bluuebunny/crossref_metadata_2025 huggingface dataset:
Detecting Rare Variants for Quantitative Traits Using Nuclear Families
Authors: Guo Wei , Shugart Yin Yao
Published: June 2012

With the advent of sequencing technology opening up a new era of personal genome sequencing, huge amounts of rare variant data have suddenly become available to researchers seeking genetic variants related to human complex disorders. There is an urgent need for the development of novel statistical methods to analyze rare variants in a statistically powerful manner. While a number of statistical tests have already been developed to analyze collapsed rare variants identified by association tests in case-control studies, to date, only two FBAT tests-for-rare (described in the updated FBAT version v2.0.4) have applied collapsing methods analogously in family-based designs. For further research in this area, this study aims to introduce three new beta-determined weight tests for detecting rare variants for quantitative traits in nuclear families. In addition to evaluating the performance of these new methods, it also evaluates that of the two FBAT tests-for-rare, using extensive simulations of situations with and without linkage disequilibrium. Results from these simulations suggest that the four tests using beta-determined weights outperform the two collapsing methods used in FBAT (-v0 and -v1). In addition, both the linear combination method (detailed in the FBAT menu v2.0.4) and the multiple regression method (mixing LASSO and Ridge penalties) performed better than the other two beta-determined weight tests we proposed. Following testing and evaluation, we submitted four new beta-determined weight methods of statistical analysis in a computer program to the Comprehensive R Archive Network (CRAN) for general use.
Model of Wound Healing for Esophagogastric Anastomoses in Rats
Authors: Drescher D.G. , Vogt J. , Gabriel M. , Baumgart J. , Schimanski C.C. , Lang H. , Gockel I.
Published: June 2012

Background: Anastomotic leakage after esophageal surgery is a significant cause of morbidity and mortality. Postoperative leakage of esophagogastric anastomosis has been reported in 2–30% of surgical patient, resulting in an increased need for reoperation and a high risk of subsequent esophageal stricture formation and fistula. So far, experimental investigations on major factors influencing the healing of esophageal anastomoses, e.g. neovascularization and collagen deposition, have been hindered by the lack of a functional rodent model. Methods: We developed a novel technique of gastric tube formation followed by end-to-end esophagogastric anastomosis in a rat model. Standardized anastomoses were carried out in 18 Brown-Norway rats and normal esophagogastric healing was studied by measuring anastomotic breaking strength 5 days after surgery. Results: Five animals showed an insufficiency of the esophagogastric anastomosis as determined by anastomotic leakage testing. Normal anastomotic healing was found in 10 animals. The anastomotic breaking strength was 1.93 ± 0.45 N. Conclusion: The rat model for performing esophagogastric anastomoses after gastric tube formation may serve as a functional and useful model in future research studies on microvascular and molecular processes of anastomotic healing.
Patterns and Predictors of Early Mortality in Incident Hemodialysis Patients: New Insights
Authors: Lukowsky Lilia R. , Kheifets Leeka , Arah Onyebuchi A. , Nissenson Allen R. , Kalantar-Zadeh Kamyar
Published: June 2012

Background: Incident hemodialysis patients have the highest mortality in the first several months after starting dialysis treatments. We hypothesized that the patterns and risk factors associated with this early mortality differ from those in later dialysis therapy periods. Methods: We examined mortality patterns and predictors during the first several months of hemodialysis treatment in 18,707 incident patients since the first week of hemodialysis therapy and estimated the population attributable fractions for selected time periods in the first 24 months. Results: The 18,707 incident hemodialysis patients were 45% women and 54% diabetics. The standardized mortality ratios (95% confidence interval) in the 1st to 3rd month of hemodialysis therapy were 1.81 (1.74–1.88), 1.79 (1.72–1.86), and 1.34 (1.27–1.40), respectively. The standardized mortality ratio reached prevalent mortality only by the 7th month. No survival advantage for African Americans existed in the first 6 months. Patients with low albumin <3.5 g/dl had the highest proportion of infection-related deaths while patients with higher albumin levels had higher cardiovascular deaths including 76% of deaths during the first 3 months. Use of catheter as vascular access and hypoalbuminemia <3.5 g/dl explained 34% (17–54%) and 33% (19–45%) of all deaths in the first 90 days, respectively. Conclusions: Incident hemodialysis patients have the highest mortality during the first 6 months including 80% higher death risk in the first 2 months. The presence of a central venous catheter and hypoalbuminemia <3.5 g/dl each explain one third of all deaths in the first 90 days.
Evaluation of a Structured Report of Functional Prostate Magnetic Resonance Imaging in Patients with Suspicion for Prostate Cancer or under Active Surveillance
Authors: Quentin M. , Blondin D. , Klasen J. , Schek J. , Buchbender C. , Miese F.R. , Antoch G. , Barski D. , Albers P. , Arsov C.
Published: June 2012

