3-week training phase before marathon while the other group received a placebo beverage. Flow cytometric analysis of dendritic cell (DC) counts and subpopulation counts (myeloid, plasmocytoid DCs) was performed. Levels of viral antigen presenting toll-like receptor (TLR) 7 messenger RNA was measured by real-time polymerase chain reaction. Marathon running induced a significant increase of circulating myeloid DCs (0.2% vs. 0.33% of whole-blood leukocytes (wbl); p < 0.01) and a significant decrease of plasmozytoid DCs (0.12% vs. 0.03% of wbl; p < 0.01) and TLR7 expression (decline of 60%; p < 0.01). Polyphenol supplementation did not significantly affect mobilization of dendritic cells but showed beneficial effects on regeneration of TLR7 expression in wbl at 3 days postmarathon (decline of 40% vs. increase of 1000%; p < 0.05). In conclusion, physical stress affects circulating DCs, with an increase of myeloid and a decrease of plasmozytoid DCs. This may partially explain the susceptibility to viral infections after strenuous exercise. These detrimental effects are not attenuated by polyphenol supplementation. However, polyphenols support regeneration of viral antigen presenting TLR7 after strenuous exercise.

Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11b(DTR) mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.

Both physiologic stress and chronic heart disease are associated with increased systemic levels of chromogranin A (CGA) and NT-proBNP. Marathon running causes physiological stress and imposes a significant cardiac burden. Polyphenol-rich Mediterranean and Asian diets have been demonstrated to exert beneficial effects on the cardiovascular system. In this study we investigated whether pretreatment with a polyphenol beverage could attenuate the physiological and cardiac stress associated with a marathon. In the BeMaGIC trial, 277 athletes were randomized into 2 groups in a double-blinded fashion, receiving 1–1.5 L/day of the same beverages either with (study beverage) or without (placebo) polyphenol enrichment (approximately 400 mg of gallic acid equivalents per day of a complex mixture of polyphenols). Blood samples were taken 3 weeks and 1 day before, and immediately, 24 h, and 72 h after running a marathon. In our current substudy, CGA and NT-proBNP levels were analyzed by ELISA in the fastest 18 and the slowest 22 runners. CGA and NT-proBNP levels increased significantly immediately after the marathon and returned to baseline at 72 h after the marathon. Neither CGA nor NT-proBNP differed significantly between athletes receiving study beverage versus placebo. Separating our cohort into fast and slow runners did not reveal any significant difference regarding CGA or NT-proBNP levels between groups. Our study provides no evidence that polyphenol supplementation attenuates marathon running-induced physiological stress and cardiac burden in fast or slow runners.

Atrial fibrillation (AF) is an all-too-common and often challenging reality of clinical care. AF leads to significant morbidity and mortality; however, currently available treatments for AF have modest efficacy and high recurrence rates. In recent years, genetic therapy approaches have been explored in preclinical models of AF, and offer potential as a treatment modality with targeted delivery, tissue specificity, and therapy tailored to address mechanisms underlying the arrhythmia. However, many challenges remain before gene therapy can advance to a clinically relevant AF treatment. In this review, we will summarize the available published data on gene therapy and discuss the challenges, opportunities, and limitations of this approach.

It has been conclusively proven that physical activity exerts beneficial effects on individual health. However, endurance activities in susceptible individuals can increase the risk of concerning cardiovascular conditions such as ventricular hypertrophy or arrhythmia. This increased risk can be attributed to a cardiac remodeling process specifically associated with endurance sports. In recent years, microRNAs (miRNAs) have been postulated to play many roles in health and disease. In the heart miRNAs regulate electrical remodeling, cardiac dilatation, fibrosis, calcium handling, heart failure, atrial fibrillation and autonomic tone in myocardial infarction. A growing body of evidence suggests that miRNAs also regulate endurance sports induced remodeling of the heart. Since miRNAs circulate in the blood they have a potential role as biomarkers in athletes indicating the degree of remodeling and predicting the risk of progression to an overt disease state.

Background: Gout and serum uric acid are associated with mortality but their simultaneous contributions have not been fully evaluated in the general population. Purpose: To explore the independent and conjoint relationships of gout and uric acid with mortality in the US population. Methods: Mortality risks of gout and serum uric acid were determined for 15 773 participants, aged 20 years or older, in the Third National Health and Nutrition Examination Survey by linking baseline information collected during 1988–1994 with mortality data up to 2006. Multivariable Cox proportional hazards regression determined adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for each exposure and all analyses were conducted in 2011 and 2012. Results: Compared with subjects without a history of gout, the multivariable HR for subjects with gout were 1.42 (CI 1.12–1.82) for total and 1.58 (CI 1.13–2.19) for cardiovascular mortality. Adjusted HRs per 59.5 µmol/l (1 mg/dl) increase in uric acid were 1.16 (CI 1.10–1.22) for total and cardiovascular mortality and this pattern was consistent across disease categories. In the conjoint analysis, the adjusted HRs for mortality in the highest two uric acid quartiles were 1.64 (CI 1.08–2.51) and 1.77 (CI 1.23–2.55), respectively, for subjects with gout, and were 1.09 (CI 0.87–1.37) and 1.37 (CI (1.11–1.70), respectively, for subjects without gout, compared with those without gout in the lowest quartile. A similar pattern emerged for cardiovascular mortality. Conclusions: Gout and serum uric acid independently associate with total and cardiovascular mortality. These risks increase with rising uric acid concentrations.

