Safety and efficacy of multipolar pulmonary vein ablation catheter vs. irrigated radiofrequency ablation for paroxysmal atrial fibrillation: a randomized multicentre trial.

AIMS: The current challenge in atrial fibrillation (AF) treatment is to develop effective, efficient, and safe ablation strategies. This randomized controlled trial assesses the medium-term efficacy of duty-cycled radiofrequency ablation via the circular pulmonary vein ablation catheter (PVAC) vs. conventional electro-anatomically guided wide-area circumferential ablation (WACA). METHODS AND RESULTS: One hundred and eighty-eight patients (mean age 62 ± 12 years, 116 M : 72 F) with paroxysmal AF were prospectively randomized to PVAC or WACA strategies and sequentially followed for 12 months. The primary endpoint was freedom from symptomatic or documented >30 s AF off medications for 7 days at 12 months post-procedure. One hundred and eighty-three patients completed 12 m follow-up. Ninety-four patients underwent PVAC PV isolation with 372 of 376 pulmonary veins (PVs) successfully isolated and all PVs isolated in 92 WACA patients. Three WACA and no PVAC patients developed tamponade. Fifty-six percent of WACA and 60% of PVAC patients were free of AF at 12 months post-procedure (P = ns) with a significant attrition rate from 77 to 78%, respectively, at 6 months. The mean procedure (140 ± 43 vs. 167 ± 42 min, P<0.0001), fluoroscopy (35 ± 16 vs. 42 ± 20 min, P<0.05) times were significantly shorter for PVAC than for WACA. Two patients developed strokes within 72 h of the procedure in the PVAC group, one possibly related directly to PVAC ablation in a high-risk patient and none in the WACA group (P = ns). Two of the 47 patients in the PVAC group who underwent repeat ablation had sub-clinical mild PV stenoses of 25-50% and 1 WACA patient developed delayed severe PV stenosis requiring venoplasty. CONCLUSION: The pulmonary vein ablation catheter is equivalent in efficacy to WACA with reduced procedural and fluoroscopy times. However, there is a risk of thrombo-embolic and pulmonary stenosis complications which needs to be addressed and prospectively monitored. CLINICALTRIALSGOV IDENTIFIER: NCT00678340.

Angiotensin injected into the neostriatum after learning disrupts retention performance.

Angiotensin II, injected into the dorsal neostriatum of rats 5 minutes after they had learned a passive avoidance task, disrupted the retention of the task 24 hours later. Identical neostriatal injections given 22 hours after learning (2 hours before retention) were without effect on retention performance. Ventral neostriatum or posterior thalamus were ineffective sites for injection of angiotensin. Injection of thyrotropin releasing hormone or lysine-8-vasopressin into the dorsal neostriatum was ineffective. These findings indicate a possible role for endogenous angiotensin in the neostriatum on retention performance and suggest potential involvement in mnemonic processes.

High altitude arrhythmias.

OBJECTIVE: To investigate the cause and nature of palpitations occurring at high altitude. METHODS: Implantable loop recorders were inserted subcutaneously in the left pectoral region of 9 healthy male volunteers. Subjects flew to Kathmandu (1,250 m) and then Lukla (2,800 m) before immediately commencing an identical ascent and descent profile to high altitude. The loop recorders were activated with any episode of palpitations and during exercise, rest and sleep. Arterial oxygen saturation was assessed concomitant with device activation. RESULTS: Above 5,000 m all subjects reported palpitations during exercise. All subjects demonstrated sinus tachycardia and marked sinus arrhythmia; one subject demonstrated atrial flutter; one subject had non-conducted p waves, and a further subject had marked ST segment depression. CONCLUSIONS: Significant arrhythmias occur at high altitude. In view of the increased risk of sudden cardiac death at high altitude, and considering that the elderly account for 15% of the 100 million visitors to altitude annually, further investigation is required.

Unlinked anonymous HIV prevalence among New Zealand sexual health clinic attenders: 2005-2006.

