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Background: Patients suffering from schizophrenia and affective disorder have an increased risk of the metabolic syndrome (MeS); hence identification of patients developing MeS may help preventing morbidity and mortality., Aims: The aim of the study was to evaluate the effect of outreach visit by clinical pharmacists to support the implementation of screening of MeS at a psychiatric ward., Methods: The study was conducted at the psychiatric ward, Odense University Hospital. In 2008, clinical guidelines for systematic screening and prevention of metabolic risk were developed and implemented by passive dissemination (PD) followed by a period of active implementation (AI). AI contained outreach visits by clinical pharmacists on a weekly basis. Patients with affective disorder or schizophrenia were included. The study was designed as a before-and-after study, and electronic patient charts were used for assessment of adherence to the clinical guidelines., Results: In total, 205 patients were included in the study (93 patients in the PD group, 112 patients in the AI group). A significant improvement of the use of the screening sheet from 36% in the PD group to 81% in the AI group was found (p < 0.001). Consequently, the quality of the screening increased significantly resulting in 45% in the AI group being identified with MeS compared with 10% in the PD group (p < 0.001)., Conclusion: The outreach visits by clinical pharmacists significantly improved the use of the screening sheet and resulted in a significant increase in the proportion of patients identified with MeS (p < 0.001)., Clinical Implications: The increase in the use of a screening sheet for MeS among patients admitted to a psychiatric ward as a result of outreach visits by clinical pharmacist improve assessment for MeS. This may lead to better identification of patients suffering from MeS and hence increase the possibility of treating MeS and preventing morbidity and mortaligy.

Background: In the Ventricular Tachycardia Ablation in Coronary Heart Disease (VTACH) study, an intention-to-treat approach was used and may have diminished the observed degree of treatment effect. We present a subanalysis of the VTACH study by treatment actually received., Methods and Results: The VTACH study was a prospective, open, randomized controlled trial, undertaken in 16 European centers, comparing defibrillator implantation with and without ventricular tachycardia (VT) ablation in patients with stable VT, previous myocardial infarction, and reduced left-ventricular ejection fraction. Of the 52 patients in the ablation group, 7 (13%) did not receive VT ablation and 19% of patients assigned to implantable cardioverter defibrillator (ICD) only treatment group crossed over and had an ablation. The primary endpoint (first recurrence of any documented VT or ventricular fibrillation [VF]) was reached after a median of 19.5 months in the ablation group and 5.9 months in the ICD only group (P = 0.01). Overall, 685 VT/VF events occurred per year of follow-up in 22 patients of the ablation group and 4,986 events in 43 patients of the control group (P = 0.024). In the ICD only group, median numbers of VT/VF episodes were 25 (IQR 5.8-45.3) and 1.5 (IQR 0-24.8) per patient and year before and after crossover (n = 12), respectively., Conclusion: On-treatment analysis of the VTACH study emphasizes the effectiveness of VT ablation in patients receiving ICD treatment because of monomorphic VT post myocardial infarction. VT ablation clearly prolonged time to recurrence of VT/VF episodes and markedly decreased VT/VF burden., (© 2012 Wiley Periodicals, Inc.)

Aims: Patients aged ≥80 years are often excluded or under-represented in trials assessing treatment modalities in STEMI. We assessed in-patient outcomes in elderly patients undergoing contemporary primary PCI (PPCI)., Methods and Results: From Sept 2005 to July 2011 patients undergoing PPCI in our centre were identified. Demographic details, procedural data and in-patient outcomes were collated. Those aged ≥80 years were compared with those aged <80 years. In the study period 1,218 patients required PPCI, of which 224(18.4%) were ≥80 years. The elderly cohort were more likely to be female (44.3% vs. 20.3%; p<0.001), and have significant comorbidities. Times from first medical contact until TIMI 3 flow were similar between the two groups (medien 102 min vs. 109 min; p=0.19). There was no difference in rates of PCI success (97.3% vs. 98.3%; p=0.24), drug-eluting stent use (63.5% vs. 63.3%; p=1.00) and number of stents used. In-patient outcomes were worse in the elderly cohort with significantly higher rates of death (11.2% vs. 3.7%; p<0.001) and acute kidney injury (12.9% vs. 4.0%; p<0.001), with a trend towards more post-procedure cardiovascular accidents (CVA), access site complications and reinfarction. Length of stay was significantly longer in the elderly cohort (median days 5 vs. 3; p<0.001)., Conclusions: Important demographic differences exist in very elderly patients presenting with STEMI compared to younger patients though procedural data and PCI success rates are similar between the two groups. Those aged ≥80 years have significantly worse in-patient outcomes though death rates are not as high as historical data suggests.

Background: There are limited data comparing radiofrequency catheter ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation., Methods: We randomly assigned 294 patients with paroxysmal atrial fibrillation and no history of antiarrhythmic drug use to an initial treatment strategy of either radiofrequency catheter ablation (146 patients) or therapy with class IC or class III antiarrhythmic agents (148 patients). Follow-up included 7-day Holter-monitor recording at 3, 6, 12, 18, and 24 months. Primary end points were the cumulative and per-visit burden of atrial fibrillation (i.e., percentage of time in atrial fibrillation on Holter-monitor recordings). Analyses were performed on an intention-to-treat basis., Results: There was no significant difference between the ablation and drug-therapy groups in the cumulative burden of atrial fibrillation (90th percentile of arrhythmia burden, 13% and 19%, respectively; P=0.10) or the burden at 3, 6, 12, or 18 months. At 24 months, the burden of atrial fibrillation was significantly lower in the ablation group than in the drug-therapy group (90th percentile, 9% vs. 18%; P=0.007), and more patients in the ablation group were free from any atrial fibrillation (85% vs. 71%, P=0.004) and from symptomatic atrial fibrillation (93% vs. 84%, P=0.01). One death in the ablation group was due to a procedure-related stroke; there were three cases of cardiac tamponade in the ablation group. In the drug-therapy group, 54 patients (36%) underwent supplementary ablation., Conclusions: In comparing radiofrequency ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation, we found no significant difference between the treatment groups in the cumulative burden of atrial fibrillation over a period of 2 years. (Funded by the Danish Heart Foundation and others; MANTRA-PAF ClinicalTrials.gov number, NCT00133211.).

The foramen ovale is a slit-like anatomical structure located in the interatrial wall of the fetal heart that enables right-to-left shunting during fetal development. Although this hole generally closes completely shortly after birth due to shifting pressures in the atrial chambers, it remains open, or 'patent', in about 25% of cases representing a potential substrate for right-to-left shunting during adult life. A patent foramen ovale (PFO) is usually haemodynamically insignificant, even when large, but is the most common cause of right-to-left shunt. Large-diameter PFOs may act as a pathway for passage of thrombus, air, fat, vegetation or vasoactive substances from the venous to the arterial circulation, potentially causing paradoxical emboli and stroke, inappropriate decompression sickness in divers, platypnoea-orthodeoxia syndrome and aural migraine. Over the past two decades, the association between PFO and the occurrence of migraine and cryptogenic stroke, particularly in younger adults, has been subject to considerable controversy and debate. Currently, semi-invasive contrast-transoesophageal echocardiography is accepted as the gold standard to detect right-to-left shunt across a PFO, but other imaging modalities utilising contrast such as second-harmonic transthoracic echocardiogram, transcranial Doppler sonography, CT and cardiac MRI have been shown to have similar sensitivity and specificity in detecting a PFO when compared with transoesophageal echocardiography. In this review the authors discuss embryological origins, diagnostic measures and evidence-based treatment options for the prevention of PFO-related paradoxical embolism, with emphasis on cryptogenic stroke and migraine.

