TY - JOUR AB - BACKGROUND AND AIMS: Recent investigations have suggested an interdependence of lipoprotein(a) [Lp(a)]-related risk for cardiovascular disease with background inflammatory burden. The aim the present analysis was to investigate whether high-sensitive C-reactive protein (hsCRP) modulates the association between Lp(a) and coronary heart disease (CHD) in the general population. METHODS: Data from 71 678 participants from 8 European prospective population-based cohort studies were used (65 661 without/6017 with established CHD at baseline; median follow-up 9.8/13.8 years, respectively). Fine and Gray competing risk-adjusted models were calculated according to accompanying hsCRP concentration (<2 and ≥2 mg/L). RESULTS: Among CHD-free individuals, increased Lp(a) levels were associated with incident CHD irrespective of hsCRP concentration: fully adjusted sub-distribution hazard ratios [sHRs (95% confidence interval)] for the highest vs. lowest fifth of Lp(a) distribution were 1.45 (1.23-1.72) and 1.48 (1.23-1.78) for a hsCRP group of <2 and ≥2 mg/L, respectively, with no interaction found between these two biomarkers on CHD risk (Pinteraction = 0.82). In those with established CHD, similar associations were seen only among individuals with hsCRP ≥ 2 mg/L [1.34 (1.03-1.76)], whereas among participants with a hsCRP concentration <2 mg/L, there was no clear association between Lp(a) and future CHD events [1.29 (0.98-1.71)] (highest vs. lowest fifth, fully adjusted models; Pinteraction = 0.024). CONCLUSIONS: While among CHD-free individuals Lp(a) was significantly associated with incident CHD regardless of hsCRP, in participants with CHD at baseline, Lp(a) was related to recurrent CHD events only in those with residual inflammatory risk. These findings might guide adequate selection of high-risk patients for forthcoming Lp(a)-targeting compounds. AU - Arnold, N.* AU - Blaum, C.* AU - Goßling, A.* AU - Brunner, F.J.* AU - Bay, B.* AU - Ferrario, M.M.* AU - Brambilla, P.* AU - Cesana, G.* AU - Leoni, V.* AU - Palmieri, L.* AU - Donfrancesco, C.* AU - Padró, T.* AU - Andersson, J.* AU - Jousilahti, P.* AU - Ojeda, F.* AU - Zeller, T.* AU - Linneberg, A.* AU - Söderberg, S.* AU - Iacoviello, L.* AU - Gianfagna, F.* AU - Sans, S.* AU - Veronesi, G.* AU - Thorand, B. AU - Peters, A. AU - Tunstall-Pedoe, H.* AU - Kee, F.* AU - Salomaa, V.* AU - Schnabel, R.B.* AU - Kuulasmaa, K.* AU - Blankenberg, S.* AU - Koenig, W.* AU - Waldeyer, C.* C1 - 69818 C2 - 55233 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 1043-1054 TI - C-reactive protein modifies lipoprotein(a)-related risk for coronary heart disease: the BiomarCaRE project. JO - Eur. Heart J. VL - 45 IS - 12 PB - Oxford Univ Press PY - 2024 SN - 0195-668X ER - TY - JOUR AB - BACKGROUND AND AIMS: In recent decades, nighttime temperatures have increased faster than daytime temperatures. The increasing prevalence of nocturnal heat exposure may pose a significant risk to cardiovascular health. This study investigated the association between nighttime heat exposure and stroke risk in the region of Augsburg, Germany, and examined its temporal variations over 15 years. METHODS: Hourly meteorological parameters, including mean temperature, relative humidity, and barometric pressure, were acquired from a local meteorological station. A data set was obtained consisting of 11 037 clinical stroke cases diagnosed during warmer months (May to October) between the years 2006 and 2020. The average age of cases was 71.3 years. Among these cases, 642 were identified as haemorrhagic strokes, 7430 were classified as ischaemic strokes, and 2947 were transient ischaemic attacks. A time-stratified case-crossover analysis with a distributed lag non-linear model was used to estimate the stroke risk associated with extreme nighttime heat, as measured by the hot night excess (HNE) index after controlling for the potential confounding effects of daily maximum temperature and other climatic variables. Subgroup analyses by age group, sex, stroke subtype, and stroke severity were performed to identify variations in susceptibility to nighttime heat. RESULTS: Results suggested a significant increase in stroke risk on days with extreme nighttime heat (97.5% percentile of HNE) (odds ratio 1.07, 95% confidence interval 1.01-1.15) during the full study period. When comparing the results for 2013-20 with the results for 2006-12, there was a significant increase (P < .05) in HNE-related risk for all strokes and specifically for ischaemic strokes during the more recent period. Furthermore, older individuals, females, and patients with mild stroke symptoms exhibited a significantly increased vulnerability to nighttime heat. CONCLUSIONS: This study found nocturnal heat exposure to be related to elevated stroke risk after controlling for maximum daytime temperature, with increasing susceptibility between 2006 and 2020. These results underscore the importance of considering nocturnal heat as a critical trigger of stroke events in a warming climate. AU - He, C. AU - Breitner-Busch, S. AU - Zhang, S. AU - Huber, V. AU - Naumann, M.* AU - Traidl-Hoffmann, C. AU - Hammel, G. AU - Peters, A. AU - Ertl, M.* AU - Schneider, A.E. C1 - 70723 C2 - 55725 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 2158-2166 TI - Nocturnal heat exposure and stroke risk. JO - Eur. Heart J. VL - 45 IS - 24 PB - Oxford Univ Press PY - 2024 SN - 0195-668X ER - TY - JOUR AB - The global prevalence of obesity has more than doubled over the past four decades, currently affecting more than a billion individuals. Beyond its recognition as a high-risk condition that is causally linked to many chronic illnesses, obesity has been declared a disease per se that results in impaired quality of life and reduced life expectancy. Notably, two-thirds of obesity-related excess mortality is attributable to cardiovascular disease. Despite the increasingly appreciated link between obesity and a broad range of cardiovascular disease manifestations including atherosclerotic disease, heart failure, thromboembolic disease, arrhythmias, and sudden cardiac death, obesity has been underrecognized and sub-optimally addressed compared with other modifiable cardiovascular risk factors. In the view of major repercussions of the obesity epidemic on public health, attention has focused on population-based and personalized approaches to prevent excess weight gain and maintain a healthy body weight from early childhood and throughout adult life, as well as on comprehensive weight loss interventions for persons with established obesity. This clinical consensus statement by the European Society of Cardiology discusses current evidence on the epidemiology and aetiology of obesity; the interplay between obesity, cardiovascular risk factors and cardiac conditions; the clinical management of patients with cardiac disease and obesity; and weight loss strategies including lifestyle changes, interventional procedures, and anti-obesity medications with particular focus on their impact on cardiometabolic risk and cardiac outcomes. The document aims to raise awareness on obesity as a major risk factor and provide guidance for implementing evidence-based practices for its prevention and optimal management within the context of primary and secondary cardiovascular disease prevention. AU - Koskinas, K.C.* AU - Van Craenenbroeck, E.M.* AU - Antoniades, C.* AU - Blüher, M. AU - Gorter, T.M.* AU - Hanssen, H.* AU - Marx, N.* AU - McDonagh, T.A.* AU - Mingrone, G.* AU - Rosengren, A.* AU - Prescott, E.B.* C1 - 71542 C2 - 56271 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 4063–4098 TI - Obesity and cardiovascular disease: An ESC clinical consensus statement. JO - Eur. Heart J. VL - 45 IS - 38 PB - Oxford Univ Press PY - 2024 SN - 0195-668X ER - TY - JOUR AU - Laufs, U.* AU - Blüher, M. AU - Isermann, B.* C1 - 67936 C2 - 54414 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 4281-4283 TI - Third generation PCSK9-Inhibitors. JO - Eur. Heart J. VL - 44 IS - 40 PB - Oxford Univ Press PY - 2023 SN - 0195-668X ER - TY - JOUR AB - AIMS : Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. METHODS AND RESULTS : We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 27% increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. CONCLUSION : This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure. AU - Garnier, S.* AU - Harakalova, M.* AU - Weiss, S.* AU - Mokry, M.* AU - Regitz-Zagrosek, V.* AU - Hengstenberg, C.* AU - Cappola, T.P.* AU - Isnard, R.* AU - Arbustini, E.* AU - Cook, S.A.* AU - van Setten, J.* AU - Calis, J.J.A.* AU - Hakonarson, H.* AU - Morley, M.P.* AU - Stark, K.* AU - Prasad, S.K.* AU - Li, J.* AU - O'Regan, D.P.* AU - Grasso, M.* AU - Müller-Nurasyid, M. AU - Meitinger, T. AU - Empana, J.P.* AU - Strauch, K. AU - Waldenberger, M. AU - Marguiles, K.B.* AU - Seidman, C.E.* AU - Kararigas, G.* AU - Meder, B.* AU - Haas, J.* AU - Boutouyrie, P.* AU - Lacolley, P.* AU - Jouven, X.* AU - Erdmann, J.* AU - Blankenberg, S.* AU - Wichter, T.* AU - Ruppert, V.* AU - Tavazzi, L.* AU - Dubourg, O.* AU - Roizes, G.* AU - Dorent, R.* AU - de Groote, P.* AU - Fauchier, L.* AU - Trochu, J.N.* AU - Aupetit, J.F.* AU - Bilinska, Z.T.* AU - Germain, M.* AU - Völker, U.* AU - Hemerich, D.* AU - Raji, I.* AU - Bacq-Daian, D.* AU - Proust, C.* AU - Remior, P.* AU - Gomez-Bueno, M.* AU - Lehnert, K.* AU - Maas, R.* AU - Olaso, R.* AU - Saripella, G.V.* AU - Felix, S.B.* AU - McGinn, S.* AU - Duboscq-Bidot, L.* AU - van Mil, A.* AU - Besse, C.* AU - Fontaine, V.* AU - Blanché, H.* AU - Ader, F.* AU - Keating, B.* AU - Curjol, A.* AU - Boland, A.* AU - Komajda, M.* AU - Cambien, F.* AU - Deleuze, J.F.* AU - Dörr, M.* AU - Asselbergs, F.W.* AU - Villard, E.* AU - Trégouët, D.A.* AU - Charron, P.* C1 - 61440 C2 - 50179 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 2000-2011 TI - Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23. JO - Eur. Heart J. VL - 42 IS - 20 PB - Oxford Univ Press PY - 2021 SN - 0195-668X ER - TY - JOUR AB - AIMS: Mental stress substantially contributes to the initiation and progression of human disease, including cardiovascular conditions. We aim to investigate the underlying mechanisms of these contributions since they remain largely unclear. METHODS AND RESULTS : Here, we show in humans and mice that leucocytes deplete rapidly from the blood after a single episode of acute mental stress. Using cell-tracking experiments in animal models of acute mental stress, we found that stress exposure leads to prompt uptake of inflammatory leucocytes from the blood to distinct tissues including heart, lung, skin, and, if present, atherosclerotic plaques. Mechanistically, we found that acute stress enhances leucocyte influx into mouse atherosclerotic plaques by modulating endothelial cells. Specifically, acute stress increases adhesion molecule expression and chemokine release through locally derived norepinephrine. Either chemical or surgical disruption of norepinephrine signalling diminished stress-induced leucocyte migration into mouse atherosclerotic plaques. CONCLUSION : Our data show that acute mental stress rapidly amplifies inflammatory leucocyte expansion inside mouse atherosclerotic lesions and promotes plaque vulnerability. AU - Hinterdobler, J.* AU - Schott, S.* AU - Jin, H.* AU - Meesmann, A.* AU - Steinsiek, A.L.* AU - Zimmermann, A.S.* AU - Wobst, J.* AU - Müller, P.* AU - Mauersberger, C.* AU - Vilne, B.* AU - Baecklund, A.* AU - Chen, C.S.* AU - Moggio, A.* AU - Braster, Q.* AU - Molitor, M.* AU - Krane, M.* AU - Kempf, W.E.* AU - Ladwig, K.-H. AU - Hristov, M.* AU - Hulsmans, M.* AU - Hilgendorf, I.* AU - Weber, C.* AU - Wenzel, P.* AU - Scheiermann, C.* AU - Maegdefessel, L.* AU - Soehnlein, O.* AU - Libby, P.* AU - Nahrendorf, M.* AU - Schunkert, H.* AU - Kessler, T.* AU - Sager, H.B.* C1 - 62556 C2 - 50940 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 4077–4088 TI - Acute mental stress drives vascular inflammation and promotes plaque destabilization in mouse atherosclerosis. JO - Eur. Heart J. VL - 42 IS - 39 PB - Oxford Univ Press PY - 2021 SN - 0195-668X ER - TY - JOUR AB - Aims The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in individuals without previous CVD or diabetes aged 40-69 years in Europe.Methods and results We derived risk prediction models using individual-participant data from 45 cohorts in 13 countries (677 684 individuals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 individuals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 individuals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65-0.68) to 0.81 (0.76-0.86). Predicted CVD risk varied several-fold across European regions. For example, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low- risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries.Conclusion SCORE2-a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations-enhances the identification of individuals at higher risk of developing CVD across Europe. AU - NCD Risk Factors Collaboration (Peters, A. AU - Thorand, B.) C1 - 62688 C2 - 51021 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 2439-2454 TI - SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe. JO - Eur. Heart J. VL - 42 IS - 25 PB - Oxford Univ Press PY - 2021 SN - 0195-668X ER - TY - JOUR AB - AIMS: Imbalances of iron metabolism have been linked to the development of atherosclerosis. However, subjects with hereditary haemochromatosis have a lower prevalence of cardiovascular disease. The aim of our study was to understand the underlying mechanisms by combining data from genome-wide association study analyses in humans, CRISPR/Cas9 genome editing, and loss-of-function studies in mice. METHODS AND RESULTS: Our analysis of the Global Lipids Genetics Consortium (GLGC) dataset revealed that single nucleotide polymorphisms (SNPs) in the haemochromatosis gene HFE associate with reduced low-density lipoprotein cholesterol (LDL-C) in human plasma. The LDL-C lowering effect could be phenocopied in dyslipidaemic ApoE-/- mice lacking Hfe, which translated into reduced atherosclerosis burden. Mechanistically, we identified HFE as a negative regulator of LDL receptor expression in hepatocytes. Moreover, we uncovered liver-resident Kupffer cells (KCs) as central players in cholesterol homeostasis as they were found to acquire and transfer LDL-derived cholesterol to hepatocytes in an Abca1-dependent fashion, which is controlled by iron availability. CONCLUSION: Our results disentangle novel regulatory interactions between iron metabolism, KC biology and cholesterol homeostasis which are promising targets for treating dyslipidaemia but also provide a mechanistic explanation for reduced cardiovascular morbidity in subjects with haemochromatosis. AU - Demetz, E.* AU - Tymoszuk, P.* AU - Hilbe, R.* AU - Volani, C.* AU - Haschka, D.* AU - Heim, C.* AU - Auer, K.* AU - Lener, D.* AU - Zeiger, L.B.* AU - Pfeifhofer-Obermair, C.* AU - Boehm, A.* AU - Obermair, G.J.* AU - Ablinger, C.* AU - Coassin, S.* AU - Lamina, C.* AU - Kager, J.* AU - Petzer, V.* AU - Asshoff, M.* AU - Schroll, A.* AU - Nairz, M.* AU - Dichtl, S.* AU - Seifert, M.* AU - von Raffay, L.* AU - Fischer, C.* AU - Barros-Pinkelnig, M.* AU - Brigo, N.* AU - Valente de Souza, L.* AU - Sopper, S.* AU - Hirsch, J.* AU - Graber, M.* AU - Gollmann-Tepeköylü, C.* AU - Holfeld, J.* AU - Halper, J.* AU - Macheiner, S.* AU - Gostner, J.* AU - Vogel, G.F.* AU - Pechlaner, R.* AU - Moser, P.* AU - Imboden, M.* AU - Marques-Vidal, P.* AU - Probst-Hensch, N.M.* AU - Meiselbach, H.* AU - Strauch, K. AU - Peters, A. AU - Paulweber, B.