Background: Functional magnetic resonance imaging (MRI) seems to be a useful tool for prostate cancer (PCa) detection in patients with a previous negative biopsy but persistently increased prostate-specific antigen (PSA) values. Additionally, it enables correct cancer localization in patients with known PCa under active surveillance to avoid misclassification on repeat biopsies. Nevertheless, suspicious lesions on MRI findings need verification by biopsy. The aim of the present study was to establish a standardized functional prostate MRI reporting scheme. Methods: Prostate MRI with T2-weighted images, T1-weighted images, diffusion-weighted imaging, and dynamic contrast-enhanced MRI of 56 consecutive patients were performed on a 3-T scanner. Patients with prior negative random transrectal ultrasound (TRUS)-guided biopsy and continuous suspicion for PCa as well as patients under active surveillance were included. The MRI localization report of suspicious lesions followed a standardized scheme. TRUS-guided random biopsy with addition of targeted biopsy cores was performed afterwards based on the structured report. Results: Of the 56 patients, 18 had suspicious MRI findings and subsequently underwent repeat biopsy under guidance of the standardized localization scheme. PCa was documented in 72% (13/18). Conclusions: A standardized reporting scheme of suspicious findings on prostate MRI leads to higher success rates as compared to standard random TRUS-guided biopsy.
Narrowed Aortoseptal Angle Is Related to Increased Central Blood Pressure and Aortic Pressure Wave Reflection
Authors: Olafiranye Oladipupo , Ibrahim Mediha , Kamran Haroon , Venner-Jones Kinda , McFarlane Samy I. , Salciccioli Louis , Lazar Jason M.
Published: June 2012

The left ventricular (LV) aortoseptal angle (ASA) decreases with age, and is associated with basal septal hypertrophy (septal bulge). Enhanced arterial pressure wave reflection is known to impact LV hypertrophy. We assessed whether ASA is related to central blood pressure (BP) and augmentation index (AI), a measure of the reflected pressure wave. We studied 75 subjects (age 62 ± 16 years; 66% female) who were referred for transthoracic echocardiography and had radial artery applanation tonometry within 24 h. Peripheral systolic BP (P-SBP), peripheral diastolic BP (P-DBP), and peripheral pulse pressure (P-PP) were obtained by sphygmomanometry. Central BPs (C-SBP, C-DBP, C-PP) and AI were derived from applanation tonometry. AI was corrected for heart rate (AI75). The basal septal wall thickness (SWT), mid SWT and ASA were measured using the parasternal long axis echocardiographic view. Mean ASA and AI75 were 117 ± 11° and 22 ± 11%, respectively. ASA correlated with AI75 (r = –0.31, p ≤ 0.01), C-SBP (r = –0.24, p = 0.04), C-PP (r = –0.29, p = 0.01), but only showed a trend towards significance with P-SBP (r = –0.2, p = 0.09) and P-PP (r = –0.21, p = 0.08). Interestingly, C-PP was correlated with basal SWT (r = 0.27, p = 0.02) but not with mid SWT (r = 0.19, p = 0.11). On multivariate linear regression analysis, adjusted for age, gender, weight, and mean arterial pressure, AI75 was an independent predictor of ASA (p = 0.02). Our results suggest that a narrowed ASA is related to increased pressure wave reflection and higher central BP. Further studies are needed to determine whether narrowed LV ASA is a cause or consequence of enhanced wave reflection and whether other factors are involved.
Testis-Specific Protein Y-Encoded Copy Number Is Correlated to Its Expression and the Field Fertility of Canadian Holstein Bulls
Authors: Hamilton C.K. , Verduzco-Gómez A.R. , Favetta L.A. , Blondin P. , King W.A.
Published: June 2012

Testis-specific protein Y-encoded (TSPY) is present in varying copy number in both human (20–76 copies) and cattle (37–200 copies), and some studies have linked this variation to semen quality in men. The purpose of this study was to determine if TSPY copy number is associated with fertility in bulls by using adjusted non-return rates, a commonly used measure of field fertility in Canada. In addition, we investigated the associations between TSPY copy number and its expression as well as specific semen parameters, such as average sperm concentration, sperm count, ejaculate volume, and motility. In 2 independent trials, TSPY copy number was shown to be positively correlated to adjusted non-return rates (trial #1: Spearman r = 0.34, p < 0.05; trial #2: Spearman r = 0.77, p < 0.01). Furthermore, TSPY copy number was inversely correlated to TSPY mRNA expression in the testis (Pearson r = –0.71, p < 0.0001). There were no correlations of TSPY copy number or expression with the semen parameters measured. Therefore, TSPY copy number might represent a potential marker of bull fertility, but its mechanism does not appear to be directly related to the semen characteristics analyzed as part of this study.
Utility of Routine Ultrasound after Laparoscopic Cholecystectomy to Detect Early Postoperative Complication
Authors: Müller Sven , Falch Claudius , Kreuzer Julia , Storz Pirmin , Konigsrainer Alfred , Kirschniak Andreas
Published: June 2012

Background and Aim: In up to 3% of laparoscopic cholecystectomies, procedure-related complications occur. Routine postoperative ultrasound is one means of screening for these complications. The aim of this study was to determine the utility of this practice after laparoscopic cholecystectomy. Methods: A series of consecutive patients (n = 1,044) undergoing laparoscopic cholecystectomy from January 2007 to January 2011 was analysed. Primary endpoint was the detection of procedure-related complications by routine ultrasound. Results: Routine ultrasound within the first 48 h after laparoscopic cholecystectomy was performed in 967 of 1,044 patients. Overall, 25 (2.4%) of the 1,044 patients suffered from procedure-related complications, but only in 2 patients was the complication detected by routine ultrasound. Findings were false-positive in 103 patients. This corresponds to a sensitivity of 8% and a specificity of 89%. Hospital stay was prolonged in the false-positive group. Conclusion: Routine postoperative ultrasound has a low sensitivity for the detection of complications after laparoscopic cholecystectomy. In almost all cases, the diagnosis is initiated by clinical findings. Therefore, routine ultrasound is of limited value in screening for postoperative complications after cholecystectomy.
Adjuvant Treatment of Recalcitrant Bullous Pemphigoid with Immunoadsorption
Authors: Müller P.A. , Bröcker E.B. , Klinker E. , Stoevesandt J. , Benoit S.
Published: June 2012

