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RATIONALE: Heart failure (HF) following heart damage leads to a decreased blood flow due to a reduced pump efficiency of the heart muscle. A consequence can be insufficient oxygen supply to the organism including the brain. While HF clearly shows neurological symptoms, such as fatigue, nausea, and dizziness, the implications for brain structure are not well understood. Few studies show regional gray matter decrease related to HF; however, the underlying mechanisms leading to the observed brain changes remain unclear. OBJECTIVE: To study the relationship between impaired heart function, hampered blood circulation, and structural brain change in a case-control study. METHODS AND RESULTS: Within a group of 80 patients of the Leipzig Heart Center, we investigated a potential correlation between HF biomarkers and the brain's gray matter density (GMD) obtained by magnetic resonance imaging. We observed a significant positive correlation between cardiac ejection fraction and GMD across the whole frontal and parietal medial cortex reflecting the consequence of HF onto the brain's gray matter. Moreover, we also obtained a relationship between GMD and the NT-proBNP (N-terminal prohormone of brain natriuretic peptide)-a biomarker that is used for screening, diagnosis, and prognosis of HF. Here, we found a significant negative correlation between NT-proBNP and GMD in the medial and posterior cingulate cortex but also in precuneus and hippocampus, which are key regions implicated in structural brain changes in dementia. CONCLUSIONS: We obtained significant correlations between brain structure and markers of heart failure including ejection fraction and NT-proBNP. A diminished GMD was found with decreased ejection fraction and increased NT-proBNP in wide brain regions including the whole frontomedian cortex as well as hippocampus and precuneus. Our observations might reflect structural brain damage in areas that are related to cognition; however, whether these structural changes facilitate the development of cognitive alterations has to be proven by further longitudinal studies.
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Daño Encefálico Crónico/diagnóstico por imagen , Sustancia Gris/diagnóstico por imagen , Insuficiencia Cardíaca/complicaciones , Lóbulo Parietal/diagnóstico por imagen , Anciano , Biomarcadores/sangre , Daño Encefálico Crónico/etiología , Gasto Cardíaco , Femenino , Insuficiencia Cardíaca/sangre , Humanos , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangreRESUMEN
AIMS: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1ß can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. METHODS AND RESULTS: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. CONCLUSION: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.
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Enfermedades Cardiovasculares/mortalidad , Inflamasomas , Inflamación , Proteína con Dominio Pirina 3 de la Familia NLR , Humanos , Inflamasomas/genética , Inflamación/genética , Leucocitos Mononucleares , Proteína con Dominio Pirina 3 de la Familia NLR/genéticaRESUMEN
BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
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Enfermedad Coronaria/genética , Factor V/genética , Genotipo , Trombosis/genética , Aterosclerosis , Ensayos Clínicos como Asunto , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/mortalidad , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple , Medicina de Precisión , Pronóstico , RiesgoRESUMEN
BACKGROUND AND AIMS: Current epidemiologic data suggest beneficial cardiovascular effects of fermented dairy products (FDP). However, the relationship between FDP consumption and angiographic coronary status has not been previously studied. Furthermore, the role of novel metabolomic biomarkers of cardiovascular risk in this context is unclear. We hypothesize that short-chain acylcarnitines (SCA) reflect the link between FDP intake and angiographic extent of stable coronary artery disease (CAD). METHODS AND RESULTS: We recruited 1185 patients admitted for suspected CAD [median age 62 years (interquartile range: 54-69); 714 men (60.3%)]. Prior to coronary angiography, each patient completed a validated Food Frequency Questionnaire. In addition, venous blood was collected from each patient for whole blood metabolomic analysis, using targeted mass-spectrometry. CAD was defined by the presence of ≥1 coronary stenosis ≥50%. Patients with CAD (n = 441) reported lower median FDP intake [86.8 g/day (IQR: 53.4-127.6)] than patients without CAD [n = 744; 103.9 g/day (IQR: 62.9-152.7); p < 0.001]. Upon adjustment for relevant confounders, increased circulating SCA, particularly level of acetylcarnitine (C2) associated with both higher CAD probability [SCA:ß(SE) = 0.584 (0.235), p = 0.013; C2:ß(SE) = 0.575 (0.242), p = 0.017] and decreased FDP consumption [SCA:ß/100 g FDP-increment/day (SE) = -0.785 (0.242), p = 0.001; C2:ß(SE) = -0.560 (0.230), p = 0.015]. By mediation analysis, neither SCA nor C2 showed relevant mediator effect linking FDP consumption to the risk of CAD. CONCLUSION: Increased consumption of fermented milk was associated with lower prevalence of CAD and correlated inversely with circulating SCA, in particular with acetylcarnitine. No substantial mediator effect of SCA linking fermented milk intake with risk of CAD was found. CLINICAL TRIAL REGISTRY: NCT00497887.
