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Utrecht, Netherlands

Jukema J.W.,Leiden University | Jukema J.W.,Durrer Center for Cardiogenetic Research | Jukema J.W.,Interuniversity Cardiology | Cannon C.P.,Brigham and Womens Hospital | And 4 more authors.
Journal of the American College of Cardiology | Year: 2012

The debate whether statins, 3-hydroxymethyl-3-methylglutaryl coenzyme A reductase inhibitors, are safe to use has been raging since their introduction in 1987. Statins are generally well tolerated and are believed to have minimal adverse effects. However, individual, specific rare adverse events have been reported, such as elevations of liver enzymes, muscle aches, and very rarely, rhabdomyolysis. Discontinuation and/or reduction in the dose of the statin usually leads to resolution of these side effects. Recently, however, debate has focused on the possible negative long-term effects of statin treatment on cognitive decline, the incidence of cancer, and the development of diabetes mellitus. Recently, the U.S. Food and Drug Administration has expanded the warning for statins with a statement that statin use may lead to cognitive impairment. In this review, we discuss all levels of evidence, from case reports to large randomized controlled clinical trials, for the possible adverse effects of statins on cognitive decline, cancer, and diabetes. After careful consideration of all discussed scientific evidence, we conclude that there is no increased risk of cognitive decline or cancer with statin use. However, statin use is related to a small increased risk of type 2 diabetes mellitus. In view of the overwhelming benefit of statins in the reduction of cardiovascular events, we believe the small absolute risk for development of diabetes is outweighed by the cardiovascular benefits in patients for whom statin therapy is recommended. We, therefore, suggest that clinical practice for statin therapy should not be changed on the basis of the most recent Food and Drug Administration informational warnings. © 2012 American College of Cardiology Foundation.

Oemrawsingh R.M.,Erasmus University Rotterdam | Oemrawsingh R.M.,Interuniversity Cardiology | Lenderink T.,Atrium Medical | Akkerhuis K.M.,Erasmus University Rotterdam | And 5 more authors.
Heart | Year: 2011

Objective: To evaluate the predictive value of seven biomarkers, which individually have been shown to be independent predictors, for use in a combined multimarker model for long-term cardiovascular outcome after non-ST-segment elevation acute coronary syndrome (NSTEACS). Design and Setting: Levels of high-sensitivity C-reactive protein (hsCRP), myeloperoxidase, pregnancy-associated plasma protein A, placental growth factor (PlGF), soluble CD40 ligand (sCD40L), interleukin 10 (IL-10) and troponin-T (TnT) were determined in patients enrolled in the CAPTURE trial. Cox proportional hazard regression analyses were applied to evaluate the relation between biomarkers and the occurrence of all-cause mortality or non-fatal myocardial infarction (MI). Patients: 1090 patients with NSTEACS. Main outcome measure: All-cause mortality and non-fatal MI during a median follow-up of 4 years. Results: The composite endpoint was reached by 15.3% of patients. Admission levels of TnT >0.01 μg/l (adjusted HR 1.8), IL-10 <3.5 ng/l (1.7), myeloperoxidase >350 μg/l (1.5) and PlGF >27 ng/l (1.9) remained significant predictors for the incidence of all-cause mortality or non-fatal MI after multivariable adjustment for other biomarkers and clinical characteristics, whereas hsCRP, pregnancy-associated plasma protein A and sCD40L were only associated with the endpoint in univariate analysis. A multimarker model consisting of TnT, IL-10, myeloperoxidase and PlGF predicted 4-year event rates that varied between 6.0% (all markers normal) and 35.8% (three or more biomarkers abnormal). Conclusion: In patients with NSTEACS, biomarkers characterising distinct aspects of the underlying atherosclerotic process and myocardial damage of the initial cardiac event can assist in predicting long-term adverse cardiac outcomes. The use of combinations of selected biomarkers adds incremental predictive value to further risk stratification in an otherwise seemingly homogeneous NSTEACS population.

Boogerd C.J.J.,University of Amsterdam | Boogerd C.J.J.,University of California at San Diego | Wong L.Y.E.,University of Amsterdam | Van Den Boogaard M.,University of Amsterdam | And 8 more authors.
Cellular and Molecular Life Sciences | Year: 2011

Tbx3, a T-box transcription factor, regulates key steps in development of the heart and other organ systems. Here, we identify Sox4 as an interacting partner of Tbx3. Pull-down and nuclear retention assays verify this interaction and in situ hybridization reveals Tbx3 and Sox4 to co-localize extensively in the embryo including the atrioventricular and outflow tract cushion mesenchyme and a small area of interventricular myocardium. Tbx3, SOX4, and SOX2 ChIP data, identify a region in intron 1 of Gja1 bound by all tree proteins and subsequent ChIP experiments verify that this sequence is bound, in vivo, in the developing heart. In a luciferase reporter assay, this element displays a synergistic antagonistic response to cotransfection of Tbx3 and Sox4 and in vivo, in zebrafish, drives expression of a reporter in the heart, confirming its function as a cardiac enhancer. Mechanistically, we postulate that Sox4 is a mediator of Tbx3 transcriptional activity. © The Author(s) 2011.

