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Hodgkin lymphoma (HL) is a lymphoid malignancy that is typically derived from germinal-center B cells. EBV infection, mutations in NF-κB pathway genes, and genetic susceptibility are known risk factors for developing HL. CD30 and NF-κB have been identified as potential biomarkers in pediatric HL patients, and these molecules may represent therapeutic targets. Although current risk adapted and response based treatment approaches yield overall survival rates of >95%, treatment of relapse or refractory patients remains challenging. Targeted HL therapy with the antibody-drug conjugate Brentuximab vedotin (Bv) has proven to be superior to conventional salvage chemotherapy and clinical trials are being conducted to incorporate Bv into frontline therapy that substitutes Bv for alkylating agents to minimize secondary malignancies. The appearance of secondary malignancies has been a concern in pediatric HL, as these patients are at highest risk among all childhood cancer survivors. The risk of developing secondary leukemia following childhood HL treatment is 10.4 to 174.8 times greater than the risk in the general pediatric population and the prognosis is significantly poorer than the other hematological malignancies with a mortality rate of nearly 100%. Therefore, identifying clinically valuable biomarkers is of utmost importance to stratify and select patients who may or may not need intensive regimens to maintain optimal balance between maximal survival rates and averting late effects. Here we discuss epidemiology, risk factors, staging, molecular and genetic prognostic biomarkers, treatment for low and high-risk patients, and the late occurrence of secondary malignancies in pediatric HL.

Biological and molecular heterogeneity of human diseases especially cancers contributes to variations in treatment response, clinical outcome, and survival. The addition of new disease- and condition-specific biomarkers to existing clinical markers to track cancer heterogeneity provides possibilities for further assisting clinicians in predicting clinical outcomes and making choices of treatment options. Ionization patterns derived from biological specimens can be adapted for use with existing clinical markers for early detection, patient risk stratification, treatment decision making, and monitoring disease progression. In order to demonstrate the application of pyrolysis, gas chromatography, and differential mobility spectrometry (Py-GC-DMS) for human diseases to predict the outcome of diseases, we analyzed the ionized spectral signals generated by instrument ACB2000 ( ACB irox universal detector 2000, ACBirox LLC, NJ, USA) from the serum samples of Mantle Cell Lymphoma (MCL) patients. Here, we have used mantle cell lymphoma as a disease model for a conceptual study only and based on the ionization patterns of the analyzed serum samples, we developed a multivariate algorithm comprised of variable selection and reduction steps followed by receiver operating characteristic curve (ROC) analysis to predict the probability of a good or poor clinical outcome as a means of estimating the likely success of a particular treatment option. Our preliminary study performed with small cohort provides a proof of concept demonstrating the ability of this system to predict the clinical outcome for human diseases with high accuracy suggesting the promising application of pyrolysis, gas chromatography, and differential mobility spectrometry (Py-GC-DMS) in the field of medicine.

Infection is a serious complication of hematopoietic stem cell transplantation (SCT). However, the optimum oral agent for antibacterial prophylaxis in SCT recipients remains uncertain. Different antibiotics might affect incidence of blood stream infections, resistance, Clostridium difficile, gut microbiome, GVHD and relapse. To explore this we started this first clinical trial of levofloxacin (Levo) versus ciprofloxacin (Cipro) at our center. Methods: This is a single center prospective randomized study. Patients who meet the SCT program criteria to undergo autologous or allogeneic hematopoietic stem cell transplantation are eligible. Results: We present interim results. 111 consecutive patients were randomized since June 2018. At the time of the present report 102 of these patients have follow up for 60 days or more. There were 62 males and 40 females. Median age at time of SCT was 61. Fifty received Cipro and 52 received Levo. Fifty-six patients had autologous (27 Cipro and 29 Levo) while 46 patients had allogeneic SCT (23 Cipro and 23 Levo). For allogeneic SCT, 12 patients in each group had ATG. Time to engraftment and length of stay were similar in both groups. In the Cipro group 6 patients (12%) had bacteremia while in the Levo group 7 (13%) had bacteremia. Of patients with bacteremia, in the Cipro group none had Gram negative bacteremia while in the Levo group 4 had gram negative bacteremia (OR 9.37, p = 0.137). In the Cipro group 6 patients had gram positive bacteremia while in the Levo group 3 patients had gram positive bacteremia (OR 2.22, p = 0.277). In the Cipro group, 6 (12%) had clostridium difficile while in the Levo group only 1 (1.9%) had Clostridium difficile (OR 6.95, p = 0.078). Acute GVHD of all grades accrued in 17 patients (34%) in Cipro group and in 16 patients (30.7%) in the Levo group. Grade III-IV aGVHD occurred in 6 patients (12%) in Cipro group and in 3 patients (5.8%) in the Levo group (OR 2.23, p = 0.277). The hazard ratio for progression free survival was 0.67 (95% CI: 0.27, 1.67), p=0.395 for Levo vs. Cipro. The hazard ratio for overall survival, adjusted for auto/allo and age at transplant was 0.29 (95% CI: 0.09, 0.95), p = 0.041, for Levo vs. Cipro. However, 3 of deaths in the Cipro group were not related to type of antibacterial prophylaxis (listeriosis from contaminated food, fungal pneumonia in a wooden-house builder and stroke from intraventricular thrombus). So, unadjusted hazard ratio for overall survival (Levo vs. Cipro): 0.41 (95% CI: 0.13, 1.34), p = 0.142. Hazard ratio for overall survival (Levo vs. Cipro), adjusting for allo/auto and age at transplant: 0.39 (95% CI: 0.11, 1.33), p = 0.132. Conclusion: At this point, in this interim analysis, there seems to be a trend for Cipro to protect patients from gram negative bacteremia compared to levo. As a trade-off, there is higher trend for Clostridium difficile in the Cipro group compared to Levo group, but none is statistically significant so far.

BackgroundDigital mobile technology presents a promising medium for reaching young adults with smoking cessation interventions because they are the heaviest users of this technology. ObjectiveThe aim of this study was to determine the efficacy of an evidence-informed smartphone app for smoking cessation, Crush the Crave (CTC), on reducing smoking prevalence among young adult smokers in comparison with an evidence-informed self-help guide, On the Road to Quitting (OnRQ). MethodsA parallel, double-blind, randomized controlled trial with 2 arms was conducted in Canada to evaluate CTC. In total, 1599 young adult smokers (aged 19 to 29 years) intending to quit smoking in the next 30 days were recruited online and randomized to receive CTC or the control condition OnRQ for a period of 6 months. The primary outcome measure was self-reported continuous abstinence at the 6-month follow-up. ResultsOverall follow-up rates were 57.41% (918/1599) and 60.48% (967/1599) at 3 and 6 months, respectively. Moreover, 45.34% (725/1599) of participants completed baseline, 3-, and 6-month follow-up. Intention-to-treat analysis (last observation carried forward) showed that continuous abstinence (N=1599) at 6 months was not significantly different at 7.8% (64/820) for CTC versus 9.2% (72/779) for OnRQ (odds ratio; OR 0.83, 95% CI 0.59-1.18). Similarly, 30-day point prevalence abstinence at 6 months was not significantly different at 14.4% (118/820) and 16.9% (132/779) for CTC and OnRQ, respectively (OR 0.82, 95% CI 0.63-1.08). However, these rates of abstinence were favorable compared with unassisted 30-day quit rates of 11.5% among young adults. Secondary measures of quit attempts and the number of cigarettes smoked per day at 6-month follow-up did not reveal any significant differences between groups. For those who completed the 6-month follow-up, 85.1% (359/422) of young adult smokers downloaded CTC as compared with 81.8% (346/423) of OnRQ, χ21(N=845)=1.6, P=.23. Furthermore, OnRQ participants reported significantly higher levels of overall satisfaction (mean 3.3 [SD 1.1] vs mean 2.6 [SD 1.3]; t644=6.87, P

