TY  - JOUR
AB  - Cardiovascular disease (CVD) is the leading cause of mortality globally, with over 20 million deaths each year. While traditional risk factors-such as hypertension, diabetes, smoking, and poor diet-are well-established, emerging evidence underscores the profound impact of environmental exposures on cardiovascular health. Air pollution, particularly fine particulate matter (PM2.5), contributes to approximately 8.3 million deaths annually, with over half attributed to CVD. Similarly, noise pollution, heat extremes, toxic chemicals, and light pollution significantly increase the risk of CVD through mechanisms involving oxidative stress, inflammation, and circadian disruption. Recent translational and epidemiological studies show that chronic exposure to transport noise increases the risk of myocardial infarction, stroke, and heart failure. Air pollution, even below regulatory thresholds, promotes atherosclerosis, vascular dysfunction, and cardiac events. Novel threats such as micro- and nano-plastics are emerging as contributors to vascular injury and systemic inflammation. Climate change exacerbates these risks, with heatwaves and wildfires further compounding the cardiovascular burden, especially among vulnerable populations. The cumulative effects of these exposures-often interacting with behavioural and socioeconomic risk factors-are inadequately addressed in current prevention strategies. The exposome framework offers a comprehensive approach to integrating lifelong environmental exposures into cardiovascular risk assessment and prevention. Mitigation requires systemic interventions including stricter pollution standards, noise regulations, sustainable urban design, and green infrastructure. Addressing environmental determinants of CVD is essential for reducing the global disease burden. This review calls for urgent policy action and for integrating environmental health into clinical practice to safeguard cardiovascular health in the Anthropocene.
AU  - Münzel, T.*
AU  - Sørensen, M.*
AU  - Lelieveld, J.*
AU  - Landrigan, P.J.*
AU  - Kuntic, M.*
AU  - Nieuwenhuijsen, M.*
AU  - Miller, M.R.*
AU  - Schneider, A.E.
AU  - Daiber, A.*
C1  - 75344
C2  - 57940
CY  - Great Clarendon St, Oxford Ox2 6dp, England
TI  - A comprehensive review/expert statement on environmental risk factors of cardiovascular disease.
JO  - Cardiovasc. Res.
VL  - 121
IS  - 11
PB  - Oxford Univ Press
PY  - 2025
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - AIMS: The Cardiac Conduction System (CCS) is progressively specified during development by interactions among a discrete number of Transcriptions Factors that ensure its proper patterning and the emergence of its functional properties. Meis genes encode homeodomain transcription factors (TFs) with multiple roles in mammalian development. In humans, Meis genes associate with congenital cardiac malformations and alterations of cardiac electrical activity, however the basis for these alterations has not been established. Here we studied the role of Meis transcription factors in cardiomyocyte development and function during mouse development and adult life. METHODS AND RESULTS: We studied Meis1 and Meis2 conditional deletion mouse models that allowed cardiomyocyte-specific elimination of Meis function during development and inducible elimination of Meis function in cardiomyocytes of the adult CCS. We studied cardiac anatomy, contractility and conduction. We report that Meis factors are global regulators of cardiac conduction, with a predominant role in the CCS. While constitutive Meis deletion in cardiomyocytes led to congenital malformations of the arterial pole and atria, as well as defects in ventricular conduction, Meis elimination in cardiomyocytes of the adult CCS produced sinus node dysfunction and delayed atrio-ventricular conduction. Molecular analyses unraveled Meis-controlled molecular pathways associated with these defects. Finally, we studied in transgenic mice the activity of a Meis1 human enhancer related to an SNP associated by GWAS to PR elongation and found that the transgene drives expression in components of the atrio-ventricular conduction system. CONCLUSIONS: Our study identifies Meis TFs as essential regulators of the establishment of cardiac conduction function during development and its maintenance during adult life. In addition, we generated animal models and identified molecular alterations that will ease the study of Meis-associated conduction defects and congenital malformations in humans.
AU  - Muñoz-Martín, N.*
AU  - Simon-Chica, A.*
AU  - Díaz-Díaz, C.*
AU  - Cadenas, V.*
AU  - Temiño, S.*
AU  - Esteban, I.*
AU  - Ludwig, A.*
AU  - Schormair, B.
AU  - Winkelmann, J.
AU  - Olejnickova, V.*
AU  - Sedmera, D.*
AU  - Filgueiras-Rama, D.*
AU  - Torres, M.*
C1  - 72848
C2  - 56748
CY  - Great Clarendon St, Oxford Ox2 6dp, England
SP  - 311-323
TI  - Meis transcription factors regulate cardiac conduction system development and adult function.
JO  - Cardiovasc. Res.
VL  - 121
IS  - 2
PB  - Oxford Univ Press
PY  - 2024
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - AIMS: Cyclophilin A (CyPA) induces leukocyte recruitment and platelet activation upon release into the extracellular space. Extracellular CyPA therefore plays a critical role in immuno-inflammatory responses in tissue injury and thrombosis upon platelet activation. To date, CD147 (EMMPRIN) has been described as the primary receptor mediating extracellular effects of CyPA in platelets and leukocytes. The receptor for advanced glycation end products (RAGE) shares inflammatory and prothrombotic properties and has also been found to have similar ligands as CD147.In this study, we investigated the role of RAGE as a previously unknown interaction partner for CyPA. METHODS AND RESULTS: Confocal imaging, proximity ligation, co-immunoprecipitation, and atomic force microscopy were performed and demonstrated an interaction of CyPA with RAGE on the cell surface. Static and dynamic cell adhesion and chemotaxis assays towards extracellular CyPA using human leukocytes and leukocytes from RAGE-deficient Ager-/- mice were conducted. Inhibition of RAGE abrogated CyPA-induced effects on leukocyte adhesion and chemotaxis in vitro. Accordingly, Ager-/- mice showed reduced leukocyte recruitment and endothelial adhesion towards CyPA in vivo. In wildtype mice, we observed a downregulation of RAGE on leukocytes when endogenous extracellular CyPA was reduced. We furthermore evaluated the role of RAGE for platelet activation and thrombus formation upon CyPA stimulation. CyPA-induced activation of platelets was found to be dependent on RAGE, as inhibition of RAGE, as well as platelets from Ager-/- mice showed a diminished activation and thrombus formation upon CyPA stimulation. CyPA-induced signaling through RAGE was found to involve central signaling pathways including the adaptor protein MyD88, intracellular Ca2+ signaling, as well as NF-κB activation. CONCLUSION: We propose RAGE as a hitherto unknown receptor for CyPA mediating leukocyte as well as platelet activation. The CyPA-RAGE interaction thus represents a novel mechanism in thrombo-inflammation.