* AU - Willeit, J.* AU - Kiechl, S.* AU - Kronenberg, F.* AU - Theurl, I.* AU - Tancevski, I.* AU - Weiss, G.* C1 - 58748 C2 - 48290 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 3949–3959 TI - The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development. JO - Eur. Heart J. VL - 41 IS - 40 PB - Oxford Univ Press PY - 2020 SN - 0195-668X ER - TY - JOUR AB - Aims To investigate the clinical value of a lower blood pressure (BP) cut-off for Stage 1 (S1) hypertension (130-139mmHg systolic or 80-89mmHg diastolic) in comparison to the currently established Stage 2 (S2) cut-off (140/90mmHg) in a population-based cohort.Methods and results We assessed the hypertension prevalence and associated cardiovascular disease (CVD) events in a sample of 11603 participants (52% men, 48% women; mean 47.6years) from the MONICA/KORA prospective study. The implementation of the new S1 cut-off increased the prevalence of hypertension from 34% to 63%. Only 24% of S2 hypertension patients were under treatment. Within a follow-up period of 10years (70148 person-years), 370 fatal CVD events were observed. The adjusted CVD-specific mortality rate per 1000 persons was 1.61 [95% confidence interval (CI) 1.10-2.25] cases in S2 and 1.07 (95% CI 0.71-1.64) cases in S1 hypertension in comparison to normal BP. Cox proportional regression models were significant for the association of S2 and CVD mortality (1.54, 95% CI 1.04-2.28, P = 0.03), also in the presence of competing risks (1.47, P = 0.05). However, statistical significance for S1 hypertension was not reached (0.93, 95% CI 0.61-1.44, P = 0.76). Among S2 participants, there was a significantly higher prevalence of depressed-mood in treated patients (47%) in comparison to non-treated patients (33%) (P < 0.0001).Conclusion The lower BP cut-off substantially increased hypertension prevalence, while capturing a population with lower CVD mortality. Additionally, participants under treatment were more likely to have depressed-mood in comparison to non-treated participants, which might reflect a negative labelling effect. AU - Atasoy, S. AU - Johar, H.* AU - Peters, A. AU - Ladwig, K.-H. C1 - 55109 C2 - 46074 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 732-738 TI - Association of hypertension cut-off values with 10-year cardiovascular mortality and clinical consequences: A real-world perspective from the prospective MONICA/KORA study. JO - Eur. Heart J. VL - 40 IS - 9 PB - Oxford Univ Press PY - 2019 SN - 0195-668X ER - TY - JOUR AB - This editorial refers to 'A novel machine learning-derived radiotranscriptomic signature of perivascular fat improves cardiac risk prediction using coronary CT angiography'(dagger), by E.K. Oikonomou et al., on page 3529. AU - Bartelt, A. AU - Leipsic, J.* AU - Weber, C.* C1 - 57104 C2 - 47533 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 3544-3546 TI - The new age of radiomic risk profiling: perivascular fat at the heart of the matter. JO - Eur. Heart J. VL - 40 IS - 43 PB - Oxford Univ Press PY - 2019 SN - 0195-668X ER - TY - JOUR AB - Aims The association between air temperature and mortality has been shown to vary over time, but evidence of temporal changes in the risk of myocardial infarction (MI) is lacking. We aimed to estimate the temporal variations in the association between short-term exposures to air temperature and MI in the area of Augsburg, Germany.Methods and results Over a 28-years period from 1987 to 2014, a total of 27 310 cases of MI and coronary deaths were recorded. Daily meteorological parameters were measured in the study area. A time-stratified case-crossover analysis with a distributed lag non-linear model was used to estimate the risk of MI associated with air temperature. Subgroup analyses were performed to identify subpopulations with changing susceptibility to air temperature. Results showed a non-significant decline in cold-related MI risks. Heat-related MI relative risk significantly increased from 0.93 [95% confidence interval (CI): 0.78-1.12] in 1987-2000 to 1.14 (95% CI: 1.00-1.29) in 2001-14. The same trend was also observed for recurrent and non-ST-segment elevation MI events. This increasing population susceptibility to heat was more evident in patients with diabetes mellitus and hyperlipidaemia. Future studies using multicentre MI registries at different climatic, demographic, and socioeconomic settings are warranted to confirm our findings.Conclusion We found evidence of rising population susceptibility to heat-related MI risk from 1987 to 2014, suggesting that exposure to heat should be considered as an environmental trigger of MI, especially under a warming climate. AU - Chen, K. AU - Breitner-Busch, S. AU - Wolf, K. AU - Hampel, R. AU - Meisinger, C. AU - Heier, M. AU - von Scheidt, W.* AU - Kuch, B.* AU - Peters, A. AU - Schneider, A.E. C1 - 55655 C2 - 46482 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 1600-1608 TI - Temporal variations in the triggering of myocardial infarction by air temperature in Augsburg, Germany, 1987-2014. JO - Eur. Heart J. VL - 40 IS - 20 PB - Oxford Univ Press PY - 2019 SN - 0195-668X ER - TY - JOUR AU - Chen, K. AU - Peters, A. AU - Schneider, A.E. C1 - 57118 C2 - 47543 SP - 3440-3441 TI - Burden of myocardial infarctions attributable to heat and cold. JO - Eur. Heart J. VL - 40 IS - 41 PY - 2019 SN - 0195-668X ER - TY - JOUR AU - Lee, J.* AU - Ahmidi, N. AU - Srinivasan, R.* AU - Alejo, D.* AU - Dinatale, J.* AU - Schena, S.* AU - Whitman, G.* AU - Sussman, M.* AU - Shpitser, I.* C1 - 58053 C2 - 48033 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 3575-3575 TI - Finding predictors and causes of cardiac surgery ICU readmission using machine learning and causal inference. JO - Eur. Heart J. VL - 40 PB - Oxford Univ Press PY - 2019 SN - 0195-668X ER - TY - JOUR AB - Aims There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29 39% of individuals aged >= 40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44 51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms.Conclusion Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need. AU - Pennells, L.* AU - Kaptoge, S.* AU - Wood, A.* AU - Sweeting, M.* AU - Zhao, X.* AU - White, I.* AU - Burgess, S.* AU - Willeit, P.* AU - Bolton, T.* AU - Moons, K.G.M.* AU - van der Schouw, Y.T.* AU - Selmer, R.* AU - Khaw, K.T.* AU - Gudnason, V.* AU - Assmann, G.* AU - Amouyel, P.* AU - Salomaa, V.* AU - Kivimaki, M.* AU - Nørdestgaard, B.G.* AU - Blaha, M.J.* AU - Kuller, L.H.* AU - Brenner, H.* AU - Gillum, R.F.* AU - Meisinger, C. AU - Ford, I.* AU - Knuiman, M.W.* AU - Rosengren, A.* AU - Lawlor, D.A.* AU - Völzke, H.* AU - Cooper, C.* AU - Marín Ibañez, A.* AU - Casiglia, E.* AU - Kauhanen, J.* AU - Cooper, J.A.* AU - Rodriguez, B.* AU - Sundström, J.* AU - Barrett-Connor, E.* AU - Dankner, R.* AU - Nietert, P.J.* AU - Davidson, K.W.* AU - Wallace, R.B.* AU - Blazer, D.G.* AU - Björkelund, C.* AU - Donfrancesco, C.* AU - Krumholz, H.M.* AU - Nissinen, A.* AU - Davis, B.R.* AU - Coady, S.* AU - Whincup, P.H.* AU - Jørgensen, T.* AU - Ducimetiere, P.* AU - Trevisan, M.* AU - Engström, G.* AU - Crespo, C.J.* AU - Meade, T.W.* AU - Visser, M.* AU - Kromhout, D.* AU - Kiechl, S.* AU - Daimon, M.* AU - Price, J.F.* AU - Gómez de la Cámara, A.* AU - Wouter Jukema, J.* AU - Lamarche, B.* AU - Onat, A.* AU - Simons, L.A.* AU - Kavousi, M.* AU - Ben-Shlomo, Y.* AU - Gallacher, J.* AU - Dekker, J.M.* AU - Arima, H.* AU - Shara, N.* AU - Tipping, R.W.* AU - Roussel, R.* AU - Brunner, E.J.* AU - Koenig, W.* AU - Sakurai, M.* AU - Pavlovic, J.* AU - Gansevoort, R.T.* AU - Nagel, D.* AU - Goldbourt, U.* AU - Barr, E.L.M.* AU - Palmieri, L.* AU - Njølstad, I.* AU - Sato, S.* AU - Monique Verschuren, W.M.* AU - Varghese, C.V.* AU - Graham, I.* AU - Onuma, O.* AU - Greenland, P.* AU - Woodward, M.* AU - Ezzati, M.* AU - Psaty, B.M.* AU - Sattar, N.* AU - Jackson, R.* AU - Ridker, P.M.* AU - Cook, N.R.* AU - D'Agostino, R.B.* AU - Thompson, S.G.* AU - Danesh, J.* AU - di Angelantonio, E.* C1 - 55003 C2 - 45986 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 621-631 TI - Equalization of four cardiovascular risk algorithms after systematic recalibration: Individual-participant meta-analysis of 86 prospective studies. JO - Eur. Heart J. VL - 40 IS - 7 PB - Oxford Univ Press PY - 2019 SN - 0195-668X ER - TY - JOUR AU - Rothenbacher, D.* AU - Rehm, M.* AU - Iacoviello, L.* AU - Tunstall-Pedoe, H.* AU - Söderberg, S.* AU - Salomaa, V.* AU - Linneberg, A.* AU - Sans, S.* AU - Thorand, B. AU - Kee, F.* AU - Kuulasmaa, K.* AU - Waldeyer, C.* AU - Zeller, T.* AU - Blankenberg, S.* AU - Koenig, W.* AU - BiomarCaRE Consortium* C1 - 58052 C2 - 48032 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 2020-2020 TI - Cystatin C based eGFR estimation compared to crea-based estimation equation for assessing risk of cardiovascular and total mortality in population-based studies and patients with manifest CVD. JO - Eur. Heart J. VL - 40 PB - Oxford Univ Press PY - 2019 SN - 0195-668X ER - TY - JOUR AU - Ruedebusch, J.* AU - Benkner, A.* AU - Nath, N.* AU - Kaderali, L.* AU - Klingel, K.* AU - Eckstein, G.N. AU - Meitinger, T. AU - Fielitz, J.* AU - Grube, K.* AU - Felix, S.B.* C1 - 58051 C2 - 48031 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 916-916 TI - Soluble guanylate cyclase as a therapeutic target in heart failure: Myocardial gene expression in response to sGC stimulation in pressure overload. JO - Eur. Heart J. VL - 40 PB - Oxford Univ Press PY - 2019 SN - 0195-668X ER - TY - JOUR AU - Santovito, D.* AU - Natarelli, L.* AU - Egea, V.* AU - Bidzhekov, K.* AU - Blanchet, X.* AU - Mourao, A. AU - Wichapong, K.* AU - Aslani, M.* AU - Horckmans, M.* AU - Lutgens, E.* AU - von Hundelshausen, P.* AU - Duchene, J.* AU - Steffens, S.* AU - Sattler, M. AU - Weber, C.* C1 - 58054 C2 - 48029 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 3127-3127 TI - Endothelial autophagy triggers nuclear enrichment of miR-126-5p via a Mex3a-dependent pathway to confers endothelial protection and prevent atherosclerosis. JO - Eur. Heart J. VL - 40 PB - Oxford Univ Press PY - 2019 SN - 0195-668X ER - TY - JOUR AU - Schrage, B.* AU - Ruebsamen, N.* AU - Thorand, B. AU - Koenig, W.* AU - Söderberg, S.* AU - Wahlin, A.* AU - Mathiesen, E.* AU - Njolstad, I.* AU - Kee, F.* AU - Linneberg, A.* AU - Kuulasmaa, K.* AU - Salomaa, V.* AU - Blankenberg, S.* AU - Zeller, T.* AU - Karakas, M.* C1 - 58055 C2 - 48028 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 3836-3836 TI - Association of functional iron deficiency with incident cardiovascular diseases and mortality in the general population. JO - Eur. Heart J. VL - 40 PB - Oxford Univ Press PY - 2019 SN - 0195-668X ER - TY - JOUR AB - Aims Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG).Methods and results In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose-response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P < 0.01 for all). PRSBrS, baseline QRS duration, presence of Type II or III BrS ECG at baseline, and family history of BrS are independently associated with the occurrence of a Type I BrS ECG, with good predictive accuracy (optimism-corrected C-statistic 0.74).Conclusion We show for the first time that genetic factors underlie the variability of cardiac electrical response to SCB. PRSBrS, family history, and a baseline ECG can predict the development of a diagnostic drug-induced Type I BrS ECG with clinically relevant accuracy. These findings could lead to the use of PRS in the diagnosis of BrS and, if confirmed in population studies, to identify patients at risk for toxicity when given SCB. AU - Tadros, R.* AU - Tan, H.L.* AU - El Mathari, S.* AU - Kors, J.A.* AU - Postema, P.G.* AU - Lahrouchi, N.* AU - Beekman, L.* AU - Radivojkov-Blagojevic, M.* AU - Amin, A.S.* AU - Meitinger, T. AU - Tanck, M.W.* AU - Wilde, A.A.* AU - Bezzina, C.R.* C1 - 56860 C2 - 47348 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 3097-3107 TI - Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores. JO - Eur. Heart J. VL - 40 IS - 37 PB - Oxford Univ Press PY - 2019 SN - 0195-668X ER - TY - JOUR AB - Aims To characterize serum metabolic signatures associated with atherosclerosis in the coronary or carotid arteries and subsequently their association with incident cardiovascular disease (CVD).Methods and results We used untargeted one-dimensional (1D) serum metabolic profiling by proton nuclear magnetic resonance spectroscopy (H-1 NMR) among 3867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3569 participants from the Rotterdam and LOLIPOP studies. Atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-media thickness (IMT). We used multivariable linear regression to evaluate associations between NMR features and atherosclerosis accounting for multiplicity of comparisons. We then examined associations between metabolites associated with atherosclerosis and incident CVD available in MESA and Rotterdam and explored molecular networks through bioinformatics analyses. Overall, 30 H-1 NMR measured metabolites were associated with CAC and/or IMT, P = 1.3 x 10(-14) to 1.0 x 10(-6) (discovery) and P = 5.6 x 10(-10) to 1.1 x 10(-2) (replication). These associations were substantially attenuated after adjustment for conventional cardiovascular risk factors. Metabolites associated with atherosclerosis revealed disturbances in lipid and carbohydrate metabolism, branched chain, and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. Analyses of incident CVD events showed inverse associations with creatine, creatinine, and phenylalanine, and direct associations with mannose, acetaminophen-glucuronide, and lactate as well as apolipoprotein B (P < 0.05).Conclusion Metabolites associated with atherosclerosis were largely consistent between the two vascular beds (coronary and carotid arteries) and predominantly tag pathways that overlap with the known cardiovascular risk factors. We present an integrated systems network that highlights a series of inter-connected pathways underlying atherosclerosis. AU - Tzoulaki, I.* AU - Castagné, R.* AU - Boulangé, C.L.* AU - Karaman, I.* AU - Chekmeneva, E.* AU - Evangelou, E.* AU - Ebbels, T.M.D.* AU - Kaluarachchi, M.R.* AU - Chadeau-Hyam, M.* AU - Mosen, D.* AU - Dehghan, A.* AU - Moayyeri, A.* AU - Ferreira, D.L.S.* AU - Guo, X.* AU - Rotter, J.I.* AU - Taylor, K.D.* AU - Kavousi, M.* AU - de Vries, P.S.* AU - Lehne, B.* AU - Loh, M.* AU - Hofman, A.* AU - Nicholson, J.K.* AU - Chambers, J.* AU - Gieger, C. AU - Holmes, E.* AU - Tracy, R.* AU - Kooner, J.* AU - Greenland, P.* AU - Franco, O.H.* AU - Herrington, D.* AU - Lindon, J.C.* AU - Elliott, P.* C1 - 56087 C2 - 46806 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 2883-2896 TI - Serum metabolic signatures of coronary and carotid atherosclerosis and subsequent cardiovascular disease. JO - Eur. Heart J. VL - 40 IS - 34 PB - Oxford Univ Press PY - 2019 SN - 0195-668X ER - TY - JOUR AB - Aims Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.Methods and results We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.Conclusions Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community. AU - Ashar, F.N.* AU - Mitchell, R.N.* AU - Albert, C.M.* AU - Newton-Cheh, C.* AU - Brody, J.A.* AU - Müller-Nurasyid, M. AU - Moes, A.* AU - Meitinger, T. AU - Mak, A.* AU - Huikuri, H.* AU - Junttila, M.J.* AU - Goyette, P.* AU - Pulit, S.L.* AU - Pazoki, R.* AU - Tanck, M.W.* AU - Blom, M.T.* AU - Zhao, X.* AU - Havulinna, A.S.* AU - Jabbari, R.* AU - Glinge, C.* AU - Tragante, V.* AU - Escher, S.A.* AU - Chakravarti, A.* AU - Ehret, G.* AU - Coresh, J.* AU - Li, M.