Methylomic profiling and replication implicates deregulation of PCSK9 in alcohol use disorder.

Alcohol use disorder (AUD) is a common and chronic disorder with substantial effects on personal and public health. The underlying pathophysiology is poorly understood but strong evidence suggests significant roles of both genetic and epigenetic components. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome-wide methylomic variation in AUD using samples from 3 discovery, 4 replication, and 2 translational cohorts. We identified a differentially methylated region in the promoter of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene that was associated with disease phenotypes. Biological validation showed that PCSK9 promoter methylation is conserved across tissues and positively correlated with expression. Replication in AUD datasets confirmed PCSK9 hypomethylation and a translational mouse model of AUD showed that alcohol exposure leads to PCSK9 downregulation. PCSK9 is primarily expressed in the liver and regulates low-density lipoprotein cholesterol (LDL-C). Our finding of alcohol-induced epigenetic regulation of PCSK9 represents one of the underlying mechanisms between the well-known effects of alcohol on lipid metabolism and cardiovascular risk, with light alcohol use generally being protective while chronic heavy use has detrimental health outcomes.

Panel report: best practices for the surgical treatment of obesity.

BACKGROUND: Bariatric surgery is a rapidly growing field. Advances in surgical technologies and techniques have raised concerns about patient safety. Bariatric surgeons and programs are under increased scrutiny from regulatory agencies, insurers, and public health officials to provide high quality and safe care for bariatric patients at all phases of care. METHODS: During the 2009 annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), a panel of experts convened to provide updated information on patient safety and best practices in bariatric surgery. The following article is a summary of this panel presentation. RESULTS AND CONCLUSIONS: Weight loss surgery is a field that is evolving and adapting to multiple external pressures. Safety concerns along with increasing public scrutiny have led to a systematic approach to defining best practices, creating standards of care, and identifying mechanisms to ensure that patients consistently receive the best and most effective care possible. In many ways, bariatric surgery and multidisciplinary bariatric surgery programs may serve as a model for other programs and surgical specialties in the near future.

The role of staging laparoscopy for intraabdominal cancers: an evidence-based review.

Diagnostic laparoscopy is minimally invasive surgery for the diagnosis of intraabdominal diseases. The aim of this review is a critical examination of the available literature on the role of laparoscopy for the staging of intraabdominal cancers. A systematic literature search of English-language articles on MEDLINE, the Cochrane database of evidence-based reviews, and the Database of Abstracts of Reviews of Effects was performed for the period 1995-2006. The level of evidence in the identified articles was graded. The search identified and reviewed seven main categories that have received attention in the literature: esophageal cancer, gastric cancer, pancreatic cancer, hepatocellular carcinoma, biliary tract cancer, colorectal cancer, and lymphoma. The indications, contraindications, risks, benefits, diagnostic accuracy of the procedure, and its associated morbidity are discussed. The limitations of the available literature are highlighted, and evidence-based recommendations for the use of laparoscopy to stage intraabdominal cancers are provided.

The role of diagnostic laparoscopy for chronic abdominal conditions: an evidence-based review.

BACKGROUND: Diagnostic laparoscopy is minimally invasive surgery for the diagnosis of intraabdominal diseases. The aim of this review is a critical examination of the available literature on the role of laparoscopy for chronic intraabdominal conditions. METHODS: A systematic literature search of English-language articles on MEDLINE, the Cochrane database of evidence-based reviews, and the Database of Abstracts of Reviews of Effects was performed for the period 1995-2006. The level of evidence in the identified articles was graded. The search identified and reviewed six main categories that have received attention in the literature: pelvic pain and endometriosis, primary and secondary infertility, nonpalpable testis, and liver disease. RESULTS: The indications, contraindications, risks, benefits, diagnostic accuracy of the procedure, and its associated morbidity are discussed. CONCLUSIONS: The limitations of the available literature are highlighted, and evidence-based recommendations for the use of laparoscopy to stage intraabdominal cancers are provided.

PCB concentrations in some foods from four European countries.