AU  - Seizer, P.*
AU  - von Ungern-Sternberg, S.N.I.*
AU  - Haug, V.*
AU  - Dicenta, V.*
AU  - Rosa, A.*
AU  - Butt, E.*
AU  - Nöthel, M.*
AU  - Rohlfing, A.K.*
AU  - Sigle, M.*
AU  - Nawroth, P.P.
AU  - Nussbaum, C.*
AU  - Sperandio, M.*
AU  - Kusch, C.*
AU  - Meub, M.*
AU  - Sauer, M.*
AU  - Münzer, P.*
AU  - Bieber, K.*
AU  - Stanger, A.*
AU  - Mack, A.F.*
AU  - Huber, R.*
AU  - Brand, K.*
AU  - Lehners, M.*
AU  - Feil, R.*
AU  - Poso, A.*
AU  - Krutzke, K.*
AU  - Schäffer, T.E.*
AU  - Nieswandt, B.*
AU  - Borst, O.*
AU  - May, A.E.*
AU  - Zernecke, A.*
AU  - Gawaz, M.*
AU  - Heinz Mann, D.*
C1  - 68999
C2  - 55180
SP  - 385-402
TI  - Cyclophilin A is a ligand for RAGE in thrombo-inflammation.
JO  - Cardiovasc. Res.
VL  - 120
IS  - 4
PY  - 2024
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - AIMS: Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cell-specific effects in this disease are not well understood. To address this, we generated a transgenic mouse model to study the role of myeloid CB1 signaling in atherosclerosis. METHODS AND RESULTS: Here, we report that male mice with myeloid-specific Cnr1 deficiency on atherogenic background developed smaller lesions and necrotic cores than controls, while only minor genotype differences were observed in females. Male Cnr1 deficient mice showed reduced arterial monocyte recruitment and macrophage proliferation with less inflammatory phenotype. The sex-specific differences in proliferation were dependent on estrogen receptor (ER)α-estradiol signaling. Kinase activity profiling identified a CB1-dependent regulation of p53 and cyclin-dependent kinases. Transcriptomic profiling further revealed chromatin modifications, mRNA processing and mitochondrial respiration among the key processes affected by CB1 signaling, which was supported by metabolic flux assays. Chronic administration of the peripherally-restricted CB1 antagonist JD5037 inhibited plaque progression and macrophage proliferation, but only in male mice. Finally, CNR1 expression was detectable in human carotid endarterectomy plaques and inversely correlated with proliferation, oxidative metabolism and inflammatory markers, suggesting a possible implication of CB1-dependent regulation in human pathophysiology. CONCLUSION: Impaired macrophage CB1 signaling is atheroprotective by limiting their arterial recruitment, proliferation and inflammatory reprogramming in male mice. The importance of macrophage CB1 signaling appears to be sex-dependent.
AU  - Wang, Y.*
AU  - Li, G.*
AU  - Chen, B.*
AU  - Shakir, G.*
AU  - Volz, M.*
AU  - van der Vorst, E.P.C.*
AU  - Maas, S.L.*
AU  - Geiger, M.*
AU  - Jethwa, C.*
AU  - Bartelt, A.
AU  - Li, Z.*
AU  - Wettich, J.*
AU  - Sachs, N.*
AU  - Maegdefessel, L.*
AU  - Nazari Jahantigh, M.*
AU  - Hristov, M.*
AU  - Lacy, M.*
AU  - Lutz, B.*
AU  - Weber, C.*
AU  - Herzig, S.
AU  - Guillamat Prats, R.*
AU  - Steffens, S.*
C1  - 70796
C2  - 55748
CY  - Great Clarendon St, Oxford Ox2 6dp, England
SP  - 1411-1426
TI  - Myeloid cannabinoid CB1 receptor deletion confers atheroprotection in male mice by reducing macrophage proliferation in a sex-dependent manner.
JO  - Cardiovasc. Res.
VL  - 120
IS  - 12
PB  - Oxford Univ Press
PY  - 2024
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - AIMS: Myocardial infarction (MI) is a major cause of death and disability worldwide. Most metabolomics studies investigating metabolites predicting MI are limited by the participant number and/or the demographic diversity. We sought to identify biomarkers of incident MI in the Consortium of Metabolomics Studies (COMETS). METHODS AND RESULTS: We included 7,897 individuals aged on average 66 years from six intercontinental cohorts with blood metabolomic profiling (n = 1,428 metabolites, of which 168 were present in at least 3 cohorts with over 80% prevalence) and MI information (1,373 cases). We performed a two-stage Individual Patients Data meta-analysis. We first assessed the associations between circulating metabolites and incident MI for each cohort adjusting for traditional risk factors, and then performed a fixed effect inverse-variance meta-analysis to pull the results together. Finally, we conducted a pathway enrichment analysis to identify potential pathways linked to MI.On meta-analysis, 56 metabolites including 21 lipids and 17 amino acids were associated with incident MI after adjusting for multiple testing (false discovery rate, FDR < 0.05), and 10 were novel. The largest increased risk was observed for the carbohydrate mannitol/sorbitol (HR [95% CI] = 1.40[1.26-1.56], p-value < 0.001), whereas the largest decrease in risk was found for glutamine (HR [95% CI] = 0.74[0.67-0.82], p-value < 0.001). Moreover, the identified metabolites were significantly enriched (corrected p-value < 0.05) in pathways previously linked with cardiovascular diseases, including aminoacyl-tRNA biosynthesis. CONCLUSIONS: In the most comprehensive metabolomics study of incident MI to date, 10 novel metabolites were associated with MI. Metabolite profiles might help to identify high-risk individuals before disease onset. Further research is needed to fully understand the mechanisms of action and elaborate pathway findings. TRANSLATIONAL PERSPECTIVE: In the largest meta-analyses covering six international cohorts, we identify 10 novel and 46 known metabolites associated with incident MI, that can be used to identify at-risk individuals before disease onset. Our results improve our understanding of the molecular changes that take place in MI development and provide potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.