Elimination of pathogenic autoantibodies by immunoadsorption (IA) has been described as an effective adjuvant treatment in severe bullous autoimmune diseases, especially in pemphigus. There is much less experience in the treatment of bullous pemphigoid (BP). BP was diagnosed in a 62-year-old Caucasian woman presenting a pruritic rash with multiple tense blisters. Standard treatments with topical and oral corticosteroids, steroid-sparing agents including dapsone, azathioprine, mycophenolate mofetil (MMF) and intravenous immunoglobulins were ineffective or had to be discontinued due to adverse events. An immediate clinical response could be achieved by two treatment cycles of adjuvant protein A immunoadsorption (PA-IA) in addition to continued treatment with MMF (2 g/day) and prednisolone (1 mg/kg/day). Tolerance was excellent. Clinical improvement remained stable after discontinuation of IA and went along with sustained reduction of circulating autoantibodies. Our data demonstrate that PA-IA might be a safe and effective adjuvant treatment in severe and recalcitrant BP.
Assessment of Venous Thromboembolism Risk and Adequacy of Prophylaxis in Selected Acute Care Medical Centres in Arabian Gulf States: Results from the ENDORSE Study
Authors: Alsayegh Faisal , Kamaliddin Hassan , Sheshah Eman , Bukhamseen Nasir , Alkhuwaitir Tarig , Elhoufi Ashraf
Published: June 2012

Objectives: To assess the prevalence of venous thromboembolism (VTE) risk in acutely ill surgical and medical patients in selected acute care centres in the Arabian Gulf States, and to determine the proportion of at-risk patients who received effective prophylaxis in accordance with 2004 American College of Chest Physicians (ACCP) guidelines. Materials and Methods: Eight hospitals from 3 countries (Kuwait, Kingdom of Saudi Arabia, and United Arab Emirates) contributed to the global ENDORSE (Epidemiological International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study. Medical records were reviewed for all the in-patients aged ≥40 years admitted to medical wards, and in patients aged ≥18 admitted to surgical wards. The VTE risk and recommended prophylaxis were assessed according to the 2004 ACCP guidelines. Results: Of 1,291 evaluable patients, 801 were considered at risk of VTE; 391 (48.8%) surgical patients and 410 (51.2%) medical patients. Of the 801 patients, 322 (40.2%) received ACCP-recommended VTE prophylaxis; 159 (40.7%) of surgical patients and 163 (39.8%) of medical patients. Conclusions: The data showed that VTE prophylaxis was underutilized in high-risk hospitalized patients. We recommend that active measures should be implemented in acute care centres in these Arabian Gulf countries to ensure identification of patients at risk of VTE and institute the appropriate prophylaxis.
Appropriateness of Pediatric Hospitalization in a General Hospital in Kuwait
Authors: Shafik Magdy H. , Seoudi Tarek M.M. , Raway Tarek S. , Al Harbash Nowair Z. , Ahmad Meshal M.A. , Al Mutairi Hanan F.
Published: June 2012

Objectives: To determine the rate of inappropriate pediatric admissions using the Pediatric Appropriateness Evaluation Protocol (PAEP) and to examine variables associated with inappropriateness of admissions. Subjects and Methods: A prospective study was conducted in the Department of Pediatrics, Farwania General Hospital, Kuwait, to examine successive admissions for appropriateness of admission as well as several sociodemographic characteristics over a 5-month period (August 2010 to December 2010). A total of 1,022 admissions were included. Results: Of the 1,022 admissions, 416 (40.7%) were considered inappropriate. Factors associated with a higher rate of inappropriate admission included older age of patients and self-referral. Conclusion: The rate of inappropriate hospitalization of children was high in Farwania Hospital, Kuwait, probably due to the relatively free health care services, parental preference for hospital care, easy access to hospital services, and insufficient education about the child’s condition.
Chromosome Evolution in Xenarthra: New Insights from an Ancient Group
Authors: Svartman M.
Published: June 2012

The Magnaorder Xenarthra is one of the four main supraordinal eutherian clades, together with Afrotheria, Euarchontoglires and Laurasiatheria. Xenarthra is an eminently Central and South American group of special interest in phylogenetic studies due to its possible position at the base of the eutherian tree. The use of modern cytogenetic techniques in some species of Xenarthra has provided important insights into the karyotypic evolution of mammals. Nevertheless, chromosome analyses in the group are still restricted, with only a few individuals of each species studied and karyotype descriptions mostly without banding patterns. In addition, it is likely that still unknown species exist and that the chromosome variability in the group is underestimated. We present a review of the currently available data on Xenarthra chromosomes and genomes and on the impact that their study has had in the understanding of mammalian genome evolution. It is clear that further cytogenetic analyses in Xenarthra, including banding patterns and molecular approaches, are likely to help in the identification of new species, reveal still undetected chromosome variations, provide information to support conservation strategies planning, and greatly contribute to a better understanding of mammalian genome evolution.
Role of Lipoprotein(a) and Apolipoprotein(a) Phenotype in Atherogenesis
Authors: Kronenberg Florian , Kronenberg Martina F. , Kiechl Stefan , Trenkwalder Evi , Santer Peter , Oberhollenzer Friedrich , Egger Georg , Utermann Gerd , Willeit Johann
Published: June 2012

Background
—Experimental studies have suggested both atherogenic and thrombogenic properties of lipoprotein(a) [Lp(a)], depending on Lp(a) plasma concentrations and varying antifibrinolytic capacity of apolipoprotein(a) [apo(a)] isoforms. Epidemiological studies may contribute to assessment of the relevance of these findings in the general population.