Objective: Minor variation in serum thyroid hormone (TH) levels can have important effects on various clinical endpoints. Although 45-65% of the inter-individual variation in serum TH levels is due to genetic factors, the causative genes are not well established. We therefore studied the effects of genetic variation in 68 TH pathway genes on serum TSH and free thyroxine (FT(4)) levels., Design and Methods: Sixty-eight genes (1512 polymorphisms) were studied in relation to serum TSH and FT(4) levels in 1121 Caucasian subjects. Promising hits (P<0.01) were studied in three independent Caucasian populations (2656 subjects) for confirmation. A meta-analysis of all four studies was performed., Results: For TSH, eight PDE8B polymorphisms (P=4×10(-17)) remained significant in the meta-analysis. For FT(4), two DIO1 (P=8×10(-12)) and one FOXE1 (P=0.0003) polymorphisms remained significant in the meta-analysis. Suggestive associations were detected for one FOXE1 (P=0.0028) and three THRB (P=0.0045) polymorphisms with TSH, and one SLC16A10 polymorphism (P=0.0110) with FT(4), but failed to reach the significant multiple-testing corrected P value (P<0.0022 and P<0.0033 respectively)., Conclusions: Using a large-scale association analysis, we replicated previously reported associations with genetic variation in PDE8B, THRB, and DIO1. We demonstrate effects of genetic variation in FOXE1 on serum FT(4) levels, and borderline significant effects on serum TSH levels. A suggestive association of genetic variation in SLC16A10 with serum FT(4) levels was found. These data provide insight into the molecular basis of inter-individual variation in TH serum levels.

Objective: The pituitary-thyroid axis (PTA) set point is determined by a combination of genetic and environmental factors. However, despite considerable efforts to characterize the background, the causative genes as well as environmental factors are not well established. Theoretically, as shown for autoimmune thyroid disease, the pattern of X chromosome inactivation (XCI) could offer a novel explanation for the observed variability of the PTA set point in women., Design and Patients: To examine the impact of XCI pattern on the PTA set point, we studied whether within-cohort (n = 318 subjects) and within-twin pair (n = 159 pairs) differences in XCI are correlated with serum concentrations of thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4)., Methods: X chromosome inactivation was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. Thyroid variables were measured using a solid-phase time-resolved fluoroimmunometric assay. Zygosity was established by DNA fingerprinting., Results: In the overall study population (within cohort), no significant correlations were found between TSH [regression coefficient (β) = -0·28 (95% confidence intervals, -0·66 to 0·11), P = 0·158], FT3 [β = -0·25 (-0·85 to 0·34), P = 0·403], FT4 [β = 0·08 (-0·91 to 1·07), P = 0·876] and XCI pattern. Essentially similar results were found in the within-pair analysis. Controlling for confounders such as age, body mass index, smoking and zygosity did not change the findings., Conclusions: In a sample of female twins, we found no evidence of a relationship between XCI pattern and PTA set point., (© 2010 Blackwell Publishing Ltd.)

An increased frequency of skewed X-chromosome inactivation (XCI) is found in clinically overt autoimmune thyroid disease (AITD) compared with controls. Whether skewed XCI is involved in the pathogenesis of autoantibodies to thyroid peroxidase (TPOAb) in euthyroid subjects is unknown. To examine the impact of XCI on the serum concentration of TPOAb, we studied whether within-cohort and within-twin-pair differences in XCI are associated with differences in serum concentrations of TPOAb. A total of 318 euthyroid female twin individuals distributed in 159 pairs were investigated. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. TPOAb concentrations were measured using a solid-phase time-resolved fluoroimmunometric assay. Overall (within cohort), there was a significant association between XCI and serum concentrations of TPOAb; regression coefficient (beta)=1.45 (95% confidence interval, 0.52-2.38), P=0.003. The association remained significant in the within-pair analysis; beta=1.74 (0.79-2.69), P<0.001. The relationship was nonsignificant within the 82 monozygotic pairs (beta=0.57 (-0.78-1.92), P=0.405), whereas the association was significant in the 77 dizygotic pairs (beta=2.17 (0.81-3.53), P=0.002). This preliminary finding of a significant association between TPOAb concentrations and XCI within cohort and within dizygotic but not within monozygotic twin pairs may indicate that XCI per se does not have a major role in the pathogenesis of TPOAb. More likely, XCI and TPOAb are influenced by shared genetic determinants.

Background: In patients with ventricular tachycardia (VT) and a history of myocardial infarction, intervention with an implantable cardioverter defibrillator (ICD) can prevent sudden cardiac death and thereby reduce total mortality. However, ICD shocks are painful and do not provide complete protection against sudden cardiac death. We assessed the potential benefit of catheter ablation before implantation of a cardioverter defibrillator., Methods: The Ventricular Tachycardia Ablation in Coronary Heart Disease (VTACH) study was a prospective, open, randomised controlled trial, undertaken in 16 centres in four European countries. Patients aged 18-80 years were eligible for enrolment if they had stable VT, previous myocardial infarction, and reduced left-ventricular ejection fraction (LVEF; 30%). Patients were followed up for at least 1 year. The primary endpoint was the time to first recurrence of VT or ventricular fibrillation (VF). Analysis was by intention to treat (ITT). This study is registered with ClinicalTrials.gov, number NCT00919373., Findings: 107 patients were included in the ITT population (ablation group, n=52; control group, n=55). Two patients (one in each group) withdrew consent immediately after randomisation without any follow-up data and one patient (ablation group) was excluded because of a protocol violaton. Mean follow-up was 22.5 months (SD 9.0). Time to recurrence of VT or VF was longer in the ablation group (median 18.6 months [lower quartile 2.4, upper quartile not determinable]) than in the control group (5.9 months [IQR 0.8-26.7]). At 2 years, estimates for survival free from VT or VF were 47% in the ablation group and 29% in the control group (hazard ratio 0.61; 95% CI 0.37-0.99; p=0.045). Complications related to the ablation procedure occurred in two patients; no deaths occurred within 30 days after ablation. 15 device-related complications requiring surgical intervention occurred in 13 patients (ablation group, four; control group, nine). Nine patients died during the study (ablation group, five; control group, four)., Interpretation: Prophylactic VT ablation before defibrillator implantation seemed to prolong time to recurrence of VT in patients with stable VT, previous myocardial infarction, and reduced LVEF. Prophylactic catheter ablation should therefore be considered before implantation of a cardioverter defibrillator in such patients., Funding: St Jude Medical., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Context: Microchimerism is the presence of small populations of cells from one individual in another genetically distinct individual. This phenomenon can arise from pregnancy, blood transfusion, or bidirectional cell trafficking between twins in utero. Microchimerism has recently been proposed to play a role in the pathogenesis of thyroid autoimmunity. In that case, twins from opposite-sex pairs (OS) should have an increased risk of thyroid autoantibodies (TA)., Aim: The aim of the study was to compare the frequency of TA in twin individuals from OS and monozygotic (MZ) twin pairs., Design: This was a case-control study of 240 individuals (120 females and 120 males) from OS twin pairs (cases) and 568 control individuals from MZ pairs (284 females and 284 males)., Methods: Antibodies toward thyroid peroxidase (TPOAb), thyroglobulin (TgAb), and the TSH receptor (TSHRAb) were measured and considered positive if greater than 60 U/ml, greater than 60 U/ml, and greater than 1.0 U/liter, respectively., Results: The frequency of TPOAb, TgAb, and TSHRAb among female cases was 15.0, 5.0, and 4.2%, respectively, which was higher than the corresponding prevalences in the female control population: 7.4% (P = 0.018), 1.1% (P = 0.023), and 0.7% (P = 0.026), respectively. However, when corrected for the number of phenotypes studied (TPOAb, TgAb, TSHRAb, and any thyroid antibody), the association remained significant only in the combined group, P(corrected) = 0.012. Essentially similar results were obtained in males., Conclusion: Both female and male twins from OS pairs, as opposed to MZ pairs, have an increased frequency of TA, indicating a potential role of microchimerism in developing TA.

Ahigher frequency of skewed X chromosome inactivation (XCI) is found in patients with autoimmune thyroid disease (AITD) than in controls. Although goitre is often present in AITD, a recent study failed to show an association between XCI and clinically overt nontoxic goitre. However, the etiology of overt goitre is complex, and the mechanisms influencing thyroid volume may involve fewer factors than the mechanisms underlying overt goitre. In order to examine the impact of XCI on thyroid volume in euthyroid females, we studied whether within cohort (n = 138) and within twin pair (n = 69) differences in XCI are correlated with differences in thyroid volume. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. Thyroid volume was determined by ultrasound. Neither in the within cohort nor in the within twin pair analysis could we demonstrate a statistically significant association between XCI and thyroid volume: Regression coefficient (beta) = 0.023 (95% confidence interval, -0.062-0.108), p = 0.592 and beta = 0.038 (-0.080-0.156), p = 0.521, respectively. Controlling for potential confounders such as zygosity, age, TSH, smoking habits and use of oral contraceptives did not change the findings. In conclusion, in a sample of euthyroid Danish female twins, we found no evidence of a relationship between XCI pattern and thyroid volume.