AU  - Nogal, A.*
AU  - Alkis, T.*
AU  - Lee, Y.*
AU  - Kifer, D.*
AU  - Hu, J.*
AU  - Murphy, R.A.*
AU  - Huang, Z.*
AU  - Wang-Sattler, R.
AU  - Kastenmüller, G.
AU  - Linkohr, B.
AU  - Barrios, C.*
AU  - Crespo, M.*
AU  - Gieger, C.
AU  - Peters, A.
AU  - Price, J.*
AU  - Rexrode, K.M.*
AU  - Yu, B.*
AU  - Menni, C.*
C1  - 68624
C2  - 54800
CY  - Great Clarendon St, Oxford Ox2 6dp, England
SP  - 2743-2754
TI  - Predictive metabolites for incident myocardial infarction: A two-step meta-analysis of individual patient data from six cohorts comprising 7,897 individuals from the the COnsortium of METabolomic Studies.
JO  - Cardiovasc. Res.
VL  - 119
IS  - 17
PB  - Oxford Univ Press
PY  - 2023
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - AIMS: Atherosclerosis is a chronic inflammatory disease of the arteries leading to the formation of atheromatous plaques. Human mesenchymal stem cells (hMSCs) are recruited from the circulation into plaques where in response to their environment they adopt a phenotype with immunomodulatory properties. However, the mechanisms underlying hMSC function in these processes are unclear. Recently, we described that miRNA let-7f controls hMSC invasion guided by inflammatory cytokines and chemokines. Here, we investigated the role of let-7f in hMSC tropism to human atheromas and the effects of the plaque microenvironment on cell fate and release of soluble factors. METHODS AND RESULTS: Incubation of hMSCs with LL-37, an antimicrobial peptide abundantly found in plaques, increased biosynthesis of let-7f and N-formyl peptide receptor 2 (FPR2), enabling chemotactic invasion of the cells towards LL-37, as determined by qRT-PCR, flow cytometry, and cell invasion assay analysis. In an Apoe  -/- mouse model of atherosclerosis, circulating hMSCs preferentially adhered to athero-prone endothelium. This property was facilitated by elevated levels of let-7f in the hMSCs, as assayed by ex vivo artery perfusion and 2-photon laser scanning microscopy. Exposure of hMSCs to homogenized human atheromatous plaque material considerably induced the production of various cytokines, chemokines, matrix metalloproteinases, and tissue inhibitors of metalloproteinases, as studied by PCR array and Western blot analysis. Moreover, exposure to human plaque extracts elicited differentiation of hMSCs into cells of the myogenic lineage, suggesting a potentially plaque-stabilizing effect. CONCLUSIONS: Our findings indicate that let-7f promotes hMSC tropism toward atheromas through the LL-37/FPR2 axis and demonstrate that hMSCs upon contact with human plaque environment develop a potentially athero-protective signature impacting the pathophysiology of atherosclerosis. TRANSLATIONAL PERSPECTIVE: Human mesenchymal stem cells (hMSCs) represent a promising therapeutic approach in various pathophysiological processes associated with inflammation including atherosclerosis. The current knowledge about the mechanisms of hMSC tropism towards human atherosclerotic plaques and their beneficial effects at the site is poor. Bridging this gap is essential for clinical application of hMSCs. Our work provides insight into the contribution of microRNA let-7f in hMSC recruitment to atheroprone areas, where hMSCs display athero-protective potential by releasing immunomodulatory factors and differentiating towards plaque-stabilizing cells. Our findings highlight circulating hMSCs as a possible therapeutic strategy for the stabilization of atherosclerotic plaques.
AU  - Egea, V.*
AU  - Megens, R.T.A.*
AU  - Santovito, D.*
AU  - Wantha, S.*
AU  - Brandl, R.*
AU  - Siess, W.*
AU  - Khani, S.*
AU  - Soehnlein, O.*
AU  - Bartelt, A.
AU  - Weber, C.*
AU  - Ries, C.*
C1  - 64524
C2  - 51922
CY  - Great Clarendon St, Oxford Ox2 6dp, England
TI  - Properties and fate of human mesenchymal stem cells upon miRNA let-7f-promoted recruitment to atherosclerotic plaques.
JO  - Cardiovasc. Res.
PB  - Oxford Univ Press
PY  - 2022
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - AIMS: Neutrophil trafficking within the vasculature strongly relies on intracellular calcium signaling. Sustained Ca2+ influx into the cell requires a compensatory efflux of potassium to maintain membrane potential. Here, we aimed to investigate whether the voltage-gated potassium channel KV1.3 regulates neutrophil function during the acute inflammatory process by affecting sustained Ca2+ signaling. METHODS AND RESULTS: Using in vitro assays and electrophysiological techniques, we show that KV1.3 is functionally expressed in human neutrophils regulating sustained store operated Ca2+ entry (SOCE) through membrane potential stabilizing K+ efflux. Inhibition of KV1.3 on neutrophils by the specific inhibitor 5-(4-Phenoxybutoxy)psoralen (PAP-1) impaired intracellular Ca2+ signaling, thereby preventing cellular spreading, adhesion strengthening and appropriate crawling under flow conditions in vitro. Using intravital microscopy, we show that pharmacological blockade or genetic deletion of KV1.3 in mice decreased neutrophil adhesion in a blood flow dependent fashion in inflamed cremaster muscle venules. Furthermore, we identified KV1.3 as a critical component for neutrophil extravasation into the inflamed peritoneal cavity. Finally, we also revealed impaired phagocytosis of E.coli particles by neutrophils in the absence of KV1.3. CONCLUSION: We show that the voltage gated potassium channel KV1.3 is critical for Ca2+ signaling and neutrophil trafficking during acute inflammatory processes. Our findings do not only provide evidence for a role of KV1.3 for sustained calcium signaling in neutrophils affecting key functions of these cells, they also open up new therapeutic approaches to treat inflammatory disorders characterized by overwhelming neutrophil infiltration. TRANSLATIONAL PERSPECTIVE: Neutrophils exert important immune functions during tissue injury or bacterial infection through leaving the vasculature and extravasate into affected tissues. Conversely, neutrophils trigger the pathogenesis of acute and chronic inflammatory disorders and are involved in the development and maintenance of various autoimmune diseases. Within this study, we show that the voltage-gated potassium channel KV1.3 is functionally expressed on neutrophils and affects calcium signaling thereby regulating neutrophil effector functions during immune responses. Hence, KV1.3 represents an interesting potential new target to treat unwanted excessive neutrophil invasion in various disorders ranging from autoinflammatory disorders to ischemic tissue injury.