This unlinked anonymous study aimed at determining the prevalence of HIV among sexual health clinic attenders having blood samples taken for syphilis and/or hepatitis B serology in six major New Zealand cities over a 12-month period in 2005-2006. Overall, seroprevalence was five per 1000 (47/9439). Among men who have sex with men (MSM), the overall prevalence and that of previously undiagnosed HIV were 44.1 and 20.1 per 1000, respectively. In heterosexual men, the overall prevalence was 1.2 per 1000 and in women 1.4 per 1000. HIV remains to be concentrated among homosexual and bisexual men. Comparison with a previous survey in 1996-1997 suggests an increase in the prevalence of undiagnosed HIV among MSM and also an increase in the number of MSM attending sexual health clinics. The low prevalence of HIV among heterosexuals suggests no extensive spread into the groups identified at risk of other sexually transmitted infections.

ECG predictors of T wave oversensing in subcutaneous implantable cardioverter defibrillators.

BACKGROUND: T wave oversensing (TWOS) is the commonest cause of inappropriate shocks in subcutaneous implantable cardioverter defibrillators (S-ICDs). We hypothesise that predictors of TWOS can be derived from surface ECG parameters. METHODS: In a cohort of SICD recipients in two UK centres, all patients who had TWOS (study group) were compared to all those who had not (control group). The pre-implant screen was scanned and the R wave, T wave amplitudes, QRS interval, time to peak T wave, QT interval and R:T ratio was measured using digital callipers. Logistic regression was performed to identify ECG predictors of TWOS. RESULTS: One hundred one patients were studied. Six (5.9%) had TWOS. The mean age of the population was 58.6±18years and the median follow-up was 19.5months. By univariate analysis, the predictors of TWOS are QRS duration (140.7±28.7 vs. 105.9±24.6, P=0.007), time to peak T wave (corrected for heart rate, pTc) (403.9±22.6 vs. 347.8±41.4, P=0.006), QTc interval (500.4±41.2 vs. 446.8±49.7, P=0.021), and R:T ratio (3.5±1.1 vs. 9.5±13.2, P=0.034). By multivariate analysis, time to pTc is the most predictive of TWOS. A time to pTc of 390ms cut-off point provided a sensitivity 38.5%, a specificity of 98.9%, a positive predictive value for TWOS of 83.3%, and a negative predictive value of 91.6% (AUC=0.687). CONCLUSION: In this study, time to pTc is the most powerful ECG predictor of TWOS.

The induction of intracellular calcium activity in cultured human myometrial smooth muscle cells.

Cells maintained in serum free medium for 24 hours were found to have a higher incidence of both spontaneous increases in intracellular calcium ([Ca2+]i) (Ca2+ spikes) and small random changes in [Ca2+]i (Ca2+ 'noise'). The spontaneous transient increases in [Ca2+]i and the Ca2+ 'noise' disappear in solutions containing nominally zero Ca2+.

Electrophysiological mapping and ablation of intra-atrial reentry tachycardia after Fontan surgery with the use of a noncontact mapping system.

BACKGROUND: Atrial tachyarrhythmias are a complication of Fontan surgery. Conventional electrophysiological mapping and ablation techniques are limited by the complex anatomic and surgical substrate and a high arrhythmia recurrence rate. This study investigates the use of noncontact mapping to identify arrhythmia circuits and guide ablation in Fontan patients. METHODS AND RESULTS: Eleven arrhythmias were recorded in 6 patients. Noncontact mapping improved recognition of the anatomic and surgical substrate and identified exit sites from zones of slow conduction in all clinical arrhythmias. Radiofrequency linear lesions were targeted across these critical zones in 5 patients. One patient underwent surgical cryotherapy. Although immediate success was achieved in 3 of 5 patients with radiofrequency ablation, 2 patients had a recurrence after a mean of 6.4 months of follow-up. The patient who underwent cryoablation remains free of arrhythmias. CONCLUSIONS: Noncontact mapping can identify arrhythmia circuits in the Fontan atrium and guide placement of ablation lesions. Arrhythmia recurrence is high, possibly because of inadequate lesion creation rather than inaccurate mapping and lesion targeting.

Dispersion of monophasic action potential duration: demonstrable in humans after premature ventricular extrastimulation but not in steady state.

