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Henry Völzke,
Carsten O Schmidt,
Sebastian E Baumeister,
Till Ittermann,
Glenn Fung,
Janina Krafczyk-Korth,
Wolfgang Hoffmann,
Matthias Schwab,
Henriette E Meyer Zu Schwabedissen,
Marcus Dörr, Stephan B Felix,
Wolfgang Lieb,
Heyo K Kroemer
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ABSTRACT: The primary goals of personalized medicine are to optimize diagnostic and treatment strategies by tailoring them to the specific characteristics of an individual patient. In this Review, we summarize basic concepts and methods of personalizing cardiovascular medicine. In-depth characterization of study participants and patients in general practice using standardized methods is a pivotal component of study design in personalized medicine. Standardization and quality assurance of clinical data are similarly important, but in daily practice imprecise definitions of clinical variables can reduce power and introduce bias, which limits the validity of the data obtained as well as their potential clinical applicability. Changes in statistical methods with personalized medicine include a shift from dichotomous outcomes towards continuously measured variables, predictive modelling, and individualized medical decisions, subgroup analyses, and data-mining strategies. A variety of approaches to personalized medicine exist in cardiovascular research and clinical practice that might have the potential to individualize diagnostic and therapeutic procedures. For some of the emerging methods, such as data mining, the most-efficient way to use these tools is not yet fully understood. In addition, the predictive models-although promising-are far from mature, and are likely to be greatly improved by using available large-scale data sets.
Nature Reviews Cardiology 03/2013; · 8.83 Impact Factor
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ABSTRACT: BACKGROUND: Besides their prognostic impact blood pressure and peak heart rate are widely used endpoint parameters for incremental exercise tests. Reference equations and ranges on both are sparse. OBJECTIVE: This study aims to describe prediction equations and reference ranges for systolic and diastolic blood pressure as well as for peak heart rate assessed during a symptom limited incremental exercise test based on a population based study - the Study of Health in Pomerania. DESIGN: For this purpose, 1708 individuals aged 25-85years underwent cardiopulmonary exercise testing. RESULTS: After exclusion of subjects with cardiopulmonary diseases and antihypertensive medications regression analyses revealed age, sex and body mass index as statistically significant interfering factors. In accordance, prediction equations and reference ranges for blood pressure and peak heart rate with respect to sex, age and BMI have been established. CONCLUSION: This study provides a reliable set of prediction equations for blood pressure and heart rate values at peak exercise, assessed in a general population over a wide age range.
Heart Lung & Circulation 03/2013; · 1.20 Impact Factor
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ABSTRACT: BACKGROUND AND AIMS: Besides exercise intolerance, the assessment of ventilatory and perfusion adequacy allows additional insights in the disease pathophysiology in many cardiovascular or pulmonary diseases. Valid measurements of dead space/tidal volume ratios (VD/VT), arterial (a') - end-tidal (et) carbon dioxide (CO2) and oxygen (O2) pressure differences (p(a'-et)CO2) and (p(et-a')O2), and alveolar (A)-a' O2 pressure differences (p(A-a')O2) require using blood samples in addition to gas exchange analyses on a breath-by-breath-basis. Smoking and nutritional status are also important factors in defining disorders. Using a large healthy population we considered the impact of these factors to develop useful prediction equations. METHODS AND RESULTS: Incremental cycle exercise protocols were applied to apparently healthy volunteer adults who did not have structural heart disease or echocardiographic or lung function pathologies. Age, height, weight, and smoking were analysed for their influence on the target parameters in each gender. Reference values were determined by regression analyses. The final study sample consisted of 476 volunteers (190 female), aged 25-85 years. Smoking significantly influences p(A-a')O2 and p(a'-et)CO2 at rest and peak exercise, and VD/VT during exercise. Obesity influences upper limits of VD/VT, p(a'-et)CO2 and p(et-a')O2 at rest as well as p(A-a')O2 and p(et-a')O2 at exercise. Reference equations for never-smokers as well as for apparently healthy smokers considering influencing factors are given. CONCLUSION: Gender, age, height, weight, and smoking significantly influence gas exchange. Considering all of these factors this study provides a comprehensive set of reference equations derived from a large number of participants of a population-based study.