Background: Catheter ablation has evolved as a possible curative treatment modality for supraventricular tachycardias (SVT) in patients with univentricular heart. However, the long-term outcome of ablation procedures is unknown. We evaluated the procedural and long-term outcome of ablative therapy of late postoperative SVT in patients with univentricular heart., Methods and Results: Patients with univentricular heart (n=19, 11 male; age, 29+/-9 years) referred for ablation of SVT were studied. Ablation was guided by 3D electroanatomic mapping in all but 2 procedures. A total of 41 SVT were diagnosed as intra-atrial reentrant tachycardia (n=30; cycle length, 310+/-68 ms), typical atrial flutter (n=4; cycle length, 288+/-42 ms), focal atrial tachycardia (n=6; cycle length, 400+/-60 ms), and atrial fibrillation (n=1). Ablation was successful in 73% of intra-atrial reentrant tachycardia, 75% of atrial flutter, and all focal atrial tachycardia and focal atrial fibrillation. During the follow-up period of 53+/-34 months, 2 patients were lost to follow-up, 3 died of heart failure, 2 underwent heart transplantation, and 1 underwent conduit replacement. Of the remaining group, 8 had sinus rhythm and 3 had SVT., Conclusions: Focal and reentrant mechanisms underlie postoperative SVT in patients with univentricular heart. Successive SVT developing over time may be caused by different mechanisms. Ablative therapy is potentially curative, with a procedural success rate of 78%. In patients who had multiple ablation procedures, the SVT originated from different atrial sites, suggesting that these new SVT were caused by progressive atrial disease. Despite recurrent SVT, sinus rhythm at the end of the follow-up period was achieved in 72%.

Introduction: Genetic factors have a considerable influence on serum thyroid hormone levels. The C785T and A1814G polymorphisms, located in the 3' untranslated region of the type 1 deiodinase (D1) gene have been associated with serum FT4 and rT3 levels., Objective: In healthy Danish twins, we examined the association of these polymorphisms with serum thyroid hormone levels and determined the proportion of genetic influence explained by these variants. We analysed the underlying functional mechanism by performing mRNA stability measurements and analysed the effect of these variants on D1 activity., Methods: Serum thyroid measurements and genotypes of the D1-C785T and D1-A1814G polymorphisms were determined in 1192 twins. Structural equation modelling was used to determine heritability estimates. Functional analyses were carried out in D1-transfected JEG3 cells., Results: Carriers of the D1-785T allele had 3.8% higher FT4 and 14.3% higher rT3 levels, resulting in a lower T3/T4 and T3/rT3 ratio and a higher rT3/T4 ratio. This polymorphism explained 0.87% and 1.79%, respectively, of the variation in serum FT4 and rT3. The D1-A1814G polymorphism was not associated with serum thyroid hormone levels. No differences in D1 mRNA decay rate or D1 activity were observed between wild-type D1 and the two variants., Conclusion: The D1-C785T polymorphism is consistently and significantly associated with serum thyroid hormone levels. However, the proportion of genetic influence explained by this particular polymorphism is small. No effect of the polymorphism on D1 mRNA decay rate or D1 activity was observed. The underlying functional mechanism needs to be elucidated.

Background: The aim of this prospective study was to evaluate the recurrences of atrial fibrillation (AF) and flutter (AFL) after circumferential pulmonary vein ablation (CPVA) using repetitive long-term Holter recordings, and to evaluate the change in quality of life (QoL), especially in patients with asymptomatic AF recurrences., Methods: A total of 149 patients with AF were followed up with 7-day Holter monitoring at 3, 6, and 12 months after CPVA. We calculated the burden of AF/AFL defined as the percentage of time in AF/AFL, and patients with documented arrhythmia were divided into isolated symptomatic episodes of arrhythmia, mixed symptomatic/asymptomatic arrhythmia, or isolated asymptomatic arrhythmia. The QoL was analyzed with SF-36 questionnaires in patients with sinus rhythm after CPVA, and in patients with recurrence of symptomatic and asymptomatic arrhythmia, respectively., Results: Asymptomatic arrhythmia was observed in 44% of the patients with documented arrhythmia at 12 months of follow-up. In patients with persistent AF, 63% of the documented arrhythmia at 12 months of follow-up was asymptomatic and often persistent. In the subgroup of patients with asymptomatic arrhythmia, the QoL improved significantly in the physical scores, in contrast to patients with symptomatic arrhythmia who had unchanged or worsened QoL scores., Conclusions: Asymptomatic arrhythmia is very common after AF ablation. Our data indicate that these patients improve their physical component of the QoL significantly, which may be considered a palliative success of treatment. We suggest that patients with asymptomatic AF recurrences are carefully evaluated before considering reablation. Repetitive rhythm monitoring after AF ablation is very important considering the postablation management of anticoagulant therapy.

Objectives: This randomised trial evaluated if patients with atrial fibrillation (AF) and no history of atrial flutter (AFL) had any benefit of prophylactic cavotricuspid isthmus block (CTIB) in addition to circumferential pulmonary vein ablation (CPVA)., Methods: 149 patients with AF (54% paroxysmal) were randomised to CPVA and CTIB (group CTIB+, n = 73) or CPVA alone (group CTIB-, n = 76). Patients were followed for 12 months with repetitive 7-day Holter monitoring after 3, 6 and 12 months., Results: Six patients (4%) had cardiac tamponade, and one patient had a stroke. No difference was found in the cumulative AFL-free rate between the two treatment groups (CTIB+: 88% vs CTIB-: 84%, hazard ratio (HR) 0.80, 95% CI (0.34 to 1.90), p = 0.61). There was no difference in the cumulative AF-free rate between the groups (CTIB+: 34% vs CTIB-: 32%, HR 0.93, 95% CI (0.63 to 1.38), p = 0.71). Overall, 33% of the patients were free of AF after a single procedure. Including reprocedures, a complete or partial beneficial effect was noted in 62% of the patients at 12 months. At 12-month follow-up, 24 (50%) patients with documented AF or AFL in the Holter recordings were asymptomatic., Conclusions: It was not possible to demonstrate any beneficial effect of CTIB in addition to CPVA with regard to AFL or AF recurrences during follow-up. Repetitive long-term Holter monitoring demonstrated a 33% rate of freedom from AF during a 1-year follow-up. Including additional CPVA procedures, a clinical effect was noted in 62% of the patients at 12 months. Patients with AF or AFL recurrences were often asymptomatic.

Shorter reperfusion times lead to better outcomes in patients with ST-elevation myocardial infarction (STEMI). We assessed the efficacy of prehospital triage with bypass of community hospitals and early activation of the cardiac catheterization team on revascularization times, left ventricular (LV) ejection fraction, and survival. Patients with STEMI (624) were divided into 3 groups determined by site of triage: ambulance field triage (163), interventional center emergency department (202), and 3 community hospital emergency departments (259). Compared with community hospital and interventional center triages, ambulance field triage resulted in a significant median decrease in door-to-balloon times of 68 and 27 minutes, respectively (p <0.001). LV ejection fraction was highest in the field triage group (52 +/- 13%) compared with the interventional center (49 +/- 12%) and community hospital (48 +/- 12%, p = 0.017) groups. Thirty-day mortality was lowest in the ambulance field group (3%) compared with the interventional facility (11%) and community hospital (4%, p = 0.007) groups. There was a significant difference in long-term survival with up to 30-month follow-up among the 3 triage groups (p = 0.041). With time-dependent Cox regression modeling the difference in survival was significant only during the first week after STEMI (p = 0.020). Every extra minute of symptom onset to reperfusion time was associated with a relative risk of long-term mortality of 1.003 (95% confidence interval 1.000 to 1.006, p = 0.027). In conclusion, field triage of patient with STEMI decreased revascularization times, which preserved LV function, and improved early survival.