* AU - Prineas, R.J.* AU - Franco, O.H.* AU - Kwok, P.Y.* AU - Lumley, T.* AU - Dumas, F.* AU - McKnight, B.* AU - Rotter, J.I.* AU - Lemaitre, R.N.* AU - Heckbert, S.R.* AU - O'Donnell, C.J.* AU - Hwang, S.J.* AU - Tardif, J.-C.* AU - VanDenburgh, M.* AU - Uitterlinden, A.G.* AU - Hofman, A.* AU - Stricker, B.H.C.* AU - de Bakker, P.I.W.* AU - Franks, P.W.* AU - Jansson, J.H.* AU - Asselbergs, F.W.* AU - Halushka, M.K.* AU - Maleszewski, J.J.* AU - Tfelt-Hansen, J.* AU - Engstrøm, T.* AU - Salomaa, V.* AU - Virmani, R.* AU - Kolodgie, F.* AU - Wilde, A.A.M.* AU - Tan, H.L.* AU - Bezzina, C.R.* AU - Eijgelsheim, M.* AU - Rioux, J.D.* AU - Jouven, X.* AU - Kääb, S.* AU - Psaty, B.M.* AU - Siscovick, D.S.* AU - Arking, D.E.* AU - Sotoodehnia, N.* C1 - 54730 C2 - 45786 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 3961-3969 TI - A comprehensive evaluation of the genetic architecture of sudden cardiac arrest. JO - Eur. Heart J. VL - 39 IS - 44 PB - Oxford Univ Press PY - 2018 SN - 0195-668X ER - TY - JOUR AU - Elhadad, M.A. AU - Wilson, R. AU - Zaghlool, S.* AU - Huth, C. AU - Kriebel, J. AU - Grallert, H. AU - Rathmann, W.* AU - Graumann, J.* AU - Suhre, K.* AU - Peters, A. AU - Gieger, C. AU - Waldenberger, M. C1 - 55675 C2 - 46434 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 998-998 TI - Using the plasma proteome to decipher metabolic syndrome pathophysiology and discover a diagnostic biomarker panel. JO - Eur. Heart J. VL - 39 PB - Oxford Univ Press PY - 2018 SN - 0195-668X ER - TY - JOUR AB - Aims: The cardiac and vascular late sequelae in long-term survivors of childhood cancer (CVSS)-study aimed to quantify the prevalence of cardiovascular risk factors (CVRF) and cardiovascular disease (CVD) in German childhood cancer survivors (CCS). Methods and results: In the CVSS-study (NCT02181049), 1002 CCS (age range 23-48 years) diagnosed with neoplasia prior to 15 years of age between 1980 and 1990 prospectively underwent a systematic, standardized clinical and laboratory cardiovascular screening, identical to the population-based Gutenberg Health Study (GHS) cohort. For 951 individuals, prevalences of CVRF and CVD were primarily compared to the GHS sample and to two further German population-based cohorts. Using log-binomial regression models, an increased risk for occurrence of arterial hypertension [relative risk (RR) 1.38, 95% confidence interval (95% CI 1.21-1.57)] and dyslipidaemia [RR 1.26 (95% CI 1.12-1.42)] was found. This indicates a premature occurrence compared to the general population of approximately 6 and 8 years, respectively [rate advancement period estimator, RAPhypertension 5.75 (95% CI 3.5-8.0) and RAPdyslipidaemia 8.16 (95% CI 4.4-11.9)]. Overall, no differences were observed for obesity and diabetes. Overt CVD was present in 4.5% (95% CI 3.0-6.6%) of CCS [RR 1.89 (95% CI 1.34-2.66), RAPCVD 7.9 (95% CI 4.1-11.7)], of which the most frequent entities were congestive heart failure and venous thromboembolism. Prevalences of CVRF and CVD increased with age without reaching a plateau over time. Conclusion: This large CCS screening examination revealed consistently in comparison to three population samples a considerably increased risk for premature CVD. The findings in these young adult CCS indicate a high burden of cardiovascular morbidity and mortality in the long term. Clinicaltrials. gov-Nr: NCT02181049. AU - Faber, J.* AU - Wingerter, A.* AU - Neu, M.A.* AU - Henninger, N.* AU - Eckerle, S.* AU - Münzel, T.* AU - Lackner, K.J.* AU - Beutel, M.E.* AU - Blettner, M.* AU - Rathmann, W.* AU - Peters, A. AU - Meisinger, C. AU - Linkohr, B. AU - Neuhauser, H.* AU - Kaatsch, P.* AU - Spix, C.* AU - Schneider, A.* AU - Merzenich, H.* AU - Panova-Noeva, M.* AU - Prochaska, J.H.* AU - Wild, P.S.* C1 - 53247 C2 - 44503 SP - 1555-1562 TI - Burden of cardiovascular risk factors and cardiovascular disease in childhood cancer survivors: Data from the German CVSS-study. JO - Eur. Heart J. VL - 39 IS - 17 PY - 2018 SN - 0195-668X ER - TY - JOUR AU - My, I.* AU - Laue, S.* AU - Dressen, M.* AU - Schmidt, F. AU - Brade, T.* AU - Dorn, T.* AU - Goedel, A.* AU - Lahm, H.* AU - Lickert, H. AU - Krane, M.* AU - Moretti, A.* AU - Laugwitz, K.L.* C1 - 55674 C2 - 46433 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 390-391 TI - Primary cilium-autophagy-cell cycle axis defects impair cardiac progenitor specification in hypoplastic left heart syndrome. JO - Eur. Heart J. VL - 39 PB - Oxford Univ Press PY - 2018 SN - 0195-668X ER - TY - JOUR AB - Aims: Risks of catheter ablation for atrial fibrillation and flutter assessed in retrospective studies, registries, and controlled trials may underestimate 'real world' conditions. Methods and results: To assess complications in a nationwide approach, we included all cases undergoing catheter ablation for atrial fibrillation and atrial flutter in Germany in 2014, using ICD-10-GM-based German Diagnosis Related Group (G-DRG) codes and the well differentiated German Operation and Procedure Classification (OPS) analysing 33 353 in-hospital cases. For left atrial ablations (19 514 cases), the overall complication rate ranged from a mean of 11.7% to 13.8% depending on type and site of applied energy, including major complications ranging from 3.8% to 7.2%. Whereas overall complication rates were lower for atrial flutter ablations (13 871 cases, 10.5%; P < 0.001), interestingly, major complications occurred more frequently (7.4%; P < 0.001). Particularly, in-hospital death was four-times more common following right than following left atrial ablations (47 vs. 18 cases, 0.34% vs. 0.09%; P < 0.001). Stratified by centre ablation volume, significantly fewer overall complications occurred in centres performing >100 vs. ≤100 left atrial ablations annually (12.7% vs. 16.4%; P < 0.002). Conclusion: Administrative data of all atrial fibrillation ablations in Germany in 2014 revealed higher overall and major complication rates than previously reported. Few patients were treated in low volume centres, but were exposed to a higher overall complication risk. Atrial flutter ablations were associated with surprisingly high rates of life-threatening complications. Advanced age combined with highly prevalent cardiac, pulmonary and, vascular comorbidities likely play a major role. In addition, individual-level clinical studies need to address the safety and benefits of catheter ablation in an elderly, diseased population. AU - Steinbeck, G.* AU - Sinner, M.F.* AU - Lutz, M. AU - Müller-Nurasyid, M. AU - Kääb, S.* AU - Reinecke, H.* C1 - 54095 C2 - 45350 SP - 4020-4029 TI - Incidence of complications related to catheter ablation of atrial fibrillation and atrial flutter: A nationwide in-hospital analysis of administrative data for Germany in 2014. JO - Eur. Heart J. VL - 39 IS - 45 PY - 2018 SN - 0195-668X ER - TY - JOUR AB - Aims Identification and treatment of the rupture prone atherosclerotic plaque remains a challenge for reducing the bur- den of cardiovascular disease. The interconnection of metabolic and inflammatory processes in rupture prone plaques is poorly understood. Herein, we investigate associations between metabolite profiles, inflammatory mediators and vulnerability in carotid atherosclerotic plaques.Methods and results We collected 159 carotid plaques from patients undergoing endarterectomy and measured 165 different metabolites in a targeted metabolomics approach. We identified a metabolite profile in carotid plaques that associated with histologically evaluated vulnerability and inflammatory mediators, as well as presence of symptoms in patients. The distinct metabolite profiles identified in high-risk and stable plaques were in line with different transcription levels of metabolic enzymes in the two groups, suggesting an altered metabolism in high-risk plaques. The altered metabolic signature in high-risk plaques was consistent with a change to increased glycolysis, elevated amino acid utilization and decreased fatty acid oxidation, similar to what is found in activated leucocytes and cancer cells.Conclusion These results highlight a possible key role of cellular metabolism to support inflammation and a high-risk phenotype of atherosclerotic plaques. Targeting the metabolism of atherosclerotic plaques with novel metabolic radiotracers or inhibitors might therefore be valid future approaches to identify and treat the high-risk atherosclerotic plaque. AU - Tomas, L.* AU - Edsfeldt, A.* AU - Mollet, I.G.* AU - Perisic Matic, L.* AU - Prehn, C. AU - Adamski, J. AU - Paulsson-Berne, G.* AU - Hedin, U.* AU - Nilsson, J.* AU - Bengtsson, E.* AU - Gonçalves, I.* AU - Björkbacka, H.* C1 - 53275 C2 - 44464 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 2301-2310 TI - Altered metabolism distinguishes high-risk from stable carotid atherosclerotic plaques. JO - Eur. Heart J. VL - 39 IS - 24 PB - Oxford Univ Press PY - 2018 SN - 0195-668X ER - TY - JOUR AB - Aims Alcohol is a risk factor for cardiac arrhythmias. Retrospective analyses suggest supraventricular arrhythmias consecutive to acute alcohol consumption, but prospective data are limited. We intended to prospectively associate acute alcohol consumption with cardiac arrhythmias. Methods and results At the 2015 Munich Octoberfest, we enrolled 3028 voluntary participants who received a smartphone-based ECG and breath alcohol concentration (BAC) measurements. ECGs were analysed for cardiac arrhythmias (sinus tachycardia, sinus arrhythmia, premature atrial/ventricular complexes, atrial fibrillation/flutter) and respiratory sinus arrhythmia. By multivariable adjusted logistic regression we associated BACs with cardiac arrhythmias. Similarly, we analysed 4131 participants of the community-based KORA S4 Study (Co-operative Health Research in the Region of Augsburg) and associated cardiac arrhythmias with chronic alcohol consumption. In our acute alcohol cohort (mean age 34.4 +/- 13.3 years, 29% women), mean BAC was 0.85 +/- 0.54 g/kg. Cardiac arrhythmias occurred in 30.5% (sinus tachycardia 25.9%; other arrhythmia subtypes 5.4%). Breath alcohol concentration was significantly associated with cardiac arrhythmias overall (odds ratio (OR) per 1-unit change 1.75, 95% confidence interval (CI) 1.50-2.05; P < 0.001) and sinus tachycardia in particular (OR 1.96, 95% CI 1.66-2.31; P < 0.001). Respiratory sinus arrhythmia measuring autonomic tone was significantly reduced under the influence of alcohol. In KORA S4, chronic alcohol consumption was associated with sinus tachycardia (OR 1.03, 95% CI 1.01-1.06; P = 0.006). Conclusions Acute alcohol consumption is associated with cardiac arrhythmias and sinus tachycardia in particular. This partly reflects autonomic imbalance as assessed by significantly reduced respiratory sinus arrhythmia. Such imbalance might lead to sympathetically triggered atrial fibrillation resembling the holiday heart syndrome. AU - Brunner, S.* AU - Herbel, R.* AU - Drobesch, C.* AU - Peters, A. AU - Massberg, S.* AU - Kaeaeb, S.* AU - Sinner, M.F.* C1 - 51659 C2 - 43372 CY - Oxford SP - 2100-2106 TI - Alcohol consumption, sinus tachycardia, and cardiac arrhythmias at the Munich Octoberfest: Results from the Munich Beer Related Electrocardiogram Workup Study (MunichBREW). JO - Eur. Heart J. VL - 38 IS - 27 PB - Oxford Univ Press PY - 2017 SN - 0195-668X ER - TY - JOUR AB - Aims Lp(a) concentrations represent a major cardiovascular risk factor and are almost entirely controlled by one single locus (LPA). However, many genetic factors in LPA governing the enormous variance of Lp(a) levels are still unknown. Since up to 70% of the LPA coding sequence are located in a difficult to access hypervariable copy number variation named KIV-2, we hypothesized that it may contain novel functional variants with pronounced effects on Lp(a) concentrations. We performed a large scale mutation analysis in the KIV-2 using an extreme phenotype approach Methods and results We compiled an discovery set of 123 samples showing discordance between LPA isoform phenotype and Lp(a) concentrations and controls. Using ultra-deep sequencing, we identified a splice site variant (G4925A) in preferential association with the smaller LPA isoforms. Follow-up in a European general population (n = 2892) revealed an exceptionally high carrier frequency of 22.1% in the general population. The variant explains 20.6% of the Lp(a) variance in carriers of low molecular weight (LMW) apo(a) isoforms (P = 5.75e-38) and reduces Lp(a) concentrations by 31.3 mg/dL. Accordingly the odds ratio for cardiovascular disease was reduced from 1.39 [95% confidence interval (CI): 1.17-1.66, P = 1.89e-04] for wildtype LMW individuals to 1.19 [95% CI: 0.92; 1.56, P = 0.19] in LMW individuals who were additionally positive for G4925A. Functional studies point towards a reduction of splicing efficiency by this novel variant. Conclusion A highly frequent but until now undetected variant in the LPA KIV-2 region is strongly associated with reduced Lp(a) concentrations and reduced cardiovascular risk in LMW individuals. AU - Coassin, S.* AU - Erhart, G.* AU - Weissensteiner, H.* AU - de Araujo, M.E.G.* AU - Lamina, C.* AU - Schoenherr, S.* AU - Forer, L.* AU - Haun, M.* AU - Losso, J.L.* AU - Koettgen, A.* AU - Schmidt, K.* AU - Utermann, G.* AU - Peters, A. AU - Gieger, C. AU - Strauch, K. AU - Finkenstedt, A.* AU - Bale, R.* AU - Zoller, H.* AU - Paulweber, B.* AU - Eckardt, K.* AU - Huettenhofer, A.* AU - Huber, L.A.* AU - Kronenberg, F.* C1 - 51517 C2 - 43500 CY - Oxford SP - 1823-1831 TI - A novel but frequent variant in LPA KIV-2 is associated with a pronounced Lp(a) and cardiovascular risk reduction. JO - Eur. Heart J. VL - 38 IS - 23 PB - Oxford Univ Press PY - 2017 SN - 0195-668X ER - TY - JOUR AB - Aims: We investigated whether traffic-related air pollution and noise are associated with incident hypertension in European cohorts. Methods and results: We included seven cohorts of the European study of cohorts for air pollution effects (ESCAPE). We modelled concentrations of particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), ≤10 µm (PM10), >2.5, and ≤10 µm (PMcoarse), soot (PM2.5 absorbance), and nitrogen oxides at the addresses of participants with land use regression. Residential exposure to traffic noise was modelled at the facade according to the EU Directive 2002/49/EC. We assessed hypertension as (i) self-reported and (ii) measured (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg or intake of BP lowering medication (BPLM). We used Poisson regression with robust variance estimation to analyse associations of traffic-related exposures with incidence of hypertension, controlling for relevant confounders, and combined the results from individual studies with random-effects meta-analysis. Among 41 072 participants free of self-reported hypertension at baseline, 6207 (15.1%) incident cases occurred within 5-9 years of follow-up. Incidence of self-reported hypertension was positively associated with PM2.5 (relative risk (RR) 1.22 [95%-confidence interval (CI):1.08; 1.37] per 5 µg/m³) and PM2.5 absorbance (RR 1.13 [95% CI:1.02; 1.24] per 10 - 5m - 1). These estimates decreased slightly upon adjustment for road traffic noise. Road traffic noise was weakly positively associated with the incidence of self-reported hypertension. Among 10 896 participants at risk, 3549 new cases of measured hypertension occurred. We found no clear associations with measured hypertension. Conclusion: Long-term residential exposures to air pollution and noise are associated with increased incidence of self-reported hypertension. AU - Fuks, K.B.