Thyroglobulin and thyroglobulin antibodies: assay-dependent management consequences in patients with differentiated thyroid carcinoma.

OBJECTIVES: International guidelines recommend fixed cut-off values for thyroglobulin (Tg). These cut-offs do not take potential assay differences into account. This study aimed to evaluate if different assays for Tg and Tg antibodies (TgAb) affect management guidance for differentiated thyroid cancer (DTC) patients. METHODS: In 793 samples derived from 413 patients with DTC, Tg and TgAb were simultaneously measured with two immunometric assays: Immulite 2000XPi and Kryptor compact plus. In addition, a qualitative measurement for TgAb interference (recovery test) was performed on the Kryptor compact plus platform. The extent to which different assays lead to different classifications of response to therapy was evaluated when applying the current cut-offs for Tg. RESULTS: Mean Tg concentrations were 37.4% lower with Kryptor as compared with Immulite. Applying guideline based cut-off values for Tg, 33 (4.7%) samples had a Tg-on concentration ≥1.0 µg/L with Immulite and <1.0 µg/L with Kryptor. Of the samples tested as TgAb+ with at least one assay (n=125), 68 (54.4%) samples showed discrepancy in TgAb status. Differences between Immulite and Kryptor measurements resulted in a change in the response to therapy classification in 94 (12.0%) measurements derived from 67 (16.2%) individual patients. CONCLUSIONS: A substantial portion of DTC patients were classified differently dependent on which Tg and TgAb assays are used, when applying the cut-off values as defined in clinical guidelines. Such differences can significantly affect clinical management. In the context of large between-method variation, the recommended Tg cut-offs in guidelines should be used with wisdom rather than as fixed cut-offs.

Management of Postthyroidectomy Hypoparathyroidism and Its Effect on Hypocalcemia-Related Complications: A Meta-Analysis.

OBJECTIVE: The aim of this Meta-analysis is to evaluate the impact of different treatment strategies for early postoperative hypoparathyroidism on hypocalcemia-related complications and long-term hypoparathyroidism. DATA SOURCES: Embase.com, MEDLINE, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and the top 100 references of Google Scholar were searched to September 20, 2022. REVIEW METHODS: Articles reporting on adult patients who underwent total thyroidectomy which specified a treatment strategy for postthyroidectomy hypoparathyroidism were included. Random effect models were applied to obtain pooled proportions and 95% confidence intervals. Primary outcome was the occurrence of major hypocalcemia-related complications. Secondary outcome was long-term hypoparathyroidism. RESULTS: Sixty-six studies comprising 67 treatment protocols and 51,096 patients were included in this Meta-analysis. In 8 protocols (3806 patients), routine calcium and/or active vitamin D medication was given to all patients directly after thyroidectomy. In 49 protocols (44,012 patients), calcium and/or active vitamin D medication was only given to patients with biochemically proven postthyroidectomy hypoparathyroidism. In 10 protocols (3278 patients), calcium and/or active vitamin D supplementation was only initiated in case of clinical symptoms of hypocalcemia. No patient had a major complication due to postoperative hypocalcemia. The pooled proportion of long-term hypoparathyroidism was 2.4% (95% confidence interval, 1.9-3.0). There was no significant difference in the incidence of long-term hypoparathyroidism between the 3 supplementation groups. CONCLUSIONS: All treatment strategies for postoperative hypocalcemia prevent major complications of hypocalcemia. The early postoperative treatment protocol for postthyroidectomy hypoparathyroidism does not seem to influence recovery of parathyroid function in the long term.

Predictors of treatment response in lymphogenic metastasized papillary thyroid cancer: a histopathological study.