Samples of salmon, butter and cabbage from Belgium, Italy, Spain and Portugal were analysed for their content in total, non-dioxin-like (as represented by the so-called seven indicator-PCBs: congeners 28, 52, 101, 118, 138, 153 and 180) and dioxin-like PCBs (mono-ortho and non-ortho PCBs). Salmon and cabbage from Belgium, and butter from Portugal and Belgium, contained less total and non-dioxin-like PCBs than those from other countries. Samples from Italy had the highest concentrations. Similar patterns were observed for dioxin-like PCBs (as represented by the TCDD-equivalents of toxicity, WHO-TEQs), with the lowest values in Belgium and Portugal for salmon, in Portugal for butter and in Belgium for cabbage. Differences up to five-fold in PCB concentrations and TEQ values were seen among commodities from the four countries. The implication is that it might be worthwhile monitoring, with selection of the least contaminated commodities, to reduce the PCB exposure of the general population. This could have health consequences, because daily intakes are higher than the tolerable levels for a considerable part of the European population.

Laparoscopic resection of curable colon and rectal cancer: an evidence-based review.

The initial enthusiastic application of laparoscopic techniques to colorectal surgical procedures was tempered in the early 1990s by reports of tumor implants in the laparoscopic incisions. Substantial evidence has accumulated, including evidence from randomized controlled trials, to support that laparoscopic resection results in oncologic outcomes similar to open resection, when performed by well-trained, experienced surgeons. This review was developed in conjunction with guidelines published by the Society of American Gastrointestinal and Endoscopic Surgeons. Data from the surgical literature concerning laparoscopic resection of curable colorectal cancer was evaluated regarding diagnostic evaluation, preoperative preparation, operative techniques, prevention of tumor implants, and training and experience. Recommendations are accompanied by an assessment of the level of supporting evidence available at the time of the development of the guidelines.

Development of an experimental model for studying bladder carcinogen metabolism using the isolated rat urinary bladder.

The isolated rat urinary bladder was used to study this organ's capacity to metabolize chemical carcinogens. In our experimental conditions, the urinary bladder carcinogen N-nitrosobutyl(4-hydroxybutyl)amine was oxidized to N-nitrosobutyl(3-carboxypropyl)amine. A time-dependent increase was observed in the amount of N-nitrosobutyl(3-carboxypropyl)amine formed and simultaneous disappearance of N-nitrosobutyl(4-hydroxybutyl)amine added, indicating that the bladder can metabolize N-nitrosobutyl(4-hydroxybutyl)amine to the metabolite considered responsible for tumor induction in the urinary bladder of laboratory animals. At 15, 30, 60, and 120 min the percentages of N-nitrosobutyl(3-carboxypropyl)amine formed were 11, 22, 36, and 64%, respectively, and 62, 48, 37, and 26% of N-nitrosobutyl(4-hydroxybutyl)amine remained unchanged. When N-nitrosodibutylamine was introduced into the isolated urinary bladder and incubated for 120 min, its oxidized metabolites N-nitrosobutyl(4-hydroxybutyl)amine and N-nitrosobutyl(3-carboxypropyl)amine were formed, amounting to, respectively, 0.13 and 0.06% of the substrate added. The glucuronide of N-nitrosobutyl(4-hydroxybutyl)amine was incubated in the isolated rat urinary bladder both as a buffer and as a urine solution in order to detect cellular and urinary beta-glucuronidase activity. In both systems N-nitrosobutyl(4-hydroxybutyl)amine released was about 1% at 4 h and this percentage did not increase at 6 h. N-Nitrosobutyl(3-carboxypropyl)amine was detectable at 2 h and reached 0.2% of the substrate incubated at 6 h. The results indicate that the urinary bladder may play a role in activating bladder carcinogens.

Urinary excretion of O6-butylguanine after the administration of N-nitroso-N-butylurea in rats.