Background: Simple goiter (SG) comprises diffuse (DG) and nodular (NG) benign nonautoimmune nontoxic goiter. In nonendemic goiter areas, the ratio of females to males may exceed 5:1, indicating that gender and/or sex hormones may play a role in the etiology of SG in these areas. Theoretically, as shown for autoimmune thyroid disease, X chromosome inactivation (XCI) and resultant tissue chimerism could offer a novel explanation for the female preponderance of SG. To examine whether skewed XCI is associated with SG, we first compared XCI in 71 twin individuals with SG with that in 142 unrelated healthy control twin individuals, and then performed a within-pair comparison of XCI in 48 twin pairs discordant for SG., Methods: DNA was extracted from peripheral blood cells. XCI analysis was performed by predigestion of DNA using the methylation-sensitive enzyme Hpall, followed by polymerase chain reaction of the polymorphic CAG repeat of the androgen receptor gene. A polymerase chain reaction product is obtained from the inactive X chromosome only. The XCI pattern was classified as skewed when 80% or more of the cells preferentially inactivated the same X chromosome. Twin zygosity was established by DNA fingerprinting., Results: The frequency of skewed XCI in female twins with SG, DG, and NG was 11% (8/71), 13% (6/46), and 8% (2/25), respectively, which was not significantly different from the prevalences in the corresponding control populations, 14% (20/142, p = 0.56), 14% (13/92, p = 1.00), and 14% (7/50, p = 0.71), respectively. Essentially, similar results were obtained when comparing the prevalence of skewed XCI in twin pairs discordant for SG (48 pairs), DG (30 pairs), and NG (18 pairs)., Conclusion: In a sample of Danish female twins, we did not find evidence for involvement of skewed XCI in the etiology or the female preponderance of SG.

Chronic arrhythmias may cause cardiomyopathy. We present two cases of severe cardiomyopathy in two young men with frequent monomorphic ventricular ectopy. In both cases radiofrequency ablation of a left ventricular ectopic focus led to normalization of cardiac function within months.

Objective: Genetic factors exert considerable influence on thyroid function variables. Single nucleotide polymorphisms (SNPs) in thyroid hormone pathway genes have been associated with serum thyroid parameters implying small alterations in the hypothalamus-pituitary-thyroid axis. However, little is known about SNPs in the THRA (17q11.2) and THRB (3p24.2) genes. The aim of this study was to map THRA and THRB for the occurrence and frequencies of SNPs and relate these to thyroid parameters., Design and Methods: SNPs were identified by sequencing all THRA and THRB exons and flanking regions in 52 randomly selected subjects. SNPs were genotyped in 1116 healthy Danish twins by TaqMan assays and related to thyroid parameters. One SNP in THRB was additionally genotyped in the elderly population of the Rotterdam Scan Study (n = 940)., Main Outcome: 15 SNPs (7 novel) in THRA and THRB were identified. Two SNPs in the 3' untranslated region of THRA were genotyped: a novel SNP (2390A/G) and 1895C/A (rs12939700). In THRB, a synonymous (735C/T; rs3752874) and an intronic SNP (in9-G/A; rs13063628) were genotyped. No associations between SNPs and thyroid hormone levels (total and free 3,3',5-triiodo-L-thyronine [T3] and thyroxine, reverse T3) were found. THRB-in9-G/A was significantly associated with higher serum thyroid stimulating hormone (TSH) (p(lnTSH) = 0.01) in the Danish twins, but not in subjects of the Rotterdam Scan Study, although it showed a similar trend., Conclusions: Analysis of the T3 receptor genes revealed 15 SNPs, including 7 novel. Only THRB-in9-G/A was associated with higher serum TSH in a large population of Danish twins.

Organic anion transporting polypeptide (OATP) 1C1 has been characterized as a specific thyroid hormone transporter. Based on its expression in capillaries in different brain regions, OATP1C1 is thought to play a key role in transporting thyroid hormone across the blood-brain barrier. For this reason, we studied the specificity of iodothyronine transport by OATP1C1 in detail by analysis of thyroid hormone uptake in OATP1C1-transfected COS1 cells. Furthermore, we examined whether OATP1C1 is rate limiting in subsequent thyroid hormone metabolism in cells cotransfected with deiodinases. We also studied the effect of genetic variation in the OATP1C1 gene: polymorphisms were determined in 155 blood donors and 1192 Danish twins and related to serum thyroid hormone levels. In vitro effects of the polymorphisms were analyzed in cells transfected with the variants. Cells transfected with OATP1C1 showed increased transport of T4 and T4 sulfate (T4S), little transport of rT3, and no transport of T3 or T3 sulphate, compared with mock transfected cells. Metabolism of T4, T4S, and rT3 by cotransfected deiodinases was greatly augmented in the presence of OATP1C1. The OATP1C1-intron3C>T, Pro143Thr, and C3035T polymorphisms were not consistently associated with thyroid hormone levels, nor did they affect transport function in vitro. In conclusion, OATP1C1 mediates transport of T4, T4S, and rT3 and increases the access of these substrates to the intracellular active sites of the deiodinases. No effect of genetic variation on the function of OATP1C1 was observed.

Background: Yersinia enterocolitica (YE) infection has long been implicated in the pathogenesis of Graves' disease (GD). The association between YE and GD could, however, also be due to common genetic or environmental factors affecting the development of both YE infection and GD. This potential confounding can be minimized by investigation of twin pairs discordant for GD., Aim: To examine whether YE infection is associated with GD., Design: We first conducted a classical case-control study of individuals with (61) and without (122) GD, and then a case-control study of twin pairs (36) discordant for GD., Methods: Immunoglobulin (Ig)A and IgG antibodies to virulence-associated Yersinia outer membrane proteins (YOPs) were measured., Main Outcome Measures: The prevalence of YOP IgA and IgG antibodies., Results: Subjects with GD had a higher prevalence of YOP IgA (49%vs. 34%, P = 0.054) and YPO IgG (51%vs. 35%, P = 0.043) than the external controls. The frequency of chronic YE infection, reflected by the presence of both IgA and IgG YOP antibodies, was also higher among cases than controls (49%vs. 33%, P = 0.042). Similar results were found in twin pairs discordant for GD. In the case-control analysis, individuals with GD had an increased odds ratio (OR) of YE infection: IgA 1.84 (95% CI 0.99-3.45) and IgG 1.90 (95% CI 1.02-3.55). In the co-twin analysis, the twin with GD also had an increased OR of YE infection: IgA 5.5 (95% CI 1.21-24.81) and IgG 5.0 (95% CI 1.10-22.81)., Conclusion: The finding of an association between GD and YE in the case-control study and within twin pairs discordant for GD supports the notion that YE infection plays an aetiological role in the occurrence of GD, or vice versa. Future studies should examine the temporal relationship of this association in more depth.

Aims: We aimed to investigate whether biventricular (BiV) pacing minimizes left ventricular (LV) dyssynchrony and preserves LV ejection fraction (LVEF) as compared with standard dual-chamber DDD(R) pacing in consecutive patients with high-grade atrio-ventricular (AV) block., Methods and Results: Fifty patients were randomized to DDD(R) pacing or BiV pacing. LVEF was measured using three-dimensional echocardiography. Tissue-Doppler imaging was used to quantify LV dyssynchrony in terms of number of segments with delayed longitudinal contraction (DLC). LVEF was not different between groups after 12 months (P = 0.18). In the DDD(R) group LVEF decreased significantly from 59.7(57.4-61.4)% at baseline to 57.2(52.1-60.6)% at 12 months of follow-up (P = 0.03), whereas LVEF remained unchanged in the BiV group [58.9(47.1-61.7)% at baseline vs. 60.1(55.2-63.3)% after 12 months (P = 0.15)]. Dyssynchrony was more prominent in the DDD(R) group than in the BiV group at baseline (2.2 +/- 2.2 vs. 1.4 +/- 1.3 segments with DLC per patient, P = 0.10); and at 12 month follow-up (1.8 +/- 1.9 vs. 0.8 +/- 0.9 segments with DLC per patient, P = 0.02). NT-proBNP was unchanged in the DDD(R) group during follow-up (122 +/- 178 pmol/L vs. 91 +/- 166 pmol/L, NS) but decreased significantly in the BiV-group (from 198 +/- 505 pmol/L to 86 +/- 95 pmol/L after 12 months, P = 0.02)., Conclusion: BiV pacing minimizes LV dyssynchrony, preserves LV function, and reduces NT-proBNP in contrast to DDD(R) pacing in patients with high-grade AV block.