Abnormal dispersion of repolarization may contribute to the arrhythmogenic physiologic substrate of ventricular arrhythmia. Geographic dispersion of monophasic action potential duration was determined in steady state (drive cycle lengths 600 and 430 ms) between widely spaced right ventricular endocardial sites (geographic dispersion) in 10 control patients with right ventricular disease and complicating ventricular tachycardia (n = 9), 6 patients with right and left ventricular disease and complicating ventricular tachycardia and 7 patients with ischemic heart disease and complicating ventricular tachycardia. No significant difference in geographic dispersion could be demonstrated among the groups. Difference of monophasic action potential duration at adjacent right ventricular endocardial sites (adjacent dispersion) was determined after ventricular extrastimulation during construction of simultaneous electrical restitution curves in the same patient groups. Maximal adjacent dispersion over the electrical restitution curve was compared between disease and control groups. There was a significant difference in observations of maximal adjacent dispersion in patients with right ventricular disease and complicating ventricular tachycardia (range 5 to 85 ms, median 22.5; 14 pairs of sites; p less than 0.05) and patients with right and left ventricular disease and complicating ventricular tachycardia (range 5 to 50 ms, median 17.5; 14 pairs of sites; p less than 0.05) compared with control patients (range 5 to 20 ms, median 10; 15 pairs of sites). This difference was not evident when patients with ischemic heart disease and complicating ventricular tachycardia (range 5 to 25 ms, median 12.5; 12 pairs of sites) were compared with control patients. Maximal percent monophasic action potential shortening from steady state was significantly greater (p less than 0.001) in both groups with greater adjacent dispersions, and prolongation of activation time at monophasic action potential recording sites after premature extrastimulation tended to be greater in patients with right or right and left ventricular disease and complicating ventricular tachycardia. It is concluded that in disease, exaggeration of monophasic action potential shortening after premature ventricular extrastimulation may contribute to the electrophysiologic arrhythmogenic substrate.

Uricosuric effect of CGS-12970, a new thromboxane synthase inhibitor.

3-Methyl-2-(3-pyridyl)-1-indoleoctanoic acid (CGS-12970) is a reversible thromboxane synthase inhibitor that was noted to lower serum uric acid during preliminary trials in humans. Our clinical research unit studied 20 healthy male volunteers who received two doses of CGS-12970 12 hours apart (100, 200, 300, or 400 mg twice a day). Four subjects received placebo as a control. Serum uric acid concentrations decreased between 34% and 47%. Urinary excretion of uric acid increased between 28% and 134% within 12 hours of the first dose. Urinary excretion of uric acid returned to baseline within 24 hours after the last dose. In vitro study of bovine-creme xanthine oxidase inhibitor activity revealed minimal inhibition of xanthine oxidase by either CGS-12970 or its metabolite, CGS-12961. CGS-12970 appears to be a potent reversible uricosuric agent. We hypothesize that the uricosuric effect may be attributable to the acidic properties of CGS-12970 rather than to its inhibition of thromboxane synthase.

Effect of renal impairment on the pharmacokinetics and pharmacodynamics of desirudin.

OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of desirudin in subjects with various degrees of renal impairment in comparison with subjects with normal renal function. METHODS: Eight subjects with normal renal function (creatinine clearance > 90 ml/min) received 0.5 mg/kg desirudin intravenously over 30 minutes. Four subjects with mild renal failure (creatinine clearance between 61 and 90 ml/min) received 0.5 mg/kg. Five subjects with moderate renal failure (creatinine clearance between 31 and 60 ml/min) received 0.25 mg/kg. Six subjects with severe renal failure (creatinine clearance < 31 ml/min) received 0.125 mg/kg. RESULTS: Specific maximum concentration values (maximum concentrations corrected to a dose of 1 mg/kg) increased slightly with decreasing creatinine clearance. Mean specific area under the plasma concentration-time curve increased by a factor of 1.15, 2.83, and 7.0 for subjects with mild, moderate, and severe renal failure, respectively, compared with healthy subjects. Total urinary excretion of desirudin was about 55% to 60% of the dose in all four groups; elimination was delayed for subjects with moderate and severe renal failure. Total and renal clearance of desirudin were proportional to creatinine clearance. Total plasma clearance of desirudin was proportional to renal clearance of the drug. Prolongation of activated partial thromboplastin time was increased among subjects with moderate and severe renal failure despite a dose reduction. Area under the dynamic activated partial thromboplastin time curve for subjects with moderate renal failure remained the same as that for healthy subjects despite a dose reduction by a factor of two. Area under the dynamic curve increased by a factor of about 1.5 for subjects with severe renal failure despite a dose reduction by a factor of four. CONCLUSION: A dose reduction by a factor of six is recommended for persons with severe renal failure.