AU  - Immler, R.*
AU  - Nadolni, W.*
AU  - Bertsch, A.*
AU  - Morikis, V.*
AU  - Rohwedder, I.*
AU  - Masgrau-Alsina, S.*
AU  - Schroll, T.*
AU  - Yevtushenko, A.*
AU  - Soehnlein, O.*
AU  - Moser, M.*
AU  - Gudermann, T.*
AU  - Barnea, E.R.*
AU  - Rehberg, M.
AU  - Simon, S.I.*
AU  - Zierler, S.*
AU  - Pruenster, M.*
AU  - Sperandio, M.*
C1  - 61889
C2  - 50505
CY  - Great Clarendon St, Oxford Ox2 6dp, England
SP  - 1289–1302
TI  - The voltage-gated potassium channel KV1.3 regulates neutrophil recruitment during inflammation.
JO  - Cardiovasc. Res.
VL  - 118
IS  - 5
PB  - Oxford Univ Press
PY  - 2022
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - AIMS: Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic-effects might be responsible for part of the unaccounted genetic variance. Here we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD. METHODS AND RESULTS: We tested for epistatic interactions in ten CAD case-control studies and UK Biobank with focus on 8,068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 and rs9458001, to be jointly associated with risk for CAD (odds ratio [OR]=1.37, p = 1.07 × 10-11), peripheral arterial disease (OR = 1.22, p = 2.32 × 10-4), aortic stenosis (OR = 1.47, p = 6.95 × 10-7), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, p = 1.41 × 10-8), and Lp(a) serum levels (beta = 0.58, p = 8.7 × 10-32), while individual SNPs displayed no association. Further exploration of the LPA locus revealed a strong dependency of these associations on a rare variant, rs140570886, that was previously associated with Lp(a) levels. We confirmed increased CAD risk for heterozygous (relative OR = 1.46, p = 9.97 × 10-32) and individuals homozygous for the minor allele (relative OR = 1.77, p = 0.09) of rs140570886. Using forward model selection, we also show that epistatic interactions between rs140570886, rs9458001, and rs1800769 modulate the effects of the rs140570886 risk allele. CONCLUSIONS: These results demonstrate the feasibility of a large-scale knowledge-based epistasis scan and provide rare evidence of an epistatic interaction in a complex human disease. We were directed to a variant (rs140570886) influencing risk through additive genetic as well as epistatic effects. In summary, this study provides deeper insights into the genetic architecture of a locus important for cardiovascular diseases. TRANSLATIONAL PERSPECTIVE: Genetic variants identified by GWAS studies explain about a quarter of the heritability of coronary artery disease by additive genetic effects. Our study demonstrates that non-additive effects contribute to the genetic architecture of the disease as well and identifies complex interaction patterns at the LPA locus, which affect LPA expression, Lp(a) plasma levels and risk of atherosclerosis. This proof-of-concept study encourages systematic searches for epistatic interactions in further studies to shed new light on the aetiology of the disease.
AU  - Zeng, L.*
AU  - Moser, S.*
AU  - Mirza-Schreiber, N.
AU  - Lamina, C.*
AU  - Coassin, S.*
AU  - Nelson, C.P.*
AU  - Annilo, T.*
AU  - Franzén, O.*
AU  - Kleber, M.E.*
AU  - Mack, S.*
AU  - Andlauer, T.F.M.*
AU  - Jiang, B.*
AU  - Stiller, B.*
AU  - Li, L.*
AU  - Willenborg, C.*
AU  - Munz, M.*
AU  - Kessler, T.*
AU  - Kastrati, A.*
AU  - Laugwitz, K.L.*
AU  - Erdmann, J.*
AU  - Moebus, S.*
AU  - Nöthen, M.M.*
AU  - Peters, A.
AU  - Strauch, K.
AU  - Müller-Nurasyid, M.
AU  - Gieger, C.
AU  - Meitinger, T.
AU  - Steinhagen-Thiessen, E.*
AU  - März, W.*
AU  - Metspalu, A.*
AU  - Björkegren, J.L.M.*
AU  - Samani, N.J.*
AU  - Kronenberg, F.*
AU  - Müller-Myhsok, B.*
AU  - Schunkert, H.*
C1  - 61826
C2  - 50306
SP  - 1088–1102
TI  - Cis-epistasis at the LPA locus and risk of cardiovascular diseases.
JO  - Cardiovasc. Res.
VL  - 118
IS  - 4
PY  - 2022
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - AIM: Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach. METHODS AND RESULTS: We employed a phenotype-driven N-ethyl-N-nitrosourea (ENU) mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6-9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4-5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs - leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to ECG indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs) and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation. CONCLUSIONS: Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome and heart failure. TRANSLATIONAL PERSPECTIVES: Development of efficient anti-arrhythmic strategies is hampered by incomplete knowledge of disease mechanisms. Using an unbiased approach, we here identified for the first time a pro-arrhythmic effect of increased levels of branched chain amino acids (BCAAs). This is of particular relevance for conditions associated with BCAA dysregulation and increased arrhythmia risk, including heart failure, obesity and diabetes, as well as for athletes supplementing their diet with BCAAs. Such metabolic dysregulation is potentially modifiable through dietary interventions, paving the way for novel preventive strategies. Our findings furthermore identify mTOR inhibition as a potential anti-arrhythmic strategy in patients with metabolic syndrome.
AU  - Portero, V.*
AU  - Nicol, T.*
AU  - Podliesna, S.*
AU  - Marchal, G.A.*
AU  - Baartscheer, A.*
AU  - Casini, S.*
AU  - Tadros, R.*
AU  - Treur, J.L.*
AU  - Tanck, M.W.T.*
AU  - Cox, I.J.*
AU  - Probert, F.*
AU  - Hough, T.A.*
AU  - Falcone, S.*
AU  - Beekman, L.*
AU  - Müller-Nurasyid, M.