Aims: Increasing evidence from randomized trials and experimental studies indicates that right ventricular (RV) pacing may induce congestive heart failure. We studied regional left ventricular (LV) dyssynchrony and global LV function in 50 consecutive patients with sick sinus syndrome (SSS) randomized to either atrial pacing [AAI(R)] or dual chamber RV-pacing [DDD(R)]., Methods and Results: Fifty consecutive patients were randomized to AAI(R) or DDD(R)-pacing. Tissue-Doppler imaging was used to quantify LV dyssynchrony in terms of number of segments with delayed longitudinal contraction (DLC). Left ventricular ejection fraction (LVEF) was measured using three-dimensional echocardiography. Dyssynchrony was more pronounced in the DDD(R)-group than in the AAI(R)-group at the 12 months follow-up (P < 0.05). This reflected a significant increase of dyssynchrony in the DDD(R)-group from baseline to the 12 months follow-up (1.3 +/- 1 to 2.1 +/- 1 segments displaying DLC per patient), P < 0.05. No change was observed in the AAI(R)-group (1.6 +/- 2 to 1.3 +/- 2 segments displaying DLC per patient, NS). No difference in LVEF, NYHA or NT-proBNP was observed between AAI(R)- and DDD(R)-mode after 12 months of pacing although LVEF decreased significantly in the DDD(R)-group from baseline (63.1 +/- 8%) to the 12 months follow-up (59.3 +/- 8%, P < 0.05), while LVEF remained unchanged in the AAI(R)-group (61.5 +/- 11% at baseline vs. 62.3 +/- 7% after 12 months, NS., Conclusion: In patients with SSS, DDD(R)-pacing but not AAI(R)-pacing induces significant LV desynchronization and reduction of LVEF.

Aims: We investigated the net benefit in the outcome of reducing treatment delay through field triage and emergency department (ED) bypass in patients with ST-elevation myocardial infarction (STEMI) treated with primary angioplasty., Methods and Results: In a prospective registry study, consecutive patients with suspected STEMI were assigned to: (i) pre-hospital ECG and triage or (ii) ECG and triage at the closest ED, solely based on ambulance availability. Four district hospitals and one regional heart centre serviced the 890,000 population metropolitan area and primary angioplasty was the only reperfusion strategy employed. Baseline characteristics were similar in STEMI patients triaged in the field (108) and the EDs (193). Symptom onset to balloon times: 154 [inter-quartile range (IQR) 120-233) vs. 249 (IQR 184-405) min (P<0.001) and peak creatine kinase in early presenters (<2 h): 1435 (95 %CI: 904-1966) U/L vs. 2320 (95% CI: 1881-2762) U/L (P=0.009) were lower in field- than in ED-triaged patients. Mortality in the PCI treated were 1.1 and 8.2% [P=0.025, RR 0.14 (95% CI: 0.01-1.08)] and overall mortality were 1.9 and 7.3% [P=0.046, RR 0.26 (95% CI: 0.05-1.11)]., Conclusion: Field-triage and ED bypass were feasible means of reducing treatment delay in patients with suspected STEMI and resulted in smaller infarct size in early presenters and a trend towards a reduction in mortality.

Objectives: The Asp727Glu polymorphism in the TSH receptor (TSHR) gene is associated with serum TSH levels. However, the proportion of genetic variation accounted for by this polymorphism is unknown. In this study, we (1) examined the association of the Asp727Glu polymorphism with thyroid size, serum levels of TSH, thyroid hormones, and thyroid antibodies in 1241 healthy Danish twin individuals and (2) assessed the contribution of the polymorphism to the trait variation and the genetic variance., Measurements: The effect of the genotype on the traits (mean +/- SD) was established; associations between the TSHR-Asp727Glu polymorphism and measures of thyroid homeostasis were assessed and the effect of the polymorphism on the trait's phenotypic variability was quantified by incorporating the genotype information in structural equation modelling., Results: The genotype distribution was Asp/Asp 84.9%; Asp/Glu 14.5% and Glu/Glu 0.6%. Carriers of the TSHR-Glu727 allele had lower TSH levels (noncarriers vs. carriers: 1.78 +/- 0.93 vs. 1.60 +/- 0.84 mU/l, P = 0.04). Regression analysis showed an association between the TSHR-Asp727Glu polymorphism and serum TSH (P = 0.007). The polymorphism accounted for 0.91% of the total phenotypic variance in serum TSH levels. Including the genotype in quantitative genetic modelling improved the model fit (P = 0.001); however, the genetic influence on serum TSH not attributable to this specific genetic variant was only reduced from 68.2% to 67.8%. The polymorphism was not significantly associated with thyroid size, thyroid hormones or thyroid antibody levels., Conclusions: The TSHR-727Glu allele was associated with decreasing TSH levels; however, the contribution to the genetic variance was very small. No association was found with other thyroid-related measures.

Background: Atrial flutter is a serious problem after surgery for congenital heart disease., Methods: We performed an intraoperative linear one-minute cryolesion between a right atriotomy and the tricuspid annulus to prevent atrial flutter in 17 consecutive adult patients undergoing surgery for congenital heart disease. Coronary angiography and electrophysiology study using an electroanatomic mapping system to assess the conduction across the line and to try to induce atrial flutter were performed three months after the operation in 15 patients., Results: Eleven patients had bidirectional block in the cryolesion, four patients did not, and two patients refused the electrophysiology study and coronary angiography. All patients with terminal temperature below -151 degrees C had bidirectional block, while only one patient with terminal temperature above -151 degrees C had bidirectional block. No patient with bidirectional block and all patients without bidirectional block had inducible or spontaneous atrial flutter (p = 0.0007). No lesion of the right coronary artery was detected at coronary angiography., Conclusions: The success rate was suboptimal and the intervention is potentially proarrhythmogenic in patients without block. Preventive strategies targeting atrial flutter should be validated with regard to the block rate achieved.

Serum thyrotropin (TSH), free thyroxine (T4), and free triiodothyronine (T3) levels illustrate the thyroid function set point, but the interrelations between these have never been characterized in detail. The aim of this study was to examine the associations between TSH and thyroid hormone levels in healthy euthyroid twins and to determine the extent to which the same genes influence more than one of these biochemical traits; 1,380 healthy euthyroid Danish twins (284 monozygotic, 286 dizygotic, 120 opposite-sex twin pairs) were recruited. Genetic and environmental associations between thyroid function measurements were examined using quantitative genetic modeling. In bivariate genetic models, the phenotypic relation between two measurements was divided into genetic and environmental correlations. Free T4 and free T3 levels were positively correlated (r=0.32, P<0.0001). The genetic correlation between serum free T4 and free T3 levels was rg=0.25 (95% CI 0.14-0.35), suggesting that a set of common genes affect both phenotypes (pleiotropy). The correlation between the environmental effects was re=0.41 (0.32-0.50). From this we calculated that the proportion of the correlation between free T4 and free T3 levels mediated by common genetic factors was 48%. Only 7% of the genetic component of serum free T3 levels is shared with serum free T4. Serum TSH and thyroid hormone levels did not share any genetic influences. In conclusion, thyroid hormone levels are partly genetically correlated genes that affect free T4 levels and exert pleiotropic effects on free T3 levels, although most of the genetic variance for these measurements is trait specific.

The effect of diabetes on sarcolemmal Na(+)-K(+) pump function is important for our understanding of heart disease associated with diabetes and design of its treatment. We induced diabetes characterized by hyperglycemia but no other major metabolic disturbances in rabbits. Ventricular myocytes isolated from diabetic rabbits and controls were voltage clamped and internally perfused with the whole cell patch-clamp technique. Electrogenic Na(+)-K(+) pump current (I(p), arising from the 3:2 Na(+)-to-K(+) exchange ratio) was identified as the shift in holding current induced by Na(+)-K(+) pump blockade with 100 micromol/l ouabain in most experiments. There was no effect of diabetes on I(p) recorded when myocytes were perfused with pipette solutions containing 80 mmol/l Na(+) to nearly saturate intracellular Na(+)-K(+) pump sites. However, diabetes was associated with a significant decrease in I(p) measured when pipette solutions contained 10 mmol/l Na(+). The decrease was independent of membrane voltage but dependent on the intracellular concentration of K(+). There was no effect of diabetes on the sensitivity of I(p) to extracellular K(+). Pump inhibition was abolished by restoration of euglycemia or by in vivo angiotensin II receptor blockade with losartan. We conclude that diabetes induces sarcolemmal Na(+)-K(+) pump inhibition that can be reversed with pharmacological intervention.