O6-Butylguanine was detected in the urine of rats given the butylating agent N-nitroso-N-butylurea. O6-Butylguanine contents in the 24-h rat urine samples after i.p. doses of 50, 100, and 200 mg/kg N-nitroso-N-butylurea were 1.03 +/- 0.41 (SE), 8.30 +/- 1.70, and 59.53 +/- 6.52 pmol, respectively. This suggests that O6-butylguanine formation in nucleic acids might be repaired in vivo, possibly by base excision, besides other mechanisms. After i.v. doses of 0.1 and 1 mg/kg of O6-butylguanine to rats urinary excretion did not exceed 2% of the administered dose, suggesting that the amount of O6-butylguanine effectively released by base excision might be much larger than that detected in the urine after N-nitroso-N-butylurea. Inhibition of the enzyme O6-alkyl-DNA transferase by N-nitrosodimethylamine increased urinary O6-butylguanine resulting from exposure to N-nitroso-N-butylurea (100 mg/kg i.p.) up to four times, thus confirming an alternative DNA repair mechanism.

Pharmacokinetic profile and metabolism of N-nitrosobutyl-(4-hydroxybutyl)amine in rats.

N-Nitrosodibutylamine and its omega-hydroxylated metabolite N-nitrosobutyl(4-hydroxybutyl)amine (NB4HBA) induce tumors in the urine bladder of different animal species through their common urinary metabolite N-nitrosobutyl(3-carboxypropyl)amine (NB3CPA), resulting from the oxidation of the alcoholic group of NB4HBA to a carboxylic group. NB4HBA disappearance from blood, the formation of its main metabolites, NB3CPA and NB4HBA-glucuronide (NB4HBA-G), and their urinary excretion, were investigated in rats after an i.v. dose of 1 mg/kg (5.7 mumol/kg). NB3CPA and NB4HBA-G formation was readily detectable 2 min after treatment and levels were still measurable at 120 and 30 min, respectively. The parent compound disappeared from blood 90 min after injection. The NB4HBA blood concentration-time profile was adequately described by a one-compartmental linear model. NB4HBA half-life was 8 min, total body clearance and renal clearance were 86.1 and 0.22 ml/min/kg, respectively. The 0-96-h urinary excretion of NB4HBA was 0.3% of the administered dose. NB3CPA half-life was 15 min; NB3CPA and NB4HBA-G urinary excretion were 36 and 11.7%, respectively, urinary excretion of known compounds accounting for less than 50%. After i.v. injection of NB3CPA equimolar to the NB4HBA dose, only 50% of unchanged compound was recovered in the urine and after NB4HBA-G, 41% of the administered dose was excreted unchanged, NB3CPA accounting for 10%. Thus NB3CPA and NB4HBA-G might undergo further biotransformation, suggesting that NB3CPA may not be the ultimate carcinogen responsible for urinary bladder tumor induction.

Determination of O6-butylguanine in DNA by immunoaffinity extraction/gas chromatography-mass spectrometry.

A sensitive, specific, and rapid method for quantitating the minor adduct O6-butylguanine (O6BuG) in hydrolyzed DNA has been developed by combining immunoaffinity chromatography and high resolution gas chromatography-negative ion chemical ionization-mass spectrometry. Polyclonal antibodies raised against O6BuG were coupled to CNBr-activated Sepharose 4B and used for sample clean-up and extraction of the specific O6-alkylguanine. After addition of O6BuG and its deuterium labeled analogue (O6BuG-D7), used as internal standard, hydrolyzed DNA was applied on the immunoaffinity column and washed with water, and the immunoadsorbed butylated guanines were eluted with acetone/water cetome/water (95/5) before gas chromatographic derivatization. O6BuG and O6BuG-D7 were analyzed and quantitated by high resolution gas chromatography-negative ion chemical ionization-mass spectrometry as their pentafluorobenzyl-trimethylsilyl derivatives. Immunoaffinity column capacity and O6BuG recovery from this column were 1.53 nmol O6BuG/column and 62 +/- 5%, respectively. The method was applied to evaluate O6BuG levels in DNA butylated in vitro with 10 mM N-nitroso-Nr-butylurea or isolated from rats given an i.p. dose of 185 mg/kg N-nitroso-N-butylurea or N-nitrosodibutylamine. In the first case the level of modifications present in calf thymus DNA was 104 mumol O6BuG/mol guanine, and in the second case O6BuG in liver DNA was about 6 times higher after N-nitroso-N-butylurea (2.11 mumol O6BuG/mol guanine) than after N-nitrosodibutylamine (0.34 mumol O6BuG/mol guanine) treatment. These results indicate that O6BuG formed in vivo can be isolated and quantitated by this method, which may also be useful for studying DNA damage and repair mechanisms.