AU  - Kastenmüller, G.
AU  - Gieger, C.
AU  - Peters, A.
AU  - Kääb, S.*
AU  - Sinner, M.F.*
AU  - Blease, A.*
AU  - Verkerk, A.O.*
AU  - Bezzina, C.R.*
AU  - Potter, P.K.*
AU  - Remme, C.A.*
C1  - 62325
C2  - 50784
CY  - Great Clarendon St, Oxford Ox2 6dp, England
TI  - Chronically elevated branched chain amino acid levels are pro-arrhythmic.
JO  - Cardiovasc. Res.
VL  - 118
IS  - 7
PB  - Oxford Univ Press
PY  - 2021
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - Aims: In patients with pulmonary hypertension, right ventricular hypertrophy (RVH) is a detrimental condition that ultimately results in right heart failure and death. The ubiquitin proteasome system has been identified as a major protein degradation system to regulate cardiac remodelling in the left heart. Its role in right heart hypertrophy, however, is still ambiguous.Methods and results: RVH was induced in mice by pulmonary artery banding (PAB). Both, expression and activity of the proteasome was found to be up-regulated in the hypertrophied right ventricle (RV) compared to healthy controls. Catalytic inhibition of the proteasome by the two proteasome inhibitors Bortezomib (BTZ) and ONX-0912 partially improved RVH both in preventive and therapeutic applications. Native gel analysis revealed that specifically the 26S proteasome complexes were activated in experimental RVH. Increased assembly of 26S proteasomes was accompanied by elevated expression of Rpn6, a rate-limiting subunit of 26S proteasome assembly, in hypertrophied cardiomyocytes of the right heart. Intriguingly, patients with RVH also showed increased expression of Rpn6 in hypertrophied cardiomyocytes of the RV as identified by immunohistochemical staining.Conclusion: Our data demonstrate that alterations in expression and activity of proteasomal subunits play a critical role in the development of RVH. Moreover, this study provides an improved understanding on the selective activation of the 26S proteasome in RVH that might be driven by the rate-limiting subunit Rpn6. In RVH, Rpn6 therefore represents a more specific target to interfere with proteasome function than the commonly used catalytic proteasome inhibitors.
AU  - Heitmeier, T.*
AU  - Sydykov, A.*
AU  - Lukas, C.
AU  - Vroom, C.*
AU  - Korfei, M.*
AU  - Petrovic, A.*
AU  - Klingel, K.*
AU  - Günther, A.*
AU  - Eickelberg, O.
AU  - Weissmann, N.*
AU  - Ghofrani, H.A.*
AU  - Seeger, W.*
AU  - Grimminger, F.*
AU  - Schermuly, R.T.*
AU  - Meiners, S.
AU  - Kosanovic, D.*
C1  - 55943
C2  - 46717
CY  - Great Clarendon St, Oxford Ox2 6dp, England
SP  - 406-415
TI  - Altered proteasome function in right ventricular hypertrophy.
JO  - Cardiovasc. Res.
VL  - 116
IS  - 2
PB  - Oxford Univ Press
PY  - 2020
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - Aims The coxsackievirus B3 (CVB3) mouse myocarditis model is the standard model for investigation of virus-induced myocarditis but the pancreas, rather than the heart, is the most susceptible organ in mouse. The aim of this study was to develop a CVB3 mouse myocarditis model in which animals develop myocarditis while attenuating viral infection of the pancreas and the development of severe pancreatitis.Methods and results We developed the recombinant CVB3 variant H3N-375TS by inserting target sites (TS) of miR-375, which is specifically expressed in the pancreas, into the 30UTR of the genome of the pancreo- and cardiotropic CVB3 variant H3. In vitro evaluation showed that H3N-375TS was suppressed in pancreatic miR-375-expressing EndoC-beta H1 cells >5 log10, whereas its replication was not suppressed in isolated primary embryonic mouse cardiomyocytes. In vivo, intraperitoneal (i.p.) administration of H3N-375TS to NMRI mice did not result in pancreatic or cardiac infection. In contrast, intravenous (i.v.) administration of H3N-375TS to NMRI and Balb/C mice resulted in myocardial infection and acute and chronic myocarditis, whereas the virus was not detected in the pancreas and the pancreatic tissue was not damaged. Acute myocarditis was characterized by myocardial injury, inflammation with mononuclear cells, induction of proinflammatory cytokines, and detection of replicating H3N-375TS in the heart. Mice with chronic myocarditis showed myocardial fibrosis and persistence of H3N-375TS genomic RNA but no replicating virus in the heart. Moreover, H3N-375TS infected mice showed distinctly less suffering compared with mice that developed pancreatitis and myocarditis after i.p. or i.v application of control virus.Conclusion In this study, we demonstrate that by use of the miR-375-sensitive CVB3 variant H3N-375TS, CVB3 myocarditis can be established without the animals developing severe systemic infection and pancreatitis. As the H3N-375TS myocarditis model depends on pancreas-attenuated H3N-375TS, it can easily be used in different mouse strains and for various applications.
AU  - Pinkert, S.*
AU  - Pryshliak, M.*
AU  - Pappritz, K.*
AU  - Knoch, K.-P.
AU  - Hazini, A.*
AU  - Dieringer, B.*
AU  - Schaar, K.*
AU  - Dong, F.*
AU  - Hinze, L.*
AU  - Lin, J.*
AU  - Lassner, D.*
AU  - Klopfleisch, R.*
AU  - Solimena, M.
AU  - Tschöpe, C.*
AU  - Kaya, Z.*
AU  - Beling, A.*
AU  - Kurreck, J.*
AU  - van Linthout, S.*
AU  - Klingel, K.*
AU  - Fechner, H.*
C1  - 57883
C2  - 47972
CY  - Great Clarendon St, Oxford Ox2 6dp, England
SP  - 1756-1766
TI  - Development of a new mouse model for coxsackievirus-inducedmyocarditis by attenuating coxsackievirus B3 virulence in the pancreas.
JO  - Cardiovasc. Res.