Respiratory medicine 03/2013; · 2.33 Impact Factor
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Ravi Kumar Chilukoti,
Jörg Mostertz,
Alicja Bukowska,
Christoph Aderkast, Stephan B Felix,
Matthias Busch,
Uwe Völker,
Andreas Goette,
Carmen Wolke,
Georg Homuth,
Uwe Lendeckel
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ABSTRACT: BACKGROUND: Atrial fibrillation (AF) is characterized by electrical and structural remodeling of the atria with atrial fibrosis being one hallmark. Angiotensin II (AngII) is a major contributing factor and blockage of its type I receptor (AT1R) prevents remodeling to some extent. Here we explored the effects of the AT1R antagonist irbesartan on global gene expression and profibrotic signaling pathways after induction of rapid atrial pacing (RAP) in vivo in pigs. METHODS AND RESULTS: Microarray-based RNA profiling was used to screen left atrial (LA) tissue specimens for differences in atrial gene expression in a model of acute RAP. RAP caused an overall expression profile that reflected AngII-induced ROS production, tissue remodeling, and energy depletion. Of special note, the mRNA levels of EDN1, SGK1, and CTGF encoding pro-endothelin, stress- and glucocorticoid activated kinase-1, and of connective tissue growth factor were identified to be significantly increased after 7h of rapid pacing. These specific expression changes were additionally validated by RT-qPCR or immunoblot analyses in LA, RA, and partly in LV samples. All RAP-induced differential gene expression patterns were partially attenuated in the presence of irbesartan. Similar results were obtained after RAP of HL-1 cardiomyocytes in vitro. Furthermore, exogenously added endothelin-1 (ET1) induced CTGF expression concomitant to the transcriptional activation of SGK1 in HL-1 cells. CONCLUSIONS: RAP provokes substantial changes in atrial and ventricular myocardial gene expression that could be partly reversed by irbesartan. ET1 contributes to AF-dependent atrial fibrosis by synergistic activity with AngII to stimulate SGK1 expression and enhance phosphorylation of the SGK1 protein which, in turn, induces CTGF. The latter has been consistently associated with tissue fibrosis. These findings suggest ETR antagonists as being beneficial in AF treatment.
International journal of cardiology 02/2013; · 7.08 Impact Factor
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ABSTRACT: Dilated cardiomyopathy (DCM) is one of the main causes for heart failure in younger adults(1). Although genetic disposition and exposition to toxic substances are known causes for this disease in about one third of the patients, the origin of DCM remains largely unclear. In a substantial number of these patients, autoantibodies against cardiac epitopes have been detected and are suspected to play a pivotal role in the onset and progression of the disease(2,3). The importance of cardiac autoantibodies is underlined by a hemodynamic improvement observed in DCM patients after elimination of autoantibodies by immunoadsorption(3-5). A variety of specific antigens have already been identified(2,3) and antibodies against these targets may be detected by immunoassays. However, these assays cannot discriminate between stimulating (and therefore functionally effective) and blocking autoantibodies. There is increasing evidence that this distinction is crucial(6,7). It can also be assumed that the targets for a number of cardiotropic antibodies are still unidentified and therefore cannot be detected by immunoassays. Therefore, we established a method for the detection of functionally active cardiotropic antibodies, independent of their respective antigen. The background for the method is the high homology usually observed for functional regions of cardiac proteins in between mammals(8,9). This suggests that cardiac antibodies directed against human antigens will cross-react with non-human target cells, which allows testing of IgG from DCM patients on adult rat cardiomyocytes. Our method consists of 3 steps: first, IgG is isolated from patient plasma using sepharose coupled anti-IgG antibodies obtained from immunoadsorption columns (PlasmaSelect, Teterow, Germany). Second, adult cardiomyocytes are isolated by collagenase perfusion in a Langendorff perfusion apparatus using a protocol modified from previous works(10,11). The obtained cardiomyocytes are attached to laminin-coated chambered coverglasses and stained with Fura-2, a calcium-selective fluorescent dye which can be easily brought into the cell to observe intracellular calcium (Ca(2+)) contents(12). In the last step, the effect of patient IgG on the cell shortening and Ca(2+) transients of field stimulated cardiomyocytes is monitored online using a commercial myocyte calcium and contractility monitoring system (IonOptix, Milton, MA, USA) connected to a standard inverse fluorescent microscope.