* AU - Weinmayr, G.* AU - Basagana, X.* AU - Gruzieva, O.* AU - Hampel, R. AU - Oftedal, B.* AU - Sørensen, M.* AU - Wolf, K. AU - Aamodt, G.* AU - Aasvang, G.M.* AU - Aguilera, I.* AU - Becker, T.* AU - Beelen, R.* AU - Brunekreef, B.* AU - Caracciolo, B.* AU - Cyrys, J. AU - Elosua, R.* AU - Eriksen, K.T.* AU - Foraster, M.* AU - Fratiglioni, L.* AU - Hilding, A.* AU - Houthuijs, D.* AU - Korek, M.* AU - Künzli, N.* AU - Marrugat, J.* AU - Nieuwenhuijsen, M.* AU - Ostenson, C.G.* AU - Penell, J.* AU - Pershagen, G.* AU - Raaschou-Nielsen, O.* AU - Swart, W.J.R.* AU - Peters, A. AU - Hoffmann, B.* C1 - 50949 C2 - 42622 SP - 983-990 TI - Long-term exposure to ambient air pollution and traffic noise and incident hypertension in seven cohorts of the European study of cohorts for air pollution effects (ESCAPE). JO - Eur. Heart J. VL - 38 IS - 13 PY - 2017 SN - 0195-668X ER - TY - JOUR AB - Aims: As promising compounds to lower Lipoprotein(a) (Lp(a)) are emerging, the need for a precise characterization and comparability of the Lp(a)-associated cardiovascular risk is increasing. Therefore, we aimed to evaluate the distribution of Lp(a) concentrations across the European population, to characterize the association with cardiovascular outcomes and to provide high comparability of the Lp(a)-associated cardiovascular risk by use of centrally determined Lp(a) concentrations. Methods and results: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project, we analysed data of 56 804 participants from 7 prospective population-based cohorts across Europe with a maximum follow-up of 24 years. All Lp(a) measurements were performed in the central BiomarCaRE laboratory (Biokit Quantia Lp(a)-Test; Abbott Diagnostics). The three endpoints considered were incident major coronary events (MCE), incident cardiovascular disease (CVD) events, and total mortality. We found lower Lp(a) levels in Northern European cohorts (median 4.9 mg/dL) compared to central (median 7.9 mg/dL) and Southern European cohorts (10.9 mg/dL) (Jonckheere-Terpstra test P < 0.001). Kaplan-Meier curves showed the highest event rate of MCE and CVD events for Lp(a) levels ≥90th percentile (log-rank test: P < 0.001 for MCE and CVD). Cox regression models adjusted for age, sex, and cardiovascular risk factors revealed a significant association of Lp(a) levels with MCE and CVD with a hazard ratio (HR) of 1.30 for MCE [95% confidence interval (CI) 1.15‒1.46] and of 1.25 for CVD (95% CI 1.12‒1.39) for Lp(a) levels in the 67‒89th percentile and a HR of 1.49 for MCE (95% CI 1.29‒1.73) and of 1.44 for CVD (95% CI 1.25‒1.65) for Lp(a) levels ≥ 90th percentile vs. Lp(a) levels in the lowest third (P < 0.001 for all). There was no significant association between Lp(a) levels and total mortality. Subgroup analysis for a continuous version of cube root transformed Lp(a) identified the highest Lp(a)-associated risk in individuals with diabetes [HR for MCE 1.31 (95% CI 1.15‒1.50)] and for CVD 1.22 (95% CI 1.08‒1.38) compared to those without diabetes [HR for MCE 1.15 (95% CI 1.08‒1.21; HR for CVD 1.13 (1.07-1.19)] while no difference of the Lp(a)- associated risk were seen for other cardiovascular high risk states. The addition of Lp(a) levels to a prognostic model for MCE and CVD revealed only a marginal but significant C-index discrimination measure increase (0.001 for MCE and CVD; P < 0.05) and net reclassification improvement (0.010 for MCE and 0.011 for CVD). Conclusion: In this large dataset on harmonized Lp(a) determination, we observed regional differences within the European population. Elevated Lp(a) was robustly associated with an increased risk for MCE and CVD in particular among individuals with diabetes. These results may lead to better identification of target populations who might benefit from future Lp(a)-lowering therapies. AU - Waldeyer, C.* AU - Makarova, N.* AU - Zeller, T.* AU - Schnabel, R.B.* AU - Brunner, F.J.* AU - Jørgensen, T.* AU - Linneberg, A.* AU - Niiranen, T.* AU - Salomaa, V.* AU - Jousilahti, P.* AU - Yarnell, J.* AU - Ferrario, M.M.* AU - Veronesi, G.* AU - Brambilla, P.* AU - Signorini, S.G.* AU - Iacoviello, L.* AU - Costanzo, S.* AU - Giampaoli, S.* AU - Palmieri, L.* AU - Meisinger, C. AU - Thorand, B. AU - Kee, F.* AU - Koenig, W.* AU - Ojeda, F.* AU - Kontto, J.* AU - Landmesser, U.* AU - Kuulasmaa, K.* AU - Blankenberg, S.* C1 - 51008 C2 - 43035 CY - Oxford SP - 2490-2498 TI - Lipoprotein(a) and the risk of cardiovascular disease in the European population: Results from the BiomarCaRE consortium. JO - Eur. Heart J. VL - 38 IS - 32 PB - Oxford Univ Press PY - 2017 SN - 0195-668X ER - TY - JOUR AB - Aims: The vascular effects of high-density lipoproteins (HDL) differ under certain clinical conditions. The composition of HDL is modified in patients with chronic kidney disease (CKD). As a consequence, uremic HDL induces endothelial dysfunction. We have previously shown that accumulation of symmetric dimethylarginine (SDMA) in HDL causes these adverse effects of HDL in CKD. The aim of the study is to determine the impact of the accumulation of SDMA on the association between HDL and mortality. Methods and results: Mortality, renal function, serum SDMA and HDL-cholesterol (HDL-C) were assessed in the LURIC study including 3310 subjects undergoing coronary angiography. All-cause mortality was 30.0% during median follow-up of 9.9 years. Serum SDMA levels significantly predicted all-cause and cardiovascular mortality, and were significantly correlated with SDMA accumulation in HDL. Notably, higher serum SDMA was independently associated with lower cholesterol efflux (P = 0.004) as a measure of HDL functionality. In subjects with low SDMA levels, higher HDL-C was associated with significantly lower mortality. In contrast, in subjects with high SDMA, HDL-C was associated with higher mortality. These findings were confirmed in 1424 participants of the MONICA/KORA S3 cohort. Of note, we derived an algorithm allowing for calculation of biologically effective HDL-C' based on measured HDL-C and SDMA. We corroborated these clinical findings with in vitro evidence showing that SDMA accumulation abolishes the anti-inflammatory and regenerative properties of HDL. Conclusion: The data identify SDMA as a marker of HDL dysfunction. These findings highlight on the pivotal role of SDMA accumulation in HDL as a mediator of pre-mature cardiovascular disease in patients with CKD. AU - Zewinger, S.* AU - Kleber, M.E.* AU - Rohrer, L.* AU - Lehmann, M.* AU - Triem, S.* AU - Jennings, R.T.* AU - Petrakis, I.* AU - Dressel, A.* AU - Lepper, P.M.* AU - Scharnagl, H.* AU - Ritsch, A.* AU - Thorand, B. AU - Heier, M. AU - Meisinger, C. AU - de Las Heras Gala, T. AU - Koenig, W.* AU - Wagenpfeil, S.* AU - Schwedhelm, E.* AU - Böger, R.H.* AU - Laufs, U.* AU - von Eckardstein, A.* AU - Landmesser, U.* AU - Lüscher, T.F.* AU - Fliser, D.* AU - März, W.* AU - Meinitzer, A.* AU - Speer, T.* C1 - 50890 C2 - 42882 CY - Oxford SP - 1597-1607 TI - Symmetric dimethylarginine, high-density lipoproteins and cardiovascular disease. JO - Eur. Heart J. VL - 38 IS - 20 PB - Oxford Univ Press PY - 2017 SN - 0195-668X ER - TY - JOUR AB - In the vast majority of cardiovascular diseases (CVDs), there are well-described differences between women and men in epidemiology, pathophysiology, clinical manifestations, effects of therapy, and outcomes.1–3 These differences arise on one hand from biological differences among women and men, which are called sex differences. They are due to differences in gene expression from the sex chromosomes and subsequent differences in sexual hormones leading to differences in gene expression and function in the CV system, e.g. in vascular function and NO signalling, in myocardial remodelling under stress, or metabolism of drugs by sex-specific cytochrome expression. Sex differences are frequently reproducible in animal models. In contrast, gender differences are unique to the human. They arise from sociocultural processes, such as different behaviours of women and men; exposure to specific influences of the environment; different forms of nutrition, lifestyle, or stress; or attitudes towards treatments and prevention. These are equally important for CVDs. Both sex and gender (S&G) influence human development (Figure 1). Since it is almost impossible to distinguish properly between effects of S&G in the medical field, the EUGenMed writing group decided to discuss both of them together and to use the term S&G for all medical relevant differences between women and men in the present review. AU - EUGenMed AU - Cardiovascular Clinical Study Group (*) AU - Regitz-Zagrosek, V.* AU - Oertelt-Prigione, S.* AU - Prescott, E.* AU - Franconi, F.* AU - Gerdts, E.* AU - Foryst-Ludwig, A.* AU - Maas, A.H.* AU - Kautzky-Willer, A.* AU - Knappe-Wegner, D.* AU - Kintscher, U.* AU - Ladwig, K.-H. AU - Schenck-Gustafsson, K.* AU - Stangl, V.* C1 - 47207 C2 - 39154 CY - Oxford SP - 24-34 TI - Gender in cardiovascular diseases: Impact on clinical manifestations, management, and outcomes. JO - Eur. Heart J. VL - 37 IS - 1 PB - Oxford Univ Press PY - 2016 SN - 0195-668X ER - TY - JOUR AB - AIMS: Our aims were to evaluate the distribution of troponin I concentrations in population cohorts across Europe, to characterize the association with cardiovascular outcomes, to determine the predictive value beyond the variables used in the ESC SCORE, to test a potentially clinically relevant cut-off value, and to evaluate the improved eligibility for statin therapy based on elevated troponin I concentrations retrospectively. METHODS AND RESULTS: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, we analysed individual level data from 10 prospective population-based studies including 74 738 participants. We investigated the value of adding troponin I levels to conventional risk factors for prediction of cardiovascular disease by calculating measures of discrimination (C-index) and net reclassification improvement (NRI). We further tested the clinical implication of statin therapy based on troponin concentration in 12 956 individuals free of cardiovascular disease in the JUPITER study. Troponin I remained an independent predictor with a hazard ratio of 1.37 for cardiovascular mortality, 1.23 for cardiovascular disease, and 1.24 for total mortality. The addition of troponin I information to a prognostic model for cardiovascular death constructed of ESC SCORE variables increased the C-index discrimination measure by 0.007 and yielded an NRI of 0.048, whereas the addition to prognostic models for cardiovascular disease and total mortality led to lesser C-index discrimination and NRI increment. In individuals above 6 ng/L of troponin I, a concentration near the upper quintile in BiomarCaRE (5.9 ng/L) and JUPITER (5.8 ng/L), rosuvastatin therapy resulted in higher absolute risk reduction compared with individuals <6 ng/L of troponin I, whereas the relative risk reduction was similar. CONCLUSION: In individuals free of cardiovascular disease, the addition of troponin I to variables of established risk score improves prediction of cardiovascular death and cardiovascular disease. AU - Blankenberg, S.* AU - Salomaa, V.* AU - Makarova, N.* AU - Ojeda, F.* AU - Wild, P.* AU - Lackner, K.J.* AU - Jørgensen, T.* AU - Thorand, B. AU - Peters, A. AU - Nauck, M.* AU - Petersmann, A.* AU - Vartiainen, E.* AU - Veronesi, G.* AU - Brambilla, P.* AU - Costanzo, S.* AU - Iacoviello, L.* AU - Linden, G.J.* AU - Yarnell, J.* AU - Patterson, C.C.* AU - Everett, B.M.* AU - Ridker, P.M.* AU - Kontto, J.* AU - Schnabel, R.B.* AU - Koenig, W.* AU - Kee, F.* AU - Zeller, T.* AU - Kuulasmaa, K.* AU - BiomarCaRE Investigators (*) C1 - 48594 C2 - 41205 CY - Oxford SP - 2428-2437 TI - Troponin I and cardiovascular risk prediction in the general population: The BiomarCaRE consortium. JO - Eur. Heart J. VL - 37 IS - 30 PB - Oxford Univ Press PY - 2016 SN - 0195-668X ER - TY - JOUR AU - Houssaini, A. AU - Abid, S.* AU - Derumeaux, G.* AU - Wan, F.* AU - Parpaleix, A.* AU - Rideau, D.* AU - Marcos, E.* AU - Czibik, G.* AU - Sawaki, D.* AU - Dubois-Rande, J.L.* AU - Zhenlin, L.* AU - Pende, M.* AU - Amsellem, V.* AU - Lipskaia, L.* AU - Adnot, A.* C1 - 50234 C2 - 42136 CY - Oxford SP - 568-568 TI - Selective TSC1 deletion in smooth muscle activates mTOR signaling and induces pulmonary hypertension. JO - Eur. Heart J. VL - 37 PB - Oxford Univ Press PY - 2016 SN - 0195-668X ER - TY - JOUR AB - AIMS: Acquired long QT syndrome (aLQTS) exhibits QT prolongation and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalaemia, or bradycardia. Sometimes, QTc remains prolonged despite elimination of triggers, suggesting the presence of an underlying genetic substrate. In aLQTS subjects, we assessed the prevalence of mutations in major LQTS genes and their probability of being carriers of a disease-causing genetic variant based on clinical factors. METHODS AND RESULTS: We screened for the five major LQTS genes among 188 aLQTS probands (55 ± 20 years, 140 females) from Japan, France, and Italy. Based on control QTc (without triggers), subjects were designated 'true aLQTS' (QTc within normal limits) or 'unmasked cLQTS' (all others) and compared for QTc and genetics with 2379 members of 1010 genotyped congenital long QT syndrome (cLQTS) families. Cardiac symptoms were present in 86% of aLQTS subjects. Control QTc of aLQTS was 453 ± 39 ms, shorter than in cLQTS (478 ± 46 ms, P < 0.001) and longer than in non-carriers (406 ± 26 ms, P < 0.001). In 53 (28%) aLQTS subjects, 47 disease-causing mutations were identified. Compared with cLQTS, in 'true aLQTS', KCNQ1 mutations were much less frequent than KCNH2 (20% [95% CI 7-41%] vs. 64% [95% CI 43-82%], P < 0.01). A clinical score based on control QTc, age, and symptoms allowed identification of patients more likely to carry LQTS mutations. CONCLUSION: A third of aLQTS patients carry cLQTS mutations, those on KCNH2 being more common. The probability of being a carrier of cLQTS disease-causing mutations can be predicted by simple clinical parameters, thus allowing possibly cost-effective genetic testing leading to cascade screening for identification of additional at-risk family members. AU - Itoh, H.* AU - Crotti, L. AU - Aiba, T.* AU - Spazzolini, C.* AU - Denjoy, I.* AU - Fressart, V.* AU - Hayashi, K.* AU - Nakajima, T.* AU - Ohno, S.* AU - Makiyama, T.* AU - Wu, J.* AU - Hasegawa, K.* AU - Mastantuono, E. AU - Dagradi, F.* AU - Pedrazzini, M.* AU - Yamagishi, M.* AU - Berthet, M.* AU - Murakami, Y.* AU - Shimizu, W.* AU - Guicheney, P.* AU - Schwartz, P.J.* AU - Horie, M.* C1 - 47614 C2 - 39428 CY - Oxford SP - 1456-1464 TI - The genetics underlying acquired long QT syndrome: Impact for genetic screening. JO - Eur. Heart J. VL - 37 IS - 18 PB - Oxford Univ Press PY - 2016 SN - 0195-668X ER - TY - JOUR AU - Lorbeer, R.* AU - Bayerl, C.* AU - Auweter, S.* AU - Rospleszcz, S. AU - Lieb, W.* AU - Peters, A. AU - Meisinger, C.* AU - Heier, M.* AU - Bamberg, F.* AU - Hetterich, H.* C1 - 50235 C2 - 42137 CY - Oxford SP - 417-417 TI - Association of MRI derived hepatic fat fraction with blood pressure in a population-based sample. JO - Eur. Heart J. VL - 37 PB - Oxford Univ Press PY - 2016 SN - 0195-668X ER - TY - JOUR AU - Makarova, N.* AU - Blankenberg, S.* AU - Salomaa, V.* AU - Ojeda, F.* AU - Wild, P.* AU - Jorgensen, T.* AU - Thorand, B. AU - Nauck, M.* AU - Veronesi, G.* AU - Everett, B.M.* AU - Yarnell, J.* AU - Koenig, W.* AU - Kee, F.* AU - Zeller, T.* AU - Kuulasmaa, K.* AU - BiomarCaRE Consortium, .