Prostaglandin and thromboxane synthesis by human intracranial tumors.

Prostaglandin (PG) and thromboxane (TX) production by homogenates of human intracranial tumors (33 gliomas, 32 meningiomas, six brain metastases) and "normal" brain (n = 26) from tumor-bearing patients was studied. PGF2 alpha, PGE2, PGD2, 6-keto-PGF1 alpha (the hydrolysis product of PGI2) and TXB2 (the hydrolysis product of TXA2) were determined by high-resolution gas chromatography-mass spectrometry after ex vivo metabolism of endogenous arachidonic acid. Prostanoid profiles (relative abundance of each metabolite) were different for gliomas and meningiomas, but similar for gliomas and their nontumoral counterpart, i.e., "normal" brain. Mean overall prostanoid production was significantly higher in gliomas (539 +/- 95) and meningiomas (523 +/- 69) than in "normal" brain (198 +/- 23). Prostanoid synthesis significantly increased with anaplastic grade (glioblastomas greater than anaplastic astrocytomas greater than slow-growing astrocytomas greater than "normal" brain), while profiles did not substantially change (TXB2 was the most and 6-keto-PGF1 alpha the least abundant product). Meningioma profiles showed no marked prevalence of any particular metabolite and no major differences between histological subgroups. All brain metastases from different carcinomas (n = 5) showed a prevalence of TXB2 and PGE2 and very low PGD2 synthesis.

Prostaglandin and thromboxane synthesis by Lewis lung carcinoma during growth.

The five stable metabolites [prostaglandin F2 alpha, prostaglandin D2, prostaglandin E2 (PGE2), thromboxane B2, and 6-keto-prostaglandin F1 alpha] of arachidonic acid (AA) via the cyclooxygenase pathway were measured by high-resolution gas chromatography-mass spectrometry in Lewis lung carcinoma homogenates at various times after tumor implantation (11 to 25 days). Vegetating and necrotic sections of the primary tumor and lung metastases were examined. Vegetating tumor showed a very active AA metabolism. Synthesis of PGE2, the most abundant product, markedly increased during tumor growth (up to 30 micrograms/g). A high and increasing synthetic capacity was also noted for prostaglandin D2 (up to 9 micrograms/g). Minor time differences and lower levels (up to 1.4 micrograms/g) were found for the other AA metabolites. PGE2 and prostaglandin D2 were the major products in necrotic tumor, too, but synthesis was markedly less than in vegetating tumor, and no increase was noted over time. Metastatic tissue showed a different AA metabolic profile, as compared to primary tumor and surrounding lung tissue, with PGE2 and 6-keto-prostaglandin F1 alpha being the main metabolites.

Prostaglandin and thromboxane synthesis by M5076 ovarian reticulosarcoma during growth: effects of a thromboxane synthetase inhibitor.

The five stable metabolites [prostaglandin F2 alpha (PGF2 alpha), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha)] of arachidonic acid (AA) via the cyclooxygenase pathway were measured by high-resolution gas chromatography-mass spectrometry in M5076 ovarian reticulosarcoma (M5) homogenates at various times after tumor implantation (Days 15, 18, 21, and 24). Vegetating tumor showed an active AA overall metabolism, which significantly increased during tumor growth. Synthesis of selected products (TXB2, PGD2, and PGE2) increased markedly over time (up to 10.6, 3.5, and 0.9 micrograms/g, respectively). The overall metabolic profile was TXB2 much greater than PGD2 greater than PGF2 alpha greater than 6-keto-PGF1 alpha greater than PGE2 on Day 15 and TXB2 much greater than PGD2 much greater than PGF2 alpha greater than 6-keto-PGF1 alpha on Day 24. TXB2 was also by far the most abundant product of in vitro-cultured M5 cells. Chronic treatment of M5-bearing mice with dazmegrel (UK-38,485), a selective thromboxane synthetase inhibitor (100 mg/kg p.o. daily, from Day 7 to killing), resulted in incomplete TXB2 synthesis inhibition, AA metabolism diversion toward the other prostaglandins, and no effects of tumor growth and metastasis. More frequent dazmegrel treatment (100 mg/kg p.o. every 8 h from Day 1 to killing) resulted in complete TXB2 synthetase inhibition, AA metabolism diversion, and increased tumor growth and metastasis. These data do not support the hypothesis of thromboxane synthetase inhibitors reducing tumor growth. However, since TXB2 suppression was accompanied by the production of other products possibly interfering in tumor growth, no conclusions on the effective role of TXA2 in malignancy can be drawn.