Journal of Visualized Experiments 01/2013;
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Birte Holtfreter,
Stefanie Richter,
Thomas Kocher,
Marcus Dörr,
Henry Völzke,
Till Ittermann,
Anne Obst,
Christoph Schäper,
Ulrich John,
Peter Meisel,
Anne Grotevendt, Stephan B Felix,
Ralf Ewert,
Sven Gläser
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ABSTRACT: This study aims to assess the potential association of periodontal diseases with lung volumes and airflow limitation in a general adult population.Based on a representative population sample of the Study of Health in Pomerania (SHIP), 1463 subjects aged 25-85 years were included. Periodontal status was assessed by clinical attachment loss (CAL), probing depth (PD), and number of missing teeth (NoMT). Lung function was measured using spirometry, body plethysmography, and diffusing capacity for carbon monoxide. Linear regression models using fractional polynomials were used to assess associations between periodontal disease and lung function. Fibrinogen and high-sensitive C-reactive protein (hs-CRP) were evaluated as potential intermediate factors.After full adjustment for potential confounders mean CAL was significantly associated with variables of mobile dynamic and static lung volumes, airflow limitation and hyperinflation (p<0.05). Including fibrinogen and hs-CRP did not change coefficients of mean CAL; associations remained statistically significant. Mean CAL was not associated with total lung capacity and diffusing capacity for carbon monoxide. Associations were confirmed for mean PD, extent measures of CAL/PD, and NoMT.Periodontal disease was significantly associated with reduced lung volumes and airflow limitation in this general adult population sample. Systemic inflammation did not provide a mechanism linking both diseases.
European Respiratory Journal 12/2012; · 5.89 Impact Factor
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ABSTRACT: BACKGROUND: Across the industrialized world, men experience an earlier onset of cardiovascular disease (CVD) and a life expectancy 5 to 10 years shorter than women. Low total testosterone (TT) concentrations in men have been suggested as a novel CVD risk factor, but its contribution to this gender gap is less well studied. METHODS: We used data of 4152 individuals (2113 women and 2039 men) aged 20 to 79 years from the longitudinal population-based cohort Study of Health in Pomerania, Germany. Multivariable Poisson and Cox proportional hazard regression models were used to investigate the risk of incident cardiovascular morbidity (5-year examination follow-up), as well as all-cause and CVD mortality (10-year follow-up) between men and women. Additionally, the added risk attributable to low TT in men (<10th percentile) was assessed. RESULTS: Compared with women, men were uniformly at higher risk of incident cardiovascular morbidity, including overweight, hypertension, dyslipidemia, metabolic syndrome, and type 2 diabetes mellitus. Men were also at increased all-cause mortality (hazard ratio = 2.05; 95% CI, 1.61-2.60) and 10-year CVD risk compared with women. In subgroup analyses, men with low TT showed the highest 10-year CVD and mortality risk compared with both men with higher TT and women. TT was also negatively associated with cardiovascular risk as defined by the Framingham risk score (P < 0.001), after multivariable adjustment. CONCLUSIONS: Analyzing a large population-based sample, we observed that men have a generally higher risk of incident cardiovascular morbidity and mortality. Furthermore, men with low TT concentrations were identified as high-risk individuals with regard to 10-year CVD and mortality risk.
