Use of a contact force-sensing ablation catheter with advanced catheter location significantly reduces fluoroscopy time and radiation dose in catheter ablation of atrial fibrillation.

AIMS: The aim of this study was to evaluate the 'real-world' impact of a novel contact force (CF)-sensing (SmartTouch™, Biosense Webster, Diamond Bar, CA, USA) catheter coupled with an advanced catheter location (ACL) system on fluoroscopy time and fluoroscopy dose during atrial fibrillation (AF) ablation. METHODS AND RESULTS: This was a retrospective observational cohort study of prospectively collected data of 1515 consecutive patients undergoing paroxysmal AF (PAF) and persistent AF (PerAF) ablation at a single institution between 2009 and 2014. Patients undergoing AF ablation with the SmartTouch catheter and the ACL system (SmartTouch group, n = 510) were compared with those undergoing AF ablation without this technology (control group, n = 1005). The primary outcomes were total fluoroscopy time (min) and fluoroscopy dose as measured by the dose-area product (mGy cm(2)). Secondary endpoints included total procedure time, total ablation time, and major cardiac complications (tamponade, pericardial effusion, and urgent cardiac surgery). The SmartTouch group had significantly lower fluoroscopy times (9.5 vs. 41 min, P < 0.001), radiation doses (1044 vs. 3571 mGy cm(2), P < 0.001), and shorter procedural time (195 vs. 240 min, P < 0.001) when compared with the control group. This was statistically significant for both PAF and PerAF ablations and for both de novo and redo AF procedures. After a learning curve, a median fluoroscopy time of 3.5 min (interquartile range 6) for all AF ablations was achieved. There was no difference in the rate of cardiac complications (∼ 1.5%). CONCLUSION: SmartTouch™ CF-sensing catheter use with ACL™ during AF ablation significantly reduces fluoroscopy times by 77%, radiation dose by 71%, and procedural time by 19% but does not improve overall safety or the risk of cardiac complications.

Point-by-Point Radiofrequency Ablation Versus the Cryoballoon or a Novel Combined Approach: A Randomized Trial Comparing 3 Methods of Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation (The Cryo Versus RF Trial).

INTRODUCTION: Catheter ablation of paroxysmal AF using the Cryoballoon (CRYO) has yielded similar success rates to conventional wide encirclement using radiofrequency catheter ablation (RFCA), but randomized data are lacking. Pilot data suggested a high success rate with a combined approach (COMBINED) using wide encirclement with RFCA followed by 2 CRYO applications to each vein. We compared these 3 strategies in a randomized controlled trial. METHODS AND RESULTS: Patients undergoing first time paroxysmal AF ablation were randomized to RFCA, CRYO, or COMBINED. Patients were followed up at 3, 6, and 12 months with 7 days of ambulatory ECG monitoring. Success was defined as freedom from arrhythmia without antiarrhythmic drugs after a single procedure. A total of 237 patients were randomized. Success at 1 year was achieved in 47% in the RFCA group, 67% in the CRYO group, and 76% in the COMBINED group (P < 0.001 for RFCA vs. CRYO, P<0.001 for RFCA vs. COMBINED, and P = 0.220 for CRYO vs. COMBINED). Procedure time was 211 (IQR 174-256) minutes for RFCA compared to 167 (136-202) minutes for CRYO and 278 (243-327) minutes for COMBINED (P < 0.001 for RFCA vs. COMBINED, RFCA vs. CRYO, and CRYO vs. COMBINED groups). CONCLUSIONS: Pulmonary vein isolation for paroxysmal AF is faster with CRYO and results in a higher single procedure success rate than conventional point by point RFCA. The COMBINED approach was not superior to CRYO alone.

Impact of diabetes mellitus and renal insufficiency on 5-year mortality following coronary artery bypass graft surgery: a cohort study of 4869 UK patients.

OBJECTIVES: Diabetes mellitus (DM) and renal impairment (RI) are both independent predictors of mortality after coronary artery bypass graft surgery (CABG). The two conditions often coexist, yet the impact on long-term prognosis after CABG of each factor relative to the other and the two in combination is uncertain. METHODS: We undertook a prospective cohort study of 4869 patients who underwent CABG between 2003 and 2007. The cohort was divided into four groups according to preoperative diabetic status and renal function: patients without either DM or RI (reference group), patients with DM alone, patients with RI alone and patients with both DM and RI. Clinical outcomes were compared between groups. Patients receiving renal replacement therapy were excluded. The primary outcome was 5-year all-cause mortality. RESULTS: The crude 5-year all-cause mortality rate was 9.0% for patients in the reference group, 11.1% for patients with DM alone, 20.3% for patients with RI alone and 28.5% for patients with both DM and RI (P < 0.0001). Five-year survival adjusted for potential confounding factors was significantly worse for patients with DM (hazard ratio (HR) 1.30; 95% confidence interval (CI) 1.06-1.59), patients with RI (HR 1.32; 95% CI 1.08-1.61) and patients with both DM and RI (HR 2.04; 95% CI 1.65-2.53) when compared with patients with neither condition. CONCLUSIONS: Preoperative DM and RI were important predictors of 5-year mortality after CABG. Patients with RI alone had a higher mortality rate than patients with DM alone, but this difference was largely accounted for by age and other comorbidities. The combination of DM and RI doubled the 5-year mortality rate after CABG independently of potential confounding factors.