A tissue field of somatic genetic alterations precedes the histopathological phenotypic changes of carcinoma. Genomic changes could be of potential use in the diagnosis and prognosis of pre-invasive squamous head and neck carcinoma (HNSCC) lesions and as markers for cancer risk assessment. Studies of sequential molecular alterations and genetic progression of pre-invasive HNSCC have not been clearly defined. Studies have shown recurring alterations at chromosome 9p21 (location of the CDKN2A) and TP53 mutations in the early stages of HNSCC. However, gene silencing via hypermethylation is still a relatively new idea in the development of HNSCC and little is known about the contribution of epigenetics to the development of neoplasia, its transformation, progression, and recurrence in HNSCC. This review examines the role of promoter hypermethylation of tumor suppressor genes in the progression continuum from benign papillomas to malignancy in HNSCC.

Background & Aim Aim The non-viral piggyBac transposon system reduces the complexity and expense of CAR T cell manufacture. piggyBac CAR19 T cells showed potent pre-clinical activity, so we now assess safety and clinical activity in a first-in-human study. Methods, Results & Conclusion Methods Eight patients (age 18-66 years, median 30; male n=7, female n=1) with relapsed/refractory CD19+ malignancies post HLA-matched sibling HSCT were treated with donor-derived T cells genetically modified using piggyBac to express a second-generation 4-1BB-based CAR19. The trial was conducted as an investigator-initiated study at a university hospital with local CAR19 T cell manufacture. CAR19 T cells were expanded ex vivo from 50 × 106 peripheral blood mononuclear cells, with CD19 stimulation and IL-15 support. Final products contained median 1.9 × 109 (range 0.8-2.5 × 109) total cells with 80.6% (39-93%) CAR T cells, and were generated in 15 (n=7) or 23 (n=1) days. Patients received up to 3 escalating doses of CAR19 T cells (10, 50 and 100 × 106/m2) following lymphodepleting cyclophosphamide and fludarabine (3 doses, n=5; 1 dose, n=3). Results Diagnoses were B-ALL (n=6), DLBCL (n=1), and Burkitt Lymphoma (n=1). Four patients each had a high or low burden of disease prior to treatment. The patient with Burkitt Lymphoma died of complications unrelated to CAR T cells 307 days with 3 doses. Toxicity included: cytokine release syndrome (n=3), B-cell aplasia with hypogammaglobulinaemia (n=7), prolonged cytopenias (n=6), bacterial infection (n=3) and exacerbation of chronic GVHD (n=1). No CAR T cell-related encephalopathy syndrome occurred. Conclusions Manufacture of piggyBac CAR19 T cells for clinical use is rapid, robust and uncomplicated, permitting application of this technology to multiple healthcare institutions. Early results suggest similar safety and activity to that of CAR19 T cells generated with viral vectors. The optimal CAR19 T cell dosing strategy remains to be determined.

In recent years, studies have suggested that promoter methylation in human papilloma virus (HPV) positive head and neck squamous cell carcinoma (HNSCC) has a mechanistic role and has the potential to improve patient survival. The present study aimed to replicate key molecular findings from previous analyses of the methylomes of HPV positive and HPV negative HNSCC in an independent cohort, to assess the reliability of differentially methylated markers in HPV-associated tumors. HPV was measured using real-time quantitative PCR and the biological significance of methylation differences was assessed by Ingenuity Pathway Analysis (IPA). Using an identical experimental design of a 450K methylation platform, 7 of the 11 genes were detected to be significantly differentially methylated and all 11 genes were either hypo- or hypermethylated, which was in agreement with the results of a previous study. IPA's enriched networks analysis identified one network with msh homeobox 2 (MSX2) as a central node. Locally dense interactions between genes in networks tend to reflect significant biology; therefore MSX2 was selected as an important gene. Sequestration in the top four canonical pathways was noted for 5-hydroxytryptamine receptor 1E (serotonin signaling), collapsin response mediator protein 1 (semaphorin signaling) and paired like homeodomain 2 (bone morphogenic protein and transforming growth factor-β signaling). Placement of 9 of the 11 genes in highly ranked pathways and bionetworks identified key biological processes to further emphasize differences between HNSCC HPV positive and negative pathogenesis.

// Arati A. Inamdar 1 , Andre Goy 2 , Nehad M. Ayoub 3 , Christen Attia 1 , Lucia Oton 1 , Varun Taruvai 1 , Mark Costales 1 , Yu-Ting Lin 1 , Andrew Pecora 2 and K. Stephen Suh 1 1 The Genomics and Biomarkers Program, The John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA 2 Clinical Divisions, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA 3 Department of Clinical Pharmacy, Jordan University of Science and Technology, Irbid, Jordan Correspondence to: K. Stephen Suh, email: // Keywords : biomarker, clinical trial, mantle cell lymphoma, personalized therapy, prognosis Received : December 24, 2015 Accepted : April 10, 2016 Published : April 23, 2016 Abstract Despite advances in the development of clinical agents for treating Mantle Cell Lymphoma (MCL), treatment of MCL remains a challenge due to complexity and frequent relapse associated with MCL. The incorporation of conventional and novel diagnostic approaches such as genomic sequencing have helped improve understanding of the pathogenesis of MCL, and have led to development of specific agents targeting signaling pathways that have recently been shown to be involved in MCL. In this review, we first provide a general overview of MCL and then discuss about the role of biomarkers in the pathogenesis, diagnosis, prognosis, and treatment for MCL. We attempt to discuss major biomarkers for MCL and highlight published and ongoing clinical trials in an effort to evaluate the dominant signaling pathways as drugable targets for treating MCL so as to determine the potential combination of drugs for both untreated and relapse/refractory cases. Our analysis indicates that incorporation of biomarkers is crucial for patient stratification and improve diagnosis and predictability of disease outcome thus help us in designing future precision therapies. The evidence indicates that a combination of conventional chemotherapeutic agents and novel drugs designed to target specific dysregulated signaling pathways can provide the effective therapeutic options for both untreated and relapse/refractory MCL.