Background The genetic basis of atrial fibrillation (AF) and congenital heart disease remains incompletely understood. Objective We sought to determine the causative mutation in a family with AF, atrial septal defects, and ventricular septal defects. Methods We evaluated a pedigree with 16 family members, 1 with an atrial septal defect, 1 with a ventricular septal defect, and 3 with AF; we performed whole exome sequencing in 3 affected family members. Given that early-onset AF was prominent in the family, we then screened individuals with early-onset AF, defined as an age of onset GATA6 . Variants were functionally characterized using reporter assays in a mammalian cell line. Results Exome sequencing in 3 affected individuals identified a conserved mutation, R585L, in the transcription factor gene GATA6 . In the Massachusetts General Hospital Atrial Fibrillation (MGH AF) Study, the mean age of AF onset was 47.1 ± 10.9 years; 79% of the participants were men; and there was no evidence of structural heart disease. We identified 3 GATA6 variants (P91S, A177T, and A543G). Using wild-type and mutant GATA6 constructs driving atrial natriuretic peptide promoter reporter, we found that 3 of the 4 variants had a marked upregulation of luciferase activity (R585L: 4.1-fold, P P = .0002; A177T; 1.7-fold, P = .03). In addition, when co-overexpressed with GATA4 and MEF2C, GATA6 variants exhibited upregulation of the alpha myosin heavy chain and atrial natriuretic peptide reporter activity. Conclusion Overall, we found gain-of-function mutations in GATA6 in both a family with early-onset AF and atrioventricular septal defects as well as in a family with sporadic, early-onset AF.

The authors deal with common coronary anomalies, discuss their anatomy and some diagnostic and clinical aspects, and describe some of the principles of management.

Dobson L, Conway C, Hanley A, Johnson A, Costello S, O’Grady A, Connolly Y, Magee H, O’Shea D, Jeffers M & Kay E (2010) Histopathology 57, 27–38 Image analysis as an adjunct to manual HER-2 immunohistochemical review: a diagnostic tool to standardize interpretation Aims: Accurate determination of HER-2 status is critical to identify patients for whom trastuzumab treatment will be of benefit. Although the recommended primary method of evaluation is immunohistochemistry, numerous reports of variability in interpretation have raised uncertainty about the reliability of results. Recent guidelines have suggested that image analysis could be an effective tool for achieving consistent interpretation, and this study aimed to assess whether this technology has potential as a diagnostic support tool. Methods and results: Across a cohort of 275 cases, image analysis could accurately classify HER-2 status, with 91% agreement between computer-aided classification and the pathology review. Assessment of the continuity of membranous immunoreactivity in addition to intensity of reactivity was critical to distinguish between negative and equivocal cases and enabled image analysis to report a lower referral rate of cases for confirmatory fluorescence in situ hybridization (FISH) testing. An excellent concordance rate of 95% was observed between FISH and the automated review across 136 informative cases. Conclusions: This study has validated that image analysis can robustly and accurately evaluate HER-2 status in immunohistochemically stained tissue. Based on these findings, image analysis has great potential as a diagnostic support tool for pathologists and biomedical scientists, and may significantly improve the standardization of HER-2 testing by providing a quantitative reference method for interpretation.

ObjectivesThe main objective of this study is to determine the correlation between fractional flow reserve (FFR)- and frequency domain optical coherence tomography (FD-OCT)-measured lumen parameters, and to determine the diagnostic competence of FD-OCT concerning the identification of severe coronary stenosis.MethodsA total of 41 coronary stenoses in 30 patients were assessed consecutively by quantitative coronary angiography (QCA), FFR, and FD-OCT. Stenoses were labeled severe if FFR≤0.80. The minimal lumen area (MLA), minimal lumen diameter (MLD), and percent lumen area stenosis (%AS) were measured using FD-OCT.ResultsFFR was ≤0.80 in 10 stenoses (24.4%). A poor but significant correlation between FFR and FD-OCT-measured MLA (r2=0.4, p

A 43-year-old woman developed a sudden-onset severe chest pain and breathlessness at home. She collapsed within minutes and received bystander cardiopulmonary resuscitation from her husband. On arrival, the paramedics identified ventricular fibrillation requiring defibrillation. She was admitted to the intensive care unit for observation. A coronary angiogram performed at our hospital demonstrated non-obstructive disease of the right coronary artery. Her antidepressant medications were discontinued and she was discharged. No specific cause was found for the arrhythmia and collapse. One week later, she developed similar chest pain. An ECG showed transient ST-elevation in the inferior leads. Symptoms and ECG changes resolved with sublingual nitroglycerin. During the course of a repeat coronary angiogram the patient developed severe spasm of the right coronary artery associated with typical chest pain and ST-elevation in the inferior leads. She was treated with insertion of a drug-eluting stent and a cardiac defibrillator.