* C1 - 50236 C2 - 42138 CY - Oxford SP - 46-47 TI - Troponin I and cardiovascular risk prediction in the general population. JO - Eur. Heart J. VL - 37 PB - Oxford Univ Press PY - 2016 SN - 0195-668X ER - TY - JOUR AU - de Las Heras Gala, T. AU - Mahabadi, A.A.* AU - Peters, A. AU - Baumert, J.J. AU - Geisel, H.* AU - Jöckel, K.-H.* AU - Moebus, S.* AU - Erbel, R.* AU - Meisinger, C. AU - Koenig, W. C1 - 47120 C2 - 39209 SP - 711 TI - Overestimation of incident ASCVD events by the ACC/AHA risk score in the German population: The KORA and the Heinz Nixdorf Recall Studies. JO - Eur. Heart J. VL - 36 PY - 2015 SN - 0195-668X ER - TY - JOUR AB - AIMS: Genome-wide association studies (GWAS) have identified many variants associating with an increased risk of coronary artery disease (CAD). We studied the possible association between these variants and the risk of sudden cardiac death (SCD). METHODS AND RESULTS: A weighted genetic risk score (GRSCAD) was formed from variants most strongly associating with CAD identified by the CARDIoGRAMplusC4D Consortium explaining 10.6% of the heritability of CAD [153 single-nucleotide polymorphisms with r(2) < 0.2]. The association between GRSCAD and the occurrence of SCD was studied in three independent autopsy series of consecutive cases combining altogether 1035 autopsies with 306 SCDs due to CAD (SCDCAD). The results were replicated in a prospective follow-up study of 2321 patients (mean follow-up time of 6.2 years with 48 incident SCDs of which 39 due to CAD) undergoing clinical exercise test at baseline. In a meta-analysis of the autopsy series, GRSCAD associated significantly with the risk of SCDCAD with age, body mass index, and sex adjusted odds ratio (OR) of 1.042 (1.023-1.061, P = 9.1 × 10(-6)) for one allele increase in GRSCAD. The same association was seen in both sexes. GRSCAD predicted significantly the risk of SCDCAD also in a prospective study setting (Cox regression analysis adjusted with all relevant clinical data): hazard ratio 1.049 (1.010-1.090, P = 0.014). In meta-analysis of all cohorts (adjusting further for other genetic markers related to traditional risk factors and QT-interval), the association was highly significant [OR 1.045 (1.028-1.063), P = 1.7 × 10(-7)]. CONCLUSION: Genetic risk estimate for CAD may also be used to predict SCD. AU - Hernesniemi, J.A.* AU - Lyytikäinen, L.-P.* AU - Oksala, N.* AU - Seppälä, I.* AU - Kleber, M.E.* AU - Mononen, N.* AU - Marz, W.* AU - Mikkelsson, J.* AU - Pessi, T.* AU - Louhelainen, A.M.* AU - Martiskainen, M.* AU - Nikus, K.* AU - Klopp, N. AU - Waldenberger, M. AU - Illig, T. AU - Kähönen, M.* AU - Laaksonen, R.* AU - Karhunen, P.J.* AU - Lehtimäki, T.* C1 - 44482 C2 - 36945 CY - Oxford SP - 1669-1675 TI - Predicting sudden cardiac death using common genetic risk variants for coronary artery disease. JO - Eur. Heart J. VL - 36 IS - 26 PB - Oxford Univ Press PY - 2015 SN - 0195-668X ER - TY - JOUR AB - AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10-6); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.   AU - Holmes, M.V.* AU - Asselbergs, F.W.* AU - Palmer, T.M.* AU - Drenos, F.* AU - Lanktree, M.B.* AU - Nelson, C.P.* AU - Dale, C.E.* AU - Padmanabhan, S.* AU - Finan, C.* AU - Swerdlow, D.I.* AU - Tragante, V.* AU - van Iperen, E.P.* AU - Sivapalaratnam, S.* AU - Shah, S.* AU - Elbers, C.C.* AU - Shah, T.* AU - Engmann, J.* AU - Giambartolomei, C.* AU - White, J.* AU - Zabaneh, D.* AU - Sofat, R.* AU - McLachlan, S.* AU - Doevendans, P.A.* AU - Balmforth, A.J.* AU - Hall, A.S.* AU - North, K.E.* AU - Almoguera, B.* AU - Hoogeveen, R.C.* AU - Cushman, M.* AU - Fornage, M.* AU - Patel, S.R.* AU - Redline, S.* AU - Siscovick, D.S.* AU - Tsai, M.Y.* AU - Karczewski, K.J.* AU - Hofker, M.H.* AU - Verschuren, W.M.* AU - Bots, M.L.* AU - van der Schouw, Y.T.* AU - Melander, O.* AU - Dominiczak, A.F.* AU - Morris, R.W.* AU - Ben-Shlomo, Y.* AU - Price, J.F.* AU - Kumari, M.* AU - Baumert, J.J. AU - Peters, A. AU - Thorand, B. AU - Koenig, W.* AU - Gaunt, T.R.* AU - Humphries, S.E.* AU - Clarke, R.* AU - Watkins, H.* AU - Farrall, M.* AU - Wilson, J.G.* AU - Rich, S.S.* AU - de Bakker, P.I.* AU - Lange, L.A.* AU - Davey Smith, G.* AU - Reiner, A.P.* AU - Talmud, P.J.* AU - Kivimaki, M.* AU - Lawlor, D.A.* AU - Dudbridge, F.* AU - Samani, N.J.* AU - Keating, B.J.* AU - Hingorani, A.D.* AU - Casas, J.P.* C1 - 30753 C2 - 33831 CY - Oxford SP - 539-550 TI - Mendelian randomization of blood lipids for coronary heart disease. JO - Eur. Heart J. VL - 36 IS - 9 PB - Oxford Univ Press PY - 2015 SN - 0195-668X ER - TY - JOUR AU - Hytoenen, J.* AU - Leppaenen, O.* AU - Jastroch, M. AU - Heuser, A.* AU - Drenckhahn, J.* AU - Mueller, D.B.* AU - Schunck, W.H.* AU - Jung, F.* AU - Ylae-Herttuala, S.* AU - Blaschke, F.* C1 - 47121 C2 - 39208 SP - 692 TI - Targeting the nuclear receptor PPARdelta as novel strategy to prevent in-stent restenosis and stent thrombosis. JO - Eur. Heart J. VL - 36 PY - 2015 SN - 0195-668X ER - TY - JOUR AU - Jacob, S.* AU - Ruidavets, J.B.* AU - Bongard, V.* AU - Meisinger, C. AU - Farmakis, D.* AU - Häkkinen, U.* AU - Fusco, D.* AU - Azevedo, A.* AU - Marrugat, J.* AU - Ferrieres, J.* C1 - 47122 C2 - 39207 SP - 121 TI - Are weight and BMI good predictors of in-hospital deaths in acute coronary syndromes? JO - Eur. Heart J. VL - 36 PY - 2015 SN - 0195-668X ER - TY - JOUR AU - Newby, D.E.* AU - Mannucci, P.M.* AU - Tell, G.S.* AU - Baccarelli, A.A.* AU - Brook, R.D.* AU - Donaldson, K.* AU - Forastiere, F.* AU - Franchini, M.* AU - Franco, O.H.* AU - Graham, I.* AU - Hoek, G.* AU - Hoffmann, B.* AU - Hoylaerts, M.F.* AU - Künzli, N.* AU - Mills, N.L.* AU - Pekkanen, J. AU - Peters, A. AU - Piepoli, M.F.* AU - Rajagopalan, S.* AU - Storey, R.F.* C1 - 42934 C2 - 35873 CY - Oxford SP - 83-93 TI - Expert position paper on air pollution and cardiovascular disease. JO - Eur. Heart J. VL - 36 IS - 2 PB - Oxford Univ Press PY - 2015 SN - 0195-668X ER - TY - JOUR AB - AIMS: High-density lipoproteins (HDLs) are considered as anti-atherogenic. Recent experimental findings suggest that their biological properties can be modified in certain clinical conditions by accumulation of serum amyloid A (SAA). The effect of SAA on the association between HDL-cholesterol (HDL-C) and cardiovascular outcome remains unknown. METHODS AND RESULTS: We examined the association of SAA and HDL-C with mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, which included 3310 patients undergoing coronary angiography. To validate our findings, we analysed 1255 participants of the German Diabetes and Dialysis study (4D) and 4027 participants of the Cooperative Health Research in the Region of Augsburg (KORA) S4 study. In LURIC, SAA concentrations predicted all-cause and cardiovascular mortality. In patients with low SAA, higher HDL-C was associated with lower all-cause and cardiovascular mortality. In contrast, in patients with high SAA, higher HDL-C was associated with increased all-cause and cardiovascular mortality, indicating that SAA indeed modifies the beneficial properties of HDL. We complemented these clinical observations by in vitro experiments, in which SAA impaired vascular functions of HDL. We further derived a formula for the simple calculation of the amount of biologically 'effective' HDL-C based on measured HDL-C and SAA from the LURIC study. In 4D and KORA S4 studies, we found that measured HDL-C was not associated with clinical outcomes, whereas calculated 'effective' HDL-C significantly predicted better outcome. CONCLUSION: The acute-phase protein SAA modifies the biological effects of HDL-C in several clinical conditions. The concomitant measurement of SAA is a simple, useful, and clinically applicable surrogate for the vascular functionality of HDL. AU - Zewinger, S.* AU - Drechsler, C.* AU - Kleber, M.E.* AU - Dressel, A.* AU - Riffel, J.* AU - Triem, S.* AU - Lehmann, M.* AU - Kopecky, C.* AU - Säemann, M.D.* AU - Lepper, P.M.* AU - Silbernagel, G.* AU - Scharnagl, H.* AU - Ritsch, A.* AU - Thorand, B. AU - de Las Heras Gala, T. AU - Wagenpfeil, S.* AU - Koenig, W.* AU - Peters, A. AU - Laufs, U.* AU - Wanner, C.* AU - Fliser, D.* AU - Speer, T.* AU - Marz, W.* C1 - 46543 C2 - 37728 SP - 3007-3016 TI - Serum amyloid A: High-density lipoproteins interaction and cardiovascular risk. JO - Eur. Heart J. VL - 36 IS - 43 PY - 2015 SN - 0195-668X ER - TY - JOUR AU - Dieplinger, H.* AU - Kollerits, B.* AU - Kiechl, S.* AU - Lamina, C.* AU - Meisinger, C. AU - Wietzorrek, G.* AU - Paulweber, B.* AU - Adham, I.M.* AU - Kronenberg, F.* C1 - 42954 C2 - 35896 SP - 448-449 TI - Plasma concentrations of afamin are associated with the prevalence and development of metabolic syndrome. JO - Eur. Heart J. VL - 35 PY - 2014 SN - 0195-668X ER - TY - JOUR AU - Jensen, M.T.* AU - Pereira, M.* AU - Araujo, C.* AU - Malmivaara, A.* AU - Ferrieres, J.* AU - Kirchberger, I. AU - Farmakis, D.* AU - Torre, M.* AU - Marrugat, J.* AU - Azevedo, A.* C1 - 42953 C2 - 35897 SP - 874 TI - Heart rate at admission is a predictor of in-hospital mortality in patients with acute coronary syndromes - results from 58 European hospitals - the EURHOBOP study. JO - Eur. Heart J. VL - 35 PY - 2014 SN - 0195-668X ER - TY - JOUR AB - AIMS: Living close to high traffic has been linked to subclinical atherosclerosis, however it is not clear, whether fine particulate matter (PM) air pollution or noise, two important traffic-related exposures, are responsible for the association. We investigate the independent associations of long-term exposure to fine PM and road traffic noise with thoracic aortic calcification (TAC), a reliable measure of subclinical atherosclerosis. METHODS AND RESULTS: We used baseline data (2000-2003) from the German Heinz Nixdorf Recall Study, a population-based cohort of 4814 randomly selected participants. We assessed residential long-term exposure to PM with a chemistry transport model, and to road traffic noise using façade levels from noise models as weighted 24 h mean noise (Lden) and night-time noise (Lnight). Thoracic aortic calcification was quantified from non-contrast enhanced electron beam computed tomography. We used multiple linear regression to estimate associations of environmental exposures with ln(TAC+1), adjusting for each other, individual, and neighbourhood characteristics. In 4238 participants (mean age 60 years, 49.9% male), PM2.5 (aerodynamic diameter ≤2.5 µm) and Lnight are both associated with an increasing TAC-burden of 18.1% (95% CI: 6.6; 30.9%) per 2.4 µg/m(3) PM2.5 and 3.9% (95% CI 0.0; 8.0%) per 5dB(A) Lnight, respectively, in the full model and after mutual adjustment. We did not observe effect measure modification of the PM2.5 association by Lnight or vice versa. CONCLUSION: Long-term exposure to fine PM and night-time traffic noise are both independently associated with subclinical atherosclerosis and may both contribute to the association of traffic proximity with atherosclerosis. AU - Kälsch, H.* AU - Hennig, F.* AU - Moebus, S.* AU - Möhlenkamp, S.* AU - Dragano, N.* AU - Jakobs, H.* AU - Memmesheimer, M.* AU - Erbel, R.* AU - Jöckel, K.-H.* AU - Hoffmann, B.* AU - Heinz Nixdorf Recall Study Investigative Group (Löwel, H.) C1 - 32356 C2 - 35020 SP - 853-860 TI - Are air pollution and traffic noise independently associated with atherosclerosis: The Heinz Nixdorf Recall Study. JO - Eur. Heart J. VL - 35 IS - 13 PY - 2014 SN - 0195-668X ER - TY - JOUR AU - Koenig, W.* AU - Zierer, A. AU - Karakas, M.* AU - Meisinger, C. AU - Peters, A. AU - Todd, J.A.* AU - Herder, C.* AU - Thorand, B. C1 - 42958 C2 - 35894 SP - 204-205 TI - Ultra-sensitive troponin I strongly predicts incident coronary heart disease in the general population. Results from the MONICA/KORA Augsburg Case-Cohort study. JO - Eur. Heart J. VL - 35 PY - 2014 SN - 0195-668X ER - TY - JOUR AB - AIMS: Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM. METHODS AND RESULTS: Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10-9) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors. CONCLUSION: The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.   AU - Meder, B.* AU - Rühle, F.* AU - Weis, T.* AU - Homuth, G.* AU - Keller, A.* AU - Franke, J.* AU - Peil, B.* AU - Lorenzo Bermejo, J.* AU - Frese, K.* AU - Huge, A.* AU - Witten, A.* AU - Vogel, B.* AU - Haas, J.* AU - Völker, U.* AU - Ernst, F.* AU - Teumer, A.* AU - Ehlermann, P.* AU - Zugck, C.* AU - Friedrichs, F.* AU - Kroemer, H.* AU - Dörr, M.* AU - Hoffmann, W.* AU - Maisch, B.* AU - Pankuweit, S.* AU - Ruppert, V.* AU - Scheffold, T.* AU - Kühl, U.* AU - Schultheiss, H.P.* AU - Kreutz, R.* AU - Ertl, G.* AU - Angermann, C.* AU - Charron, P.* AU - Villard, E.* AU - Gary, F.* AU - Isnard, R.* AU - Komajda, M.* AU - Lutz, M.* AU - Meitinger, T. AU - Sinner, M.F.* AU - Wichmann, H.-E. AU - Krawczak, M.* AU - Ivandic, B.* AU - Weichenhan, D.* AU - Gelbrich, G.* AU - El-Mokhtari, N.E.* AU - Schreiber, S.* AU - Felix, S.B.* AU - Hasenfuß, G.* AU - Pfeufer, A. AU - Hubner, N.* AU - Kääb, S.* AU - Arbustini, E.* AU - Rottbauer, W.* AU - Frey, N.* AU - Stoll, M.* AU - Katus, H.A.* C1 - 28927 C2 - 33580 CY - Oxford SP - 1069-1077 TI - A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy. JO - Eur. Heart J. VL - 35 IS - 16 PB - Oxford Univ Press PY - 2014 SN - 0195-668X ER - TY - JOUR AU - Pereira, M.* AU - Araujo, C.* AU - Häkkinen, U.* AU - Ferrieres, J.* AU - Meisinger, C. AU - Farmakis, D.* AU - Fusco, D.* AU - Dergano, I.R.* AU - Marrugat, J.* AU - Azevedo, A.* C1 - 42955 C2 - 35895 SP - 563 TI - Effect of smoking on the age at incidence of first acute coronary syndrome in patients from 58 European hospitals: The EURHOBOP study. JO - Eur. Heart J. VL - 35 PY - 2014 SN - 0195-668X ER - TY - JOUR AU - Dreger, H.* AU - Meiners, S. AU - Weller, A.* AU - Ludwig, A.* AU - Stangl, V.* AU - Baumann, G.* AU - Stangl, K.* C1 - 44245 C2 - 36857 CY - Oxford SP - 806 TI - The expression of the inducible nitric oxide synthase is epigenetically suppressed by the histone methyltransferase enhancer of zeste homolog 2 in human endothelial cells. JO - Eur. Heart J. VL - 34 PB - Oxford Univ Press PY - 2013 SN - 0195-668X ER - TY - JOUR AU - Sluka, S.H.M.* AU - Akhmedov, A.* AU - Klein-Rodewald, T. AU - Horsch, M. AU - Rathkolb, B.* AU - Neff, F. AU - Hrabě de Angelis, M. AU - Ruf, W.* AU - Luescher, T.F.* AU - Tanner, F.C.* C1 - 44244 C2 - 36858 CY - Oxford SP - 1058 TI - Single housing reduces lung hemorrhages in male mice with tissue factor disulfide mutation and protects them from lethality. JO - Eur. Heart J. VL - 34 PB - Oxford Univ Press PY - 2013 SN - 0195-668X ER - TY - JOUR AB - Aims Heterozygous mutations in KCNQ1 cause type 1 long QT syndrome (LQT1), a disease characterized by prolonged heart rate-corrected QT interval (QTc) and life-threatening arrhythmias. It is unknown why disease penetrance and expressivity is so variable between individuals hosting identical mutations. We aimed to study whether this can be explained by single nucleotide polymorphisms (SNPs) in KCNQ1's 3' untranslated region (3'UTR). Methods and results This study was performed in 84 LQT1 patients from the Academic Medical Center in Amsterdam and validated in 84 LQT1 patients from the Mayo Clinic in Rochester. All patients were genotyped for SNPs in KCNQ1's 3'UTR, and six SNPs were found. Single nucleotide polymorphisms rs2519184, rs8234, and rs10798 were associated in an allele-specific manner with QTc and symptom occurrence. Patients with the derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while the opposite was also true: patients with the derived SNP variants on their normal KCNQ1 allele had significantly longer QTc and more symptoms. Luciferase reporter assays showed that the expression of KCNQ1's 3'UTR with the derived SNP variants was lower than the expression of the 3'UTR with the ancestral SNP variants. Conclusion Our data indicate that 3'UTR SNPs potently modify disease severity in LQT1. The allele-specific effects of the SNPs on disease severity and gene expression strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside, and thereby influence the balance between proteins stemming from either the normal or the mutant KCNQ1 allele. AU - Amin, A.S.