Gender Medicine 11/2012; · 2.10 Impact Factor
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Sabine Ameling,
Lars R Herda,
Elke Hammer,
Leif Steil,
Alexander Teumer,
Christiane Trimpert,
Marcus Dörr,
Heyo K Kroemer,
Karin Klingel,
Reinhard Kandolf,
Uwe Völker, Stephan B Felix
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ABSTRACT: AimsImmunoadsorption with subsequent immunoglobulin G substitution (IA/IgG) represents a novel therapeutic approach in the treatment of dilated cardiomyopathy (DCM) which leads to the improvement of left ventricular ejection fraction (LVEF). However, response to this therapeutic intervention shows wide inter-individual variability. In this pilot study, we tested the value of clinical, biochemical, and molecular parameters for the prediction of the response of patients with DCM to IA/IgG.Methods and resultsForty DCM patients underwent endomyocardial biopsies (EMBs) before IA/IgG. In eight patients with normal LVEF (controls), EMBs were obtained for clinical reasons. Clinical parameters, negative inotropic activity (NIA) of antibodies on isolated rat cardiomyocytes, and gene expression profiles of EMBs were analysed. Dilated cardiomyopathy patients displaying improvement of LVEF (≥20 relative and ≥5% absolute) 6 months after IA/IgG were considered responders. Compared with non-responders (n = 16), responders (n = 24) displayed shorter disease duration (P = 0.006), smaller LV internal diameter in diastole (P = 0.019), and stronger NIA of antibodies. Antibodies obtained from controls were devoid of NIA. Myocardial gene expression patterns were different in responders and non-responders for genes of oxidative phosphorylation, mitochondrial dysfunction, hypertrophy, and ubiquitin-proteasome pathway. The integration of scores of NIA and expression levels of four genes allowed robust discrimination of responders from non-responders at baseline (BL) [sensitivity of 100% (95% CI 85.8-100%); specificity up to 100% (95% CI 79.4-100%); cut-off value: -0.28] and was superior to scores derived from antibodies, gene expression, or clinical parameters only.Conclusion
Combined assessment of NIA of antibodies and gene expression patterns of DCM patients at BL predicts response to IA/IgG therapy and may enable appropriate selection of patients who benefit from this therapeutic intervention.
European Heart Journal 10/2012; · 10.48 Impact Factor
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ABSTRACT: An early response to high arterial pressure is the development of cardiac hypertrophy. Functional and transcriptional regulation of ion channels and Ca(2+) handling proteins are involved in this process but the relative contribution of each is unclear. In this study, we investigated the expression of genes involved in action potential generation and Ca(2+) homeostasis of cardiomyocytes in hypertensive cyp1a1ren-2 transgenic rats. In this model, the transgene prorenin was induced by indole-3-carbinol for 2 weeks allowing the induction of hypertension. Electrophysiological recordings from cardiomyocytes of hypertensive rats revealed a slight increase in membrane capacitance consistent with cellular hypertrophy. L-type calcium current density was reduced by 30%. Left ventricles of hypertensive rats showed a significant increase in transcript and protein levels of the cation channel TRPC6 and FK506-binding protein, whereas levels of SERCA2 and voltage-dependent potassium channels K(v)4.2 and K(v)4.3 were found to be decreased. Further, a marked nuclear localization of the transcription factors GATA4 and NFATC4 was observed in cardiac tissue of hypertensive rats. The cyp1a1ren-2 transgenic rat thus appears to be a valid model to investigate early changes in cardiac hypertrophy. This study points to roles for TRPC6, FK506BP, SERCA2, K(v)4.2, and K(v)4.3 in the development of cardiac hypertrophy.
Journal of Renin-Angiotensin-Aldosterone System 10/2012; · 2.44 Impact Factor
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ABSTRACT: BACKGROUND: Psoriasis has been associated with cardiovascular diseases, but its relationship to markers of subclinical atherosclerosis has not been fully elucidated. The aim of the study is to analyze the association of psoriasis with common carotid artery intima-media thickness (CCA-IMT) and plaque prevalence of the carotid arteries. METHODS: Data of 1987 men and women aged 25-88 years from the population-based Study of Health in Pomerania (SHIP) in north-eastern Germany were used. Cross-sectional associations of psoriasis with IMT and carotid plaque prevalence were analyzed using linear and logistic regression models adjusted for relevant confounders (age, sex, smoking, alcohol consumption, waist circumference, physical activity, systolic blood pressure, anti-hypertensive medication, acetylsalicylic acid, HbA(1c), total/HDL cholesterol ratio, lipid-lowering medication). RESULTS: Psoriasis was associated with mean CCA-IMT, but not with carotid plaque prevalence. Comparisons between subjects with and without psoriasis showed an adjusted mean difference of the CCA-IMT of 0.016 mm (95% confidence interval [CI]: 0.004 mm-0.028 mm, p < 0.01) and an odds ratio for plaque prevalence of 1.12 (95% CI: 0.85-1.47) after adjusting for confounders. CONCLUSION: Our findings suggest that psoriasis is associated with increased carotid mean IMT and might therefore contribute to the atherosclerotic process and subsequent cardiovascular events.