Background The goal of treating patients with coronary artery disease is to improve survival and relieve symptoms. Several studies have compared the safety and efficacy of left main coronary artery (LMCA) stenting and coronary-artery bypass grafting in case control and randomized trials. Objective In this study we present the long term outcome of stenting unprotected LMCA stenosis in day to day practice in unselected patients. Methods One hundred and fifty eight patients were prospectively recruited with symptomatic unprotected LMCA stenosis undergoing percutaneous coronary intervention (PCI). Using the euroSCORE, each patient's surgical mortality risk was estimated. Study end-points were any major adverse cardiac event (MACE) defined as cardiac death, nonfatal myocardial infarction, or target lesion revascularization at follow-up with either CABG or repeat PCI. Results The mean follow-up was 54 ± 25 months. The mean euroSCORE was 10.6 ± 13.4 (0.9–71) and the mean SYNTAX score was 39.6 ± 10.7 (10–65). The MACE rate was 11.4% at a mean follow up of 54 months. Six (3.8%) patients suffered postprocedure myocardial infarction. There were 24 (15%) deaths of which 12 were cardiac (mean euroSCORE 21.6 ± 5.5 P

Cecal intubation and polyp detection rates are objective measures of colonoscopy performance. Minimum cecal intubation rates greater than 90% have been endorsed by the American Society for Gastrointestinal Endoscopy (ASGE) and the Joint Advisory Group (JAG) UK. Performance data for medical and surgical trainee endoscopists are limited, and we used endoscopy quality parameters to compare these two groups.Retrospective review of all single-endoscopist colonoscopies done by gastroenterology and surgical trainees ("registrars," equivalent to fellows, postgraduate year 5) with more than two years' endoscopy experience, in 2006 and 2007 at a single academic medical center. Completion rates and polyp detection rates for endoscopists performing more than 50 colonoscopies during the study period were audited. Colonoscopy withdrawal time was prospectively observed in a representative subset of 140 patients.Among 3079 audited single-endoscopist colonoscopies, seven gastroenterology trainees performed 1998 procedures and six surgery trainees performed 1081. The crude completion rate was 82%, 84% for gastroenterology trainees and 78% for surgery trainees (P0.0001). Adjusted for poor bowel preparation quality and obstructing lesions, the completion rate was 89%; 93% for gastroenterology trainees, and 84% for surgical trainees (P0.0001). The polyp detection rate was 19% overall, with 21% and 14% for gastroenterology and surgical trainees, respectively (P0.0001). The adenoma detection rate in patients over 50 was 12%; gastroenterology trainees 14% and surgical trainees 9% (P = 0.0065). In the prospectively audited procedures, median withdrawal time was greater in the gastroenterology trainee group and polyp detection rates correlated closely with withdrawal time (r = 0.99).The observed disparity in endoscopic performance between surgical and gastroenterology trainees suggests the need for a combined or unitary approach to endoscopy training for specialist medical and surgical trainees.

Background and objectives Congestive heart failure (CHF) is a major risk factor for death in end-stage kidney disease; however, data on prevalence and survival trends are limited. The objective of this study was to determine the prevalence and mortality effect of CHF in successive incident dialysis cohorts. Design, setting, participants, & measurements This was a population-based cohort of incident US dialysis patients (n = 926,298) from 1995 to 2005. Age- and gender-specific prevalence of CHF was determined by incident year, whereas temporal trends in mortality were compared using multivariable Cox regression. Results The prevalence of CHF was significantly higher in women than men and in older than younger patients, but it did not change over time in men (range 28% to 33%) or women (range 33% to 36%). From 1995 to 2005, incident death rates decreased for younger men (5-70 years) and increased for older men (>70 years). For women, the pattern was similar but less impressive. During this period, the adjusted mortality risks (relative risk [RR]) from CHF decreased in men (from RR = 1.06 95% Confidence intervals (CI) 1.02-1.11 in 1995 to 0.91 95% CI 0.87-0.96 in 2005) and women (from RR = 1.06 95% Cl 1.01-1.10 in 1995 to 0.90 95% CI 0.85-0.95 in 2005 compared with referent year 2000; RR = 1.00). The reduction in mortality over time was greater for younger than older patients (20% to 30% versus 5% to 10% decrease per decade). Conclusions Although CHF remains a common condition at dialysis initiation, mortality risks in US patients have declined from 1995 to 2005. Clin J Am Soc Nephrol 6: 1982-1989, 2011. doi: 10.2215/CJN.01130211