BACKGROUND: Lymph node metastases in papillary thyroid cancer (PTC) increase the risk for persistent and recurrent disease. Data on the predictive value of histopathological features of lymph node metastases, however, are inconsistent. The aim of this study was to evaluate the prognostic significance of known and new histopathological features of lymph node metastases in a well-defined cohort of PTC patients with clinically evident lymph node metastases. METHODS: A total of 1042 lymph node metastases, derived from 129 PTC patients, were reexamined according to a predefined protocol and evaluated for diameter, extranodal extension, cystic changes, necrosis, calcifications, and the proportion of the lymph node taken up by tumor cells. Predictors for a failure to achieve a complete biochemical and structural response to treatment were determined. RESULTS: The presence of more than 5 lymph node metastases was the only independent predictor for a failure to achieve a complete response to treatment (odds ratio [OR] 3.39 [95% CI, 1.57-7.33], P < .05). Diameter nor any of the other evaluated lymph node features were significantly associated with the response to treatment. CONCLUSIONS: Detailed reexamination of lymph nodes revealed that only the presence of more than 5 lymph node metastases was an independent predictor of failure to achieve a complete response to treatment. No predictive value was found for other histopathological features, including the diameter of the lymph node metastases. These findings have the potential to improve risk stratification in patients with PTC and clinically evident lymph node metastases.

Regional Collaboration and Trends in Clinical Management of Thyroid Cancer.

OBJECTIVE: This study examines the trends in the management of thyroid cancer and clinical outcomes in the Southwestern region of The Netherlands from 2010 to 2021, where a regional collaborative network has been implemented in January 2016. STUDY DESIGN: Retrospective cohort study. SETTING: This study encompasses all patients diagnosed with thyroid cancer of any subtype between January 2010 and June 2021 in 10 collaborating hospitals in the Southwestern region of The Netherlands. METHODS: The primary outcome of this study was the occurrence of postoperative complications. Secondary outcomes were trends in surgical management, centralization, and waiting times of patients with thyroid cancer. RESULTS: This study included 1186 patients with thyroid cancer. Median follow-up was 58 [interquartile range: 24-95] months. Surgery was performed in 1027 (86.6%) patients. No differences in postoperative complications, such as long-term hypoparathyroidism, permanent recurrent nerve paresis, or reoperation due to bleeding were seen over time. The percentage of patients with low-risk papillary thyroid carcinoma referred to the academic hospital decreased from 85% (n = 120/142) in 2010 to 2013 to 70% (n = 120/171) in 2014 to 2017 and 62% (n = 100/162) in 2018 to 2021 (P < .01). The percentage of patients undergoing a hemithyroidectomy alone was 9% (n = 28/323) in 2010 to 2013 and increased to 20% (n = 63/317; P < .01) in 2018 to 2021. CONCLUSION: The establishment of a regional oncological network coincided with a de-escalation of thyroid cancer treatment and centralization of complex patients and interventions. However, no differences in postoperative complications over time were observed. Determining the impact of regional oncological networks on quality of care is challenging in the absence of uniform quality indicators.

Not-in-trial simulation I: Bridging cardiovascular risk from clinical trials to real-life conditions.

AIMS: The assessment of heart rate-corrected QT (QTc) interval prolongation relies on the evidence of drug effects in healthy subjects. This study demonstrates the relevance of pharmacokinetic-pharmacodynamic (PKPD) relationships to characterize drug-induced QTc interval prolongation and explore the discrepancies between clinical trials and real-life conditions. METHODS: d,l-Sotalol data from healthy subjects and from the Rotterdam Study cohort were used to assess treatment response in a phase I setting and in a real-life conditions, respectively. Using modelling and simulation, drug effects at therapeutic doses were predicted in both populations. RESULTS: Inclusion criteria were shown to restrict the representativeness of the trial population in comparison to real-life conditions. A significant part of the typical patient population was excluded from trials due to weight and baseline QTc interval criteria. Relative risk was significantly different between sotalol users with and without heart failure, hypertension, diabetes and myocardial infarction (P < 0.01). Although drug effects do cause an increase in the relative risk of QTc interval prolongation, the presence of diabetes represented an increase from 4.0 [95% confidence interval (CI) 2.7-5.8] to 6.5 (95% CI 1.6-27.1), whilst for myocardial infarction it increased from 3.4 (95% CI 2.3-5.13) to 15.5 (95% CI 4.9-49.3). CONCLUSIONS: Our findings show that drug effects on QTc interval do not explain the observed QTc values in the population. The prevalence of high QTc values in the real-life population can be assigned to co-morbidities and concomitant medications. These findings substantiate the need to account for these factors when evaluating the cardiovascular risk of medicinal products.