Atherosclerosis 09/2012; · 3.79 Impact Factor
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Nicole Aumann,
Sebastian E Baumeister,
André Werner,
Henri Wallaschofski,
Anke Hannemann,
Matthias Nauck,
Rainer Rettig, Stephan B Felix,
Marcus Dörr,
Henry Völzke,
Wolfgang Lieb,
Sylvia Stracke
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ABSTRACT: BACKGROUND: Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular disease in the general population and in patients with chronic kidney disease. The objective of this study was to investigate the association of estimated glomerular filtration rate (eGFR) with left ventricular mass index (LVMI), LVH and left ventricular geometry. A question of clinical relevance is whether estimated glomerular filtration rate based on cystatin C (eGFR(cystatinC)) is a better marker for cardiovascular risk than estimated glomerular filtration rate based on creatinine (eGFR(creatinine)). METHODS: The study sample included 2830 individuals from the population-based Study of Health in Pomerania (SHIP). LVH was defined as echocardiographic LVMI >48g/m(2.7) in men and >44g/m(2.7) in women. Kidney function, as assessed by eGFR, was determined from established equations: the creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and a cystatin-based multivariable equation. RESULTS: We found an inverse association between eGFR and LVMI. This association was stronger in models with eGFR(cystatinC) than in models with eGFR(creatinine). Subjects with moderately-to-severely decreased kidney function (defined as eGFR 15-<60mL/min per 1.73m(2)) had higher odds for abnormal geometric patterns of the left ventricle than subjects with normal eGFR when eGFR(cystatinC) was used. CONCLUSIONS: The findings suggest that eGFR(cystatinC) is superior to eGFR(creatinine) for assessing the risk of cardiovascular disease.
International journal of cardiology 08/2012; · 7.08 Impact Factor
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ABSTRACT: AimsIncreased serum prolactin (PRL) concentrations have been associated with adverse cardiovascular risk profiles, but the relation between PRL and mortality risk is unknown.Methods and resultsWe evaluated 3929 individuals (1946 men and 1983 women) aged 20-81 (mean 50.3 years) from the population-based Study of Health in Pomerania (SHIP). Associations of continuous [per standard deviation (SD) increase] and categorized (sex-specific tertiles) serum PRL concentrations with all-cause and cause-specific mortality were analysed separately for men and women by age- and multivariable-adjusted Cox regression models. During a median follow-up period of 10.1 years (38 231 person-years), 419 deaths (10.7%), 132 cardiovascular deaths (3.4%), and 152 cancer deaths (3.9%) were observed. After multivariable adjustment, we observed a positive association of PRL with all-cause mortality in men and women [hazard ratio (HR) per SD increase: 1.17, 95% confidence interval (CI): 1.07-1.29 and HR: 1.22, 95% CI: 1.03-1.46, respectively]. Similarly, individuals with PRL concentrations in the highest tertile (when compared with lowest PRL tertile) experienced the highest mortality risk (men: HR, 1.75; 95% CI, 1.32-2.32; women: HR, 1.66; 95% CI, 1.08-2.56), with a significant trend across PRL tertiles (P- for trend <0.05). Cause-specific mortality analyses yielded similar associations for cardiovascular death in both sexes, but for cancer death only in men.Conclusion
This is the first study to report an independent positive association of PRL concentrations with all-cause and cardiovascular mortality. Further studies are required to confirm our findings and to elucidate the potential role of PRL as a useful biomarker of cardiovascular risk and mortality assessment.