The effect of valsartan on the angiotensin II pressor response in healthy normotensive male subjects.

OBJECTIVE: Valsartan is an oral antagonist of angiotensin II that competes with angiotensin II for the AT1-receptor and is being developed as an antihypertensive agent. This study assessed the ability of 80 mg valsartan to inhibit the pressor effect of exogenous angiotensin II in healthy normotensive men, first after a single dose and then after multiple doses once daily for 7 days. METHODS: This was a single-center, double-blind, placebo-controlled, randomized crossover study. Six healthy men underwent angiotensin II challenges to determine a suitable dose required to increase their systolic blood pressure by approximately 30 mm Hg. Each subject then received an 80 mg dose of valsartan or matching placebo. The inhibition of the angiotensin II pressor effect was determined by the systolic blood pressure response to repeated angiotensin II challenges at multiple time points. RESULTS: Systolic blood pressure responses to angiotensin II challenges after single and multiple doses of valsartan were significantly lower than placebo, indicating that valsartan blocked the blood pressure response to angiotensin II. The maximum blocking effect was observed within 2 to 3 hours. Mean data suggested that differences in effect between valsartan and placebo were similar after both single and multiple doses and persisted up to 24 hours after administration. The angiotensin II blocking effect was maintained up to this time, despite low plasma valsartan levels and minimal accumulation after multiple doses. CONCLUSION: Valsartan, 80 mg, is a potent angiotensin II antagonist with a rapid onset of action and persistent angiotensin II inhibition up to 24 hours. There is no attenuation of this effect after multiple doses.

The modulation and characterisation of the Ca(2+)-induced Ca2+ release mechanism in cultured human myometrial smooth muscle cells.

The process of Ca(2+)-induced Ca2+ release (CICR) was studied in saponin permeabilised human myometrial smooth muscle cells in which the sarcoplasmic reticulum (SR) was pre-loaded with 45Ca2+. A rise in the free Ca2+ concentration of the bathing solution from 100 nM to 10 microM increased the rate of 45Ca2+ loss, while a reduction to 10 nM decreased the rate of 45Ca2+ loss. Ruthenium red (20 microM) lowered the basal rate of 45Ca2+ loss and reduced CICR. Caffeine did not activate 45Ca2+ release although ryanodine induced 45Ca2+ release and CICR was augmented in the presence of caffeine. These data suggest the operation of a Ca(2+)-activated 45Ca2+ release process which is similar in many of its properties to the CICR process described in many cells. The basic properties of the CICR mechanism in myometrium differs in many respects from the CICR process recently described in human vascular smooth muscle.

A novel ryanodine sensitive calcium release mechanism in cultured human myometrial smooth-muscle cells.

In cultured human myometrial cells application of caffeine (1-30 mM) did not result in an elevation of intracellular Ca2+ ([Ca2+]i). Caffeine was found to reversibly inhibit both spontaneous and agonist-induced repetitive rises in [Ca2+]i possibly as a consequence of its ability to interfere with the binding of inositol trisphosphate (IP3) to the receptor on the sarcoplasmic reticulum. Brief applications of ryanodine (1-10 microM) were observed to elevate [Ca2+]i and repeated exposures to ryanodine could elicit Ca2+ transients of similar magnitude. Ryanodine was also observed to mobilise Ca2+ in cells bathed in nominally Ca(2+)-free solution. These observations suggest the presence of a novel type of ryanodine-sensitive Ca(2+)-induced Ca2+ release (R-CICR) system in human myometrial cells.

Isolation and partial cloning of ryanodine-sensitive Ca2+ release channel protein isoforms from human myometrial smooth muscle.

Partial cDNAs of the ryanodine receptor were cloned using PCR analysis from reverse transcribed total and mRNA, extracted from freshly isolated pregnant, non-pregnant, and cultured human myometrial smooth muscle. The identity of these clones was confirmed by nucleotide sequencing of the fragments and indicate the expression of both the skeletal and brain ryanodine receptor isoforms in these preparations. In freshly isolated non-pregnant myometrial tissue, membrane fractions displaying specific [3H]ryanodine binding activities were isolated using density gradient centrifugation. SDS-PAGE of the sucrose gradient fractions indicated the specific comigration of a polypeptide with a molecular mass of approximately 544 kDa with the ryanodine binding activity.