Methods and Results
—This study prospectively investigated the association between Lp(a) plasma concentrations, apo(a) phenotypes, and the 5-year progression of carotid atherosclerosis assessed by high-resolution duplex ultrasound in a random sample population of 826 individuals. We differentiated early atherogenesis (incident nonstenotic atherosclerosis) from advanced (stenotic) stages in atherosclerosis that originate mainly from atherothrombotic mechanisms. Lp(a) plasma concentrations predicted the risk of early atherogenesis in a dose-dependent fashion, with this association being confined to subjects with LDL cholesterol levels above the population median (3.3 mmol/L). Apo(a) phenotypes were distributed similarly in subjects with and without early carotid atherosclerosis. In contrast, apo(a) phenotypes of low molecular weight emerged as one of the strongest risk predictors of advanced stenotic atherosclerosis, especially when associated with high Lp(a) plasma concentrations (odds ratio, 6.4; 95% CI, 2.8 to 14.9).

Conclusions
—Lp(a) is one of the few risk factors capable of promoting both early and advanced stages of atherogenesis. Lp(a) plasma concentrations predicted the risk of early atherogenesis synergistically with high LDL cholesterol. Low-molecular-weight apo(a) phenotypes with a putatively high antifibrinolytic capacity in turn emerged as one of the leading risk conditions of advanced stenotic stages of atherosclerosis.
Geometric Vascular Remodeling After Balloon Angioplasty and β-Radiation Therapy
Authors: Sabaté Manel , Serruys Patrick W. , van der Giessen Willem J. , Ligthart Jurgen M.R. , Coen Veronique L.M.A. , Kay I. Patrick , Gijzel Anthonie L. , Wardeh Alexander J. , den Boer Ad , Levendag Peter C.
Published: June 2012

Background
—Endovascular radiation appears to inhibit intimal thickening after overstretching balloon injury in animal models. The effect of brachytherapy on vascular remodeling is unknown. The aim of the study was to determine the evolution of coronary vessel dimensions after intracoronary irradiation after successful balloon angioplasty in humans.

Methods and Results
—Twenty-one consecutive patients treated with balloon angioplasty and β-radiation according to the Beta Energy Restenosis Trial-1.5 were included in the study. Volumetric assessment of the irradiated segment and both edges was performed after brachytherapy and at 6-month follow-up. Intravascular ultrasound images were acquired by means of ECG-triggered pullback, and 3-D reconstruction was performed by automated edge detection, allowing the calculation of lumen, plaque, and external elastic membrane (EEM) volumes. In the irradiated segments, mean EEM and plaque volumes increased significantly (451±128 to 490.9±159 mm
3
and 201.2±59 to 241.7±74 mm
3
;
P
=0.01 and
P
=0.001, respectively), whereas luminal volume remained unchanged (250.8±91 to 249.2±102 mm
3
;
P
=NS). The edges demonstrated an increase in mean plaque volume (26.8±12 to 32.6±10 mm
3
,
P
=0.0001) and no net change in mean EEM volume (71.4±24 to 70.9±24 mm
3
,
P
=NS), resulting in a decrease in mean luminal volume (44.6±16 to 38.3±16 mm
3
,
P
=0.01).

Conclusions
—A different pattern of remodeling is observed in coronary segments treated with β-radiation after successful balloon angioplasty. In the irradiated segments, the adaptive increase of EEM volume appears to be the major contributor to the luminal volume at follow-up. Conversely, both edges showed an increase in plaque volume without a net change in EEM volume.
Regular Aerobic Exercise Augments Endothelium-Dependent Vascular Relaxation in Normotensive As Well As Hypertensive Subjects
Authors: Higashi Yukihito , Sasaki Shota , Kurisu Satoshi , Yoshimizu Atsunori , Sasaki Nobuo , Matsuura Hideo , Kajiyama Goro , Oshima Tetsuya
Published: June 2012

Background
—Several nonpharmacological interventions, including exercise, are recommended in primary prevention of hypertension and other cardiovascular diseases in which the pathogenetic role of endothelial dysfunction has been suggested. We studied the effects of long-term aerobic exercise on endothelial function in patients with essential hypertension.

Methods and Results
—The forearm blood flow was measured by strain-gauge plethysmography. The responses of forearm vasculature to acetylcholine were smaller in the hypertensive patients than in the normotensive subjects. There was no significant difference in forearm vascular responses to isosorbide dinitrate in the normotensive and hypertensive subjects. We evaluated the effects of physical exercise for 12 weeks on forearm hemodynamics in untreated patients with mild essential hypertension who were divided randomly into an exercise group (n=10) and a control group (n=7). After 12 weeks, the forearm blood flow response to acetylcholine increased significantly, from 25.8±9.8 to 32.3±11.2 mL · min
−1
· 100 mL tissue
−1
(
P
<0.05), in the exercise group but not in the control group. The increase in the forearm blood flow after isosorbide dinitrate was similar before and after 12 weeks of follow-up in both groups. The infusion of
N
G
-monomethyl-
l
-arginine abolished the exercise-induced enhancement of forearm vasorelaxation evoked by acetylcholine in the exercising group. In normotensive subjects also, long-term aerobic exercise augmented acetylcholine-stimulated nitric oxide release.

Conclusions
—These findings suggest that long-term physical exercise improves endothelium-dependent vasorelaxation through an increase in the release of nitric oxide in normotensive as well as hypertensive subjects.
Catheter Ablation of Paroxysmal Atrial Fibrillation Using a 3D Mapping System
Authors: Pappone Carlo , Oreto Giuseppe , Lamberti Filippo , Vicedomini Gabriele , Loricchio Maria Luisa , Shpun Shlomo , Rillo Mariano , Calabrò Maria Pia , Conversano Andrea , Ben-Haim Shlomo A. , Cappato Riccardo , Chierchia Sergio
Published: June 2012

Background
—We treated paroxysmal recurrent atrial fibrillation (AF) with radiofrequency (RF) catheter ablation by creating long linear lesions in the atria. To achieve line continuity, a 3D electroanatomic nonfluoroscopic mapping system was used.