European Heart Journal 07/2012; · 10.48 Impact Factor
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ABSTRACT: Resident cardiac progenitor cells have emerged as a potential source of adult stem cells for regeneration of damaged myocardium. Sca-1 cells, expressing Stem cell antigen-1 as a cell surface marker, are multipotent cells that were shown to differentiate into different cell types i.e. cardiomyocytes. Previous studies have reported that Sca-1 positive cells are able to home to the injured heart. However, the mechanism of improving cardiac function is still unclear. In the current study, we have profiled the proteome and transcriptome of Sca-1 positive cells in comparison with other endogenous heart cell types to unravel the molecular phenotype of the progenitor cells. Among the 861 proteins identified with high confidence in total, 331 non-redundant proteins were overrepresented in Sca-1 positive cells. Highly abundant candidates were mostly associated with cell growth and proliferation, cell migration and cytoskeletal organization. Transcriptional profiling disclosed significant expression of surface antigens such as CD31, CD36, CD38, CD66a, CD102, and CD202B. Growth factors like KITL, JAG2, PDGFB and VEGFC showed a higher expression in Sca-1 progenitor cells than in Sca-1 negative cells. Selective candidates were validated by Western blotting. These global findings provide a basis for the study of their capability to participate in the cardiac regeneration process.
Journal of proteomics 06/2012; 75(17):5304-15. · 5.07 Impact Factor
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Alexander Riad,
Henriette Meyer zu Schwabedissen,
Kerstin Weitmann,
Lars R Herda,
Marcus Dörr,
Klaus Empen,
Arne Kieback,
Astrid Hummel,
Marcus Reinthaler,
Marcus Grube,
Karin Klingel,
Matthias Nauck,
Reinhard Kandolf,
Wolfgang Hoffmann,
Heyo K Kroemer, Stephan B Felix
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ABSTRACT: The clinical course of patients with dilated cardiomyopathy (DCM) varies from cardiac recovery to end stage heart failure. The etiology of this variability is largely unknown. In this study, we investigated the impact of coding polymorphisms of the innate immune protein Toll-like receptor 4 (TLR4) on left ventricular performance in patients with DCM. Two variants of TLR4 (rs4986790, TLR4 c.1187A→G, p.299D→G and rs4986791,TLR4 c.1487C→T, p.T399I) were investigated in 158 patients with DCM. Other reasons for heart failure were excluded by coronary angiography, myocardial biopsy, and echocardiography. Risk factors, age, gender, or treatment did not differ among the groups. At the follow-up evaluation (median 4.0-5.4 months), patients carrying the TLR4 wild type gene displayed cardiac recovery under intense medical heart failure therapy indexed by reduced left ventricular dilation, improved left ventricular ejection fraction, and reduced NT-probrain natriuretic peptide blood level when compared with the initial evaluation. In contrast, patients carrying both the rs4986790 and the rs4986791 variant showed significantly reduced improvement of left ventricular ejection fraction (p = 0.006) and left ventricular dilation (p = 0.015) at the follow-up evaluation when compared with carriers of the wild type gene under the same treatment conditions. In addition, NT-probrain natriuretic peptide level in carriers of both TLR4 variants did not change significantly at the follow up when compared with the first evaluation. Among patients with DCM, the presence of the TLR4 variants rs4986790 and rs4986791 predicts impaired cardiac recovery independently of medical treatment or cardiac risk factors.
Journal of Biological Chemistry 05/2012; 287(32):27236-43. · 4.77 Impact Factor
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Patrick T Ellinor,
Kathryn L Lunetta,
Christine M Albert,
Nicole L Glazer,
Marylyn D Ritchie,
Albert V Smith,
Dan E Arking,
Martina Müller-Nurasyid,
Bouwe P Krijthe,
Steven A Lubitz, [......],
Bruno H Ch Stricker, Stephan B Felix,
Alvaro Alonso,
Dawood Darbar,
John Barnard,
Daniel I Chasman,
Susan R Heckbert,
Emelia J Benjamin,
Vilmundur Gudnason,
Stefan Kääb
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ABSTRACT: Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
Nature Genetics 04/2012; 44(6):670-5. · 35.53 Impact Factor
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Charlotte van Noord,
Marcus Dörr,
Miriam C. J. M. Sturkenboom,
Sabine M. J. M. Straus,
Thorsten Reffelmann, Stephan B. Felix,
Albert Hofman,
Jan A. Kors,
Robin Haring,
Frank H. de Jong,
Matthias Nauck,
André G. Uitterlinden,
Henri Wallaschofski,
Jacqueline C. M. Witteman,
Henry Völzke,
Bruno H. Ch. Stricker
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ABSTRACT: 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 (≥55years) 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 [−3.4ms (−6.5; −0.3)]. However, the third tertile of serum testosterone was not associated with a lower QT
interval compared to the first tertile [−0.7ms (−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 [33.5ms (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.