A symptom-based algorithm for calcium management after thyroid surgery: a prospective multicenter study.

Objective: Evidence-based treatment guidelines for the management of postthyroidectomy hypocalcemia are absent. The aim of this study was to evaluate a newly developed symptom-based treatment algorithm including a protocolized attempt to phase out supplementation. Methods: In a prospective multicenter study, patients were treated according to the new algorithm and compared to a historical cohort of patients treated with a biochemically based approach. The primary outcome was the proportion of patients receiving calcium and/or alfacalcidol supplementation. Secondary outcomes were calcium-related complications and predictors for supplementation. Results: One hundred thirty-four patients were included prospectively, and compared to 392 historical patients. The new algorithm significantly reduced the proportion of patients treated with calcium and/or alfacalcidol during the first postoperative year (odds ratio (OR): 0.36 (95% CI: 0.23-0.54), P < 0.001), and persistently at 12 months follow-up (OR: 0.51 (95% CI: 0.28-0.90), P < 0.05). No severe calcium-related complications occurred, even though calcium-related visits to the emergency department and readmissions increased (OR: 11.5 (95% CI: 4.51-29.3), P <0.001) and (OR: 3.46 (95% CI: 1.58-7.57), P < 0.05), respectively. The proportional change in pre- to postoperative parathyroid hormone (PTH) was an independent predictor for supplementation (OR: 1.04 (95% CI: 1.02-1.07), P < 0.05). Conclusions: Symptom-based management of postthyroidectomy hypocalcemia and a protocolized attempt to phase out supplementation safely reduced the proportion of patients receiving supplementation, although the number of calcium-related hospital visits increased. For the future, we envision a more individualized treatment approach for patients at risk for delayed symptomatic hypocalcemia, including the proportional change in pre- to post- operative PTH.

Establishing a Multicenter Network for Patients With Thyroid Nodules and Cancer: Effects on Referral Patterns.

OBJECTIVE: To perform a qualitative evaluation of the Thyroid Network, with a quantitative analysis of second opinion referrals for patients in the southwestern part of the Netherlands who have thyroid nodules and cancer. METHODS: This prospective observational study registered all patients with thyroid nodules and cancer who were referred to the academic hospital from 2 years before and 4 years after the foundation of the Thyroid Network. We implemented biweekly regional multidisciplinary tumor boards using video conference and a regional patient care pathway for patients with thyroid nodules and cancer. For qualitative evaluation, interviews were conducted with a broad selection of stakeholders via maximum variation sampling. The primary outcome was the change in second opinions after the foundation of the Thyroid Network. RESULTS: Second opinions from Thyroid Network hospitals to the academic hospital decreased from 10 (30%) to 2 (7%) two years after the start of the Thyroid Network (P = .001), while patient referrals remained stable (n = 108 to 106). Qualitative evaluation indicated that the uniform care pathway and the regional multidisciplinary tumor board were valued high. DISCUSSION: Establishing a regional network, including multidisciplinary tumor boards and a care pathway for patients with thyroid nodules and cancer, resulted in a decrease in second opinions of in-network hospitals and high satisfaction of participating specialists. IMPLICATIONS FOR PRACTICE: The concept of the Thyroid Network could spread to other regions as well as to other specialties in health care. Future steps would be to assess the effect of regional collaboration on quality of care and patient satisfaction.

Preferences of patients, clinicians, and healthy controls for the management of a Bethesda III thyroid nodule.