Urinary excretion of thromboxane and prostacyclin metabolites during chronic low-dose aspirin: evidence for an extrarenal origin of urinary thromboxane B2 and 6-keto-prostaglandin F1 alpha in healthy subjects.

In vivo biosynthesis of thromboxane and prostacyclin is currently evaluated by measuring urinary excretion of selected metabolites. Urinary thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) (non-enzymatic hydrolysis products of thromboxane and prostacyclin) are thought to derive from renal biosynthesis of the parent compounds, while enzymatic metabolites such as 2,3-dinor-TXB2 and 2,3-dinor-6-keto-PGF1 alpha appear to be mainly derived from systemic (platelet) thromboxane and (vascular) prostacyclin, respectively. Using immunoaffinity extraction and high-resolution gas chromatography-negative ion chemical ionization mass spectrometry (HRGC-NICIMS), we measured the paired excretion of non-enzymatic and enzymatic metabolites of thromboxane and prostacyclin in healthy subjects before, during and after an eight-day schedule of oral low-dose aspirin (30 mg/day), a treatment known to inhibit platelet and perhaps vascular but not renal cyclooxygenase. Low-dose aspirin cumulatively reduced urinary excretion of TXB2 and 2,3-dinor-TXB2 (about 80% inhibition on day 8 of aspirin treatment, P less than 0.01), as well as 6-keto-PGF1 alpha and 2,3-dinor-6-keto-PGF1 alpha (about 45% inhibition on day 8 of aspirin treatment, P less than 0.01). Excretion of all metabolites recovered slowly after aspirin withdrawal. Urinary PGE2, taken as an index of renal cyclooxygenase activity, was not inhibited by aspirin. A highly significant correlation was found between paired excretion values of non-enzymatic vs. enzymatic metabolites of thromboxane and prostacyclin in all individuals studied (TXB2 vs. 2,3-dinor-TXB2 (r = 0.91 +/- 0.03); 6-keto-PGF1 alpha vs. 2,3-dinor-6-keto-PGF1 alpha (r = 0.92 +/- 0.06], irrespective of aspirin treatment. TXB2/2,3-dinor-TXB2 and 6-keto-PGF1 alpha/2,3-dinor-6-keto-PGF1 alpha mean ratios remained unchanged throughout the experiment. These data do not support the view that urinary TXB2 and 6-keto-PGF1 alpha derive mainly from renal biosynthesis in healthy subjects, but rather suggest that they may represent a fraction of systemic (platelet) thromboxane and (vascular) prostacyclin escaping metabolism. These data also suggest that chronic low-dose aspirin may partly inhibit vascular prostacyclin in addition to platelet thromboxane biosynthesis.

Characterization of arachidonic acid metabolic profiles in animal tissues by high-resolution gas chromatography-mass spectrometry.

A standardized, highly specific routine method was developed for the quantitative profiling of cyclooxygenase metabolites of arachidonic acid in animal tissues. Whole homogenates were used to assess the potential capacity of tissues to metabolize endogenous arachidonic acid. Samples were analyzed by high-resolution gas chromatography-mass spectrometry in the selected ion monitoring mode. The screening of several rat tissues by this method revealed marked tissue-specificity in both the synthesis capacity and prostaglandin profile. The major products detected were: 6-ketoprostaglandin F1alpha for lung, stomach, muscle and heart; prostaglandin D2 for spleen, brain and liver; prostaglandin F2alpha for kidney and prostaglandin E2 for seminal vesicles. Marked species differences were found when guinea pig tissues were analyzed.

Metabolism of thromboxane B2 in the isolated perfused rat kidney: mass spectrometric identification of urinary products.