ObjectiveThere is a lack of consensus regarding the causes of the differences in the higher incidence of and the mortality from head and neck squamous cell carcinoma (HNSCC) in African Americans (AA) versus Caucasian Americans (CA). We examined a comprehensive array of risk factors influencing health and disease in an access-to-care, racially diverse, primary HNSCC cohort.Study DesignCross-sectional study.SettingPrimary care academic health care system.Subjects and MethodsThe cohort of 673 patients comprised 391 CA and 282 AA (42%). Risk variables included demographic, histopathology, and clinical/epidemiologic factors. Tumor DNA was interrogated for loss and gain of 113 genes with known involvement in HNSCC/cancer. Logistic regression for univariate analysis was followed by multivariate modeling with determination of model predictability (c-index).ResultsOf the 39 univariate differences between AA and CA, multivariate modeling (c-index = 0.81) retained 7 differences (P < .05). AA were less likely to be m...

Around the world, teams of researchers continue to develop a wide range of systems to capture, store, and analyze data including treatment, patient outcomes, tumor registries, next-generation sequencing, single-nucleotide polymorphism, copy number, gene expression, drug chemistry, drug safety, and toxicity. Scientists mine, curate, and manually annotate growing mountains of data to produce high-quality databases, while clinical information is aggregated in distant systems. Databases are currently scattered, and relationships between variables coded in disparate datasets are frequently invisible. The challenge is to evolve oncology informatics from a "systems" orientation of standalone platforms and silos into an "integrated knowledge environments" that will connect "knowable" research data with patient clinical information. The aim of this article is to review progress toward an integrated knowledge environment to support modern oncology with a focus on supporting scientific discovery and improving cancer care.

Background: Implantable cardioverter-defibrillators (ICDs) reduce the rate of sudden cardiac death (SCD) in patients with cardiomyopathy and reduced left ventricular systolic function. It is unclear if this benefit extends to the very elderly patient population. Methods: Patients who underwent initial ICD implantation at age 80 or older between January 1995 and April 2010 for primary SCD prevention were identified. Clinical data were collected from the medical record, including periprocedural complications, device type, and therapies delivered. Results: Three-hundred eighty patients were identified; 84 patients met eligibility criteria. The mean age was 82.68 years; mean follow-up was 34 months. Mean left ventricular ejection fraction was 28.1%. Mortality during follow-up was 17.9%. One- and 5-year survival estimates were 100% and 60%, respectively. Periprocedural complications occurred in 9.4% of patients; serious complications occurred in 4.8% with no periprocedural deaths. Device therapies occurred in 11.9% (n = 10) of patients (9.5% appropriate, n = 8; 2.4% inappropriate, n = 2). Cardiac resynchronization therapy-defibrillator (CRT-D) implantation was associated with prolonged median survival and decreased risk of death (hazard ratio 0.212; 95% confidence interval 0.048−.942, P = 0.042) compared to ICD alone. Conclusions: Implantation of primary prevention ICDs in patients 80 years of age or older was associated with a low risk of serious complications and a 5-year survival estimate of 60%. Inappropriate therapies after implantation were uncommon. CRT-D implantation was associated with a decreased risk of death compared to ICD alone. These data suggest that, in selected patients in this age group, ICD implantation is safe and effective. (PACE 2011; 34:900–906)

Aman P. Mann 1,6 , Rohan C. Bhavane 2 , Anoma Somasunderam 3 , Brenda Liz Montalvo-Ortiz 4 , Ketan B. Ghaghada 2 , David Volk 3 , Rene Nieves-Alicea 5 , K. Stephen Suh 5 , Mauro Ferrari 6 , Ananth Annapragada 2 , David G. Gorenstein 3 , Takemi Tanaka 4 1 Department of Nanomedicine, University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston, Texas, 77030 2 School of Biomedical Informatics, University of Texas Health Science Center at Houston, 7000 Fannin, Houston, Texas, 77030 3 Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston, Texas, 77030 4 Department of Pharmaceutical Sciences, Thomas Jefferson University,130 South 9th Street, Philadelphia, PA, 19107 5 The John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey, 07601 6 The Methodist Hospital Research Institute, Houston, Texas, 77030 Keywords: drug delivery; aptamer; E-selectin Received: April 11, 2011; Accepted: May 6, 2011; Published: May 7, 2011; Correspondence: Takemi Tanaka, e-mail: // // Abstract Recent developments in multi-functional nanoparticles offer a great potential for targeted delivery of therapeutic compounds and imaging contrast agents to specific cell types, in turn, enhancing therapeutic effect and minimizing side effects. Despite the promise, site specific delivery carriers have not been translated into clinical reality. In this study, we have developed long circulating liposomes with the outer surface decorated with thioated oligonucleotide aptamer (thioaptamer) against E-selectin (ESTA) and evaluated the targeting efficacy and PK parameters. In vitro targeting studies using Human Umbilical Cord Vein Endothelial Cell (HUVEC) demonstrated efficient and rapid uptake of the ESTA conjugated liposomes (ESTA-lip). In vivo , the intravenous administration of ESTA-lip resulted in their accumulation at the tumor vasculature of breast tumor xenografts without shortening the circulation half-life. The study presented here represents an exemplary use of thioaptamer for targeting and opens the door to testing various combinations of thioaptamer and nanocarriers that can be constructed to target multiple cancer types and tumor components for delivery of both therapeutics and imaging agents.

OBJECTIVE Differentiation of the tachycardia originating from the superior vena cava (SVC) or the right superior pulmonary vein (RSPV) is limited by the similar surface P-wave morphology and intraatrial activation pattern during tachycardia. We sought to find a simple method to distinguish between the two tachycardias by analyzing the interatrial conduction time. METHODS Sixteen consecutive patients consisting of 8 with SVC tachycardia and the other 8 with RSPV tachycardia were studied. The interatrial conduction time from the high right atrium (HRA) to the distal coronary sinus (DCS) and the intraatrial conduction time from the HRA to the atrial electrogram at the His bundle region (HIS) were measured during the sinus beat (SR) and during the tachycardia-triggering ectopic atrial premature beat (APB). The differences of interatrial (Delta[HRA-DCS](SR-APB)) and intraatrial (Delta[HRA-HIS](SR-APB)) conduction time between SR and APB were then obtained. RESULTS The mean Delta[HRA-DCS](SR-APB) was 1.0 +/- 5.2 ms (95% confident interval [CI]-3.3-5.3 ms) in SVC tachycardia and 38.5 +/- 8.8 ms (95% CI 31.1-45.9 ms) in RSPV tachycardia. The mean Delta[HRA-HIS](SR-APB) was 1.5 +/- 5.3 ms (95% CI -2.9-5.9 ms) in SVC tachycardia and 19.9 +/- 12.0 ms (95% CI 9.9-29.9 ms) in RSPV tachycardia. The difference of Delta[HRA-DCS](SR-APB) between SVC and RSPV tachycardias was wider than that of Delta[HRA-HIS](SR-APB) (37.5 +/- 9.3 ms vs. 18.4 +/- 15.4 ms, P < 0.01). CONCLUSIONS The wide difference of the interatrial conduction time Delta[HRA-DCS](SR-APB) between SVC and RSPV tachycardias is a useful parameter to distinguish the two tachycardias and may avoid unnecessary atrial transseptal puncture.