Methods and Results
—In 27 patients with recurrent AF, a catheter incorporating a passive magnetic field sensor was navigated in both atria to construct a 3D activation map. RF energy was delivered to create continuous linear lesions: 3 lines (intercaval, isthmic, and anteroseptal) in the right atrium and a long line encircling the pulmonary veins in the left atrium. After RF application, the atria were remapped to validate completeness of the block lines, demonstrated by late activation of the areas circumscribed by the lines. The mean procedure duration was 312±103 minutes (range, 187 to 495), with mean fluoroscopy time of 107±44 minutes (range, 32 to 185 minutes). No acute complications occurred, but 1 patient experienced early prolonged sinus pauses and received a pacemaker. During the first day, 17 patients (63%) had AF episodes, but at discharge, 25 patients were in sinus rhythm. After a follow-up of 6.0 to 15.3 months (average, 10.5±3.0 months), 16 patients are asymptomatic, 3 have an almost complete disappearance of symptoms, 1 patient is improved, and 7 patients have their AF attacks unchanged.

Conclusions
—Paroxysmal recurrent drug-refractory AF can be treated by RF catheter ablation. Creation of long continuous linear lesions necessary to compartmentalize the atria is facilitated by a nonfluoroscopic electroanatomic mapping system.
Diuretics and Risk of Arrhythmic Death in Patients With Left Ventricular Dysfunction
Authors: Cooper Howard A. , Dries Daniel L. , Davis C. E. , Shen Yuan Li , Domanski Michael J.
Published: June 2012

Background
—Treatment with diuretics has been reported to increase the risk of arrhythmic death in patients with hypertension. The effect of diuretic therapy on arrhythmic death in patients with left ventricular dysfunction is unknown.

Methods and Results
—We conducted a retrospective analysis of 6797 patients with an ejection fraction <0.36 enrolled in the Studies Of Left Ventricular Dysfunction (SOLVD) to assess the relation between diuretic use at baseline and the subsequent risk of arrhythmic death. Participants receiving a diuretic at baseline were more likely to have an arrhythmic death than those not receiving a diuretic (3.1 vs 1.7 arrhythmic deaths per 100 person-years,
P
=0.001). On univariate analysis, diuretic use was associated with an increased risk of arrhythmic death (relative risk [RR] 1.85,
P
=0.0001). After controlling for important covariates, diuretic use remained significantly associated with an increased risk of arrhythmic death (RR 1.37,
P
=0.009). Only non–potassium-sparing diuretic use was independently associated with arrhythmic death (RR 1.33,
P
=0.02). Use of a potassium-sparing diuretic, alone or in combination with a non–potassium-sparing diuretic, was not independently associated with an increased risk of arrhythmic death (RR 0.90,
P
=0.6).

Conclusions
—In SOLVD, baseline use of a non–potassium-sparing diuretic was associated with an increased risk of arrhythmic death, whereas baseline use of a potassium-sparing diuretic was not. These data suggest that diuretic-induced electrolyte disturbances may result in fatal arrhythmias in patients with systolic left ventricular dysfunction.
Plasma Urokinase Antigen and Plasminogen Activator Inhibitor-1 Antigen Levels Predict Angiographic Coronary Restenosis
Authors: Strauss Bradley H. , Lau Herbert K. , Bowman Kimberley A. , Sparkes John , Chisholm Robert J. , Garvey M. Bernadette , Fenkell Louis L. , Natarajan Madhu K. , Singh Inderbir , Teitel Jerome M.
Published: June 2012

Background
—The fibrinolytic system is intimately involved in several processes that contribute to restenosis, including clot dissolution, cell migration, and tissue remodeling. However, the role of the individual activators (urokinase [uPA] and tissue plasminogen [tPA] activators) and inhibitors (plasminogen activator inhibitor [PAI-1]) of the fibrinolytic system in maintaining patency after coronary artery angioplasty and stenting is unclear.

Methods and Results
—We prospectively studied 159 patients with stable angina who underwent successful elective angioplasty (n=110) or stenting (n=49) of de novo native coronary artery lesions. Plasma samples were drawn at baseline (before angioplasty) and serially after angioplasty (immediately afterward and 6 hours, 24 hours, 3 days, 7 days, 1 month, 3 months, and 6 months afterward). Antigen and activity assays were performed for uPA, tPA, and PAI-1. Follow-up quantitative coronary angiography was performed in 92% of eligible patients. The overall angiographic restenosis rate (diameter stenosis >50%) was 31% (37% in PTCA patients, 17% in stented patients). At all time periods, including baseline, uPA antigen levels were significantly higher and PAI-1 antigen levels were significantly lower in patients with restenosis. Restenosis rates for patients in the upper tertile of baseline uPA antigen levels were 2-fold higher than for those in the lower 2 tertiles (46% versus 24% and 22%, respectively;
P
<0.004). In a stepwise regression multivariate analysis, obstruction diameter after the procedure and uPA antigen were significant predictors of follow-up diameter stenosis.