The goal of treating patients with coronary artery disease is to improve survival and relieve symptoms. Several studies have compared the safety and efficacy of left main coronary artery (LMCA) stenting and coronary-artery bypass grafting in case control and randomized trials.In this study we present the long term outcome of stenting unprotected LMCA stenosis in day to day practice in unselected patients.One hundred and fifty eight patients were prospectively recruited with symptomatic unprotected LMCA stenosis undergoing percutaneous coronary intervention (PCI). Using the euroSCORE, each patient's surgical mortality risk was estimated. Study end-points were any major adverse cardiac event (MACE) defined as cardiac death, nonfatal myocardial infarction, or target lesion revascularization at follow-up with either CABG or repeat PCI.The mean follow-up was 54 ± 25 months. The mean euroSCORE was 10.6 ± 13.4 (0.9-71) and the mean SYNTAX score was 39.6 ± 10.7 (10-65). The MACE rate was 11.4% at a mean follow up of 54 months. Six (3.8%) patients suffered postprocedure myocardial infarction. There were 24 (15%) deaths of which 12 were cardiac (mean euroSCORE 21.6 ± 5.5 P0.001). Repeat angiography was performed in 88 (55.7%) patients. Seven (4.4%) patients had in-stent restenosis; three occurred in BMS (P = 0.06). Two patients underwent revascularization with CABG and five had successful repeat PCI.In this on-going registry of high risk patients with LMCA stenosis, stenting was found to be safe and clinically effective in maintaining event-free survival.

Dobson L, Conway C, Hanley A, Johnson A, Costello S, O’Grady A, Connolly Y, Magee H, O’Shea D, Jeffers M & Kay E (2010) Histopathology57, 27–38 Image analysis as an adjunct to manual HER-2 immunohistochemical review: a diagnostic tool to standardize interpretation Aims: Accurate determination of HER-2 status is critical to identify patients for whom trastuzumab treatment will be of benefit. Although the recommended primary method of evaluation is immunohistochemistry, numerous reports of variability in interpretation have raised uncertainty about the reliability of results. Recent guidelines have suggested that image analysis could be an effective tool for achieving consistent interpretation, and this study aimed to assess whether this technology has potential as a diagnostic support tool. Methods and results: Across a cohort of 275 cases, image analysis could accurately classify HER-2 status, with 91% agreement between computer-aided classification and the pathology review. Assessment of the continuity of membranous immunoreactivity in addition to intensity of reactivity was critical to distinguish between negative and equivocal cases and enabled image analysis to report a lower referral rate of cases for confirmatory fluorescence in situ hybridization (FISH) testing. An excellent concordance rate of 95% was observed between FISH and the automated review across 136 informative cases. Conclusions: This study has validated that image analysis can robustly and accurately evaluate HER-2 status in immunohistochemically stained tissue. Based on these findings, image analysis has great potential as a diagnostic support tool for pathologists and biomedical scientists, and may significantly improve the standardization of HER-2 testing by providing a quantitative reference method for interpretation.

Renal transplantation remains the preferred method of renal replacement therapy in terms of patient survival, quality of life and cost. However, patients have a high risk of complications ranging from rejection episodes, infection and cancer, amongst others.In this study, we sought to determine the long-term health outcomes and preventive health measures undertaken for the 1,536 living renal transplant patients in Ireland using a self-reported questionnaire. Outcomes were divided into categories, namely, general health information, allograft-related information, immunosuppression-related complications and preventive health measures.The results demonstrate a high rate of cardiovascular, neoplastic and infectious complications in our transplant patients. Moreover, preventive health measures are often not undertaken by patients and lifestyle choices can be poor.This study highlights the work needed by the transplantation community to improve patient education, adjust immunosuppression where necessary and aggressively manage patient risk factors.

Falls in the elderly are a significant public health problem. Previous studies have shown that most falls are multifactorial and an efficacious way of reducing the risk of falling is provided by a falls clinic.A falls clinic runs every 2 weeks at Mayo General Hospital; we report on the activity of this clinic during its first year.We performed a chart review and collected the following data. Thirty-seven patients attended the clinic. All patients were seen by a physiotherapist, occupational therapist, physician and pharmacist. Six patients had a further fall within a 12-month period; 2 of these suffered a further fracture. No patients were readmitted to hospital.The results show a reduction in fall occurrence from previously reported rates in this at-risk population. We find the falls clinic a convenient and effective method of managing elderly people who are at increased risk of falling.