Background Large-scale clinical trials have demonstrated that patients with atrial fibrillation (AF), when treated with a rhythm-control strategy, are still at risk for embolic events. We hypothesized that left atrial (LA) dysfunction persisted even after successful maintenance of sinus rhythm for > 3 months. Methods A total of 93 patients with AF and satisfactory rhythm control for > 3 months were included. Satisfactory rhythm control was defined as being free of AF based on patient-reported symptoms, monthly ECG follow-up, and ambulatory Holter ECG if needed. Among the 93 patients, 25 patients had sustained AF that was terminated by electrical or pharmacologic cardioversion, while 68 patients had paroxysmal AF under good medical control. Clinical data were obtained, and transthoracic and transesophageal echocardiography were performed after satisfactory rhythm control for > 3 months. Results Among the 93 patients, 34 patients (37%) had LA dysfunction, defined as LA appendage (LAA) peak emptying velocity 65 years, and prior cerebral vascular accident. LA dysfunction was found in 10 of 17 patients (59%) with three or more risk factors. The odds ratio for having LA dysfunction was 3.1 (p = 0.04; 95% confidence interval, 1.1 to 9.1) when compared with patients with less than three risk factors. Conclusions LA dysfunction was present in more than one third of AF patients after satisfactory rhythm control for > 3 months. Patients with higher burden (three or more) of clinical risk factors were more likely to have impaired LA function.

We prospectively studied 42 consecutive patients who had symptomatic sinus node dysfunction and 17 age-matched controls by measuring maximal and corrected maximal sinus node recovery times with an atrial overdrive suppression test and single-bolus adenosine administration (0.15 mg/kg). We found a positive correlation between the 2 methods, with reasonably good sensitivity, specificity, and predictive accuracy.

In 1992, Brugada and Brugada described 8 patients with a history of aborted sudden death and a distinct ECG pattern of right bundle-branch block with ST segment elevation in leads V1–V3 and normal QT interval in the absence of any structural heart disease. It is called Brugada syndrome now and is believed to be responsible for 4–12% of all sudden deaths and around 20% of deaths in patients with structurally normal hearts. Although this syndrome is observed worldwide and the exact prevalence is unknown, it is more common in the Southeast Asian countries. Repeated syncope, ventricular fibrillation, and sudden cardiac death have been reported in patients with Brugada syndrome. The clinical presentation of Brugada syndrome is distinguished by a male predominance and the appearance of arrhythmic events at an average age of 40 years. The Brugada syndrome is inherited in an autosomal dominant manner with incomplete penetrance and an incidence ranging between 5 and 66 per 10,000. The surface ECG manifestations of the syndrome can transiently disappear, but can be unmasked by potent sodium channel blockers in some cases. Mutations of the cardiac sodium channel SCN5A have been detectable in

Accumulation of somatic mutations of mitochondrial DNA (mtDNA) contributes to the aging process and progressive organ dysfunction. We investigated the mitochondrial DNA with 4977-base-pair mtDNA deletion mutation (mtDNA(4977)) in human atrial tissue and correlated the amount of mtDNA(4977) to clinical atrial fibrillation (AF).Atrial tissue from the right atrial appendage was obtained in 88 patients during open-heart surgery (22 children/adolescents and 66 adults). The amount of mtDNA(4977) was measured using a nested polymerase chain reaction protocol and normalized to wild-type mtDNA. We found that the mtDNA(4977) was absent in all 22 pediatric/adolescent patients. In the adult group, the relative amount of mtDNA(4977) was significantly higher in patients with AF than in patients without AF (0.55 +/- 0.26 vs 0.35 +/- 0.29, p0.007) [mean +/- SD]. The amount of mtDNA(4977) was also positively associated with age (r = 0.29, p0.01). Left and right atrial pressures, left atrial dimension, hypertension, and cardiac diagnosis did not influence the amount of mtDNA(4977) significantly. Further multivariate analysis showed that both aging and AF contributed independently to the accumulation of mtDNA(4977).AF is associated with an increase of mtDNA(4977). This change is similar to the aging process of atrial tissue and might contribute to atrial dysfunction in AF.

Sudden cardiac death in athletes, although relatively uncommon, is a well-recognized condition generally associated with some congenital abnormalities. It, however, continues to be of vast interest to the public as athletes are seen as a distinct group of individuals who are especially able to tolerate more intense physical activities than the general population. Obviously, intense activities predispose susceptible athletes to sudden cardiac death, hence the importance of pre-participation screening tests. As the cost of healthcare continues to be on the rise, there will be increasing difficulty justifying a nation-wide method of screening cost-effectively. This article is intended to describe the possible underlying causes of sudden cardiac death discovered thus far, as well as methods for detection, pre-participation guidelines, and emerging therapy.

Objectives: Interventional elimination of chronic persistent atrial fibrillation (AFib) remains difficult. An animal model mimicking the clinical situation is important. Methods and Results: Twenty-five adult pigs were implanted with a high-speed atrial pacemaker. After continuous pacing at 600 bpm for 6 weeks, 20 (91%) of the 22 survivals developed sustained AFib lasting for at least 24 h. Epicardial dense mapping revealed multiple coexisting reentrant wavelets in the left and the right atrium (LA and RA, respectively; 10.6 ± 2.9 vs. 7.6 ± 2.4 wavelets/cm2/s; p < 0.002). The mean local A-A intervals were 87.2 ± 14.6 ms in the LA and 103.3 ± 19.0 ms in the RA (p < 0.0002). Acute termination of sustained AFib was successful in 3 of the 5 pigs by propafenone, but in none of the 6 by dl-sotalol. Epicardial cryothermal ablation failed to terminate any AFib by compartmentalization of the RA free wall alone (4 pigs) or together with the LA appendage (4 pigs). Electron microscopic examination demonstrated diffuse perinuclear myolysis, myofibrillar fragmentation and mitochondrial crystal disruption in the atrium. Conclusions: Pacing-induced sustained AFib (≧24 h) in adult pigs is a feasible and efficient animal model with electrophysiological and histological characteristics closely similar to those seen in humans.