Comparison of patients with idiopathic calcium phosphate and calcium oxalate stones.

Our primary objective was to test the hypothesis that a defect in acidification is more common in patients who have idiopathic calcium phosphate kidney stones than in those whose stones are formed mainly of calcium oxalate. Additionally, other risk factors might differ for these 2 stone types. Urine pH was measured serially over 24 hours, and along with ammonium and titratable acid, it was measured before and serially after ingestion of ammonium chloride in 3 groups of subjects: 24 patients with predominantly calcium phosphate stones, 30 patients with calcium oxalate stones, and 15 health non-stone-formers. Twenty-six parameters potentially related to stone formation and acidification were assayed on urines collected over 24 hours, and 15 parameters on blood. The data base was a computerized list of 5900 analyses of stones from patients living in Newfoundland. Patients not known by their physician to have had urinary tract infection, anatomical abnormality, hyperparathyroidism, or renal tubular acidosis were asked to participate in the study. Differences between means were considered significant if p values were less than 0.05 for F by analysis of variance and also less than 0.01 by t-test. In all patients with calcium oxalate stones and all non-stone-formers, urine acidified to pH less than 5.25, but in 8 of the 23 phosphate stone formers who completed the ammonium chloride study urine failed to acidify to pH less than 5.25. As all 8 had normal values for venous pH, total CO2, and chloride, they were considered to have incomplete renal tubular acidosis (IRTA). The 8 phosphate stone formers with IRTA had greater mean values for urine pH on all 9 specimens collected serially over 24 hours (all means greater than 6.2), and after administration of ammonium chloride (p less than 0.01), as well as lower mean values for urine titratable acid excretion (p less than 0.01), both after administration of ammonium chloride and in 24-hour urine samples, compared with the remaining phosphate stone formers whose urine acidified and the oxalate and non-stone-forming control groups. Nearly all the phosphate stone formers had 1 or more risk factors for stone formation, but with frequencies not significantly higher than those found in the oxalate group. Hypercalciuria and hypocitruria were the commonest, but increased oxalate or urate also occurred. Thus, idiopathic calcium phosphate stone formation can be associated with 1 or more of several risk factors, and, with the possible exception of those with IRTA, treatment should be similar to that given to patients with calcium oxalate stones.

Rigid analogues of dopamine: synthesis and interaction of 6-exo- and 6-endo-(3',4'-dihydroxyphenyl)-2-azabicyclo[2.2.2]octanes with dopamine uptake sites and receptors.

Two isomeric 6-endo- and 6-exo-(3',4'-dihydroxyphenyl) derivatives (1 and 2) of 2-azabicyclo[2.2.2]octane were synthesized as semirigid analogues of dopamine (DA) to help evaluate the preferred conformation of dopamine at the uptake site of the presynaptic nerve terminal and at the DA receptor. Against the uptake of 0.1 microM [3H]DA by a synaptosomal preparation of corpus striatum from the reserpine-pretreated rat, 2 was found to have a weak inhibitory effect that was three times greater than that of 1 (IC50 = 32 vs. 110 microM). Interactions with DA receptors were assessed with competition for binding of [3H]apomorphine (APO) and on the effect on DA-sensitive adenylate cyclase. Compounds 1 and 2 were both virtually inactive against the binding of 0.5 nM [3H]APO at a screening concentration of 100 microM. The experimental compounds also exhibited only slight adenylate cyclase stimulation in rat striatal homogenates, with 1 appearing to be somewhat more active (at 50 or 400 microM). The weak activities of 1 and 2 and their relatively small differences in activity in these test systems suggest that the DA analogues interact only weakly with the DA transport and receptor sites, possibly as a result of the steric interference caused by the bulky bicyclic ring.

Light microscopic immunocytochemical demonstration of thyroid-stimulating hormone (TSH) receptors on normal rat thyroid cells.