Background: Several studies suggest that the superior transseptal approach to mitral valve surgery leads to sinus node dysfunction. The clinical consequences are not known., Methods: Consecutive patients undergoing surgery for mitral valve disease from November 16, 1994 through January 26, 2004 were retrospectively evaluated. The surgeons used either the superior transseptal (group A) or left atrial approach (group B). The risk of pacemaker implantation associated with the superior transseptal approach as compared with the left atrial approach was estimated using the multivariate Cox regression analysis to adjust for possible confounders., Results: We included 577 patients, 150 in group A and 427 in group B. Forty-four patients had a pacemaker implanted after the surgery; 17 in group A and 27 in group B (p = 0.010). The superior transseptal approach was an independent risk factor of pacemaker implantation in multivariate analysis (hazard ratio 2.2 [1.2 to 4.1], p = 0.014). Nineteen patients had a pacemaker implanted because of sinus node dysfunction; 9 in group A and 10 in group B (p = 0.017). Group A was an independent predictor of pacemaker implantation because of sinus node dysfunction in bivariate analyses. The risk of pacemaker implantation because of atrioventricular conduction disturbances was not different between the groups (p = 0.178)., Conclusions: The superior transseptal approach has a higher risk of clinically significant sinus node dysfunction than the left atrial approach.

Understanding of the aetiological basis of thyroid autoimmunity may be gained by studying the early stages of the disease process. We aimed to (1) investigate the relationship between thyroid antibody status and Yersinia enterocolitica (YE) infection in euthyroid subjects and (2) explore the relative importance of genetic and environmental risk factors in the acquisition of YE infection. The association between thyroid antibody status and YE infection was explored using a case-control design. Furthermore, thyroid antibody-positive twins were compared with their thyroid antibody-negative co-twin. In 468 twins, IgA and IgG antibodies to virulence-associated outer-membrane proteins (YOPs) of YE were measured. Of these, 147 were thyroid antibody-positive (cases). A total of 147 age- and gender-matched twins were chosen as controls. The prevalence of YOP antibodies was lower among thyroid antibody-positive individuals than among controls. Yersinia infection was not associated with a positive thyroid antibody status: the odds ratio (with 95% CI) for YOP IgA-ab was 0.66 (0.42-1.05), P = 0.078 and for YOP IgG-ab it was 0.95 (0.60-1.50), P = 0.816. Within discordant twin pairs, the thyroid antibody-positive twin did not have an increased risk of Yersinia infection compared to the thyroid antibody-negative co-twin [odds ratio: YOP IgA-Ab: 0.94 (0.49-1.83), P = 0.866, and YOP IgG-Ab: 1.35 (0.72-2.53), P = 0.345]; 41% (95% CI 10-67% of the liability of being YOP antibody-positive was due to genetic effects. In conclusion, Yersinia infection does not confer an increased risk of thyroid antibodies. The genetic contribution in the acquisition of Yersinia infection is modest.

Context: Low birth weight has been proposed as a risk factor for the development of antibodies toward thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) in adult life. However, the association could also be due to genetic or environmental factors affecting both birth weight and the development of thyroid autoantibodies. The effect of these confounders can be minimized through investigation of twin pairs., Objective and Design: To examine the impact of low birth weight on the development of thyroid autoimmunity, we studied whether within-twin-cohort and within-twin-pair differences in birth weight are associated with differences in the serum concentration of TPOAb and TgAb in adult life., Participants: We studied 1024 euthyroid twin individuals who were distributed in 512 same-sex twin pairs., Methods: Original midwife protocols were traced manually through the Provincial Archives of Denmark. TPOAb and TgAb were measured using solid-phase time-resolved fluoroimmunometric assays., Results: There were no statistically significant associations between birth weight and serum concentrations of TPOAb [regression coefficient (beta) = 0.003 (95% confidence interval, -0.010 to 0.015); P = 0.67] or TgAb [beta = 0.002 (-0.010 to 0.014); P = 0.77]. When restricting the analysis to twin pairs with a within-pair difference in birth weight of 500 g or greater or to twin pairs born 4 wk or more before term, the regression coefficients were almost unchanged. Controlling for potential confounders (sex, zygosity, gestational age, TSH, and smoking) did not change the findings of nonsignificant regression coefficients., Conclusion: Low birth weight per se has no evident role in the etiology of thyroid autoimmunity.

Background: Tako-tsubo cardiomyopathy (TTC) is an acute reversible cause of segmental myocardial dysfunction that is poorly understood. We have noted a variant of this condition where a tiny segment at the apex retains some contractile function. This paper delineates the frequency of this variant relative to the classical form and the clinical differences between patients suffering from the two forms., Methods: All cases of TTC (n = 35) were identified from our infarct angiography database and separated on the basis of apical sparing (n = 14) or no apical sparing (n = 21)., Results: Compared with the classical form, those with apical sparing were significantly younger (63 +/- 12 vs 72 +/- 13 years) and were more likely premenopausal (5/14 vs 0/21) and had higher ejection fractions (35 +/- 6% vs 32 +/- 4%). There was a trend towards higher recurrence (4/21 vs 0/14). There were no differences in time or season of presentation, precipitant stressor, premorbid drug therapy, haemodynamics at catheterization or acute outcomes., Conclusion: The apical sparing variant of TTC is common, accounting for 40% of cases. While the patients are younger and more likely premenopausal, there are no other distinguishing features between the classical and the variant form.

Background: Atrial tachycardia is very frequent after mitral valve surgery using the superior transseptal approach., Methods: Sixteen patients operated on for mitral valve disease (superior transseptal approach = Group A, n = 9, and left atrial approach = Group B, n = 7) underwent radiofrequency catheter ablation of atrial tachycardia guided by electroanatomic mapping. Twenty-six consecutive patients without previous cardiac surgery with typical atrial flutter served as controls (Group C)., Results: Atrial tachycardia occurred earlier after the operation in Group A than in Group B (median 97 vs 2,159 days, P = 0.003). Typical atrial flutter was the most frequent circuit in all groups (Group A-7 patients, Group B-5 patients, Group C-26 patients). Three patients in Group A developed right atrial incisional tachycardia. Ten of 14 tachycardia circuits (typical atrial flutter, n = 7, incisional tachycardia, n = 3) in Group A depended on the corridor between the right atrial part of the atriotomy and the tricuspid annulus. Slow conduction during typical atrial flutter was detected in this corridor in Group A, but not in the corresponding region in Groups B and C (P < 0.001). The cycle length of typical atrial flutter was longer in Groups A and B than in Group C (mean 283 ms and 282 ms vs 233 ms, P = 0.003). Patients in Group B with typical atrial flutter had larger right atria than patients in Group A or Group C (mean 156 mL vs 96 mL and 113 mL, P = 0.033)., Conclusions: The superior transseptal incision may predispose to atrial tachycardia by creating slow conduction between the atriotomy and the tricuspid annulus.