Recurrence of atrial fibrillation (AF) after electrical cardioversion of chronic AF is not uncommon. However, it remains unclear which parameter(s) predict clinical recurrence. To assess the potential predictors of clinical recurrence after successful electrical cardioversion, we analyzed clinical, echocardiographic and electrophysiologic parameters in 36 patients (age 63 ± 11 years; 26 males, 10 females) with chronic persistent AF lasting more than 3 months. The dimensions of the left atrium and left ventricular end diastole and end systole were measured by echocardiography. The P wave characteristics from the surface 12-lead electrocardiogram (ECG) were studied in sinus rhythm. Atrial local activations were studied by biatrial basket electrode mapping in AF. With a mean of 7 ± 2 months of follow-up, 17 (47%) patients had AF recurrence despite multiple antiarrhythmic drug therapy. None of the clinical or echocardiographic parameters were relevant to the recurrence. However, among the surface ECG and intraatrial electrophysiological parameters, the mean P wave duration was the only independent predictor of the risk of clinical recurrence after successful electrical cardioversion. The sensitivity and predictive accuracy of recurrence were 82 and 70%, respectively, when the mean P wave duration was more than 125 ms.

The unique structure and function of normal tissues is known to be regulated by epigenetic mechanisms. Understanding how normal cells in their respective tumor milieus might affect their susceptibility to become not only malignant but acquire breast cancer (BC) subtype-specific phenotypes, may determine tumor clinical behavior outcomes. The goal was to compare genome wide methylation profiles of non-coding miRNAs of breast cancer tissue and normal breast epithelium from estrogen receptor (ER) negative (-) and ER positive (+) tumors, and assess their miRNA methylomes in the context of tumor ER phenotypes as either ER- or ER+. BC tissue from 79 patients (39 ER- and 40 ER+) and normal tissue from 39 of these patients (19 ER- and 20-ER+) were assayed using the Illumina 450K bead array. A sub analysis focused on 2249 miRNA CpGs assigned to 615 unique miRNAs. M-values were computed as a logit function [(log (beta/ (1-beta))] of the methylation beta values. T-tests were used to compare the means of the M-values for the ER+ and ER- groups. The t-test p-values were used to generate adaptive FDR (aFDR) levels and aFDRs of 0.05 or lower were considered to be statistically significant (Tier 1). Tier 1 CpGs were subsequently filtered to select only those with a mean beta ratio between ER+ and ER- of under 0.5 or over 2.0 (Tier 2). The Tier 2 CpGs were further filtered to select only those with a mean beta difference of 0.2 or more (Tier 3). In the tumor cohort, 1224/2249 (54%) CpGs were differentially methylated between ER- and ER+ BC at Tier 1. Of the 1224, 963 (78.7%) were hypermethylated, and 1035 (84.6%) were in promoter regions. The 1224 CpGs at Tier 1, the 24 at Tier 2, and 2 CpGs at Tier 3 were associated with 379, 22 and 2 genes respectively. When the same analysis was performed on normal tissue only (19 ER- and 20-ER+), 76 of the 2249 CpGs had significant aFDR values and none of those met the Tier 2 or Tier 3 criteria. Seventy-one of the 76 (93.4%) were hypermethylated, and 65 (85.5%) were in promoter regions. The 76 significant Tier 1 (aFDR) differentially methylated CpGs were associated with 48 genes of which 43 were common to tumor Tier 1 differentially methylated miRNA genes, 10 were common to tumor Tier 2 genes, and 5 were restricted to normal tissue only. Normal epithelial tissues demonstrated similar differential methylation directionality as their respective tumor counterparts, favoring promoter region localization. Accordingly, the recognition of normal breast tissue-specific epigenetic propensities that align with their tumor phenotypes, suggest the possibility of progression markers specific for ER status as well as markers not associated with progression. This provides insights into our view of possible links between epigenetic programming, progression continuums, and how hormonal receptor subtypes may be determined. Support: Komen Foundation: KG110218 Citation Format: Kang Mei Chen, Josena K. Stephen, Indrani Datta, Dhananjay Chitale, George Divine, Maria J. Worsham. MicroRNA methylomes of normal breast tissue from ER negative and ER positive breast cancer identify progression markers specific for estrogen receptor status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4434. doi:10.1158/1538-7445.AM2017-4434

This study was undertaken to assess the effects of sotalol on the transthoracic cardioversion energy requirement for chronic atrial fibrillation (AF) and on the atrial electrograms during AF recorded by two basket electrodes.The effects of sotalol infusion on transthoracic electrical cardioversion for chronic atrial fibrillation in humans have not been well investigated.We included 18 patients with persistent AF for more than three months. Atrial electrograms were recorded by two basket electrodes positioned in each atrium respectively. Transthoracic cardioversion was performed before and after sotalol 1.5 mg/kg i.v. infusion.In the 14 patients whose AF could be terminated by cardioversion before sotalol infusion, the atrial defibrillation energy was significantly reduced after sotalol infusion (236 +/- 74 jules [J] vs. 186 +/- 77 J; p0.01). Atrial fibrillation was refractory to cardioversion in four patients at baseline and was converted to sinus rhythm by cardioversion after sotalol infusion in two of them. We further divided the patients into two groups. Group A consisted of 10 patients in whom the energy requirement was decreased by sotalol while group B consisted of eight patients in whom the energy requirement was not decreased. The mean A-A (atrial local electrogram) intervals during AF were significantly increased after sotalol infusion in both groups, but the increment of A-A interval was significantly larger in group A than it was in group B patients (36 +/- 13 ms vs. 22 +/- 8 ms for the right atrium; 19 +/- 7 ms vs. 9 +/- 7 ms for the left atrium; both p0.05). The spatial and temporal dispersions of A-A intervals were not significantly changed after sotalol infusion in both atria in both groups.Sotalol decreases the atrial defibrillation energy requirement by increasing atrial refractoriness but not by decreasing the dispersion of refractoriness.

OBJECTIVESWe investigated the gene expression of calcium-handling genes including L-type calcium channel, sarcoplasmic reticular calcium adenosine triphosphatase (Ca2+-ATPase), ryanodine re...

Background —The purpose of this study was to evaluate the safety and efficacy of a temperature-controlled radiofrequency catheter ablation system. Methods and Results —The patient population included 1050 patients who had undergone ablation of atrioventricular nodal reentrant tachycardia (AVNRT), an accessory pathway (AP), or the atrioventricular junction (AVJ). Ablation was successful in 996 patients. The probability of success was highest among patients who had undergone ablation of the AVJ, lowest in patients who had undergone ablation of an AP, and in between for patients who had undergone ablation of AVNRT. A major complication occurred in 32 patients. Four variables predicted ablation success (AVJ, AVNRT, or left free wall AP ablation and an experienced center). Four factors predicted arrhythmia recurrence (right free wall, posteroseptal, septal, and multiple APs). Two variables predicted development of a complication (structural heart disease and the presence of multiple targets), and 3 variables predicted an increased risk of death (heart disease, lower ejection fraction, and AVJ ablation). Conclusions —These findings may serve as a guide to clinicians considering therapeutic options in patients who are candidates for ablation.