VL  - 116
IS  - 10
PB  - Oxford Univ Press
PY  - 2020
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - Inflammation is an important driver of atherosclerosis, and the favourable outcomes of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial revealed the large potential of anti-inflammatory drugs for treatment of cardiovascular disease, especially in patients with a pro-inflammatory constitution. However, the complex immune reactions driving inflammation in the vascular wall in response to an atherosclerotic microenvironment are still being unravelled. Novel insights into the cellular processes driving immunity and inflammation revealed that alterations in intracellular metabolic pathways are strong drivers of survival, growth and function of immune cells. This position paper therefore presents a brief overview of the recent developments in the immunometabolism field, focusing on its role in atherosclerosis. We will also highlight the potential impact of immunometabolic markers and targets in clinical cardiovascular medicine.
AU  - Ketelhuth, D.F.J.*
AU  - Lutgens, E.*
AU  - Bäck, M.*
AU  - Binder, C.J.*
AU  - Van den Bossche, J.*
AU  - Daniel, C.*
AU  - Dumitriu, I.E.*
AU  - Hoefer, I.*
AU  - Libby, P.*
AU  - O'Neill, L.*
AU  - Weber, C.*
AU  - Evans, P.*
C1  - 56386
C2  - 47044
SP  - 1385-1392
TI  - Immunometabolism and atherosclerosis: perspectives and clinical significance- A position paper from the working group on atherosclerosis and vascular biology of the European Society of Cardiology.
JO  - Cardiovasc. Res.
VL  - 115
IS  - 9
PY  - 2019
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - Women and men, female and male animals and cells are biologically different, and acknowledgement of this fact is critical to advancing medicine. However, incorporating concepts of sex-specific analysis in basic research is largely neglected, introducing bias into translational findings, clinical concepts and drug development. Research funding agencies recently approached these issues but implementation of policy changes in the scientific community is still limited, probably due to deficits in concepts, knowledge and proper methodology.This expert review is based on the EUGenMed project (www.eugenmed.eu) developing a roadmap for implementing sex and gender in biomedical and health research. For sake of clarity and conciseness, examples are mainly taken from the cardiovascular field that may serve as a paradigm for others, since a significant amount of knowledge how sex and estrogen determine the manifestation of many cardiovascular diseases (CVD) has been accumulated. As main concepts for implementation of sex in basic research, the study of primary cell and animals of both sexes, the study of the influence of genetic versus hormonal factors and the analysis of sex chromosomes and sex specific statistics in genome wide association studies (GWAS) are discussed. The review also discusses methodological issues, and analyses strength, weaknesses, opportunities and threats in implementing sex-sensitive aspects into basic research.
AU  - Ventura-Clapier, R.*
AU  - Dworatzek, E.*
AU  - Seeland, U.*
AU  - Kararigas, G.*
AU  - Francois Arnal, J.*
AU  - Brunelleschi, S.*
AU  - Carpenter, T.*
AU  - Erdmann, J.*
AU  - Franconi, F.*
AU  - Giannetta, E.*
AU  - Glezerman, M.*
AU  - Hofmann, S.M.
AU  - Junien, C.*
AU  - Katai, M.*
AU  - Kublickiene, K.*
AU  - König, I.R.*
AU  - Majdic, G.*
AU  - Malorni, W.*
AU  - Mieth, C.*
AU  - Miller, V.*
AU  - Reynolds, R.*
AU  - Shimokawa, H.*
AU  - Tannenbaum, C.*
AU  - Maria Anna, D.U.*
AU  - Regitz-Zagrosek, V.*
C1  - 51080
C2  - 42696
CY  - Oxford
SP  - 711-724
TI  - Sex in basic research - Concepts in the cardiovascular field.
JO  - Cardiovasc. Res.
VL  - 113
IS  - 7
PB  - Oxford Univ Press
PY  - 2017
SN  - 0008-6363
ER  - 

TY  - JOUR
AU  - Legchenko, E.*
AU  - Küffner, R.
AU  - Hansmann, G.*
C1  - 49273
C2  - 33277
CY  - Oxford
SP  - S43-S43
TI  - Differential transcriptome and microRNA expression signatures in the healthy heart (RV vs. LV) and the failing, pressure-overloaded right ventricle (SuHx model).
JO  - Cardiovasc. Res.
VL  - 111
PB  - Oxford Univ Press
PY  - 2016
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - BACKGROUND: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. OBJECTIVES: We aimed to identify genetic variation in BrS cases at loci associated with QRS duration. METHODS AND RESULTS: A multi-centre study sequenced 7 candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBΧ3 and ΤΒΧ5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF <1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for 4/7 probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10A SNP V1073 was however associated strongly with BrS (66.9% vs 40.1% [UK10K] OR [95% CI]=3.02 [2.35-3.87], P=8.07x10-19). Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared to ancestral allele A1073 (rs6795970). CONCLUSION: Rare variants in the screened QRS associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.
AU  - Behr, E.R.*
AU  - Savio-Galimberti, E.*
AU  - Barc, J.*
AU  - Holst, A.G.*
AU  - Petropoulou, E.*
AU  - Prins, B.P.*
AU  - Jabbari, J.*
AU  - Torchio, M.*
AU  - Berthet, M.*
AU  - Mizusawa, Y.*
AU  - Yang, T.*
AU  - Nannenberg, E.A.*
AU  - Dagradi, F.*
AU  - Weeke, P.*
AU  - Bastiaenan, R.*
AU  - Ackerman, M.J.*
AU  - Haunso, S.*
AU  - Leenhardt, A.*
AU  - Kääb, S.
AU  - Probst, V.*
AU  - Redon, R.*
AU  - Sharma, S.*
AU  - Wilde, A.A.*
AU  - Tfelt-Hansen, J.*
AU  - Schwartz, P.*
AU  - Roden, D.M.*
AU  - Bezzina, C.R.*
AU  - Olesen, M.S.*
AU  - Darbar, D.*
AU  - Guicheney, P.*
AU  - Crotti, L.
AU  - Jamshidi, Y.*
C1  - 43381
C2  - 36572
CY  - Oxford
SP  - 520-529
TI  - Role of common and rare variants in SCN10A: Results from the Brugada syndrome QRS locus gene discovery collaborative study.
JO  - Cardiovasc. Res.