Background: Atrial fibrillation is common after mitral valve surgery. We do not know the incidence of atrial tachycardia and how it depends on the surgical approach used., Methods: The subjects of the study were 213 consecutive patients who had surgery for mitral valve disease from January 1, 2001, through January 26, 2004. The surgeons used either the superior transseptal approach (69 patients, group A) or left atrial approach (144 patients, group B). An investigator, blinded for the approach used, analyzed all 12-lead electrocardiograms taken during the admission after the operation. The data were analyzed using the Cox regression analysis as time from the operation until documentation of atrial tachycardia or atrial fibrillation on a 12-lead electrocardiogram. Hazard ratio (95% confidence interval) is reported., Results: The superior transseptal approach (2.0 [1.1 to 3.5], p = 0.023), age 60 years or more (2.3 [1.2 to 4.6], p = 0.015), and male sex (2.6 [1.3 to 5.2], p = 0.007) were independent predictors of atrial tachycardia. Age 60 years or more was the only independent predictor of atrial fibrillation (2.0 [1.2 to 3.3], p = 0.007). Although atrial tachycardia was less frequent than atrial fibrillation in group B (p < 0.001), atrial tachycardia was as common as atrial fibrillation in group A (p = 0.149)., Conclusions: The superior transseptal approach has a higher risk of atrial tachycardia than the left atrial approach. Atrial tachycardia has different predictors than atrial fibrillation and constitutes a significant problem, especially after the superior transseptal approach. These results emphasize the need to distinguish between atrial tachycardia and atrial fibrillation-two entities with different pathophysiology, therapy, and also epidemiology.

Segmental pulmonary vein isolation (SPVI) and circumferential pulmonary vein isolation (CPVI) are the two main approaches to radiofrequency ablation in patients with atrial fibrillation (AF). The aim of this retrospective study was to investigate the safety level and patient outcome of both approaches. The overall freedom from symptoms was 73% and 25% after CPVI and SPVI, respectively. Our study concludes that CPVI is an effective treatment of highly symptomatic and drug-resistant AF and when used in laboratories by experienced electrophysiologists has a promising and reproducible outcome ratio and safety level.

Objective: In euthyroid individuals, autoantibodies to thyroid peroxidase (TPOab) and thyroglobulin (Tgab) are regarded as early markers of thyroid autoimmunity. Family and twin studies suggest that development of thyroid autoantibodies in first-degree relatives of patients with autoimmune thyroid disease is under genetic influence. We aimed to estimate the relative importance of genetic and environmental effects for the presence of thyroid autoantibodies in euthyroid subjects., Methods: A representative sample of healthy twin pairs was identified through the Danish Twin Registry; 1372 individuals, divided into 283 monozygotic (MZ), 285 dizygotic same sex (DZ), and 118 opposite sex twin pairs were investigated. Serum TPOab and serum Tgab were measured. Proband-wise concordance and intraclass correlations were calculated, and quantitative genetic modelling was performed., Results: Probandwise concordance and intraclass correlations were consistently higher for MZ than for DZ twin pairs indicating genetic influence. Genetic components (with 95% confidence intervals) accounted for 73% (46-89%) of the liability of being thyroid antibody positive. Adjusting for covariates (age, TSH and others), the estimate for genetic influence on serum TPOab concentrations was 61% (49-70%) in males and 72% (64-79%) in females. For serum Tgab concentrations, the estimates were 39% (24-51%) and 75% (66-81%) respectively., Conclusions: Early markers of thyroid autoimmunity appear to be under strong genetic influence. The analyses suggest that it is the same set of genes that operate in males and females. However, complex mechanisms such as dominance and/or epistasis may be involved.

Background: The National Academy of Clinical Biochemistry (NACB) stresses that the reference intervals for thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and thyroid stimulating hormone (TSH)-receptor antibodies (TRAb) should be based on young men who lack certain risk factors and have serum TSH between 0.5 and 2.0 mIU/L. However, some young men without any of the risk factors have autoantibodies, and cannot be identified by the present tools. A model for reference intervals and cut-off values should not be influenced by the prevalence of risk factors., Methods: We developed a model of "composite logarithmic Gaussian distributions" and tested it in 1441 well-characterised subjects without clinically overt thyroid disease., Results: TPOAb and TgAb could be measured in all individuals. The 97.5% upper limits 1) on a traditional non-parametric scale, 2) according to the NACB criteria, and 3) for our model were 284, 24 and 9.8 kIU/L for TPOAb, and 84, 22 and 19 kIU/L for TgAb, respectively. The decision value (defined as the concentration corresponding to 0.1% false positives) was 15 kIU/L for TPOAb and 31 kIU/L for TgAb. Concentrations above our reference intervals affected the corresponding distribution of TSH values. For TRAb the upper reference limits were 1) 0.75 and 2) 0.75 IU/L, while our model was not applicable to TRAb because only 2-3% of the results were above the functional assay sensitivity., Conclusions: In contrast to the NACB guidelines, our model for TPOAb and TgAb is more robust, as it is independent of the characteristics of the reference population.

Objective: Although earlier a feared complication of congenital cardiac surgery, the incidence of heart-block and sinus node dysfunction has been lowered to 1-4% due to improved surgical techniques and better anatomical understanding of the cardiac conduction system. Development of feasible pacemaker technologies has further lowered mortality and morbidity. However, pacemaker implantation in paediatric patients is in itself associated with significant morbidity due to pacemaker system failure and replacement. The aim of the present study was to examine prognostic factors of mortality, failure of systems and timing of implantation after surgery in post-surgical pacemaker patients., Methods: We carried out a historical prospective follow-up analysis of all patients (age less than 18 years) who underwent pacemaker implantation due to post-surgical heart-block or sinus node dysfunction in the period 1981-2002 at our institution. Data was extracted from the Danish Pacemaker Register and hospital records. Kaplan-Meier survival time estimates and Cox proportional hazards analysis (Relative Risk, RR) were used to identify prognostic factors., Results: High RACHS score (RR, 16.57), low age at implantation (RR, 0.22), low age at operation (RR, 0.06) and epicardial lead (RR, 0.18) were significant predictors for early mortality. Similarly, high RACHS score (RR, 4.84), low age at implantation (RR, 0.32), low age operation (RR, 0.38) and epicardial lead (RR, 0.40) were significant predictors failure of 1st pacemaker system., Conclusions: We identified a number of prognostic factors of patient mortality and failure of systems. One factor, high RACHS score, was previously shown to predict mortality and length of ICU stay in paediatric cardiac surgery; however, this study is the first to show a correlation between RACHS score and mortality as well as failure of pacemaker systems. This may have future implications for preoperative risk stratification of patients and counselling of parents to patients with congenital heart disease.

Introduction: Cardiac resynchronization therapy (CRT) using left ventricular (LV) pacing from the coronary sinus tributary is increasingly and frequently used in patients with severe congestive heart failure. The present study investigates LV lead performance in different anatomic locations., Methods: The LV pacing site was defined by bi-plane fluoroscopy. In the left anterior oblique view, the coronary sinus is encircling the mitral ring with the tributaries radiating out like the hands of a watch. Using this clockwise method, Group A had an LV pacing site before 3 o'clock and Group B at or after 3 o'clock. In right anterior oblique view, the LV was divided into three segments: basal, mid-ventricular, and apical., Results: LV lead implantation was successful in all of 120 consecutive patients. Mean follow-up was 16.7 months. Implantation time decreased from mean 190 to 80 minutes during the period (P = 0.01). The mean LV lead stimulation threshold increased initially and stabilized afterwards. The threshold measured at last follow-up was higher than at implantation (2.3 vs 2.7 microJ, P = 0.04). Useful venograms were obtained in 94 patients. No significant difference in thresholds was observed between Groups A and B. Phrenic nerve stimulation was most commonly seen in Group B (8/70 vs 1/24, P = 0.001)., Conclusion: Implantation of an LV lead for CRT is possible in patients with congestive heart failure and associated with an acceptable low complication rate. LV lead implantation is associated with a learning curve. At mid-term follow-up, LV lead performance is stable and unrelated to the LV implantation site.