* AU - Giudicessi, J.R.* AU - Tijsen, A.J.* AU - Spanjaart, A.M.* AU - Reckman, Y.J.* AU - Klemens, C.A.* AU - Tanck, M.W.* AU - Kapplinger, J.D.* AU - Hofman, N.* AU - Sinner, M.F.* AU - Müller, M. AU - Wijnen, W.J.* AU - Tan, H.L.* AU - Bezzina, C.R.* AU - Creemers, E.E.* AU - Wilde, A.A.* AU - Ackerman, M.J.* AU - Pinto, Y.M.* C1 - 7305 C2 - 29666 SP - 714-723 TI - Variants in the 3' untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. JO - Eur. Heart J. VL - 33 IS - 6 PB - Oxford Univ. Press PY - 2012 SN - 0195-668X ER - TY - JOUR AU - Dreger, H.* AU - Meiners, S. AU - Weller, A.* AU - Ludwig, A.* AU - Stangl, V.* AU - Baumann, G.* AU - Stangl, K.* C1 - 47037 C2 - 40479 SP - 594 TI - Epigenetic regulation of the inducible nitric oxide synthase (iNOS) by the histone methyltransferase Ezh2 in human endothelial cells. JO - Eur. Heart J. VL - 33 PY - 2012 SN - 0195-668X ER - TY - JOUR AU - Dreger, H.* AU - Ludwig, A.* AU - Weller, A.* AU - Stangl, V.* AU - Baumann, G.* AU - Meiners, S. AU - Stangl, K.* C1 - 47038 C2 - 40478 SP - 678 TI - Epigenetic regulation of cell adhesion and communication by enhancer of zeste homolog 2 in human endothelial cells. JO - Eur. Heart J. VL - 33 PY - 2012 SN - 0195-668X ER - TY - JOUR AB - AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study. CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels. AU - Grallert, H. AU - Dupuis, J.* AU - Bis, J.C.* AU - Dehghan, A.* AU - Barbalic, M.* AU - Baumert, J.J. AU - Lu, C.* AU - Smith, N.L.* AU - Uitterlinden, A.G.* AU - Roberts, R.* AU - Khuseyinova, N.* AU - Schnabel, R.B.* AU - Rice, K.M.* AU - Rivadeneira, F.* AU - Hoogeveen, R.C.* AU - Fontes, J.D.* AU - Meisinger, C. AU - Keaney, J.F.* AU - Lemaitre, R.* AU - Aulchenko, Y.S.* AU - Vasan, R.S.* AU - Ellis, S.* AU - Hazen, S.L.* AU - van Duijn, C.M.* AU - Nelson, J.J.* AU - Marz, W.* AU - Schunkert, H.* AU - McPherson, R.M.* AU - Stirnadel-Farrant, H.A.* AU - Psaty, B.M.* AU - Gieger, C. AU - Siscovick, D.* AU - Hofman, A.* AU - Illig, T. AU - Cushman, M.* AU - Yamamoto, J.F.* AU - Rotter, J.I.* AU - Larson, M.G.* AU - Stewart, A.F.* AU - Boerwinkle, E.* AU - Witteman, J.C.* AU - Tracy, R.P.* AU - Koenig, W.* AU - Benjamin, E.J.* AU - Ballantyne, C.M.* C1 - 7176 C2 - 29521 SP - 238-251 TI - Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: Meta-analysis of genome-wide association studies from five community-based studies. JO - Eur. Heart J. VL - 33 IS - 2 PB - Oxford Univ. Press PY - 2012 SN - 0195-668X ER - TY - JOUR AU - Dreger, H.* AU - Meiners, S. AU - Weller, A.* AU - Ludwig, A.* AU - Stangl, V.* AU - Baumann, G.* AU - Stangl, K.* C1 - 47044 C2 - 40475 SP - 191 TI - Epigenetic regulation of cell adhesion and cell communication pathways by the histone methyltransferase Ezh2 in human endothelial cells. JO - Eur. Heart J. VL - 32 PY - 2011 SN - 0195-668X ER - TY - JOUR AB - Aims Recent genome-wide association (GWA) studies identified 10 chromosomal loci for coronary artery disease (CAD) or myocardial infarction (MI). However, these loci explain only a small proportion of the genetic variability of these pertinent diseases. We sought to identify additional CAD/MI loci by applying a three-stage approach. Methods and results We genotyped n = 1157 MI cases and n = 1748 controls from a population-based study population [German MI Family Study (GerMIFS) III (KORA)] with genome-wide SNP arrays. At this first stage, n = 462 SNPs showed association with MI at P<1 × 10(-3) in two-sided logistic regression. In a second stage, 415 of these SNPs were evaluated in silico in two independent GWA samples, the GerMIFS I (875 cases/1644 controls) and GerMIFS II (1222 cases/1298 controls). Nine SNPs, representing three regions, displayed consistent replication in this in silico analysis (P<0.05 for each GWA sample): five SNPs at 9p21.3, a well-known CAD/MI locus, two SNPs at 10p11.21, and two SNPs at 2p24.3. Wet-lab replication, i.e. the third stage, of SNP rs3739998 (representing the novel locus at 10p11.21, p.S1002T in the KIAA1462 gene) in additional 5790 cases and 5302 controls confirmed the association (P=9.54 × 10(-4)), but not for the 2p24.3 locus. The combined P-value across all stages for SNP rs3739998 is P=1.27 × 10(-11) [odds ratio (OR) = 1.15 (1.11-1.20)]. Conclusion Analysis of a GWA study followed by in silico and wet-lab replication steps identified the KIAA1462 gene, encoding a yet uncharacterized protein, on chromosome 10p11.23 with genome-wide significant association for CAD/MI. Further studies are needed to characterize the functional role of this locus in the aetiology of these diseases. AU - Erdmann, J.* AU - Willenborg, C.* AU - Nahrstaedt, J.* AU - Preuss, M.* AU - König, IR.* AU - Baumert, J.J.* AU - Linsel-Nitschke, P.* AU - Gieger, C.* AU - Tennstedt, S.* AU - Belcredi, P.* AU - Aherrahrou, Z* AU - Klopp, N. AU - Loley, C.* AU - Stark, K.* AU - Hengstenberg, C.* AU - Bruse, P.* AU - Freyer, J.* AU - Wagner, AK.* AU - Medack, A.* AU - Lieb, W.* AU - Großhennig, A.* AU - Sager, HB.* AU - Reinhardt, A.* AU - Schäfer, A.* AU - Schreiber, S.* AU - El Mokhtari, N.E.* AU - Raaz-Schrauder, D.* AU - Illig, T. AU - Garlichs, C.D.* AU - Ekici, A.B.* AU - Reis, A.* AU - Schrezenmeir, J.* AU - Rubin, D.* AU - Ziegler, A.* AU - Wichmann, H.-E. AU - Döring, A. AU - Meisinger, C. AU - Meitinger, T. AU - Peters, A. AU - Schunkert, H.* C1 - 5032 C2 - 27844 SP - 158-168 TI - Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23. JO - Eur. Heart J. VL - 32 IS - 2 PB - Oxford Univ. Press PY - 2011 SN - 0195-668X ER - TY - JOUR AB - Aims Cardiac energy requirement is met to a large extent by oxidative phosphorylation in mitochondria that are highly abundant in cardiac myocytes. Human mitochondrial thioredoxin reductase (TXNRD2) is a selenocysteine-containing enzyme essential for mitochondrial oxygen radical scavenging. Cardiac-specific deletion of Txnrd2 in mice results in dilated cardiomyopathy (DCM). The aim of this study was to investigate whether TXNRD2 mutations explain a fraction of monogenic DCM cases. Methods and results Sequencing and subsequent genotyping of TXNRD2 in patients diagnosed with DCM (n = 227) and in DCM-free (n = 683) individuals from the general population sample KORA S4 was performed. The functional impact of observed mutations on Txnrd2 function was tested in mouse fibroblasts. We identified two novel amino acid residue-altering TXNRD2 mutations [175G > A (Ala59Thr) and 1124G > A (Gly375Arg)] in three heterozygous carriers among 227 patients that were not observed in the 683 DCM-free individuals. Both DCM-associated mutations result in amino acid substitutions of highly conserved residues in helices contributing to the flavin-adenine dinucleotide (FAD)-binding domain of TXNRD2. Functional analysis of both mutations in Txnrd2(-/-) mouse fibroblasts revealed that contrasting to wild-type (wt) Txnrd2, neither mutant did restore Txnrd2 function. Mutants even impaired the survival of Txnrd2 wt cells under oxidative stress by a dominant-negative mechanism. Conclusion For the first time, we describe mutations in DCM patients in a gene involved in the regulation of cellular redox state. TXNRD2 mutations may explain a fraction of human DCM disease burden. AU - Sibbing, D.* AU - Pfeufer, A. AU - Perisic, T. AU - Mannes, A.M. AU - Fritz-Wolf, K.* AU - Unwin, S.* AU - Sinner, M.F.* AU - Gieger, C. AU - Gloeckner, C.J. AU - Wichmann, H.-E. AU - Kremmer, E. AU - Schäfer, Z. AU - Walch, A.K. AU - Hinterseer, M.* AU - Näbauer, M.* AU - Kääb, S.* AU - Kastrati, A.* AU - Schömig, A.* AU - Meitinger, T. AU - Bornkamm, G.W. AU - Conrad, M. AU - von Beckerath, N.* C1 - 6296 C2 - 28329 SP - 1121-1133 TI - Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy. JO - Eur. Heart J. VL - 32 IS - 9 PB - Oxford Univ Press PY - 2011 SN - 0195-668X ER - TY - JOUR AU - Karakas, M.* AU - Baumert, J.J. AU - Müller-Nurasyid, M. AU - Klopp, N. AU - Thorand, B. AU - Meredith, D.* AU - Meisinger, C. AU - Herder, C.* AU - Illig, T. AU - Koenig, W.* C1 - 60087 C2 - 0 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 813-813 TI - Associations between variations in the TLR4 gene and incident coronary heart disease (CHD) in middle-aged men and women: Results from the MONICA/KORA Augsburg case-cohort study, 1984-2002. JO - Eur. Heart J. VL - 31 PB - Oxford Univ Press PY - 2010 SN - 0195-668X ER - TY - JOUR AB - 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. 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. 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. AU - Kääb, S.* AU - Darbar, D.* AU - van Noord, C.* AU - Dupuis, J.* AU - Pfeufer, A. AU - Newton-Cheh, C.* AU - Schnabel, R. AU - Makino, S.* AU - Sinner, M.F.* AU - Kannankeril, P.J.* AU - Beckmann, B.M.* AU - Choudry, S.* AU - Donahue, B.S.* AU - Heeringa, J.* AU - Perz, S. AU - Lunetta, K.L.* AU - Larson, M.G.* AU - Levy, D.* AU - MacRae, C.A.* AU - Ruskin, J.N.* AU - Wacker, A.* AU - Schömig, A.* AU - Wichmann, H.-E. AU - Steinbeck, G.* AU - Meitinger, T. AU - Uitterlinden, A.G.* AU - Witteman, J.C.M.* AU - Roden, D.M.* AU - Benjamin, E.J.* AU - Ellinor, P.T.* C1 - 1107 C2 - 26163 SP - 813-819 TI - Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation. JO - Eur. Heart J. VL - 30 IS - 7 PB - Oxford Univ Press PY - 2009 SN - 0195-668X ER - TY - JOUR AB - The aim of this study was to assess the impact of myocardial infarction (MI) on health-related quality of life (HRQL) in MI survivors measured by EuroQol (EQ-5D) and to compare it with the general population. A follow-up study of all MI survivors included in the MONICA/KORA registry was performed. About 2950 (67.1%) patients responded. Moderate or severe problems were most frequent in EQ-5D dimension pain/discomfort (55.0%), anxiety/depression (29.2%), and mobility (27.9%). Mean EQ VAS score was 65.8 (SD 18.5). Main predictors of lower HRQL included older age, diabetes, increasing body mass index, current smoking, and experience of re-infarction. Type of revascularizational treatment showed no impact on HRQL. Compared with the general population, adjusted EQ VAS was 6.2 (95% confidence interval 3.4-8.9) points lower in 45-year-old MI patients converging with growing age up to the age of 80. With regard to HRQL dimensions, MI survivors had a significantly higher risk of incurring problems in the dimension pain/discomfort, usual activities, and especially in anxiety/depression which was more pronounced in younger age. Mobility was the single dimension, in which MI showed an inverse effect. MI is combined with significant reduction in HRQL compared with the general population. The main impairments occur in the dimension pain/discomfort, usual activities, and particularly anxiety/depression. The relative impairment decreases with higher ages. AU - Schweikert, B. AU - Hunger, M. AU - Meisinger, C. AU - König, H.H.* AU - Gapp, O. AU - Holle, R. C1 - 2260 C2 - 26193 SP - 436-443 TI - Quality of life several years after myocardial infarction: Comparing the MONICA/KORA registry to the general population. JO - Eur. Heart J. VL - 30 IS - 4 PB - Oxford Univ Press PY - 2009 SN - 0195-668X ER - TY - JOUR AB - Degenerative aortic valve disease (DAVD), a common finding in the elderly, is associated with an increased risk of death due to cardiovascular causes. Taking advantage of its longitudinal design, this study evaluates the prevalence of DAVD and its temporal associations with long-term exposure to cardiovascular risk factors in the general population. We studied 953 subjects (aged 25-74 years) from a random sample of German residents. Risk factors had been determined at a baseline investigation in 1994/95. At a follow-up investigation, 10 years later, standardized echocardiography determined aortic valve morphology and aortic valve area (AVA) as well as left ventricular geometry and function. At the follow-up study, the overall prevalence of DAVD was 28%. In logistic regression models adjusting for traditional cardiovascular risk factors at baseline age (OR 2.0 [1.7-2.3] per 10 years, P < 0.001), active smoking (OR 1.7 [1.1-2.4], P = 0.009) and elevated total cholesterol levels (OR 1.2 [1.1-1.3] per increase of 20 mg/dL, P < 0.001) were significantly related to DAVD at follow-up. Furthermore, age, baseline status of smoking, and total cholesterol level were significant predictors of a smaller AVA at follow-up study. In contrast, hypertension and obesity had no detectable relationship with long-term changes of aortic valve structure. In the general population we observed a high prevalence of DAVD that is associated with long-term exposure to elevated cholesterol levels and active smoking. These findings strengthen the notion that smoking cessation and cholesterol lowering are promising treatment targets for prevention of DAVD. AU - Stritzke, J.* AU - Linsel-Nitschke, P.* AU - Markus, M.R.* AU - Mayer, B.* AU - Lieb, W.* AU - Luchner, A.* AU - Döring, A. AU - Koenig, W.* AU - Keil, U.* AU - Hense, H.W.* AU - Schunkert, H.* C1 - 1104 C2 - 26472 SP - 2044-2053 TI - Association between degenerative aortic valve disease and long-term exposure to cardiovascular risk factors: Results of the longitudinal population-based KORA/MONICA survey. JO - Eur. Heart J. VL - 30 IS - 16 PB - Oxford Univ Press PY - 2009 SN - 0195-668X ER - TY - JOUR AU - von Klot, S. AU - Mittleman, M.A.* AU - Peters, A. C1 - 556 C2 - 26194 SP - 251-252 TI - Physical exertion and triggering of myocardial infarction: Reply. JO - Eur. Heart J. VL - 30 IS - 2 PB - Oxford Univ Press PY - 2009 SN - 0195-668X ER - TY - JOUR AB - AIMS: Modern imaging technology allows us the visualization of coronary artery calcification (CAC), a marker of subclinical coronary atherosclerosis. The prevalence, quantity, and risk factors for CAC were compared between two studies with similar imaging protocols but different source populations: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR). METHODS AND RESULTS: The measured CAC in 2220 MESA participants were compared with those in 3,126 HNR participants with the inclusion criteria such as age 45-75 years, Caucasian race, and free of baseline cardiovascular disease. Despite similar mean levels of CAC of 244.6 among participants in MESA and of 240.3 in HNR (P = 0.91), the prevalence of CAC > 0 was lower in MESA (52.6%) compared with HNR (67.0%) with a prevalence rate ratio of CAC > 0 of 0.78 [95% confidence interval (CI): 0.72-0.85] after adjustment for known risk factors. Consequently, among participants with CAC > 0, the participants in MESA tended to have higher levels of CAC than those in HNR (ratio of CAC levels: 1.39; 95% CI: 1.19-1.63), since many HNR participants have small (near zero) CAC values. CONCLUSIONS: The CAC prevalence was lower in the United States (MESA) cohort than in the German (HNR) cohort, which may be explained by more favourable risk factor levels among the MESA participants. The predictors for increased levels of CAC were, however, similar in both cohorts with the exception that male gender, blood pressure, and body mass index were more strongly associated in the HNR cohort. AU - Erbel, R.* AU - Delaney, J.A.