VL  - 106
IS  - 3
PB  - Oxford Univ Press
PY  - 2015
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - AIMS: The relevance of lipoprotein(a) [Lp(a)] concentrations and low-molecular-weight (LMW) apo(a) phenotypes in peripheral arterial disease (PAD) has only been investigated by few studies. Therefore, we analysed this association in three independent cohorts and performed a Mendelian Randomization approach using instrumental variable regression. METHODS AND RESULTS: Lp(a) concentrations, apo(a) phenotypes, and one SNP in the LPA gene (rs10455872) were measured in the CAVASIC study, including 241 male patients with intermittent claudication and 246 age- and diabetes-matched controls as well as in the two population-based studies KORA F3 (n = 3184) and KORA F4 (n = 3080). In KORA F3/F4, 109/80 persons suffered from intermittent claudication, 200/144 from PAD, and 128/103 showed an ankle-brachial index (ABI) <0.9. In CAVASIC, adjusted logistic regression analyses revealed significant associations between an increase of log-Lp(a) per one standard deviation (SD) (OR = 1.28, P = 0.02) as well as LMW apo(a) phenotypes and symptomatic PAD (OR = 1.65, P = 0.03). Linear regression models with continuous ABI showed a significant association in the combined analyses of KORA F3/F4: an increase in log-Lp(a) per one SD (β = -0.006, P = 0.005) and the presence of LMW apo(a) phenotypes (β = -0.011, P = 0.02) or the minor allele of rs10455872 (ß = -0.016, P = 0.03) were associated with a decrease in ABI in the fully adjusted linear and instrumental variable regression models. CONCLUSION: Analyses in three independent populations showed significant associations of Lp(a) concentrations, LMW apo(a) phenotypes, and rs10455872 with PAD. This points to a causal relationship between Lp(a) and PAD since the genetically determined apo(a) phenotypes and SNP alleles are indeed associated with PAD.
AU  - Laschkolnig, A.*
AU  - Kollerits, B.*
AU  - Lamina, C.*
AU  - Meisinger, C.
AU  - Rantner, B.*
AU  - Stadler, M.*
AU  - Peters, A.
AU  - Koenig, W.*
AU  - Stöckl, A.*
AU  - Dähnhardt, D.*
AU  - Böger, C.A.*
AU  - Krämer, B.K.*
AU  - Fraedrich, G.*
AU  - Strauch, K.
AU  - Kronenberg, F.*
C1  - 31526
C2  - 34508
CY  - Oxford
SP  - 28-36
TI  - Lipoprotein (a) concentrations, apolipoprotein (a) phenotypes, and peripheral arterial disease in three independent cohorts.
JO  - Cardiovasc. Res.
VL  - 103
IS  - 1
PB  - Oxford Univ Press
PY  - 2014
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - AIMS: Our recent work demonstrated that common cardiovascular progenitor cells are characterized and induced by the expression of the transcription factor mesoderm posterior1 (MesP1) in vertebrate embryos and murine embryonic stem cells. As the proliferative potential of stem cell-derived cardiomyocytes is limited, it is crucial to understand how MesP1 expression is mediated in order to achieve reasonable and reliable yields for novel stem cell-based therapeutic options. As potential upstream regulators of MesP1, we therefore analysed Eomes and Brachyury(T), which had been controversially discussed as being crucial for cardiovasculogenic lineage formation. METHODS AND RESULTS: Wild-type and transgenic murine embryonic stem cell lines, mRNA analyses, embryoid body formation, and cell sorting revealed that the MesP1 positive population emerges from the Brachyury(T) positive fraction. In situ hybridizations using wild-type mouse embryos confirmed that Brachyury(T) colocalises with MesP1 in vivo. Likewise, shRNA-based loss of Brachyury(T) causes a dramatic decrease in MesP1 expression accompanied by reduced cardiac markers in differentiating embryonic stem cells, which is reflected in vivo via in situ hybridizations using Brachyury(T) knock-out embryos where MesP1 mRNA is greatly abolished. We finally defined a 3.4 kb proximal MesP1-promoter fragment which is directly bound and activated by Brachyury(T) via a T responsive element as shown via bandshift, chromatin immuneprecipitation, and reporter assays. CONCLUSION: Our work contributes to the understanding of the earliest cardiovasculogenic events and may become an important prerequisite for cell therapy, tissue engineering, and pharmacological testing in the culture dish using pluripotent stem cell-derived as well as directly reprogrammed cardiovascular cell types.
AU  - David, R.*
AU  - Jarsch, V.B.*
AU  - Schwarz, F.*
AU  - Nathan, P.*
AU  - Gegg, M.
AU  - Lickert, H.
AU  - Franz, W.M.*
C1  - 6050
C2  - 28782
SP  - 115-122
TI  - Induction of MesP1 by Brachyury(T) generates the common multipotent cardiovascular stem cell.
JO  - Cardiovasc. Res.
VL  - 92
IS  - 1
PB  - Oxford Univ Press
PY  - 2011
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - Genome-wide association studies (GWAS) for atrial fibrillation (AF) have identified three distinct genetic loci on chromosomes 1q21, 4q25, and 16q22 that are associated with the arrhythmia. Susceptibility loci also have been identified by GWAS for PR interval duration, a quantitative phenotype related to AF. In this review article, we have sought to summarize the latest findings for population-based genetic studies of AF, to highlight ongoing functional studies, and to explore the future directions of genetic research on AF.
AU  - Sinner, M.F.*
AU  - Ellinor, P.T.*
AU  - Meitinger, T.
AU  - Benjamin, E.J.*
AU  - Kääb, S.*
C1  - 5650
C2  - 28361
SP  - 701-709
TI  - Genome-wide association studies of atrial fibrillation: Past, present, and future.
JO  - Cardiovasc. Res.