Objective—To investigate the electrophysiological determinant underlying the electrical induction of counterclockwise and clockwise isthmus dependent atrial flutter. Patients and methods—The isthmus bordered by the inferior vena caval orifice-tricuspid annulus-coronary sinus ostium (IVCO-TA-CSO) has been assumed to be the site of both slow conduction and unidirectional block critical to the initiation of atrial flutter. Trans-isthmus and the global atrial conduction were studied in 25 patients with isthmus dependent atrial flutter (group A) and in 21 patients without atrial flutter (group B), by pacing at the coronary sinus ostium and the low lateral right atrium (LLRA) and mapping with a 20 pole Halo catheter in the right atrium. Results—Mean (SD) fluoroscopic isthmus length between the coronary sinus ostium and LLRA sites was 28.1 (4.0) mm in group A and 28.0 (3.9) mm in group B (p = 0.95), but the trans-isthmus conduction velocity of both directions at various pacing cycle lengths was nearly halved in group A compared with group B (mean 0.39-0.46 m/s v 0.83-0.89 m/s, p

Background Standard clinical practice permits the use of either single-chamber ventricular pacemakers or dual-chamber pacemakers for most patients who require cardiac pacing. Ventricular pacemakers are less expensive, but dual-chamber pacemakers are believed to be more physiologic. However, it is not known whether either type of pacemaker results in superior clinical outcomes. Methods The Pacemaker Selection in the Elderly study was a 30-month, single-blind, randomized, controlled comparison of ventricular pacing and dual-chamber pacing in 407 patients 65 years of age or older in 29 centers. Patients received a dual-chamber pacemaker that had been randomly programmed to either ventricular pacing or dual-chamber pacing. The primary end point was health-related quality of life as measured by the 36-item Medical Outcomes Study Short-Form General Health Survey. Results The average age of the patients was 76 years (range, 65 to 96), and 60 percent were men. Quality of life improved significantly after pacemake...

The entrance site of the slow conduction zone was identified by entrainment study in an 18 year-old woman with verapamil-sensitive idiopathic left ventricular tachycardia. Radiofrequency catheter ablation at this site eliminated the tachycardia. The entrance site was at a mid-septal location and was more than 2 cm away from the exit site. Electrophysiologic findings suggested macroreentry in the Purkinje system as the mechanism of idiopathic left ventricular tachycardia.

Human papilloma virus type 16 (HPV16) is a causative agent for some head and neck squamous cell carcinoma (HNSCC) and an independent risk factor for oropharyngeal SCC. The goal of this study was to examine HPV16 associated gene methylation in paired saliva and tumor DNA with assessment of the sensitivity, specificity, positive predictive, and negative predictive value for saliva HPV as a test for HNSCC. HPV16 status was determined by quantitative PCR (qPCR) in 35 primary HNSCC paired tumor and saliva specimens. Tumor cut points >=0.03 and >=0.1 and saliva cut points >0 and ?0.001 were used to classify results as HPV positive or negative. Aberrant methylation was determined by the methylation-specific multiplex ligation probe amplification (MS-MLPA) assay. The frequency of promoter hypermethylation in tumor samples was 66% (23/35) versus 17% (6/35) in saliva. Two of 35 paired tumor and saliva samples had commonly methylated genes. HPV and methylation were correlated for IGSF4 (p=0.01) in tumor samples (cut point ?0.03) and for ESR1 in saliva samples (cut point >0). Although the sensitivity of HPV detection in saliva was significantly reduced when saliva cut points were increased from >0 to >=0.001, the specificity and positive predictive values were 100% at saliva cut point of >=0.001, regardless of tumor cut points. Within clearly defined parameters, HPV detection in saliva DNA shows promise as a non invasive approach for tumor HPV status. Methylated genes detected in saliva may be useful in early detection and as potential predictive markers of HNSCC. Further confirmation and validation in larger cohorts is required.

Coronary artery fistulae that drain into the left ventricle are extremely rare, and even fewer cases of fistulae involving all three of the coronary arteries have so far been reported. We herein report a 64-year-old woman with a unique pattern of coronary artery-left ventricular fistulae that involved all three of the coronary arteries. The multiple fistulae presented in a diffuse plexus-like arrangement. The fistulae resulted in a diastolic volume overload of the left ventricle (left-to-left shunt), as well as "coronary steal" with the shunting of blood away from the myocardium since the fistulae represented the path of least resistance.

Implantable cardioverter-defibrillator (ICD) technology has progressed through the years decreasing the size of the device, and its effectiveness in preventing sudden cardiac death has made it a mainstay of treatment for many patients. As the use of ICDs in younger patients has increased, issues with placement of an ICD in the usual prepectoral, infraclavicular region have arisen. Subglandular placement through an inframammary incision provides a unique approach and an aesthetically pleasing outcome for ICD placement. We present a review of the current literature and 3 cases of young female patients who had placement of an ICD using this approach.

Unsuspected cardiac complications have been occasionally identified on postablation echocardiographic studies; however, the clinical utility of route echocardiographic studies following uncomplicated radiofrequency catheter ablation procedures has not been established. Two-dimensional/Doppler echocardiographic studies obtained preablation (within 3 months of the procedure) in 355 consecutive patients (180 males and 175 females, mean age 37 +/- 21 years) were compared to postablation (within 24 hours of the procedure) studies obtained after a total of 387 uncomplicated RF catheter ablation procedures for AV node slow pathway (n = 120), accessory AV pathways (n = 214), and complete AV junction (n = 39). Postablation studies identified 6 new cases (1.5%) of new wall motion abnormalities, and 3 additional patients had septal wall motion abnormalities during ventricular pacing. LVEF remained unchanged from baseline (62 +/- 10 vs 62 +/- 11). A small pericardial effusion was detected after 11 procedures (2.8%), and there were 9 (2.3%), 21 (5.4%), and 20 (5.2%) new findings of mild (1+) aortic, mitral, and tricuspid regurgitation, respectively; and no cases of significant valvular dysfunction in any patient. There were no new cases of cavity thrombus. There was no clear relationship between postablation echocardiographic findings and the type and approach to ablation, and no patient had any clinical sequelae possibly related to any of the new echocardiographic findings during a mean follow-up of 15 +/- 6.0 months (range 1-26 months). Routine transthoracic echocardiographic studies after uncomplicated RF catheter ablation procedures identify occasional minor abnormalities that (1) may or may not be procedure related, (2) are of no apparent clinical consequence, and (3) thus appear to be of limited value.