Conclusions
—Plasma uPA antigen levels and PAI-1 antigen levels identify patients at increased risk for restenosis after percutaneous coronary revascularization.
Preserved Endothelium-Dependent Vasodilation in Coronary Segments Previously Treated With Balloon Angioplasty and Intracoronary Irradiation
Authors: Sabaté Manel , Kay I. Patrick , van der Giessen Willem J. , Cequier Angel , Ligthart Jurgen M. R. , Gómez-Hospital Joan Antoni , Carlier Stéphane G. , Coen Veronique L. M. A. , Marijnissen Johannes P. A. , Wardeh Alexander J. , Levendag Peter C. , Serruys Patrick W.
Published: June 2012

Background
—Abnormal endothelium-dependent coronary vasomotion has been reported after balloon angioplasty (BA), as well as after intracoronary radiation. However, the long-term effect on coronary vasomotion is not known. The aim of this study was to evaluate the long-term vasomotion of coronary segments treated with BA and brachytherapy.

Methods and Results
—Patients with single de novo lesions treated either with BA followed by intracoronary β-irradiation (according to the Beta Energy Restenosis Trial-1.5) or with BA alone were eligible. Of these groups, those patients in stable condition who returned for 6-month angiographic follow-up formed the study population (n=19, irradiated group and n=11, control group). Endothelium-dependent coronary vasomotion was assessed by selective infusion of serial doses of acetylcholine (ACh) proximally to the treated area. Mean luminal diameter was calculated by quantitative coronary angiography both in the treated area and in distal segments. Endothelial dysfunction was defined as a vasoconstriction after the maximal dose of ACh (10
−6
mol/L). Seventeen irradiated segments (89.5%) demonstrated normal endothelial function. In contrast, 10 distal nonirradiated segments (53%) and 5 control segments (45%) demonstrated endothelium-dependent vasoconstriction (−19±17% and −9.0±5%, respectively). Mean percentage of change in mean luminal diameter after ACh was significantly higher in irradiated segments (
P
=0.01).

Conclusions
—Endothelium-dependent vasomotion of coronary segments treated with BA followed by β-radiation is restored in the majority of stable patients at 6-month follow-up. This functional response appeared to be better than those documented both in the distal segments and in segments treated with BA alone.
When Throughout the Year Is Coronary Death Most Likely to Occur?
Authors: Kloner Robert A. , Poole W. Kenneth , Perritt Rebecca L.
Published: June 2012

Background
—Previous studies have suggested that there is an increase in cardiac events in the morning. Fewer data relate cardiac events to months of the year and season.

Methods and Results
—We analyzed all monthly death certificate data from Los Angeles County, California, for death caused by coronary artery disease from 1985 through 1996 (n=222 265). The mean number of deaths was highest in December at 1808 and January at 1925; the lowest rates were in June, July, August, and September at 1402, 1424, 1418, and 1371, respectively. December and January had significantly higher rates than would be expected from a uniform distribution of monthly deaths (
P
=0.00001). The percent of yearly coronary deaths was defined by the quadratic U-shaped equation [percent=13.1198−1.5238(month)+0.0952(month
2
), where January=1, February=2, etc]. When monthly deaths were plotted by year, there was a decrease from 1985 through 1996. Monthly mortality correlated inversely with temperature. During the months with the highest frequency of death (December, January), however, there was an increase in deaths that peaked around the holiday season and then fell, which could not be explained solely on the basis of the daily temperature change.

Conclusions
—Even in the mild climate of Los Angeles County, there are seasonal variations in the development of coronary artery death, with ≈33% more deaths occurring in December and January than in June through September. Although cooler temperatures may play a role, other factors such as overindulgence or the stress of the holidays might also contribute to excess deaths during these peak times.
Diuretics Shift Circadian Rhythm of Blood Pressure From Nondipper to Dipper in Essential Hypertension
Authors: Uzu Takashi , Kimura Genjiro
Published: June 2012

Background
—Recently, we found that sodium restriction shifted the circadian rhythm of blood pressure from nondipper to dipper in patients with the sodium-sensitive essential hypertension. This study examined whether diuretics can transform the circadian rhythm of blood pressure from nondipper to dipper.

Methods and Results
—We studied 21 patients with essential hypertension during both a baseline period and a period of treatment with hydrochlorothiazide (25 mg daily). The periods lasted 4 weeks each. Twenty-four hour ambulatory blood pressures were measured on the same day of the week at the end of the each period. In nondippers (n=11), but not in dippers (n=10), a significant interaction existed between diuretic therapy and nocturnal fall in systolic and diastolic blood pressure, which indicated that the degree of nocturnal blood pressure fall was affected by diuretic therapy. Nocturnal fall, which was diminished in nondippers, was restored by diuretic therapy with hydrochlorothiazide, indicating that the circadian rhythm of blood pressure shifted from nondipper to dipper patterns.

Conclusions
—The present study demonstrated that diuretics can restore nocturnal blood pressure decline in a manner similar to sodium restriction, which suggests that the kidneys and sodium metabolism may play important roles in the genesis of the circadian rhythm of blood pressure. Diuretic-based treatment may have an additional therapeutic advantage of reducing the risk for cardiovascular complications by transforming the circadian rhythm of blood pressure.
Mechanical Remodeling of the Left Atrium After Loss of Atrioventricular Synchrony
Authors: Sparks Paul B. , Mond Harry G. , Vohra Jitendra K. , Yapanis Anthony G. , Grigg Leeanne E. , Kalman Jonathan M.
Published: June 2012

Background
—Tachycardia-mediated mechanical remodeling of the atrium is considered central to the pathogenesis of thromboembolism associated with chronic atrial fibrillation. Whether atrial mechanical remodeling also occurs in response to atrial stretch induced by chronic asynchronous ventricular pacing in patients with permanent pacemakers is unknown.