BACKGROUND: Active surveillance is propagated as an alternative for hemithyroidectomy in the management of Bethesda III thyroid nodules. METHODS: A cross-sectional survey questioned respondents on their willingness to accept risks related to active surveillance and hemithyroidectomy. RESULTS: In case of active surveillance, respondents (129 patients, 46 clinicians, and 66 healthy controls) were willing to accept a risk of 10%-15% for thyroid cancer and 15% for needing more extensive surgery in the future. Respondents were willing to accept a risk of 22.5%-30% for hypothyroidism after hemithyroidectomy. Patients and controls were willing to accept a higher risk on permanent voice changes compared with clinicians (10% vs. 3%, p < 0.001). CONCLUSION: Real-life risks associated which active surveillance and hemithyroidectomy for Bethesda III nodules are equivalent or less than the risks people are willing to accept. Clinicians accepted less risk for permanent voice changes.

Persistent post-thyroidectomy hypoparathyroidism: A multicenter retrospective cohort study.

BACKGROUND AND OBJECTIVE: The reported incidence of persistent hypoparathyroidism varies widely, and consensus on a definition is lacking. The objective was to evaluate the real-life incidence of persistent hypoparathyroidism by investigating a new pragmatic definition. METHODS: This retrospective multicenter cohort study evaluated the effect of different definitions for persistent hypoparathyroidism on the incidence of hypoparathyroidism. In addition, risk factors for hypoparathyroidism were analyzed. RESULTS: In total, 749 patients were included. Using the new pragmatic definition, we report an incidence of 7.9% of persistent hypoparathyroidism. When applying other commonly used definitions, incidence varied between 11.8% and 22.1%. Risk factors were parathyroid autotransplantation, presence of another surgical complication, and low postoperative serum calcium. CONCLUSIONS: Our data show that the incidence of persistent hypoparathyroidism in the literature may vary through the use of different definitions. This study indicates that a new pragmatic definition of persistent hypoparathyroidism has the potential to enable unbiased comparison between studies.

Impact of Thyroglobulin and Thyroglobulin Antibody Assay Performance on the Differential Classification of DTC Patients.

CONTEXT: Measurements of thyroglobulin (Tg) and Tg antibodies are crucial in the follow-up of treated differentiated thyroid cancer (DTC) patients. Interassay differences may significantly impact follow-up. OBJECTIVE: The aim of this multicenter study was to explore the impact of Tg and Tg antibody assay performance on the differential classification of DTC patients, as described in national and international guidelines. DESIGN: Four commonly used Tg and Tg antibody assays were technically compared to reflect possible effects on patients with DTC follow-up. Storage stability at different storage temperatures was also investigated for LIAISON® and Kryptor assays, as this is an underexposed topic in current literature. RESULTS: B.R.A.H.M.S. assays yield approximately 50% lower Tg values over the whole range compared to the DiaSorin and Roche assays investigated. These differences between assays may result in potential misclassification in up to 7% of patients if fixed cutoffs (eg, 1 ng/mL) are applied. Poor correlation was also observed between the Tg antibody assays when the method-specific upper limits of normal are used as cutoffs. Storage of Tg and Tg antibodies was possible for 3 to 4 weeks at -20°C and -80°C. Calibration of the assays, however, was found to be crucial for stable results over time. CONCLUSIONS: Technical aspects of Tg and Tg antibody assays, including interassay differences, calibration and standardization, and cutoff values, may have a significant clinical impact on the follow-up of DTC patients.

Independent susceptibility markers for atrial fibrillation on chromosome 4q25.

BACKGROUND: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus. METHODS AND RESULTS: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2 x 10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals. CONCLUSIONS: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.

Invited commentary: sex-steroid hormones and QT-interval duration.

In this issue of the Journal, Zhang et al. (Am J Epidemiol. 2011;174(4):403-411) make a substantial contribution to research in the area of hormonal influences on cardiac repolarization by demonstrating an inverse association between testosterone levels and the Bazett's adjusted QT interval (QTc) and RR-adjusted QT interval in men but not in postmenopausal women. They suggest that testosterone levels might explain the difference in QTc-interval duration between men and women and could contribute to population variability in QTc-interval duration among men. In this commentary, the gender difference and the role of testosterone in human cardiac repolarization are addressed. In addition, the gender differences in the congenital long-QT syndrome, drug-induced ventricular arrhythmias, and sudden cardiac death are discussed.