The metabolism of thromboxane B2 (TXB2), the stable breakdown product of thromboxane A2, has been studied in isolated perfused kidney preparations using a recirculating system. In a first experiment, TXB2 was infused at a rate of 20 micrograms/kg per min. In a second experiment, a 1:1 mixture of TXB2 and octadeuterated TXB2 (0.4 microgram/kg per min each) was infused. Urinary samples collected during the infusion of TXB2 or vehicle were extracted on C18 cartridges and derivatized to methyl or pentafluorobenzyl ester, methyloxime, trimethylsilyl ether. Samples were analyzed by high-resolution gas chromatography-mass spectrometry in the electron impact and negative ion chemical ionization modes. Products of beta-oxidation, reduction of the delta 5,6 double bond and dehydrogenation at C-11 (2,3-dinor-TXB2, 2,3-dinor-TXB1, 2,3,4,5-tetranor-TXB1 and 11-dehydro-TXB2) were identified in addition to unmetabolized TXB2. 2,3,4,5-tetranor-TXB1 and 2,3-dinor-TXB1 were the most abundant metabolites.

Central pulmonary artery lesions in chronic obstructive pulmonary disease: A transesophageal echocardiography study.

BACKGROUND: In patients with acute pulmonary embolism, transesophageal echocardiography (TEE) often reveals presumably thrombotic lesions within the central pulmonary arteries (CPAs). These CPA lesions, when found in patients with primary pulmonary hypertension, have been attributed to in situ thrombosis or atherosclerosis. We hypothesized that similar CPA lesions may also develop in patients with chronic obstructive pulmonary disease (COPD) in the absence of pulmonary embolism. METHODS AND RESULTS: We examined by TEE 25 patients with COPD and 27 control patients with left heart disease. None of the patients had previous pulmonary embolism or ileofemoral and popliteal vein thrombosis. By use of TEE, CPA lesions were found in 12 COPD patients (48%) and 2 control patients (7.4%) (P<0.01). When CPA lesions were subdivided into types 1 (protruding and mobile) and 2 (wall-adherent), type 1 lesions proved to be uncommon, being found within the pulmonary trunk in 12% and 3.7% of COPD and control patients, respectively (P=NS). Conversely, type 2 lesions, which were always localized in the right pulmonary artery, were frequent in COPD patients (36%) and rare in control patients (3.7%) (P<0.01). When available, helical CT and MR angiography confirmed TEE findings, supporting an atherosclerotic origin of type 2 lesions, which were different from typical thrombotic lesions. FEV(1)/FVC ratio, RV/TLC ratio, PaO(2), hematocrit value, and pulmonary artery systolic pressure were not significantly different in COPD patients with and without CPA lesions. At TEE, however, COPD patients with CPA lesions showed a larger size of the main and right pulmonary arteries. CONCLUSIONS: TEE often reveals CPA lesions in stable patients with COPD even in the absence of significant pulmonary hypertension and not in close relation with the severity of pulmonary dysfunction.

First human experience with pulmonary vein isolation using a through-the-balloon circumferential ultrasound ablation system for recurrent atrial fibrillation.

BACKGROUND: Standard mapping and ablation of focal sources of atrial fibrillation are associated with very long procedure times and low efficacy. An anatomic approach to complete pulmonary vein isolation could overcome these limitations. METHODS AND RESULTS: Fifteen patients with atrial fibrillation refractory to medication underwent circumferential isolation of the pulmonary veins by using a novel catheter, with an ultrasound transducer (8-MHz) mounted near the tip, in a saline-filled balloon. Twelve atrial foci and/or atrial fibrillation triggers were identified in 9 patients (pulmonary vein locations: left upper, 3; right upper, 6; right middle, 1; right lower, 1; and left inferior, 1). In 5 patients, lesions were placed in the absence of any mapped triggers. Irrespective of trigger mapping, circumferential isolation of both upper pulmonary veins was attempted in all patients. The lower pulmonary veins were ablated when sinus rhythm activation mapping revealed evidence of a sleeve of atrial muscle in the vein. The median number of lesions per patient required to isolate 1 pulmonary vein was 4 (range, 1 to 29). After ablation, no evidence of narrowing was seen with repeat venography or follow-up computed tomography scan. After a mean follow-up of 35+/-6 weeks, 5 patients had recurrence of atrial fibrillation. Three responded to drugs that were previously ineffective, and 2 remained in atrial fibrillation. CONCLUSIONS: This novel ultrasound ablation system can successfully isolate multiple pulmonary veins. At early follow-up, this approach seems to be effective in preventing recurrent atrial fibrillation in a significant number of patients.