Methods and Results
—The study design was a prospective randomized comparison between 21 patients paced chronically in the VVI mode and 11 patients paced chronically in the DDD mode for 3 months. Left atrial appendage (LAA) function and the presence of spontaneous echo contrast (SEC) were determined with transesophageal echocardiography (TEE) within 24 hours of pacemaker implantation and after 3 months. The VVI patients were then programmed to DDD and underwent a third TEE after DDD pacing for an additional 3 months. After chronic VVI pacing, LAA velocity decreased from 82.4±29.0 to 42.1±25.4 cm/s (
P
<0.01), LAA fractional area change decreased from 74.9±17.2% to 49.8±22.0% (
P
<0.01), and 4 patients (19%) developed left atrial SEC (
P
<0.05). With the reestablishment of chronic AV synchrony, LAA velocity increased to 61.6±18.5 cm/s (
P
<0.01), LAA fractional area change increased to 76.4±18.1% (
P
<0.01), and SEC resolved. In the 11 patients undergoing chronic DDD pacing, no significant changes in LAA velocity (baseline, 86.0±28.8 cm/s versus 3 months, 79.6±14.9 cm/s) or LAA fractional area change (baseline, 76.2±19.4% versus 72.5±15.7%) were demonstrated, and SEC did not develop.

Conclusions
—Chronic loss of AV synchrony induced by VVI pacing is associated with mechanical remodeling of the left atrium, which may reverse after the reestablishment of AV synchrony with DDD pacing. This process may be partly responsible for the higher incidence of thromboembolism observed in patients undergoing VVI pacing compared with AV sequential pacing.
Effects of Acute Myocardial Ischemia on Intramyocardial Contraction Heterogeneity
Authors: Colonna Paolo , Montisci Roberta , Galiuto Leonarda , Meloni Luigi , Iliceto Sabino
Published: June 2012

Background
—Subendocardial thickening is greater than subepicardial thickening and acute myocardial ischemia mainly impairs the former. Integrated backscatter cyclic variations (IBScv) reflect regional myocardial contractility and are blunted during myocardial ischemia. We hypothesized that stress-induced myocardial ischemia mainly affects subendocardial IBScv.

Methods and Results
—Multiplane transesophageal echocardiography and simultaneous atrial pacing were performed in 12 patients without coronary artery disease (CAD) and in 25 with significant CAD. In a transgastric 2-chamber view, we calculated IBScv in subendocardium and subepicardium and a heterogeneity index, both at rest and at peak-pacing. In 27 myocardial segments of patients with normal coronary arteries, and in 16 myocardial segments supplied by coronary artery without significant stenosis in patients with CAD, there was a transmural gradient of IBScv at rest and the heterogeneity index did not change during all the protocol steps. In the 53 myocardial segments related to a significantly narrowed coronary artery, the transmural gradient of IBScv, present at rest, significantly decreased at peak-pacing because of subendocardial blunting, but promptly recovered 5 seconds after pacing interruption. Moreover, the myocardial thickening at rest and peak pacing correlated with the subendocardial IBScv behavior and not with the subepicardial one.

Conclusions
—IBScv are greater in the subendocardium than in the subepicardium. Atrial pacing stress test does not affect IBScv in segments supplied by nonstenotic coronary arteries, whereas it affects segments supplied by diseased coronary arteries, blunting exclusively subendocardial IBScv. Heterogeneity of IBScv intramyocardial changes caused by stress-induced ischemia must be taken into account when using IBScv for investigating myocardial ischemia.
Downregulation of Protein Kinase Cδ Activity Enhances Endothelial Cell Adaptation to Hypoxia
Authors: Shizukuda Yukitaka , Helisch Armin , Yokota Ryoji , Ware J. Anthony
Published: June 2012

Background
—Although protein kinase C (PKC) has been implicated in ischemic cell death, the role of individual PKC isoenzymes in the response of endothelial cells (ECs) to hypoxia is unknown.

Methods and Results
—To test the effect of hypoxia on the activity of individual PKC isoenzymes, human ECs were exposed to 95% N
2
with 5% CO
2
for 24 hours. This severe hypoxia reduced PKCδ specific activity in both human umbilical vein ECs (HUVECs) and a HUVEC-derived EC line (ECVs) significantly (80.5±5.7% and 55.5±8.6% of normoxia controls, respectively); the activities of PKCα and PKCε were unchanged. The protein levels of PKCα, PKCδ, and PKCε were unchanged by hypoxia. To determine whether PKCδ downregulation by hypoxia was linked to EC function, ECVs in which PKCδ was stably overexpressed (PKCδ-ECs) were exposed to hypoxia. A significant increase in cell death was observed in PKCδ-ECs compared with controls (5.8±0.6% versus 2.3±0.4% at 24 hours, 13.2±1.2% versus 4.1±0.4% at 48 hours,
P
<0.05) during hypoxia. Neither the DNA laddering assay nor TUNEL staining revealed an increase in apoptosis of PKCδ-ECs exposed to hypoxia, suggesting a hypoxia-induced increase in nonapoptotic cell death of PKCδ-ECs. Inhibition of NO synthase with
N
G
-monomethyl-
l
-arginine (L-NMMA) affected neither the decline in PKCδ activity nor the EC death induced by hypoxia.

Conclusions
—PKCδ activity is decreased by hypoxia by a mechanism that does not involve NO synthase; this downregulation appears to enhance EC survival during hypoxia by decreasing nonapoptotic cell death.
Subunit Expression of the Cardiac L-Type Calcium Channel Is Differentially Regulated in Diastolic Heart Failure of the Cardiac Allograft
Authors: Hullin Roger , Asmus Friedrich , Ludwig Andreas , Hersel Joachim , Boekstegers Peter
Published: June 2012

Background
—Left ventricular diastolic dysfunction is a major cause of cardiac allograft failure. Multimeric L-type calcium channels (α
1
-, α
2
/δ-, and β-subunits) are essential for excitation/contraction coupling in the heart. Their gene expression was studied in allografts that developed diastolic heart failure.