Genetic variation in NOS1AP is associated with sudden cardiac death: evidence from the Rotterdam Study.

Common variation within the nitric oxide-1 synthase activator protein (NOS1AP) locus is strongly related to QT interval, a sudden cardiac death (SCD) risk factor. A recent report describes common variation in NOS1AP associated with SCD in a US population of European ancestry. The objective of the current study was to obtain additional evidence by investigating the association between NOS1AP variants and SCD in the prospective population-based Rotterdam Study. The study population consisted of 5974 European ancestry subjects, aged 55 years and older, genotyped on Illumina arrays. SCD was defined according to European Society of Cardiology guidelines. Smoking, body mass index, diabetes mellitus, hypertension, heart failure and myocardial infarction were used as covariates in Cox proportional hazard models. Results were combined with reported evidence using inverse-variance weighted meta-analysis. Two hundred and eight (109 witnessed) cases of SCD occurred during a mean follow-up of 10.4 years. Within the Rotterdam Study alone, no significant associations were observed. Upon pooling of results with existing data, we observed strengthening of existing evidence for rs16847549 (US data HR = 1.31, P = 0.0024; Rotterdam Study HR = 1.18, P = 0.16; joint HR = 1.26, P = 0.0011). When the case definition in the Rotterdam Study was restricted to witnessed SCD, association of rs16847549 with SCD became stronger (joint P = 0.00019) and additionally the association between rs12567209 and SCD gained significance (US data HR = 0.57, P = 0.0035; Rotterdam Study HR = 0.69, P = 0.23; joint HR = 0.60, P = 0.0018). In conclusion, this study provided additional evidence for association between genetic variation within NOS1AP and SCD. The mechanism by which this effect is exerted remains to be elucidated.

Proton pump inhibitors and the risk of overanticoagulation during acenocoumarol maintenance treatment.

In the Netherlands, several reports have described a potentiation of acenocoumarol-induced anticoagulation by co-medication of omeprazole or esomeprazole and competitive inhibition of CYP2C19 has been suggested as a possible mechanism for this interaction. We conducted an observational cohort study to investigate the effects of various proton pump inhibitors (PPIs) on acenocoumarol effectiveness. All 2755 subjects from the Rotterdam Study who received acenocoumarol maintenance treatment between April 1st, 1991 and September 9th, 2009 were followed for events of an international normalized ratio (INR)≥6, until death, end of treatment, or end of the study period. The Andersen-Gill extension of the Cox proportional hazards model was used to calculate risks for repeated events of overanticoagulation in relation to concomitant PPI use. The risk for overanticoagulation was most pronounced for esomeprazole (HR 1·99, 95% CI 1·55-2·55) and lansoprazole (HR 1·49, 95% CI 1·05-2·10). There was also a lower and non-significant risk increase for the other PPIs. We did not detect a modification of these results by CYP2C19*2 genotype. Caution should be paid to co-medication with esomeprazole and lansoprazole during acenocoumarol treatment and possibly also with other PPIs.

Preferences of patients and clinicians for treatment of Graves' disease: a discrete choice experiment.

OBJECTIVE: Treatment options for Graves' disease (GD) consist of antithyroid drugs (ATD), radioactive iodine (RAI) and total thyroidectomy (TT). Guidelines recommend to discuss these options with patients, taking into account patients' preferences. This study aims to evaluate and compare patients' and clinicians' preferences and the trade-offs made in choosing treatment. DESIGN AND METHODS: A discrete choice experiment (DCE) was performed with GD patients with a first diagnosis or recurrence in the previous year, and with clinicians. Participants were offered hypothetical treatment options which differed in type of treatment, rates of remission, severe side effects, permanent voice changes and hypocalcemia. Preference heterogeneity was assessed by latent-class analysis. RESULTS: In this study, 286 (82%) patients and 61 (18%) clinicians participated in the DCE. All treatment characteristics had a significant effect on treatment choice (P < 0.05). Remission rate was the most important determinant and explained 37 and 35% of choices in patients and clinicians, respectively. Both patients and clinicians preferred ATD over surgery and RAI. A strong negative preference toward RAI treatment was observed in a subclass of patients, whereas clinicians preferred RAI over surgery. CONCLUSION: For both patients and clinicians, remission rate was the most important determinant of treatment choice and ATD was the most preferred treatment option. Patients had a negative preference toward RAI compared to alternatives, whereas clinicians preferred RAI over surgery. Clinicians should be aware that their personal attitude toward RAI differs from that of their patients. This study on patients' and clinicians' preferences can support shared decision making and thereby improve clinical treatment.