European Journal of Epidemiology 04/2012; 25(1):21-28. · 4.71 Impact Factor
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A Hannemann,
M Bidlingmaier,
N Friedrich,
J Manolopoulou,
A Spyroglou,
H Völzke,
F Beuschlein,
J Seissler,
R Rettig, S B Felix,
R Biffar,
A Döring,
C Meisinger,
A Peters,
H E Wichmann,
M Nauck,
H Wallaschofski,
M Reincke
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ABSTRACT: The prevalence of primary aldosteronism in unselected hypertensive patients is currently unknown. We investigated the frequency of positive screening results for primary aldosteronism based on the aldosterone-to-renin ratio (ARR) in hypertensive subjects aged 30-79 years from two German epidemiological studies. We further examined the frequency of positive screening results in subjects with resistant hypertension or stage III hypertension and assessed possible disparities between untreated and treated hypertensive subjects.
Data were obtained from the first follow-ups of the population-based study of health in Pomerania (SHIP; n=1392) and the cooperative health research in the region of Augsburg (KORA; n=1052). Study-specific reference ranges for plasma aldosterone concentration (PAC), plasma renin concentration (PRC) and the ARR were applied. Confirmation tests for primary aldosteronism were not performed in these epidemiological studies.Three definitions for a positive screening for primary aldosteronism were applied: A) increased ARR; B) increased ARR and decreased PRC; and C) increased ARR and increased PAC and decreased PRC.
The frequency of positive screening results was 7.0, 3.8 and 0.2% according to definitions A-C respectively. In the subgroups of subjects with resistant hypertension (11.9, 5.5 and 0.9%) or stage III hypertension (18.3, 14.0 and 1.1%), these frequencies were markedly higher than those in the general hypertensive population. There was no difference in the frequency of positive screening results between the treated and untreated hypertensive subjects.
A maximum of 7.0% of the hypertensive population in Germany shows a positive screening result for primary aldosteronism. Thus, primary aldosteronism may be less frequent than previously expected based on data from referred hypertensive patients.
European Journal of Endocrinology 04/2012; 167(1):7-15. · 3.42 Impact Factor
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ABSTRACT: Previous experimental and patient-based studies suggest that prolactin (PRL) and its 16 kDa fragment influence cardiovascular phenotypes by modulating angiogenesis. The association between serum PRL and cardiac remodeling in the general population is unknown.
We evaluated 804 individuals (441 women) from the population-based Study of Health in Pomerania, aged ≥ 45 years, with available baseline serum PRL who underwent serial echocardiography at baseline and five-year follow-up. Left ventricular mass (LVM) was calculated and left ventricular hypertrophy (LVH) defined by sex-specific distributions of LVM. LV geometry was defined on the basis of relative wall thickness (RWT) and LVH. Sex-specific multivariable regression analyses were performed relating PRL (independent variable modelled as a continuous variable and as sex-specific quartiles) to change in LVM, RWT, and to incident LVH and abnormal geometry.
Baseline PRL concentrations were inversely associated with LVM change in men, but not in women (β per 10% decrease in PRL: 0.37; 95% CI, 0.13-0.60 in men and -0.02; 95% CI, -0.21 to 0.17 in women, respectively). In men, baseline PRL concentrations were also inversely associated with incident LVH [first vs. fourth PRL quartile: relative risk (RR) 2.26 (95% CI, 1.20-4.24)] and altered LV geometry on follow-up [RR for incident concentric hypertrophy per 10% decrease in PRL: 1.20 (95% CI, 1.06-1.37)]. None of the longitudinal associations were observed in women.