We present a method for immunohistochemical demonstration of surface-associated thyroid-stimulating hormone (TSH) receptors on direct imprints of rat thyroid follicular cells at the light microscopic level, by use of dinitrophenyl (DNP)-labeled bovine TSH as the primary probe in a DNP-hapten sandwich staining (DHSS) procedure. The light microscopically invisible diaminobenzidine (DAB) product of the enzyme reaction was amplified with a DAB enhancement technique (silver amplification), which yielded a reliable and distinct light microscopically visible cell surface staining. The consistently negative control results after inhibition with TSH receptor-specific reagents provide evidence in support of immunohistochemical localization of surface membrane-associated TSH receptors.

Quantitative immunohistochemical evaluation by image analysis of metallothionein in copper-loaded rat kidney.

Kidneys of copper-loaded rats were investigated immunohistochemically with a directly peroxidase-conjugated monoclonal antibody against metallothionein (MT). By means of an image analyzing system the area and the staining intensity of MT immunoreactivity in the proximal convoluted tubule (PCT) cells were determined. In the present study we compared the data obtained by image analysis with analytically determined tissue copper and MT concentrations of rats fed a high-copper diet (1 g/kg) for 16 weeks and sacrificed sequentially during this period. Our results provide evidence that the area of MT immunoreactivity correlates significantly with tissue copper and MT concentrations. Both the copper and MT concentrations in kidney rose to a maximum at 8 weeks and remained constant thereafter. The observed rise in the staining intensity of MT in PCT cells to a maximum at 6 weeks, which subsequently declined, suggests a continuing redistribution of copper and MT in the kidneys even after a maximum of concentration copper and MT is reached in the tissue.

A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients.

Immediate-release niacin manifests beneficial effects in cardiovascular disease with respect to dyslipidemic states. It lowers low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein(a), and apoprotein B; at the same time, it increases high-density lipoprotein (HDL) cholesterol, HDL2, and apoprotein A-I. However, use of crystalline niacin has drawbacks: therapy requires multidose regimens, and side effects include flushing and pruritus. Slowing absorption with sustained-release formulations succeeds in decreasing flushing and increasing tolerance, but increases in hepatic enzyme levels have raised safety concerns. A new extended-release, once-daily formulation of niacin (Niaspan) shows promise in minimizing flushing while avoiding hepatotoxicity. A multicenter, randomized, double-blind clinical trial of Niaspan enrolled 122 patients with confirmed diagnosis of primary dyslipidemia (LDL cholesterol >4.14 mmol/L [160 mg/dL] and triglycerides <9 mmol/L [800 mg/dL]) into 3 treatment groups: (1) Niaspan 1,000 mg/day; (2) Niaspan 2,000 mg/day; and (3) placebo. The primary treatment endpoint was LDL-cholesterol level. This endpoint was not significantly affected by placebo (0.2% increase), but Niaspan decreased LDL cholesterol by 5.8% (1,000 mg/day) and 14.6% (2,000 mg/day) (p <0.001). Likewise, with placebo there were significant changes in total cholesterol, triglycerides, lipoprotein(a), and apoprotein B, whereas both Niaspan 1,000 and 2,000 mg/day significantly (p <0.001) decreased these parameters. In addition, both Niaspan groups showed significant (p <0.001) increases in HDL cholesterol (17% and 23%, respectively), including HDL subfractions. With respect to flushing, 20% of the placebo group reported at least 1 episode, whereas 88% and 83% of the Niaspon 1,000- and 2,000-mg/day groups, respectively, reported episodes. There was no hepatotoxicity as liver enzyme levels remained within clinically accepted limits in all treatment groups. However, Niaspan 2,000 mg/day showed a significant increase in aspartate aminotransferase compared with baseline and placebo. This trial demonstrated a cholesterol-modifying effect of Niaspan consistent with those reported for niacin, but demonstrated a better tolerance for flushing. Moreover, in contrast to sustained-release formulations, Niaspan showed relatively mild hepatic effects.

Incremental reduction of serum total cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to statin therapy.

This study compares the effect of plant stanol ester spread with a placebo spread on cholesterol in patients taking statin therapy, but who still had elevated low-density lipoprotein (LDL) cholesterol. This was a randomized, double-blind, placebo-controlled clinical trial, with 67 women and 100 men with LDL cholesterol >/=130 mg/dl and triglycerides