The impact of acute kidney injury on midterm outcomes after coronary artery bypass graft surgery: a matched propensity score analysis.

BACKGROUND: The development of acute kidney injury (AKI) after coronary artery bypass graft (CABG) surgery is associated with increased short- and long-term mortality. Whether AKI has a causal relationship with subsequent mortality or whether the development of AKI simply occurs in patients with more comorbidity undergoing more complex procedures remains unresolved. METHODS AND RESULTS: This was an observational cohort study of prospectively collected data from 4694 patients discharged from the hospital after first-time CABG surgery at a tertiary cardiac center between 2003 and 2008. AKI was defined using the Risk, Injury, Failure, Loss, and End stage (RIFLE) criteria, which require at least a 50% increase in serum creatinine. The primary outcome measure was all-cause mortality determined via UK Office of National Statistics. A total of 562 (12.0%) of patients developed AKI after CABG surgery. Patients who developed AKI were older, more likely to be female, and had more comorbidity than patients who did not develop AKI. In a Cox multivariable analysis, the development of AKI was an independent predictor of midterm mortality (hazard ratio, 1.80; 95% confidence interval, 1.50-2.16). Subsequently, a comparison of 562 patients who sustained AKI with 562 propensity score-matched patients who did not sustain AKI was undertaken. After propensity matching, baseline clinical and operative characteristics were similar between both groups. After Cox multivariable analysis of the propensity-matched cohort, AKI remained an independent predictor of midterm mortality (hazard ratio, 1.52; 95% confidence interval, 1.19-1.93). CONCLUSIONS: The development of AKI after CABG is a serious event associated with worse midterm survival. This excess mortality cannot be explained simply by coexisting comorbidity and surgical complexity.

Bone marrow mononuclear cells reduce myocardial reperfusion injury by activating the PI3K/Akt survival pathway.

OBJECTIVE: Adult bone marrow mononuclear cells (BMMNCs) can restore cardiac function following myocardial necrosis. Protocols used to date have administered cells relatively late after ischaemia/reperfusion injury, but there is the opportunity with elective procedures to infuse cells shortly after restoration of blood flow, for example after angioplasty. Our aim was therefore to try and quantify protection from myocardial injury by early infusion of BMMNCs in a rat ischaemia reperfusion (I/R) model. METHODS AND RESULTS: Male Wistar rats underwent 25 min of ischaemia followed by 2 h reperfusion of the left anterior descending coronary artery. Ten million BMMNCs were injected i.v. at reperfusion. We found BMMNCs caused a significant reduction in infarct size at 2 h when assessed by staining the area at risk with p-nitro blue tetrazolium (42% reduction, P<0.01). Apoptosis and necrosis of isolated cardiomyocytes was significantly reduced in the area at risk. Functional assessment at 7 days using echocardiography and left ventricular catheterisation showed improved systolic and diastolic function in the BMMNC treatment group (LVEF: BMMNC 71 ± 3% vs. PBS 48 ± 4%, P<0.0001). In functional studies BMMNC injected animals showed increased activation of Akt, inhibition of GSK-3ß, amelioration of p38 MAP kinase phosphorylation and NF-κB activity compared to control myocardium. Inhibition of PI3K with LY294002 abolished all beneficial effects of BMMNC treatment. Proteomic analysis also demonstrated that BMMNC treatment induced alterations in proteins within known cardioprotective pathways, e.g., heat shock proteins, stress-70 protein as well as the chaperone protein 14-3-3 epsilon. CONCLUSIONS: Early BMMNC injection during reperfusion preserves the myocardium, with evidence of reduced apoptosis, necrosis, and activation of survival pathways.

Cardiac stem cell therapy: progress from the bench to bedside.

In the rush to assess the role of stem cell therapy for cardiovascular disease the details of translation are easily overlooked. This review summarises the progress to date in translating the exciting preclinical results of cardiac repair into man and considers the questions that this area of research has stimulated about the challenges of moving from bench to bedside.

Mechanisms underlying erythrocyte and endothelial nitrite reduction to nitric oxide in hypoxia: role for xanthine oxidoreductase and endothelial nitric oxide synthase.

Reduction of nitrite (NO(2)(-)) provides a major source of nitric oxide (NO) in the circulation, especially in hypoxemic conditions. Our previous studies suggest that xanthine oxidoreductase (XOR) is an important nitrite reductase in the heart and kidney. Herein, we have demonstrated that conversion of nitrite to NO by blood vessels and RBCs was enhanced in the presence of the XOR substrate xanthine (10 micromol/L) and attenuated by the XOR inhibitor allopurinol (100 micromol/L) in acidic and hypoxic conditions only. Whereas endothelial nitric oxide synthase (eNOS) inhibition had no effect on vascular nitrite reductase activity, in RBCs L-NAME, L-NMMA, and L-arginine inhibited nitrite-derived NO production by >50% (P<0.01) at pH 7.4 and 6.8 under hypoxic conditions. Western blot and immunohistochemical analysis of RBC membranes confirmed the presence of eNOS and abundant XOR on whole RBCs. Thus, XOR and eNOS are ideally situated on the membranes of RBCs and blood vessels to generate intravascular vasodilator NO from nitrite during ischemic episodes. In addition to the proposed role of deoxyhemoglobin, our findings suggest that the nitrite reductase activity within the circulation, under hypoxic conditions (at physiological pH), is mediated by eNOS; however, as acidosis develops, a substantial role for XOR becomes evident.

Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells.

BACKGROUND & AIMS: How mutations are established and spread through the human stomach is unclear because the clonal structure of gastric mucosal units is unknown. Here we investigate, using mitochondrial DNA (mtDNA) mutations as a marker of clonal expansion, the clonality of the gastric unit and show how mutations expand in normal mucosa and gastric mucosa showing intestinal metaplasia. This has important implications in gastric carcinogenesis. METHODS: Mutated units were identified by a histochemical method to detect activity of cytochrome c oxidase. Negative units were laser-capture microdissected, and mutations were identified by polymerase chain reaction sequencing. Differentiated epithelial cells were identified by immunohistochemistry for lineage markers. RESULTS: We show that mtDNA mutations establish themselves in stem cells within normal human gastric body units, and are passed on to all their differentiated progeny, thereby providing evidence for clonal conversion to a new stem cell-derived unit-monoclonal conversion, encompassing all gastric epithelial lineages. The presence of partially mutated units indicates that more than one stem cell is present in each unit. Mutated units can divide by fission to form patches, with each unit sharing an indentical, mutant mtDNA genotype. Furthermore, we show that intestinal metaplastic crypts are clonal, possess multiple stem cells, and that fission is a mechanism by which intestinal metaplasia spreads. CONCLUSIONS: These data show that human gastric body units are clonal, contain multiple multipotential stem cells, and provide definitive evidence for how mutations spread within the human stomach, and show how field cancerization develops.

Mechanisms of disease: from stem cells to colorectal cancer.

Over the past decade, the advances in our understanding of stem cell biology and the role of stem cells in diseases, such as colorectal cancer, have been remarkable. In particular, discoveries related to the control of stem cell proliferation and how dysregulation of proliferation leads to oncogenesis have been foremost. For intestinal stem cells, the WNT family of growth factors, and events such as the regulation of the nuclear localization of beta-catenin, seem to be central to normal homeostasis, and mutations in the components of these pathways seem to lead to the development of colorectal cancer. A paradigm of abnormal stem cell biology is illustrated by patients with familial adenomatous polyposis, who have mutations in the adenomatous polyposis coli gene. The wild-type protein encoded by this gene is important for the prevention of mass beta-catenin accumulation in the nucleus and the subsequent overtranscription of cell cycle proteins. This review discusses the basic mechanisms behind stem cell regulation in the gut and follows their role in the natural history of tumor progression.

Stem cell plasticity and tumour formation.

Stem cell plasticity refers to the ability of certain stem cells to switch lineage determination and generate unexpected cell types. This review applies largely to bone marrow cells (BMCs), which appear to contribute positively to the regeneration of several damaged non-haematopoietic tissues. This beneficial effect on regeneration may be a direct result of BMCs giving rise to organ parenchymal cells. Alternatively, it could be due to BMCs fusing with existing parenchymal cells, or providing paracrine growth factor support, or contributing to neovascularisation. In the context of oncology, BMC derivation of the tumour stroma and vasculature has profound biological and therapeutic implications, and there are several examples of carcinomas seemingly being derived from BMCs.

Clonal expansion in the human gut: mitochondrial DNA mutations show us the way.

The mechanisms of how DNA mutations are fixed within the human gastrointestinal tract and how they spread are poorly understood and are hotly debated. It has been well documented that human colonic crypts are clonal units; one epithelial stem cell within the crypt becoming dominant and taking over the crypts' entire stem cell population--so called monoclonal conversion. Studies have revealed that crypts can exist as families and develop into patches. The questions have been how do such patches in the human colon develop? Does this have implications on how DNA mutations spread? We have previously shown that mitochondrial DNA (mtDNA) mutations, which result in the deficiency of cytochrome c oxidase, are established within a single colonic crypt stem cell, resulting in a crypt with a mixed phenotype. Over time that mutated stem cell can take over the entire stem cell population resulting in a wholly-mutated crypt. We have furthered this research by showing that entirely cytochrome c oxidase-deficient crypts are able to divide by a process called crypt fission, to form two cytochrome c oxidase-deficient daughter crypts, each sharing the exact parental mtDNA mutation. Furthermore, patches of these crypts also possess a founder mtDNA mutation suggesting that fission repeats itself to form patches, which increase in size with age. Here, we hypothesize that this can be expanded into other areas of the gastrointestinal tract, especially the stomach, where there is a paucity of data regarding clonality and the spread of DNA mutations. We ask if these mutated crypts expand at a different rate to wild type ones. We also discuss the implications for the spread of potential carcinogenic mutations within the gut.