* AU - Lehmann, N.* AU - McClelland, R.L.* AU - Möhlenkamp, S.* AU - Kronmal, R.A.* AU - Schmermund, A.* AU - Moebus, S.* AU - Dragano, N.* AU - Stang, A.* AU - Jöckel, K.-H.* AU - Budoff, M.J.* AU - Heinz Nixdorf Recall Study Investigative Group (Löwel, H.) C1 - 32350 C2 - 39153 SP - 2782-2791 TI - Signs of subclinical coronary atherosclerosis in relation to risk factor distribution in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR). JO - Eur. Heart J. VL - 29 IS - 22 PY - 2008 SN - 0195-668X ER - TY - JOUR AB - Torsades de pointes arrhythmias (TdP) occur by definition in the setting of prolonged QT intervals. Animal models of drug induced Long-QT syndrome (dLQTS) have shown higher predictive value for proarrhythmia with beat-to-beat variability of repolarization duration (BVR) when compared with QT intervals. Here, we evaluate variability of QT intervals in patients with a history of drug-induced long QT syndrome (dLQTS) and TdP in absence of a mutation in any of the major LQTS genes. METHODS AND RESULTS: Twenty patients with documented TdP under drugs with QT-prolonging potential were compared with 20 matched control individuals. An observer blinded to diagnosis manually measured lead-II, RR, and QT intervals from 30 consecutive beats. BVR was determined from Poincaré plots of QT intervals as short-term variability (STV(QT) = Sigma AU - Hinterseer, M.* AU - Thomsen, M.B.* AU - Beckmann, B.M.* AU - Pfeufer, A. AU - Schimpf, R.* AU - Wichmann, H.-E. AU - Steinbeck, G.* AU - Vos, M.A.* AU - Kääb, S.* C1 - 602 C2 - 25273 SP - 185-190 TI - Beat-to-beat variability of QT intervals is increased in patients with drug-induced long-QT syndrome: A case control pilot study. JO - Eur. Heart J. VL - 29 IS - 2 PB - Oxford Univ. Press PY - 2008 SN - 0195-668X ER - TY - JOUR AU - Khuseyinova, N.* AU - Baumert, J.J. AU - Müller-Nurasyid, M. AU - Klopp, N. AU - Kolz, M. AU - Meisinger, C. AU - Illig, T. AU - Thorand, B. AU - Koenig, W.* C1 - 60090 C2 - 0 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 477-477 TI - Genetic variants within the CRP gene and incident type 2 diabetes mellitus in middle-aged men and women: MONICA/KORA Augsburg case-cohort study, 1984-2002. JO - Eur. Heart J. VL - 29 PB - Oxford Univ Press PY - 2008 SN - 0195-668X ER - TY - JOUR AB - C-reactive protein represents the classical acute-phase protein produced in the liver in response to inflammatory stimuli. This study evaluated the association of gene polymorphisms with differences in C-reactive protein concentrations and assessed its intra-individual variability as a marker of individual response. METHODS AND RESULTS: One thousand and three myocardial infarction (MI) survivors were recruited in six European cities, and C-reactive protein concentrations were measured repeatedly during a 6-month period. We investigated 114 polymorphisms in 13 genes, all involved in the innate inflammatory pathway. We found two polymorphisms within the C-reactive protein (CRP) gene rs1800947 and rs1205, of which the minor alleles were strongly associated with lower levels of C-reactive protein (P < 10(-6)). A haplotype, identified by those two polymorphisms, was associated with the lowest C-reactive protein concentrations (P < 10(-6)). Additionally, the minor alleles of several variants were significantly associated with greater individual variability of C-reactive protein concentrations (P < 10(-3)). CONCLUSION: The present study investigated the association of polymorphisms with inter- and intra-individual variability of C-reactive protein levels. Two minor alleles of C-reactive protein variants were associated with lower C-reactive protein concentrations. Regarding intra-individual variability, we observed associations with the minor alleles of several variants in selected candidate genes, including the CRP gene itself. AU - Kolz, M. AU - Koenig, W.* AU - Müller, M. AU - Andreani, M.* AU - Greven, S.* AU - Illig, T. AU - Khuseyinova, N.* AU - Panagiotakos, D.* AU - Pershagen, G.* AU - Salomaa, V.* AU - Sunyer, J.* AU - Peters, A. AU - AIRGENE Study Group (*) C1 - 3643 C2 - 25491 SP - 1250-1258 TI - DNA variants, plasma levels and variability of C-reactive protein in myocardial infarction survivors: Results from the AIRGENE study. JO - Eur. Heart J. VL - 29 IS - 10 PB - Oxford. Univ. Press PY - 2008 SN - 0195-668X ER - TY - JOUR AB - AIMS: Atrial fibrillation (AF) is the most frequent arrhythmia in humans. Rare familial forms exist. Recent evidence indicates a genetic susceptibility to common forms of AF. The alpha-subunit of the myocardial I(Kr)-channel, encoded by the KCNH2 gene, is crucial to ventricular and atrial repolarization. Patients with mutations in KCNH2 present with higher incidence of AF. Common variants in KCNH2 have been shown to modify ventricular repolarization. We intended to investigate, whether such variants may also modulate atrial repolarization and predispose to AF. METHODS AND RESULTS: In a two-stage association study we analysed 1207 AF-cases and 2475 controls. In stage I 40 tagSNPs (single nucleotide polymorphisms) from the KCNH2 genomic region were genotyped in 671 AF-cases and 694 controls. Of five associated variants, the common K897-allele of the KCNH2-K897T variant was replicated in n = 536 independent AF cases and n = 1781 controls in stage II [overall odds ratio 1.25, 95% confidence interval 1.11-1.41, P = 0.00033]. This association remained significant after adjustment for gender and age. CONCLUSION: We report a genetic association finding including positive replication between the K897-allele and higher incidence of AF. This provides a molecular correlate for complex genetic predispositions to AF. The consequences of the K897T variant at the atrial level will require further functional investigations. AU - Sinner, M.F. AU - Pfeufer, A. AU - Akyol, M. AU - Beckmann, B.M.* AU - Hinterseer, M.* AU - Wacker, A.* AU - Perz, S. AU - Sauter, W. AU - Illig, T. AU - Näbauer, M.* AU - Schmitt, C.* AU - Wichmann, H.-E. AU - Schömig, A.* AU - Steinbeck, G.* AU - Meitinger, T. AU - Kääb, S.* C1 - 2025 C2 - 25256 SP - 907-914 TI - The non-synonymous coding IKr-channel variant KCNH2-K897T is associated with atrial fibrillation: Results from a systematic candidate gene-based analysis of KCNH2 (HERG). JO - Eur. Heart J. VL - 29 IS - 7 PB - Oxford. Univ. Press PY - 2008 SN - 0195-668X ER - TY - JOUR AB - AIMS: Acute myocardial infarction (AMI) can be precipitated or triggered by discrete transient exposures including physical exertion. We evaluated whether the risk of having an AMI triggered by physical exertion exhibits an exposure-response relationship, and whether it varies by ambient temperature or by taking place indoors or outdoors. METHODS AND RESULTS: We conducted a case-crossover study within the Myocardial Infarction Registry in Augsburg, Germany in 1999-2003. One thousand three hundred and one patients reported levels of activity and time spent outdoors on the day of AMI and three preceding days in an interview. The case-crossover analyses showed an association of physical exertion with AMI symptom onset within 2 h, which was strong for strenuous exertion (METs >or= 6) [relative risk (RR) 5.7, 95% confidence interval (CI) 3.6-9.0), and still significant for moderate exertion (METs = 5) (RR 1.6, 95% CI 1.2-2.1) compared to very light or no exertion. Strenuous exertion outside was associated with a four-fold larger RR of AMI symptom onset than exertion performed indoors, which was not explained by temperature. CONCLUSION: This study confirms previous results and shows a graded exposure-response relationship between physical exertion intensity and triggering of AMI onset. These findings may have implications for behavioural guidance of people at risk of AMI. AU - von Klot, S. AU - Mittleman, M.A.* AU - Dockery, D.W.* AU - Heier, M. AU - Meisinger, C. AU - Hörmann, A. AU - Wichmann, H.-E. AU - Peters, A. C1 - 3365 C2 - 25567 SP - 1881-1888 TI - Intensity of physical exertion and triggering of myocardial infarction : A case-crossover study. JO - Eur. Heart J. VL - 29 IS - 15 PB - Oxford. Univ. Press PY - 2008 SN - 0195-668X ER - TY - JOUR AB - Aims The QT interval in the general population is a complex trait with 30-50% heritability. QT prolongation is associated with an increased risk of sudden death. A recent family-based study found an association between QT interval and the common non-synonymous Glycin 38 Serine variant (G38S, rs1805127) of the KCNE1 gene coding for the minK-potassium channel subunit. We intended to replicate this finding in a large population sample of central European Caucasian ancestry as part of our ongoing search for genetic variants predisposing to arrhythmias. We studied 3966 unrelated individuals from the KORA S4 population-based study without atrial fibrillation, pacemaker implant, or pregnancy. Individuals were genotyped by MALDI-TOF mass spectrometry. We did not detect any significant association between the genotypes of the G38S variant and the QT interval in the entire population or in any gender. Unlike the common Lysine 897 Threonine variant of KCNH2 (K897T, rs1805123) the G38S variant of KCNE1 does not appear to have a strong modifying effect on QT interval. However, we cannot rule out an effect of G38S on QT in other ethnic groups, under exercise or medications or on the risk for arrhythmias and sudden death. AU - Akyol, M. AU - Jalilzadeh, S. AU - Sinner, M.F. AU - Perz, S. AU - Beckmann, B.M.* AU - Gieger, C. AU - Illig, T. AU - Wichmann, H.-E. AU - Meitinger, T. AU - Kääb, S.* AU - Pfeufer, A. C1 - 4883 C2 - 24624 SP - 305-309 TI - The common non-synonymous variant G38S of the KCNE1-(minK)-gene is not associated to QT interval in Central European Caucasians: Results from the KORA study. JO - Eur. Heart J. VL - 28 IS - 3 PB - Oxford Univ. Press PY - 2007 SN - 0195-668X ER - TY - JOUR AB - A South-to-North gradient across Europe exists for the incidence of coronary artery disease (CAD) rates. Low-density lipoprotein (LDL) oxidation is a hallmark of atherosclerosis and CAD development. The aim of our study was to determine whether differences exist in the degree of LDL oxidation in stable CAD patients from different regions of Europe. METHODS AND RESULTS: A cross-sectional multicentre study included 790 stable CAD male subjects aged 35-79 years (61.4 +/- 9.5) from six European countries in three regions by latitude: Northern (Finland and Sweden), Central (Germany), and Southern (Greece, Spain, and Italy). Plasma oxidized LDL (oxLDL) levels were determined. Alcohol intake and lipid profile were significantly associated with oxLDL. The Italian participants had the highest oxLDL levels. A sensitivity analysis showed the models yielded higher adjusted oxLDL values in Northern (63.8 U/L) than in Central (57.6 U/L) and Southern populations (56.5 U/L), P < 0.001, after excluding Italian subjects. The probability of Southern Europe scoring the lowest oxLDL levels was >71% in all fitted models. CONCLUSION: Our findings suggest a gradient in LDL oxidation from Southern to Northern Europe that consistently holds for all levels of LDL, except for Italy; this country displays the highest levels in Europe, for unknown reasons. AU - Grau, M.* AU - Guxens, M.* AU - Subirana, I.* AU - Fitó, M.* AU - Covas, M.I.* AU - Jacquemin, B.* AU - Sunyer, J.* AU - Lanki, T.* AU - Picciotto, S.* AU - Bellander, T.* AU - Katsouyanni, K.* AU - Schneider, A.E. AU - Peters, A. AU - Marrugat, J.* AU - AIRGENE Study Group (*) C1 - 2599 C2 - 25180 SP - 2841-2849 TI - South-to-North gradient in lipid peroxidation in men with stable coronary artery disease in Europe. JO - Eur. Heart J. VL - 28 IS - 23 PB - Oxford. Univ. Press PY - 2007 SN - 0195-668X ER - TY - JOUR AB - Non-invasive coronary angiography by multislice spiral computed tomography (MSCT) is a promising method for the diagnosis of coronary artery disease (CAD). However, the clinical role of this method has not been established for specific patient cohorts. Therefore, the objective of the current prospective, blinded study was to investigate the diagnostic value of coronary MSCT angiography in patients with an intermediate pre-test probability for having CAD when compared with invasive angiography. Methods and results A total of 243 patients with an intermediate pre-test probability for having CAD were asked to undergo coronary 16- or 64-slice CT angiography before planned invasive angiography from 12 September 2003 to 13 July 2005. The primary end point was defined as the diagnostic accuracy in the detection of significant coronary stenosis (>/=50% lumen diameter reduction) on a per-patient and an 'intention-to-diagnose'-based analysis. Secondary end points comprised per-artery and per segment-based analyses as well as the comparison of diagnostic accuracy of 16- vs. 64-slice MSCT angiography. Of 243 enrolled patients, 129 and 114 patients were studied by 16- and 64-slice CT angiography, respectively. The overall sensitivity, negative predictive value, and specificity for CAD detection by MSCT were 99% (95% CI, 94-99%), 99% (95% CI, 94-99%), and 75% (95% CI, 67-82%), respectively. On a per-segment basis, the use of 64-slice CT was associated with significantly less inconclusive segments (7.4 vs. 11.3%, P < 0.01), resulting in a trend to an improved specificity (92 vs. 88%, P = 0.09). Conclusion In patients with an intermediate pre-test probability for having CAD this large, prospective trial demonstrates that non-invasive coronary CT angiography is a very sensitive method for CAD detection. Furthermore, this method allows ruling out CAD very reliably and safely. Finally, 64-slice CT appears to be superior for CAD detection when compared with 16-slice CT. AU - Hausleiter, J.* AU - Meyer, T.* AU - Hadamitzkym, M.* AU - Zankl, M. AU - Gerein, P.* AU - Dörrler, K.* AU - Kastrati, A.* AU - Martinoff, S.* AU - Schömig, A.* C1 - 2908 C2 - 25047 SP - 3034-3041 TI - Non-invasive coronary computed tomographic angiography for patients with suspected coronary artery disease: The Coronary Angiography by Computed Tomography with the Use of a Submillimeter resolution (CACTUS) tria.l. JO - Eur. Heart J. VL - 28 IS - 24 PB - Oxford. Univ. Press PY - 2007 SN - 0195-668X ER - TY - JOUR AU - Thorand, B. AU - Baumert, J.J. AU - Herder, C.* AU - Klopp, N.* AU - Kolz, M.* AU - Khuseyinova, N.* AU - Müller-Nurasyid, M. AU - Loewel, H.* AU - Illig, T.* AU - Koenig, W.* C1 - 60092 C2 - 0 CY - Great Clarendon St, Oxford Ox2 6dp, England SP - 692-692 TI - Interleukin-18 gene polymorphisms, interleukin-18 serum concentrations and risk of coronary heart disease: Results from the MONICA/KORA Augsburg case-cohort study, 1984-2002. JO - Eur. Heart J. VL - 28 PB - Oxford Univ Press PY - 2007 SN - 0195-668X ER - TY - JOUR AU - Bigalke, B.* AU - Lindemann, S.* AU - Ehlers, R.* AU - Seizer, P.* AU - Daub, K.* AU - Langer, H.* AU - Schönberger, T.* AU - Kremmer, E. AU - Siegel-Axel, D.* AU - May, A.E.* AU - Gawaz, M.* C1 - 4972 C2 - 24134 SP - 2165-2169 TI - Expression of platelet collagen receptor glycoprotein VI is associated with acute coronary syndrome. JO - Eur. Heart J. VL - 27 PY - 2006 SN - 0195-668X ER - TY - JOUR AU - Koch, W.* AU - Hoppmann, P.* AU - Pfeufer, A. AU - Schömig, A.* AU - Kastrati, A.* C1 - 5254 C2 - 24180 SP - 2524-2529 TI - Toll-like receptor 4 gene polymorphisms and myocardial infarction: No association in a Caucasian population. JO - Eur. Heart J. VL - 27 PY - 2006 SN - 0195-668X ER - TY - JOUR AU - Lamina, C. AU - Meisinger, C. AU - Heid, I.M. AU - Löwel, H. AU - Rantner, B.* AU - Koenig, W.* AU - Kronenberg, F.