We observed inverse associations of PRL with LVM change, incident LVH, and altered LV geometry in men, but not in women. Additional studies are warranted to confirm our findings and to elucidate the mechanisms underlying these sex-specific associations.
Atherosclerosis 01/2012; 221(2):570-6. · 3.79 Impact Factor
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ABSTRACT: Biomarkers may help clinicians predict cardiovascular risk. We aimed to determine if the addition of endocrine, metabolic, and obesity-associated biomarkers to conventional risk factors improves the prediction of cardiovascular and all-cause mortality.
In a population-based cohort study (the Study of Health in Pomerania) of 3,967 subjects (age 20-80 years) free of cardiovascular disease with a median follow-up of 10.0 years (38,638 person-years), we assessed the predictive value of conventional cardiovascular risk factors and the biomarkers thyrotropin; testosterone (in men only); insulin-like growth factor-1 (IGF-1); hemoglobin A1c (HbA1c); creatinine; high-sensitive C-reactive protein (hsCRP); fibrinogen; urinary albumin-to-creatinine ratio; and waist-to-height ratio (WHtR) on cardiovascular and all-cause death. During follow-up, we observed 339 all-cause including 103 cardiovascular deaths. In Cox regression models with conventional risk factors, the following biomarkers were retained as significant predictors of cardiovascular death after backward elimination: HbA1c, IGF-1, and hsCRP. IGF-1 and hsCRP were retained as significant predictors of all-cause death. For cardiovascular death, adding these biomarkers to the conventional risk factors changed the C-statistic from 0.898 to 0.910 (p = 0.02). The net reclassification improvement was 10.6%. For all-cause death, the C-statistic changed from 0.849 to 0.853 (P = 0.09).
HbA1c, IGF-1, and hsCRP predict cardiovascular death independently of conventional cardiovascular risk factors. These easily assessed endocrine and metabolic biomarkers might improve the ability to predict cardiovascular death.
PLoS ONE 01/2012; 7(3):e33084. · 4.09 Impact Factor
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Claudia Schurmann,
Katharina Heim,
Arne Schillert,
Stefan Blankenberg,
Maren Carstensen,
Marcus Dörr,
Karlhans Endlich, Stephan B Felix,
Christian Gieger,
Harald Grallert, [......],
Konstantin Strauch,
Uwe Völker,
Henry Völzke,
Simone Wahl,
Henri Wallaschofski,
Philipp S Wild,
Tanja Zeller,
Alexander Teumer,
Holger Prokisch,
Andreas Ziegler
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ABSTRACT: Microarray profiling of gene expression is widely applied in molecular biology and functional genomics. Experimental and technical variations make meta-analysis of different studies challenging. In a total of 3358 samples, all from German population-based cohorts, we investigated the effect of data preprocessing and the variability due to sample processing in whole blood cell and blood monocyte gene expression data, measured on the Illumina HumanHT-12 v3 BeadChip array.Gene expression signal intensities were similar after applying the log(2) or the variance-stabilizing transformation. In all cohorts, the first principal component (PC) explained more than 95% of the total variation. Technical factors substantially influenced signal intensity values, especially the Illumina chip assignment (33-48% of the variance), the RNA amplification batch (12-24%), the RNA isolation batch (16%), and the sample storage time, in particular the time between blood donation and RNA isolation for the whole blood cell samples (2-3%), and the time between RNA isolation and amplification for the monocyte samples (2%). White blood cell composition parameters were the strongest biological factors influencing the expression signal intensities in the whole blood cell samples (3%), followed by sex (1-2%) in both sample types. Known single nucleotide polymorphisms (SNPs) were located in 38% of the analyzed probe sequences and 4% of them included common SNPs (minor allele frequency >5%). Out of the tested SNPs, 1.4% significantly modified the probe-specific expression signals (Bonferroni corrected p-value<0.05), but in almost half of these events the signal intensities were even increased despite the occurrence of the mismatch. Thus, the vast majority of SNPs within probes had no significant effect on hybridization efficiency.In summary, adjustment for a few selected technical factors greatly improved reliability of gene expression analyses. Such adjustments are particularly required for meta-analyses.
PLoS ONE 01/2012; 7(12):e50938. · 4.09 Impact Factor