Methods and Results
—mRNA levels of calcium channel subunits were measured by competitive reverse transcriptase–polymerase chain reaction in microbiopsy samples from the interventricular septum. Size and tissue variabilities between biopsy samples were assessed by determination of cardiac calsequestrin mRNA levels. In the cardiac allografts studied, mRNA levels in microbiopsy samples were considered to represent left ventricular gene expression, because septal and left ventricular gene expression in Northern blots was equivalent, and left ventricles contracted homogeneously. Biopsy samples (n=72) were taken from allografts with normal left ventricular end-diastolic pressure (LVEDP; 8 to 13 mm Hg; n=30), moderately elevated LVEDP (14 to 18 mm Hg; n=26), and elevated LVEDP (19 to 28 mm Hg; n=16). Increased LVEDP was related to slowed diastolic relaxation determined by the time constant τ (
r
2
=0.86), whereas systolic performance (dP/dt; ejection fraction) was preserved. With increasing LVEDP, mRNA levels of the pore-forming α
1c
-subunit (n=15) and of the regulatory α
2
/δ-subunit (n=17) remained unchanged but decreased exponentially (
r
2
=−0.83) for the regulatory β-subunit (n=40). Compared with cardiac allografts with normal LVEDP (n=15), β-subunit mRNA level was reduced by 75% at elevated LVEDP (n=9;
P
=0.012). In an explanted, diastolically failing cardiac allograft, β-subunit expression was reduced correspondingly by 72% and 76% on the mRNA level in septal and left ventricular myocardium and by 80% on the protein level.

Conclusions
—The downregulated expression of the calcium channel β-subunit might contribute to altered calcium handling in diastolically failing cardiac allografts.
Altered Complexity and Correlation Properties of R-R Interval Dynamics Before the Spontaneous Onset of Paroxysmal Atrial Fibrillation
Authors: Vikman Saila , Mäkikallio Timo H. , Yli-Mäyry Sinikka , Pikkujämsä Sirkku , Koivisto Anna-Maija , Reinikainen Pekka , Airaksinen K. E. Juhani , Huikuri Heikki V.
Published: June 2012

Background
—Trigger mechanisms for the onset of paroxysmal atrial fibrillation (AF) in patients without structural heart disease are not well established. New analysis methods of heart rate (HR) variability based on nonlinear system theory may reveal features and abnormalities in R-R interval behavior that are not detectable by traditional analysis methods. The purpose of this study was to reveal possible alterations in the dynamics of R-R intervals before the spontaneous onset of paroxysmal AF.

Methods and Results
—Traditional time and frequency domain HR variability indices, along with the short-term scaling exponent α
1
and approximate entropy (ApEn), were analyzed in 20-minute intervals before 92 episodes of spontaneous, paroxysmal AF in 22 patients without structural heart disease. Traditional HR variability measures showed no significant changes before the onset of AF. A progressive decrease occurred both in ApEn (1.09±0.26 120 to 100 minutes before AF; 0.88±0.24 20 to 0 minutes before AF;
P
<0.001) and in α
1
(1.01±0.28 120 to 100 minutes before AF, 0.89±0.28 20 to 0 minutes before AF;
P
<0.05) before the AF episodes. Both ApEn (0.89±0.27 versus 1.02±0.30;
P
<0.05) and α
1
(0.91±0.28 versus 1.27±0.21;
P
<0.001) were also lower before the onset of AF compared with values obtained from matched healthy control subjects.

Conclusions
—A decrease in the complexity of R-R intervals and altered fractal properties in short-term R-R interval dynamics precede the spontaneous onset of AF in patients with no structural heart disease. Further studies are needed to determine the physiological correlates of these new, nonlinear HR variability measures.
Modification of the Substrate for Maintenance of Idiopathic Human Atrial Fibrillation
Authors: Ernst Sabine , Schlüter Michael , Ouyang Feifan , Khanedani Afsaneh , Cappato Riccardo , Hebe Joachim , Volkmer Marius , Antz Matthias , Kuck Karl-Heinz
Published: June 2012

Background
—Catheter ablative techniques to modify the substrate to maintain atrial fibrillation (AF) require the creation of continuous radiofrequency current-induced ablation lines. This study was designed to assess the efficacy and safety of nonfluoroscopic mapping in this setting.

Methods and Results
—A total of 45 consecutive patients with idiopathic AF were studied. The first 13 underwent ablation confined to the left atrium by creating a circular line isolating the pulmonary vein ostia and a second line connecting the former with the mitral annulus. Subsequently, 12 of these patients underwent a procedure confined to the right atrium (RA), where attempts were made to create an isthmus line between the inferior vena cava and the tricuspid annulus, an anterior line connecting the tricuspid annulus with the superior vena cava, and an intercaval line between the ostia of the inferior and superior venae cavae. In the last 32 patients, only the RA approach was performed. Technical difficulties prevented the creation of the intended left atrial line pattern: all patients experienced recurrences. A 100% recurrence rate was also observed after subsequent RA ablation, despite creation of a complete line pattern in 4 of 12 patients. Of the final 32 patients, AF recurred in 94%; a complete ablation line pattern had been achieved in 18 patients (56%), 16 of whom had recurrences.

Conclusions
—The electroanatomically-guided creation of extended radiofrequency current lesions is technically feasible only in the RA. However, procedural success in the RA does not suppress recurrences of AF in the majority of patients.