High-flow Nasal Cannula therapy: A feasible treatment for vulnerable elderly COVID-19 patients in the wards.

BACKGROUND: Invasive mechanical ventilation is the treatment of choice in COVID-19 patients when hypoxemia persists, despite maximum conventional oxygen administration. Some frail patients with severe hypoxemic respiratory failure are deemed not eligible for invasive mechanical ventilation. OBJECTIVES: To investigate whether High-flow nasal cannula (HFNC) in the wards could serve as a rescue therapy in these frail patients. METHODS: This retrospective cohort study included frail COVID-19 patients admitted to the hospital between March 9th and May 1st 2020. HFNC therapy was started in the wards. The primary endpoint was the survival rate at hospital discharge. RESULTS: Thirty-two patients with a median age of 79.0 years (74.5-83.0) and a Clinical Frailty Score of 4 out of 9 (3-6) were included. Only 6% reported HFNC tolerability issues. The overall survival rate was 25% at hospital discharge. CONCLUSIONS: This study suggests that, when preferred, HFNC in the wards could be a potential rescue therapy for respiratory failure in vulnerable COVID-19 patients.

Genetic variance in CYP2C8 and increased risk of myocardial infarction.

BACKGROUND: Epoxyeicosatrienoic acids (EETs) are important mediators in vasodilatation, acting as endothelium-derived hyperpolarizing factors. CYP2C enzymes catalyze the metabolism of arachidonic acid to EETs. Genetic variation within the genes encoding for these enzymes may result in differences in vascular response, among others in myocardial tissue, and may therefore increase the risk of myocardial infarction (MI). CYP2C8 and CYP2C9 are encoded by the genes of the same name. CYP2C9 polymorphisms have been associated with an increased risk of MI. As CYP2C8 is genetically linked to CYP2C9 and on account of its role in EET production, we hypothesized that CYP2C8 polymorphisms are associated with the risk of MI. METHODS: This study was embedded within the Rotterdam study, a prospective population-based cohort study. The study population included all participants with successful genotyping and without prevalent MI (n=5199). Twenty-five tagging single nucleotide polymorphisms within and around the gene-coding areas of CYP2C8 and CYP2C9 were tested for an association with incident MI using survival analysis techniques with multivariable adjustment for potential confounders. RESULTS: During follow-up, 290 persons developed an incident MI. One tag-SNP in the CYP2C8 gene was associated with incident MI after Bonferroni correction, rs1058932C>T (variant genotype hazard ratio 1.54; 95% CI: 1.22-1.95). There was a significant gene-sex interaction with a relative excess risk of 1.40 (95% CI: 0.33-2.47) for men. CONCLUSION: SNP rs1058932C>T within the CYP2C8 gene is associated with an increased risk of MI, which is, possibly because of a vascular effect of sex steroids, highest in males.

Drug- and non-drug-associated QT interval prolongation.