VL  - 89
IS  - 4
PB  - Oxford Univ Press
PY  - 2011
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - Background: Recent studies suggest that female gender is associated with a lower prevalence and a more benign prognosis of heart failure. In the current population-based study, it was our objective to evaluate the implications of gender on the association between impaired left ventricular (LV) function and mass as well as neurohumoral activation. Methods and results: A total of 1883 subjects (992 female, 891 male) of two MONICA surveys in Augsburg, Germany, were analyzed. Participants of one of these surveys were additionally characterized with respect to neurohormonal activation. As compared to men, women were characterized by a slightly higher LV ejection fraction (EF, Teichholz-Method, 65.4±0.3% vs. 63.4±0.3, P<0.01) and a markedly lower LV mass index (LVMI 81±1 g/m2 vs. 96±1, P<0.01). As compared to men with normal LV function, those with LV dysfunction (EF below mean minus two standard deviations, S.D.) were characterized by significantly increased LV mass (LVMI +48%, P<0.01), plasma BNP (+373%, P<0.01) and ANP (+57%, P<0.01), while no significant changes were observed in women (LVMI +3%, BNP +48%, ANP +27%, all P=n.s). Only a small subgroup of women with severe LVD (EF below mean — 3 S.D.) was characterized by significantly increased LV mass (LVMI +23%, P<0.05 vs. control and LVD), however, this increase was less pronounced as compared to men with severe LVD (LVMI +46%, P<0.01 vs. control). Gender-specific differences between LV function and structure were also confirmed by multivariate analysis. While LVMI was independently and significantly correlated with EF in male subjects in addition to systolic blood pressure, age, and body mass index (all P<0.01), these parameters displaced EF as a predictor of LVMI in female subjects. Conclusions: Men with moderate or severe LV dysfunction are characterized by an increase in both LV mass and cardiac natriuretic peptide plasma concentrations. In contrast, LV mass and natriuretic peptide concentrations increase to a lesser extent and only with severe LV dysfunction in women. These observational data suggest gender-specific control of myocardial adaptations to hemodynamic overload and a more rapid induction of LV hypertrophy during myocardial dysfunction in male subjects.
AU  - Luchner, A.*
AU  - Bröckel, U.*
AU  - Muscholl, M.*
AU  - Hense, H.-W.
AU  - Döring, A.
AU  - Riegger, A.J.*
AU  - Schunkert, H.
C1  - 22068
C2  - 20707
SP  - 720-727
TI  - Gender-specific differences of cardiac remodeling in subjects with left ventricular dysfunction : A population-based study.
JO  - Cardiovasc. Res.
VL  - 53
PY  - 2002
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - Objective: A polymorphism at position 825(C-->T) of the G protein beta3 (GNB3) gene was found to be associated with enhanced transmembrane signalling as well as with rut increased prevalence of arterial hypertension. The aim of the present study was to further investigate the association of the GNB3 C825T allele status with arterial hypertension in a large population-based sample and its association with specific end organ damage, i.e. myocardial infarction (MI). Methods: Individuals from a population-based sample (n=2052) and patients suffering from premature MI (age at first MI less than or equal to 60 years, n=606) were studied by questionnaire as well as by physical examination and biochemical analyses. Results: In the population-based sample, the prevalence of arterial hypertension (blood pressure greater than or equal to 160/95 mmHg and/or antihypertensive medication) was higher in individuals with the TT genotype (41.8%) as compared to heterozygote individuals (36.6%) or those with the CC genotype (32.75%) (P=0.02). This association was predominantly found in men. Moreover, men without antihypertensive medication carrying the TT genotype shelved higher diastolic blood pressure than those carrying the CC genotype (86.5 vs. 83.7 mmHg, P=0.04). However, the genotype distribution and the allele frequencies were similar in both, the population-based and the MI patient sample. Furthermore, neither the age at the time of MI nor the location of the MI were related to the genotype distribution. Similarly, gender and age stratified analyses did not show any association of the GNB3 genotype and MI. Conclusions: In male individuals from a large population-based sample, the T allele of the GNB3 polymorphism was associated with arterial hypertension. However, the effects of the GNB3 825T allele on blood pressure were small and did not translate to a clinically relevant increase of risk for MI.
AU  - Hengstenberg, C.*
AU  - Schunkert, H.*
AU  - Mayer, B.*
AU  - Döring, A.
AU  - Löwel, H.
AU  - Hense, H.-W.*
AU  - Fischer, M.*
AU  - Riegger, G. A. J.*
AU  - Holmer, S. R.*
C1  - 10302
C2  - 19872
SP  - 820-827
TI  - Association between a polymorphism in the G protein ß3 subunit gene (GNB3) with arterial hypertension but not with myocardial infarction.
JO  - Cardiovasc. Res.
VL  - 49 
IS  - 4
PB  - Elsevier Science BV
PY  - 2001
SN  - 0008-6363
ER  - 

TY  - JOUR
AB  - Objective: Genetic variants of the lipoprotein lipase gene have been associated with dyslipidemia and coronary artery disease. However, data have been inconsistent and are mainly based on selected predominantly male patient groups. Methods: We evaluated the influence of the HindIII restriction fragment length polymorphism on lipid levels in the general population (1361 participants of a large population-based survey from Augsburg, Germany; 50% women) as well as the association of this polymorphism with the risk of myocardial infarction (MI; genotype frequencies in 1159 patients with documented MI under 60 years of age). Results: In the population-based survey, a highly significant association between the frequent H2H2 genotype and unfavorable cholesterol subfraction levels was observed in men and in postmenopausal women whereas no significant association was observed in premenopausal women (uni- and multivariate analysis). Such unfavorable lipid levels in homozygotes for the H2 allele may be expected to be associated with a 19–25% increased risk to suffer from myocardial infarction (MI). Nevertheless, genotype and allele frequencies in the general population were not different from those in patients with previous MI (H2H2 genotype frequency 51.3% vs. 53.2%, respectively; P=0.63). Conclusion: This large study shows that the H2H2 genotype of the lipoprotein lipase gene polymorphism is associated with unfavorable lipid levels. Estrogen status may modulate this association in women. The effects of the genotype on lipid levels were apparently not strong enough to reveal a significant association with MI.
AU  - Holmer, S.R.*
AU  - Hengstenberg, C.*
AU  - Mayer, B.*
AU  - Döring, A.
AU  - Löwel, H.
AU  - Engel, B.
AU  - Hense, H.-W.*
AU  - Wolf, M.*
AU  - Klein, G.*
AU  - Riegger, A.J.*
AU  - Schunkert, H.*
C1  - 21593
C2  - 19720
SP  - 806-812
TI  - Lipoprotein lipase gene polymorphism, cholesterol subfractions and myocardial infarction in large samples of the general population.
JO  - Cardiovasc. Res.
VL  - 47
PY  - 2000
SN  - 0008-6363
ER  -