Luijkx T.,University Utrecht | Velthuis B.K.,University Utrecht | Prakken N.H.J.,University Utrecht | Cox M.G.P.J.,University Utrecht | And 5 more authors.
European Journal of Preventive Cardiology | Year: 2012

Background: Cardiac magnetic resonance (CMR) evaluation of athletes for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is complicated by overlapping features such as right ventricular (RV) volume increase. The revised ARVC/D diagnostic Task Force Criteria (TFC) incorporate cut-off values for RV ejection fraction (EF) and RV end-diastolic volume (EDV) on CMR.Design: To distinguish ARVC/D patients from athletes we compared CMR ventricular volumes, function, TFC cut-off values, and LV/RV ratios since athletes show proportionate, and ARVC/D patients disproportionate, changes in LV and RV.Methods: Quantitative CMR parameters of 33 ARVC/D patients (64% male, mean age 45.4 years, diagnosed by revised TFC), 66 healthy athletes and 66 healthy non-athletes (sex and age matched) were compared using revised TFC and new cut-off values representing LV/RV balance.Results and conclusions: Absolute values for ARVC/D patients/athletes/non-athletes were: in males, RV EDV 149/133/106 ml/m2, ratio EDV LV/RV 0.70/0.91/0.93, RV EF 34/52/54%, LV EF 48/57/58%, ratio EF LV/RV 1.49/1.10/1.09; and in females, RV EDV 115/115/91 ml/m2, ratio EDV LV/RV 0.86/0.94/0.97, RV EF 43/54/58%, LV EF 52/57/61%, ratio EF LV/RV 1.23/1.08/1.04 (p-values < 0.05). Areas under the ROC-curve are 0.68 (RV EDV index), 0.84 (LV/RV EDV ratio) and 0.93 (RV EF), demonstrating significantly (p < 0.001) better performance of RV EF and LV/RV EDV ratio. If a wall motion abnormality is present (observed in 30 ARVC/D patients and not in healthy subjects), RV EF can help distinguish ARVC/D from physiological cardiac adaptation in athletes on CMR whereas RV EDV index cannot. A good alternative in athletes is the LV/RV EDV ratio, representing normal proportionate adaptation of both ventricles. © 2011 The European Society of Cardiology.

Brouwer W.P.,VU University Amsterdam | Brouwer W.P.,Interuniversity Cardiology | Germans T.,VU University Amsterdam | Head M.C.,VU University Amsterdam | And 4 more authors.
European Heart Journal Cardiovascular Imaging | Year: 2012

Aims: Crypts can be found with cardiovascular magnetic resonance imaging (CMR) in hypertrophic cardiomyopathy (HCM) mutation carriers without hypertrophy (carriers) using a modified two-chamber view through the inferoseptum, but also in other patients and healthy individuals with standard long-axis views. Since it is currently unknown if carriers display a specific crypt morphology, we compared crypts in carriers with other cardiac pathologies (controls). Besides, we aimed to determine the optimal imaging plane for the detection of crypts by comparing modified two-chamber views with standard long-axis views. Finally, we evaluated the accuracy of crypts to identify carriers in HCM family screening. Methods and results: Standard CMR long-axis views with additional modified two-chamber views were prospectively performed in carriers (n = 43), consecutive CMR control patients (n = 252), and mutation-negative family members (n = 15). Crypts were found in 70% (30/43) of carriers and in 12% (31/252) of controls (P < 0.001). Crypts in carriers showed deeper penetrance into the myocardium compared with controls (74 ± 21% vs. 59 ± 22%, P < 0.01). Detection of two or more crypts had a sensitivity of 51% and specificity of 94% for carriership. Modified two-chamber views doubled the sensitivity to detect crypts compared with standard long-axis views. In family screening, ≥2 crypts had a 100% positive predictive value to identify carriers. Conclusions: Multiple crypts in the absence of left ventricular hypertrophy are highly specific for HCM mutation carriership and warrant clinical follow-up. A modified two-chamber view has a superior sensitivity compared with standard long-axis views for crypt detection. CMR may be of additional value to identify carriers in family screening. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012.

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