Sudden cardiac death is among the most common causes of cardiovascular death in developed countries. The majority of sudden cardiac deaths are caused by acute ventricular arrhythmia following repolarization disturbances. An important risk factor for repolarization disturbances is use of QT prolonging drugs, probably partly explained by gene-drug interactions. In this review, we will summarize QT interval physiology, known risk factors for QT prolongation, including drugs and the contribution of pharmacogenetics. The long QT syndrome can be congenital or acquired. The congenital long QT syndrome is caused by mutations in ion channel subunits or regulatory protein coding genes and is a rare monogenic disorder with a mendelian pattern of inheritance. Apart from that, several common genetic variants that are associated with QT interval duration have been identified. Acquired QT prolongation is more prevalent than the congenital form. Several risk factors have been identified with use of QT prolonging drugs as the most frequent cause. Most drugs that prolong the QT interval act by blocking hERG-encoded potassium channels, although some drugs mainly modify sodium channels. Both pharmacodynamic as well as pharmacokinetic mechanisms may be responsible for QT prolongation. Pharmacokinetic interactions often involve drugs that are metabolized by cytochrome P450 enzymes. Pharmacodynamic gene-drug interactions are due to genetic variants that potentiate the QT prolonging effect of drugs. QT prolongation, often due to use of QT prolonging drugs, is a major public health issue. Recently, common genetic variants associated with QT prolongation have been identified. Few pharmacogenetic studies have been performed to establish the genetic background of acquired QT prolongation but additional studies in this newly developing field are warranted.

The association of serum testosterone levels and ventricular repolarization.

UNLABELLED: It is assumed that testosterone is an important regulator of gender-related differences in ventricular repolarization. Therefore, our aim was to study whether serum levels of testosterone are associated with QTc, QT and RR interval variation. SETTING: two independent population-based cohort studies. PARTICIPANTS: 445 male participants (> or =55 years) from the Rotterdam study cohort and 1,428 male participants from the study of health in Pomerania (SHIP) with an electrocardiogram who were randomly sampled for assessment of serum testosterone at baseline, after exclusion of participants with testosterone altering drugs, QTc prolonging drugs or dig(it)oxin, left ventricular hypertrophy and left and right bundle branch block. ENDPOINTS: length of the QTc, QT and RR intervals. ANALYSIS: linear regression model, adjusted for the two individual studies and a pooled analysis of both studies. The pooled analysis of the Rotterdam study and SHIP showed that the QTc interval gradually decreased among the tertiles (P value for trend 0.024). The third tertile of serum testosterone was associated with a lower QTc interval compared to the first tertile [-3.4 ms (-6.5; -0.3)]. However, the third tertile of serum testosterone was not associated with a lower QT interval compared to the first tertile [-0.7 ms (-3.1; 1.8)]. The RR interval gradually increased among the tertiles (P value for trend 0.002) and the third tertile of serum testosterone showed an increased RR interval compared to the first tertile [33.5 ms (12.2; 54.8)]. In the pooled analysis of two population-based studies, serum testosterone levels were not associated with the QT interval, which could be due to a lack of power. Lower QTc intervals in men with higher serum testosterone levels could be due to the association of serum testosterone with prolongation of the RR interval.

Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation.

AIMS: A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts. METHODS AND RESULTS: The Framingham Heart Study and Rotterdam Study are community-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) are case-control studies. Participants with AF (n = 3508) were more likely to be male and were older than referent participants (n = 12 173; Framingham 82 +/- 10 vs. 71 +/- 13 years; Rotterdam 73 +/- 8 vs. 69 +/- 9 years; Vanderbilt 54 +/- 14 vs. 57 +/- 14 years; AFNet 62 +/- 12 vs. 49 +/- 14 years). Single nucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios (ORs) ranging from 1.37 in Rotterdam [95% confidence interval (CI) 1.18-1.59; P = 3.1 x 10(-5)] to 2.52 in AFNet (95% CI 2.22-2.8; P = 1.8 x 10(-49)). There also was a significant association between AF and rs10033464 in Framingham (OR 1.34; 95% CI 1.03-1.75; P = 0.031) and AFNet (OR 1.30; 95% CI 1.13-1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95% CI 0.86-1.56; P = 0.33). A meta-analysis of the current and prior AF studies revealed an OR of 1.90 (95% CI 1.60-2.26; P = 3.3 x 10(-13)) for rs2200733 and of 1.36 (95% CI 1.26-1.47; P = 6.7 x 10(-15)) for rs10033464. CONCLUSION: The non-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of European descent. These results confirm the significant relations between AF and intergenic variants on chromosome 4.