Prospective randomized comparison of antiarrhythmic therapy versus first-line radiofrequency ablation in patients with atrial flutter.

BACKGROUND: Despite the high success rate of radiofrequency (RF) ablation, pharmacologic therapy is still considered the standard initial therapeutic approach for atrial flutter. OBJECTIVE: We prospectively compared the outcome at follow-up of patients with atrial flutter randomly assigned to drug therapy or RF ablation. METHODS: Patients with at least two episodes of symptomatic atrial flutter in the last four months were randomized to regimens of either antiarrhythmic drug therapy or first-line RF ablation. After institution of therapy, end points included recurrence of atrial flutter, rehospitalization and quality of life. RESULTS: A total of 61 patients entered the study, 30 of whom were randomized to drug therapy and 31 to RF ablation. After a mean follow-up of 21 +/- 11 months, 11 of 30 (36%) patients receiving drugs were in sinus rhythm, versus 25 of 31 (80%) patients who underwent RF ablation (p < 0.01). Of the patients receiving drugs, 63% required one or more rehospitalizations, whereas post-RF ablation, only 22% of patients were rehospitalized (p < 0.01). Following RF ablation, 29% of patients developed atrial fibrillation which was seen in 53% of patients receiving medications (p < 0.05). Sense of well being (pre-RF 2.0 +/- 0.3 vs. post-RF 3.8 +/- 0.5, p < 0.01) and function in daily life (pre-RF 2.3 +/- 0.4 vs. post-RF 3.6 +/- 0.6, p < 0.01) improved after ablation, but did not change significantly in patients treated with drugs. CONCLUSION: In a selected group of patients with atrial flutter, RF ablation could be considered a first-line therapy due to the better success rate and impact on quality of life, the lower occurrence of atrial fibrillation and the lower need for rehospitalization at follow-up.

Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension.

OBJECTIVES: This study sought to determine the circulating levels of cytokines and their respective endogenous modulators in patients with congestive heart failure of variable severity. BACKGROUND: Activation of immune elements localized in the heart or periphery, or both, may promote release of cytokines in patients with congestive heart failure. Although an increased circulating level of tumor necrosis factor-alpha (TNF-alpha) and its soluble receptor type II (sTNF-RII) is well documented, less is known about other cytokines (i.e., interleukin-1-beta [IL-1-beta], interleukin-6 [IL-6] and interleukin-2 [IL-2] and their soluble receptor/receptor antagonists). METHODS: Circulating levels of TNF-alpha and sTNF-RII, IL-1-beta, IL-1 receptor antagonist (IL-1-Ra), IL-6, IL-6 soluble receptor (IL-6-sR), IL-2 and IL-2 soluble receptor-alpha were measured using enzyme-linked immunosorbent assay kits (Quantikine, R&D Systems) in 80 patients with congestive heart failure due to coronary artery disease or hypertension. The severity of their symptoms, which ranged from New York Heart Association functional class I to IV, was confirmed by measurement of peak oxygen consumption. RESULTS: The percentage of patients with elevated levels of cytokines and their corresponding soluble receptor/receptor antagonists significantly increased with functional class. For TNF-alpha and IL-1-beta, the percentage of patients with elevated levels of soluble receptor/receptor antagonists was higher than that of patients with elevated levels of the cytokine itself. For IL-6, the percentage of patients with elevated levels of IL-6-sR tended to be lower than that of patients with elevated levels of IL-6. All but two patients had undetectable levels of IL-2, and all but seven had levels of IL-2-sR within a normal range. CONCLUSIONS: In patients with congestive heart failure, circulating levels of cytokines increased with the severity of symptoms. In these patients, circulating levels of sTNF-RII and IL-1-Ra are more sensitive markers of immune activation than are circulating levels of TNF-alpha and IL-1-beta, respectively. Levels of IL-2 and IL-2-sR are not elevated when congestive heart failure is due to coronary artery disease or hypertension.