* C1 - 4583 C2 - 24278 SP - 2580-2587 TI - Association of ankle-brachial index and plaques in the carotid and femoral arteries with cardiovascular events and total mortality in a population-based study with 13 years of follow-up. JO - Eur. Heart J. VL - 27 PY - 2006 SN - 0195-668X ER - TY - JOUR AU - Meisinger, C. AU - Döring, A. AU - Löwel, H. C1 - 862 C2 - 23699 SP - 1245-1250 TI - Chronic kidney disease and risk of incident myocardial infarction and all-cause and cardiovascular disease mortality in middle-aged men and women from the general population. JO - Eur. Heart J. VL - 27 PY - 2006 SN - 0195-668X ER - TY - JOUR AB - Aims C-reactive protein and depressive mood (DM) are novel risk factors for coronary heart disease (CHD). The goal of the present study was to assess possible combined effects of these factors on the prediction of a future fatal and non-fatal coronary event. Methods and results Baseline highly sensitive (hs) C-reactive protein and DM were analysed in 3021 apparently healthy male subjects aged 45–74 from three subsequent population based surveys (1984–95) of the MONICA–KORA Augsburg Cohort Study. During a median follow-up period of 7.7 years (IQR=6.9 years), 165 CHD events occurred. Risks of CHD were estimated from Cox proportional hazard models adjusted for age and survey and multiple risk factors. The age and survey adjusted interaction term of continuous hs-C-reactive protein by DM disclosed a significant effect (HR 1.03; 95% CI 1.00–1.06; P=0.037). A stratified analysis of subpopulations with (n=986) and without (n=2035) DM revealed that high hs-C-reactive protein (>3 mg/L) was predictive in the group with DM (HR 2.69; 95% CI 1.32–5.47) but was not significant in the low-level depression group (HR 1.55; 95% CI 0.89–2.69). Relative to the low C-reactive protein/no depression subgroup (n=712), high C-reactive protein/no depression (n=565) did not significantly predict a future CHD event. However, combined high C-reactive protein and DM (n=282) significantly predicted future CHD events (HR 2.91; 95% CI 1.25–2.18; P>0.0001). Conclusion In apparently healthy men, a DM substantially increases the power of elevated C-reactive protein to predict a subsequent myocardial infarction. Both conditions may share a common underlying mechanism.   AU - Ladwig, K.-H. AU - Marten-Mittag, B.* AU - Löwel, H. AU - Döring, A. AU - König, W.* C1 - 4417 C2 - 23336 SP - 2537-2542 TI - C-reactive protein, depressed mood, and the prediction of coronary heart disease in initially healthy men: Results from the MONICA-KORA Augsburg Cohort Study 1984-1998. JO - Eur. Heart J. VL - 26 PY - 2005 SN - 0195-668X ER - TY - JOUR AB - Aims To investigate the association between apolipoprotein B (apoB), A-I (apoA-I), the apoB/apoA-I ratio, and the incidence of coronary events. Methods and results Analysis included 1414 men and 1436 women aged 35–64 years without a prior coronary event who participated in the population-based MONICA Augsburg survey 1984–85 (median followed-up period 13 years). Incidence of fatal and non-fatal myocardial infarction, and sudden cardiac death was assessed using data of the MONICA/KORA Augsburg coronary event registry. During follow-up, 114 incident coronary events occurred in men and 31 in women. In multivariable analysis, an increase of 1 standard deviation in the serum concentration of apoB was associated with an increased risk of coronary events in men [hazard ratio (HR)=1.49; 95% confidence interval (CI); 1.25–1.78] and in women (HR=1.73; 95% CI; 1.32–2.27). By contrast, elevated concentrations of apoA-I were not associated with a significantly decreased risk of coronary events in either sex (HR=0.91). Furthermore, the predictive power of the apoB/apoA-I ratio was similar to that of the total cholesterol/HDL cholesterol ratio in men and women. Conclusion ApoB and the apoB/apoA-I ratio were strong predictors of coronary events in middle-aged men and women, whereas apoA-I did not add significantly to the estimation of future coronary risk.   AU - Meisinger, C. AU - Löwel, H. AU - Mraz, W.* AU - König, W.* C1 - 1742 C2 - 22622 SP - 271-278 TI - Prognostic value of apolipoprotein B and A-I in the prediction of myocardial infarction in middle-aged men and women: Results from the MONICA/KORA Augsburg cohort study. JO - Eur. Heart J. VL - 26 PY - 2005 SN - 0195-668X ER - TY - JOUR AB - Aims Classical risk factors do not fully explain international differences in risk of coronary heart disease (CHD). We therefore measured thrombotic and inflammatory markers in a substudy of the WHO MONICA project and correlated these with CHD event rates. Methods and results We measured levels of fibrinogen (clottable and nephelometric), von Willebrand factor (vWf), tissue plasminogen activator antigen, plasminogen activator inhibitor activity, fibrin D-dimer, plasma viscosity, C-reactive protein, and total cholesterol in 12 MONICA populations (listed at the end of this paper), all but one European. Men and women aged 45–64 years were studied from 10 countries. All samples were collected using a carefully standardized protocol, and analysed centrally. Results were available for 3996 subjects (nephelometric fibrinogen and viscosity), 2378 subjects (other thrombotic assays), and 1757 subjects (C-reactive protein and total cholesterol). Significant differences in levels of thrombotic and inflammatory factors exist in MONICA populations mainly from European countries. These differences persist after adjustment for age, smoking habit, and body mass index. Cross-sectional correlations between coronary event rates and these thrombotic/inflammatory markers were significant for vWF antigen in both sexes, nephelometric fibrinogen in men, and D-dimer in women. Conclusion In particular, vWF, nephelometric fibrinogen, and D-dimer should be examined in further research as potential risk factors which may help explain differences in coronary risk between European populations.   AU - Yarnell, J.* AU - McCrum, E.* AU - Rumley, A.* AU - Patterson, C.* AU - Salomaa, V.* AU - Lowe, G.* AU - Evans, A.* AU - Koenig, W.* AU - Hense, H.W.* AU - Döring, A. C1 - 2031 C2 - 22678 SP - 332-342 TI - Association of European population levels of thrombotic and inflammatory factors with risk of coronary heart disease: The MONICA optional haemostasis study. JO - Eur. Heart J. VL - 26 PY - 2005 SN - 0195-668X ER - TY - JOUR AB - Aim Anti-inflammatory effects of moderate alcohol consumption have been proposed to explain why moderate alcohol intake lowers coronary heart disease risk. We investigated the relationship between overall alcohol, beer or wine consumption and markers of systemic inflammation in three different geographical areas in Europe. Methods and results Cross-sectional samples, each representative of the general population from Germany, Scotland, and France (MONICA Augsburg 1994/95, 2275 men and 2186 women, 25–74 years; Glasgow MONICA 1994/95, 561/616, 25–74 years, and MONICA Lille 1994/95, 581/574, 35–64 years) were studied. Alcohol intake was assessed by standardized interview. Adjusted means of C-reactive protein (CRP), fibrinogen, white blood cell (WBC) count, plasma viscosity (PV), and albumin were calculated among categories of alcohol intake, and separately for beer or wine consumption, by multiple linear regression. Self-reported moderate daily alcohol intake up to 40 g was associated with lower concentrations of CRP, fibrinogen, PV and WBC count, compared to non-drinking and heavy drinking, even after adjustment for various potential confounders. Conclusions Moderate consumption of either wine or beer is associated with lower levels of systemic inflammatory markers in three different European areas, suggesting that ethanol itself might be largely responsible for the potential anti-inflammatory effects of these beverages.   AU - Imhof, A.* AU - Woodward, M.* AU - Döring, A. AU - Helbecque, N.* AU - Löwel, H. AU - Amouyel, P.* AU - Lowe, G.D.O.* AU - König, W.* C1 - 2666 C2 - 22466 SP - 2092-2100 TI - Overall alcohol intake, beer, wine, and systemic markers of inflammation in western Europe: Results from three MONICA samples (Augsburg, Glasgow, Lille). JO - Eur. Heart J. VL - 25 PY - 2004 SN - 0195-668X ER - TY - JOUR AB - AIMS: Aim of the study was to investigate the association between various markers of systemic inflammation and a detailed history of smoking in a large representative sample of the general population. METHODS AND RESULTS: The effects of chronic smoking on white blood cell (WBC) count, fibrinogen, albumin, plasma viscosity (PV), and high-sensitivity C-reactive protein (CRP) were measured in 2305 men and 2211 women, age 25-74 years, participating in the third MONICA Augsburg survey 1994/95. In men, current smokers showed statistically significantly higher values for WBC count, fibrinogen, PV, and CRP, compared to never smokers, with intermediate, but only slightly increased values for ex-smokers and for occasional smokers. No consistent associations were seen with albumin. Duration of smoking was positively associated with markers of inflammation as were pack-years of smoking. Conversely, duration of abstinence from smoking was inversely related to these markers. Except for WBC count, no such associations were found in women. CONCLUSION: Data from this large representative population show strong associations between smoking and various markers of systemic inflammation in men. They also show that cessation of smoking is associated with a decreased inflammatory response, which may represent one mechanism responsible for the reduced cardiovascular risk in these subjects. AU - Fröhlich, M.* AU - Sund, M. AU - Löwel, H. AU - Imhof, A.* AU - Hoffmeister, A.* AU - Koenig, W.* C1 - 24006 C2 - 31377 SP - 1365-1372 TI - Independent association of various smoking characteristics with markers of systemic inflammation in men. Results from a representative sample of the general population (MONICA Augsburg Survey 1994/95). JO - Eur. Heart J. VL - 24 IS - 14 PB - Oxford Univ. Press PY - 2003 SN - 0195-668X ER - TY - JOUR AB - Aims To examine the general influence of the definition of fatal and non-fatal acute myocardial infarction and coronary deaths on the estimation of in-hospital case- fatality, and to show how the definition of acute myocardial infarction influences time-trends of hospital mortality over 11 years. Methods and Results As part of the World Health Organization’s MONICA (multinational Monitoring of Trends and Determinants in Cardiovascular Disease) Project in Augsburg all patients aged 25–74 years with a suspected diagnosis of acute myocardial infarction who were hospitalized in the study region’s major clinic were registered prospectively between 1985 to 1995 (n = 4889). Patient information, including short-term survival status, was obtained from medical records, by interview of surviv- ing patients, and municipal death certificate files which were validated by an extended identification and validation pro- cess. In-hospital case fatality was estimated according to di ff erent definitions which closely followed the international MONICA criteria. Epidemiological definitions comprised definite and possible acute myocardial infarction, and events with unclassifiable deaths, while the clinical defi- nition was restricted to definite infarction. Overall, case fatality by the epidemiological definitions was 28 to 29·8% (23·5% of those treated in a coronary care unit) compared to 13·5% using the clinical definition. While over the 11 years, the reduction in case fatality according to the epi- demiological definitions was modest, highly significant decreases were observed by applying the clinical definition (from 15·8% in 1985–1988 to 10·8% in 1993–1995, P <0·001 adjusted for age and sex). The discrepancy in case fatality between the definitions is explained by the high proportion of patients who die very early (about 70% of all fatal events during the first 24 h) with the consequence of missing data which may preclude a definite diagnosis of acute myocardial infarction. Conclusions Applying a broader definition of acute myo- cardial infarction reveals that in-hospital mortality is higher than believed until now, and it implies that our e ff orts must be intensified to reduce overall in-hospital coronary heart disease mortality. AU - Kuch, B.* AU - Bolte, H.-D.* AU - Hoermann, A. AU - Meisinger, C. AU - Löwel, H. C1 - 22056 C2 - 20683 SP - 714-720 TI - What is the real hospital mortality from acute myocardial infarction ? : Epidemiological vs clinical view. JO - Eur. Heart J. VL - 23 IS - 9 PY - 2002 SN - 0195-668X ER - TY - JOUR AB - Background Differences between socioeconomic groups in mortality from and risk factors for cardiovascular diseases have been reported in many countries. We have made a comparative analysis of these inequalities in the United States and 11 western European countries. The aims of the analysis were (1) to compare the size of inequalities in cardiovascular disease mortality between countries, and (2) to explore the possible contribution of cardiovascular risk factors to the explanation of between-country differences in inequalities in cardiovascular disease mortality. Data and Methods Data on ischaemic heart disease, cerebrovascular disease and total cardiovascular disease mortality by occupational class and/or educational level were obtained from national longitudinal or unlinked cross-sectional studies. Data on smoking, alcohol consumption, overweight and infrequent consumption of fresh vegetables by occupational class and/or educational level were obtained from national health interview or multipurpose surveys and from the European Union's Eurobarometer survey. Age-adjusted rate ratios for mortality were correlated with age-adjusted odds ratios for the behavioural risk factors. Results In all countries mortality from cardiovascular diseases is higher among persons with lower occupational class or lower educational level. Within western Europe, a north–south gradient is apparent, with relative and absolute inequalities being larger in the north than in the south. For ischaemic heart disease, but not for cerebrovascular disease, an even more striking north–south gradient is seen, with some ‘reverse’ inequalities in southern Europe. The United States occupy intermediate positions on most indicators. Inequalities in cardiovascular disease mortality are associated with inequalities in some risk factors, especially cigarette smoking and excessive alcohol consumption. Conclusions Socioeconomic inequalities in cardiovascular disease mortality are a major public health problem in most industrialized countries. Closing the gap between low and high socioeconomic groups offers great potential for reducing cardiovascular disease mortality. Developing effective methods of behavioural risk factor reduction in the lower socioeconomic groups should be a top priority in cardiovascular disease prevention.   AU - Mackenbach, J.P.* AU - Cavelaars, A.E.J.M.* AU - Kunst, A.E.* AU - Groenhof, F. C1 - 21488 C2 - 19609 SP - 1141-1151 TI - Socioeconomic inequalities in cardiovascular disease mortality: An international study. JO - Eur. Heart J. VL - 21 IS - 14 PY - 2000 SN - 0195-668X ER - TY - JOUR AU - Willems, J.L. AU - Abreu-Lima, C. AU - Arnaud, P. AU - van Bemmel, J.H. AU - Brohet, C. AU - Degani, R. AU - Denis, B. AU - Graham, I. AU - van Herpen, G. AU - Macfarlane, P.W. AU - Michaelis, J. AU - Moulopoulos, S. AU - Pöppl, S.J. AU - Zywietz, C. C1 - 17928 C2 - 11360 SP - 1348-1355 TI - Effect of combining electrocardiographic interpretation results on diagnostic accuracy. JO - Eur. Heart J. VL - 9 PY - 1988 SN - 0195-668X ER -