Expression of p16INK4A (p16 positive) is highly correlated with human papilloma virus (HPV) infection in head and neck squamous cell carcinoma (HNSCC), however, p16-positivity is not limited to HPV positive tumors and therefore, not a perfect surrogate for HPV. p16 survival outcomes are best documented for the oropharyngeal site (OP); non-OP sites such as the oral cavity (OC), larynx, and hypopharynx (HP) are understudied. The goal of this study was to evaluate p16 in the context of HPV16 and examine p16 survival outcomes in HPV16 positive and HPV16 negative site-specific HNSCC. p16 and HPV16 status were determined by immunohistochemistry and qPCR respectively, on 80 primary HNSCC from four sites: OC, OP, larynx and HP. p16 expression was different across sites (p

The ability of single paced ventricular beats during tachycardia to penetrate the tachycardia circuit and reset the subsequent atrial depolarization (atrial preexcitation), enabling calculation of the "preexcitation index," can be helpful in analyzing supraventricular tachycardias. However, the ventricular refractory period often prevents ventricular capture of beats with the necessary prematurity to demonstrate atrial preexcitation, particularly in atrioventricular nodal reentrant tachycardia (AVNRT). We hypothesized that the use of double premature stimuli could overcome this limitation. In 25 consecutive patients with either AVNRT or atrioventricular reciprocating tachycardia (AVRT) we attempted to demonstrate atrial preexcitation with single and double ventricular extrastimuli. Whereas atrial preexcitation with a single extrastimulus could only be achieved in 3 of 11 patients with AVNRT, all but 1 patient demonstrated atrial preexcitation with the use of double ventricular extrastimuli. On the other hand, in all but 1 patient with AVRT, atrial preexcitation could be achieved with single and double extrastimuli. A formula was derived for obtaining a preexcitation index with double extrastimuli and shown to correspond closely with the preexcitation index obtained with a single extrastimulus in the 16 patients in whom atrial preexcitation could be achieved with single and double extrastimuli. Thus, this technique significantly enhances the ability to achieve atrial preexcitation and to calculate the preexcitation index in patients with AVNRT, and thus may be useful in deciphering tachycardia mechanism in some patients, as well as being a useful technique in studying the electrophysiological properties of the antegrade and retrograde limbs of AVNRT.

Objective: For optimal feasibility using saliva rinse screening of HPV for head and neck cancer (HNC), the prevalence should be 5% or higher in the population screened. The aim of our study was to determine the prevalence of HPV16 infection in a screening population in Detroit, MI.Method: Real time quantitative PCR was applied to detect HPV16 in saliva DNA from 349 screening subjects without HNC, 157 HNC, and 19 controls. Cut points for HPV positivity were: >0 and >0.001 copy/cell. Proportions were compared between groups using exact chi-square or Fisher’s exact tests as appropriate (set at P 0, each group had an overall HPV prevalence of over 5%, with a much higher prevalence of 31.2% in the HNC patient group. At cut point >0.001, the prevalence was lower in each group, 0% in the control, 1.2% in the screening, and 17.2% in the HNC group. At >0, females in the screening group had a higher prevalence of HPV than males (P = .010), and at >0.001, prevalence was higher for males...

Human papillomavirus (HPV), particularly HPV16, is a causative agent for 25% of head and neck squamous cell cancer, including laryngeal squamous cell cancer (LSCC). HPV-positive (HPV+ve) patients, particularly those with oropharyngeal SCC, have improved prognosis. For LSCC patients, this remains to be established. The goal was to determine stage and survival outcomes in LSCC in the context of HPV infection.Historical cohort study.Primary care academic health system.In 79 patients with primary LSCC, HPV was determined using real-time quantitative polymerase chain reaction. χ(2) or Fisher exact test was used to test the association of HPV+ve with 21 risk factors including race, stage, gender, age, smoking, alcohol, treatment, and health insurance. Kaplan-Meier and log-rank tests were used to study the association of HPV and LSCC survival outcome.HPV16 was detected in 27% of LSCC patients. Caucasian American (CA) patients had higher HPV prevalence (33%) than did African American (AA) LSCC patients (16%; P = .058). HPV was significantly associated with gender (P = .016) and insurance type (P = .001). There were no differences in survival between HPV+ve and HPV-negative (HPV-ve) patients. There was no association with HPV and other risk factors including stage (early vs late).We found a high prevalence of HPV in men and a lower prevalence of HPV infection in AA compared with CA. Despite the strikingly better survival of patients with HPV+ve oropharyngeal tumors, even when adjusted for smoking, this correlation does not seem to hold true in the larynx. Larger multiethnic LSCC cohorts are needed to more clearly delineate HPV-related survival across ethnicities.

Despite the widespread use of conventional and contemporary methods to detect ovarian cancer development, ovarian cancer remains a common and commonly fatal gynecological malignancy. The identification and validation of early detection biomarkers highly specific to ovarian cancer, which would permit development of minimally invasive screening methods for detecting early onset of the disease, are urgently needed. Current practices for early detection of ovarian cancer include transvaginal ultrasonography, biomarker analysis, or a combination of both. In this paper we review recent research on novel and robust biomarkers for early detection of ovarian cancer and provide specific details on their contributions to tumorigenesis. Promising biomarkers for early detection of ovarian cancer include KLK6/7, GSTT1, PRSS8, FOLR1, ALDH1, and miRNAs.

In a study of genetic alterations, the Multiplex Ligation-dependent Probe Amplification (MLPA) assay was used to measure gain or loss of 113 gene-probes in tumor and non-tumor tissue samples collected from each of the 220 patients with squamous head and neck cancer (HNSCC). Conditional and marginal models were available; both models account for correlated data but have different aspects. The conditional logistic regression model was proposed to estimate the subject-specific risk of tumor based on the paired tumor and non-tumor data collection, which was in contrast with the marginal model to estimate population-average risk. The modeling process included rigorous variable selection, an initial multivariable model, a final model selection, and model validation. Genes with individual effect (p

Objective: Oncogenic human papillomavirus (HPV) has been established as a causative agent for 25% of head and neck squamous cell cancer (HNSCC), including laryngeal squamous cell cancer (LSCC). HPV-positive oropharyngeal patients have improved prognosis. We determined outcomes in LSCC in the context of HPV infection.Method: Seventy-nine primary LSCC were examined for 21 risk factors. HPV status was determined using real-time quantitative PCR. Chi-square/Fisher exact test were used to test association of HPV-positive with the other risk factors. Kaplan-Meier and log rank test were used to study the risk of HPV-positive status for overall survival.Results: HPV-16 was detected in 21 out of 77 (27%) primary LSCC, 16% (5/32) African American (AA) and 33% (15/45) Caucasian American (CA). Significance between race and HPV status was marginal (P = .058). HPV-positive status was significantly associated with male gender (P = .017) and insurance type (P = .001). HPV-positive LSCC had longer median survival (6.64 ye...