Background: A large proportion of healthy, euthyroid, nongoitrous individuals have thyroid nodules. The aetiology of these ultrasonographically detected morphological abnormalities is largely unknown. Factors such as age, gender, iodine intake, smoking and parity are associated with nodularity of the thyroid. Whether there is a genetic susceptibility is unclear., Aim: To gain insight into the aetiology of thyroid nodularity by investigating a large cohort of healthy euthyroid monozygotic and dizygotic twins., Design: A cross-sectional twin study., Participants: A representative sample of self-reported healthy twin pairs was identified through the Danish Twin Registry. A total of 520 individuals divided into 104 monozygotic (MZ), 107 dizygotic same sex (DZ) and 49 opposite sex (OS) twin pairs were investigated., Measurements: Probandwise concordance and tetrachoric correlations. Quantitative genetic modelling was used to elucidate the relative importance of genetic and environmental effects for the variation in the liability of nodularity., Results: A higher concordance rate for thyroid nodularity was found in MZ twins [0.57 (95% CI 0.36-0.76)] than in DZ twins [0.36 (95% CI 0.17-0.56, P = 0.074)]. The same was true for tetrachoric correlations: 0.67 (95% CI 0.34-0.87) in MZ twins and 0.17 (CI - 0.28-0.56, P = 0.053) in DZ twins. The difference, although not significant, was more pronounced for multiple nodules than for solitary nodules. Controlling for covariates (age, gender and smoking habits), it was calculated that genetic factors accounted for 67% (95% CI 35-87%) and environmental factors for 33% (95% CI 13-65%) of the individual differences in the liability to thyroid nodularity., Conclusions: This study suggests that genetic factors are of aetiological importance for thyroid nodularity in clinically healthy and euthyroid individuals, and indicates a difference in the aetiology of solitary and multiple thyroid nodules.

Dysgonomonas capnocytophagoides, formerly known as CDC group DF-3, is an opportunistic pathogen associated with diarrhoea and very rarely bacteraemia. We report a case of D. capnocytophagoides found in blood cultures from a severely neutropenic patient treated for acute myeloid leukaemia. The isolate was found resistant to penicillin, cephalosporins, meropenem, aminoglycosides and ciprofloxacin, and susceptible to ampicillin, tetracycline, chloramphenicol, clindamycin and trimethoprim-sulphamethoxazole. It was identified using conventional phenotypic testing but remained unidentified by the automated identification system (Vitek-2) as this system did not contain DF-3 or D. capnocytophagoides in its database.

Objectives: The purpose of this study was to compare atrial tachycardia circuits after a range of cardiac operations., Background: Knowledge of circuits occurring in a given postsurgical substrate should help to ablate these challenging tachycardias and develop potential preventive strategies., Methods: We analyzed tachycardia circuits in 83 consecutive patients (60 males; median age 47 years, range 9-73) after atrial incisions undergoing ablation of atrial tachycardias. A combined strategy of electroanatomic (CARTO) and entrainment mapping was used. Fifty-two patients (63%) underwent operation for congenital and 31 (37%) for acquired heart disease. Patients were divided into subgroups based on the intervention performed in the atria: right lateral atriotomy (39 patients), left atrial (11) and superior transseptal (10) approach to the mitral valve, biatrial heart transplantation (8), Mustard (8) and Fontan (4) procedure, and other interventions (3)., Results: Most of the 119 tachycardias mapped were isthmus-dependent atrial flutter (66) and incisional tachycardia (30). Isthmus-dependent atrial flutter was the most frequent arrhythmia in all subgroups except for Fontan patients, in whom incisional tachycardia was most frequent. The distribution of tachycardia circuits did not differ significantly among groups., Conclusions: The observed circuits did not differ among the postsurgical substrates. Isthmus-dependent atrial flutter should be the first circuit considered in patients after atrial incisions.

Objectives: The aim of this study was to evaluate irrigated-tip catheter for ablation of intraatrial reentrant tachycardias late after surgical repair of congenital heart disease., Background: In congenital heart disease patients, the right atrium can be markedly enlarged with areas of low blood flow. Radiofrequency (RF) lesion creation may be hampered by insufficient electrode cooling at sites with low blood flow., Methods: Thirty-six consecutive patients with intraatrial reentrant tachycardia refractory to antiarrhythmic therapy from two centers were included in the study. Entrainment pacing and electroanatomic mapping (CARTO) were used to delineate reentrant circuits and critical isthmus sites. RF ablation was performed using an irrigated-tip catheter (Navistar Thermocool)., Results: Fifty-two intraatrial reentrant tachycardia circuits were identified, and 48 were targeted with RF ablation. RF ablation was performed using a mean of 13 +/- 11 irrigated RF applications per tachycardia isthmus with a mean power of 36 +/- 8 W. In a historical control group of congenital heart disease patients managed with conventional catheter ablation, the number of lesions per isthmus was higher (23 +/- 11) and mean power was lower (27 +/- 14 W). Acute success was achieved in 45 intraatrial reentrant tachycardias (94% of targeted tachycardias and 87% of all tachycardias). After a mean follow-up of 17 +/- 7 months, 33 (92%) of 36 patients were free of recurrence. Five patients (14%) developed paroxysmal atrial fibrillation., Conclusions: The combination of modern techniques including electroanatomic mapping and catheter irrigation allows safe and highly effective ablation of intraatrial reentrant tachycardia in patients with surgically repaired congenital heart disease.

Factors such as iodine intake, serum TSH concentration, gender, age, body mass index, parity, and cigarette smoking are thought to influence thyroid size. The purpose of our study was to determine the relative roles of these environmental and physiological factors compared with genetic factors in euthyroid subjects with a clinically normal thyroid gland. A representative sample of self-reported healthy twin pairs was identified through the Danish Twin Registry. A total of 520 individuals divided into 104 monozygotic (MZ), 107 dizygotic same sex (DZ), and 49 opposite sex twin pairs were investigated. After adjustment for age, gender, and other covariates, intraclass correlations were calculated. To elucidate the relative importance of genetic and environmental factors to the variation of ultrasonically determined thyroid volume, quantitative genetic modeling was used. Regression analysis suggested that serum TSH, serum free T(4), gender, age, smoking, and body mass index each played a small, but significant, role for variation in thyroid volume. The intraclass correlations for thyroid volume were consistently higher for MZ than for DZ twin pairs (r(MZ) = 0.71; r(DZ) = 0.18; P < 0.001). Using quantitative genetic modeling, it was calculated that genetic factors (with 95% confidence intervals) accounted for 71% (61-78%) of the individual differences in thyroid volume. Genetic influences are important in the regulation of normal thyroid size. This fits the observation that goiter may be seen also in the absence of evident environmental goitrogens such as iodine deficiency and that not all individuals develop goiter even in iodine-deficient areas.

Background: Family studies have repeatedly shown aggregation of thyroid autoantibodies to thyroid peroxidase (TPOab) and thyroglobulin (Tgab) in first-degree relatives of patients with autoimmune thyroid disease (AITD). This phenomenon has generally been interpreted as evidence of a genetic component in the development of thyroid autoantibodies. However, family studies cannot determine whether the observed familial aggregation of these antibodies is due to shared genes or shared environment., Aim: To test the hypothesis that the familial aggregation of thyroid autoantibodies is mainly genetically determined., Design: A cross-sectional study of healthy twin siblings to twins with AITD., Participants: Thirty-eight healthy twin siblings to twins with AITD and a control group of 76 healthy twins, matched for age, sex and zygosity, but without AITD among their first-degree relatives., Main Outcome Measures: Prevalence of TPOab, Tgab and TSH-receptor antibodies (TSHRab)., Methods: All antibodies were measured by routine commercial kits. TPOab, Tgab and TSHRab were regarded as positive if > 60 U/ml, > 60 U/ml and > 1.0 U/l, respectively. Zygosity was established by DNA fingerprinting., Results: The prevalence of TPOab, Tgab and TSHRab in the 38 healthy twin siblings was 34% (13/38), 26% (10/38) and 13% (5/38), respectively, which was higher than the corresponding prevalences in the control population, 9% (7/76; P = 0.002), 7% (5/76; P = 0.006) and 1.3% (1/76; P = 0.015), respectively. Combination of two or more thyroid autoantibodies was also significantly more common among index subjects (10/38 or 26%) than in the control group (2/76 or 3%), P = 0.0001. Among the healthy monozygotic twin siblings, 53%, 47% and 20% had TPOab, Tgab and TSHRab, respectively, compared with 22% (P = 0.045), 13% (P = 0.02) and 9% (P = 0.36), respectively, in the dizygotic twin siblings. Significantly more monozygotic twin siblings were positive for two or more autoantibodies than dizygotic twin siblings (8/15 vs. 2/23; P = 0.006)., Conclusion: Healthy first-degree relatives to patients with AITD show significant clustering of thyroid autoantibodies. Moreover, healthy monozygotic and dizygotic twin siblings to twins with AITD differ in prevalence of thyroid autoantibodies. These observations strongly support the hypothesis that the familial aggregation of thyroid autoantibodies is mainly genetically determined.