The goal was to determine recurrent or second primary status for late stomal malignancies, 16 and 17 years post-total laryngectomy in two laryngeal squamous cell carcinoma (LSCC) patients, based on DNA methylation signatures and HPV typing. Adopting a literature review based definition of late stomal recurrences as new primaries at the site of the stoma or neopharynx occurring more than 5 years after total laryngectomy, we employed a multi-gene candidate approach to examine promoter methylation in 24 tumor suppressor genes and PCR-based assays for HPV status offered additional insights into whether the late stomal tumors post total laryngectomy were related or not. The primary tumor for Patient 1 was negative for HPV but had aberrant hypermethylation of APC, MLH1, and BRCA1. The stomal biopsy 17-years later showed presence of HPV-16 without any methylated genes. In Patient 2, HPV-11 and promoter methylation of APC identified in the primary tumor was also observed in the stomal malignancy 16 years post total laryngectomy. Additional information provided by molecular typing for HPV and methylation markers underscored Patient 1’s and 2’s late stomal presentation as most likely a second primary and recurrence, respectively. DNA methylation markers are particularly advantageous because DNA methylation is an early event in tumorigenesis, and the epigenetic modification, 5-methylcytosine, is a stable marker. Molecular marks to discern genetic heterogeneity or relatedness of stomal malignancies several years post-total laryngectomy can provide clues to their status as either second primaries or likely recurrences. Our results support the hypothesis that a subset of stomal recurrences after total laryngectomy represents second primary tumors.

In this report, we describe two pacemaker dependent patients with outer-coil fractures in their bipolar ventricular leads who averted potentially catastrophic consequences because of a new safety feature incorporated into their pulse generators (Intermedics Cosmos II, model 284-05). Both patients were asymptomatic; the malfunctions were discovered at routine pacemaker evaluation. Magnet application resulted in symptomatic loss of ventricular capture. In each instance, the pulse generator detected an outer-coil fracture and reprogrammed itself from bipolar DDD to unipolar DOO pacing to prevent loss of capture. Subsequent lead replacement resulted in resumption of normal function. We suggest that this feature be incorporated into all devices with programmable polarity.

Background Anatomic characteristics of the cavotricuspid isthmus (CTI) have been reported to be related to the outcome of atrial flutter ablation therapy. However, preprocedural evaluation of CTI anatomy using modified transthoracic echocardiography to guide atrial flutter ablation has not been well described. Methods Transthoracic echocardiography was prospectively performed before atrial flutter ablation in 42 patients with typical CTI-dependent atrial flutter. A modified apical long-axis view was designed to visualize and evaluate anatomic characteristics of the CTI and Eustachian ridge (ER). A prominent ER, extending from the inferior vena cava to the interatrial septum, is defined as an extensive ER. Results Twenty-eight patients had straightforward ablation procedures, and 14 patients had difficult ablation procedures. Two patients with difficult procedures had unsuccessful ablation. Multivariate analysis (using CTI length, the presence of a pouch or recess, ER morphology, and significant tricuspid regurgitation as variables) showed that the presence of extensive ER was the only independent predictor of a difficult ablation procedure. The ablation time in patients with extensive ER ( n = 13) was significantly longer than in those patients with nonextensive ER ( n = 29) (1,638.4 ± 1,548.3 vs 413.8 ± 195.5 sec, P = .015). The incidence of difficulty in achieving bidirectional isthmus block was also higher in patients with extensive ER (10 of 13 vs four of 29, P Conclusion Preprocedural transthoracic echocardiography using a modified apical long-axis view is useful to characterize the morphology of the CTI and the ER. An extensive ER is a strong predictor for difficult ablation of CTI-dependent atrial flutter.

Although the pig has been used as an experimental model for ischemic heart disease and sudden death, relatively little is known about the anatomy of the conduction system (CS) of this animal. We attempted to correlate electrophysiologic and anatomic differences between the pig and human CS. Invasive electrophysiologic studies were performed in five healthy anesthetized pigs. In contrast to the adult human, the pig has sinus tachycardia, shortened PR and H-V intervals, and a relatively short sinoatrial conduction time. Compared with the human CS, serial sections of the CS of pig hearts showed the following differences: (1) the atrioventricular node is located more to the right of the summit of the ventricular septum; (2) the penetrating bundle is very short, and the bifurcation of the bundle into bundle branches occurs more proximally; (3) there is more connective tissue and less elastic tissue; and (4) there is a copious amount of nerve fibers (about 50 percent throughout the CS). The presence of the abundant neural tissue implies that there is an important neurogenic component to conduction in the pig. Because of the above differences from the human, the pig should be used with caution as an experimental model in ischemic heart disease and sudden death where arrhythmias are studied.

Background Angiotensin II and its downstream mitogen-activated protein kinase signaling pathways are involved in the pathogenesis of AF. Pro-inflammatory JAK/STAT is another downstream signaling pathway of Angiotensin II, and its status in AF remains unknown. Objective The aim of this study was to characterize the status of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways in pacing-induced sustained atrial fibrillation (AF). Methods AF was induced by atrial pacing at 600/min in 10 adult pigs (AF group), while 10 sham-operated pigs served as the control group. Results Significant structural and inflammatory changes were noted in the AF group. Atrial tissue angiotensin II level was elevated and STAT1 and STAT3 were activated in the AF group. Nuclear translocation of activated STAT3 and binding to STAT3 consensus DNA sequence were also increased in the AF group. Rac1, the molecular target of statin, which mediates the activation of STAT3 by angiotensin II, was also activated in the AF group. The tissue levels of interleukin-6, leukemia inhibitory factor (LIF) and cardiotrophin-1 (CT-1), which are known to activate STATs through membrane gp130 and JAKs, were not increased in the AF group. Membrane gp130 and JAKs were also not activated in the AF group. Conclusion Activated angiotensin II/Rac1/STAT may be associated with or perhaps contribute to the structural and inflammatory changes in pacing-induced sustained trial fibrillation. It may further imply the therapeutic option of combination of angiotensin receptor blocker and statin.

Remodeling of atrial extracellular matrix (ECM) in atrial fibrillation (AF) involves changes in the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). The contributions of MMPs and TIMPs to the pathogenesis of AF development have not been clearly defined. This study evaluated the in situ activity and expression of gelatinases (MMP-2 and MMP-9) and their relationship with TIMP-1 or TIMP-3 in atria undergoing rapid atrial pacing for the induction of AF (4 weeks' pacing followed by 2 weeks of maintained AF) in pigs. In AF atria, in situ gelatinase activity was mainly localized in the interstitium of atrial myocardium, and was significantly larger than that of sinus rhythm control (i.e., sham control). The significant increase of MMP-9 in its pro-form and mRNA level, but not MMP-2, was shown to be responsible for the increased gelatinase activity in atria with AF. The inhibitory activities of glycosylated TIMP-1 and TIMP-3, but not TIMP-2, in AF tissues were markedly elevated and also localized in the atrial interstitium. TIMP-1 was found to be mostly colocalized with gelatinase activity over the AF tissues, implying the coexistence of gelatinase activity and TIMP-1, but TIMP-3 appeared only partially colocalized and discontinued the gelatinase activity surrounding the cardiomyocytes. TIMP-1 and TIMP-3 may play differential roles in the inhibition of gelatinase activity in vivo. Together with the survey of several MMPs transcripts and the level of transforming growth factor-beta1 (TGF-beta1), we proposed that the increased activity of gelatinase (i.e., MMP-9), TIMP-1 and TIMP-3 and their interaction may contribute to atrial ECM remodeling of AF.