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Carnitina/análogos & derivados , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Estenosis Coronaria/diagnóstico por imagen , Productos Lácteos Cultivados , Anciano , Biomarcadores/sangre , Carnitina/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/prevención & control , Estenosis Coronaria/sangre , Estenosis Coronaria/epidemiología , Estenosis Coronaria/prevención & control , Estudios Transversales , Femenino , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prevalencia , Factores Protectores , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
Profiling amino acids and acylcarnitines in whole blood spots is a powerful tool in the laboratory diagnosis of several inborn errors of metabolism. Emerging data suggests that altered blood levels of amino acids and acylcarnitines are also associated with common metabolic diseases in adults. Thus, the identification of common genetic determinants for blood metabolites might shed light on pathways contributing to human physiology and common diseases. We applied a targeted mass-spectrometry-based method to analyze whole blood concentrations of 96 amino acids, acylcarnitines and pathway associated metabolite ratios in a Central European cohort of 2,107 adults and performed genome-wide association (GWA) to identify genetic modifiers of metabolite concentrations. We discovered and replicated six novel loci associated with blood levels of total acylcarnitine, arginine (both on chromosome 6; rs12210538, rs17657775), propionylcarnitine (chromosome 10; rs12779637), 2-hydroxyisovalerylcarnitine (chromosome 21; rs1571700), stearoylcarnitine (chromosome 1; rs3811444), and aspartic acid traits (chromosome 8; rs750472). Based on an integrative analysis of expression quantitative trait loci in blood mononuclear cells and correlations between gene expressions and metabolite levels, we provide evidence for putative causative genes: SLC22A16 for total acylcarnitines, ARG1 for arginine, HLCS for 2-hydroxyisovalerylcarnitine, JAM3 for stearoylcarnitine via a trans-effect at chromosome 1, and PPP1R16A for aspartic acid traits. Further, we report replication and provide additional functional evidence for ten loci that have previously been published for metabolites measured in plasma, serum or urine. In conclusion, our integrative analysis of SNP, gene-expression and metabolite data points to novel genetic factors that may be involved in the regulation of human metabolism. At several loci, we provide evidence for metabolite regulation via gene-expression and observed overlaps with GWAS loci for common diseases. These results form a strong rationale for subsequent functional and disease-related studies.
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Aminoácidos/sangre , Carnitina/análogos & derivados , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Carnitina/sangre , Estudios de Cohortes , Enfermedad/genética , Humanos , Sitios de Carácter CuantitativoRESUMEN
BACKGROUND: The LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies. METHODS/DESIGN: The study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography. DISCUSSION: The participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016.
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Indicadores de Salud , Estado de Salud , Vigilancia de la Población/métodos , Población Urbana/estadística & datos numéricos , Adulto , Anciano , Estudios de Cohortes , Femenino , Alemania/epidemiología , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Examen Físico , Proyectos de InvestigaciónRESUMEN
BACKGROUND: Ankle-brachial-Index (ABI) measured by manual Dopplersonography is an easily assessable marker of global cardiovascular risk. The aim of this study was to establish novel photo-plethysmography (PPG)-based ABI assessments in an epidemiologic context and to compare its results with those of Doppler. METHODS: Two devices for PPG-based ABI assessments (Vicorder, Vascular Explorer) were tested and compared against Doppler in 56 putatively healthy subjects. We determined acceptance, time requirements, agreement of repeat measurements, agreement with Doppler and intra- and inter-observer concordances for both devices and compared the results. Differences between cuff inflation- and deflation-based methods were also studied for Vascular Explorer. RESULTS: Acceptance was similar for both devices but Vascular Explorer was more time consuming. Agreement of multiple measurements was moderate for both methods highlighting the importance of measurement replicates. Both automated devices showed significantly higher ABI compared to Doppler which can be traced back to higher brachial pressures (Vicorder) or higher ankle pressures (Vascular Explorer). This effect is more pronounced for Vascular Explorer but can be ameliorated using the deflation method of measurement. Intra-observer concordances were similar. Inter-observer concordance was non-significantly better for Vicorder. CONCLUSIONS: Both devices proved to be feasible in epidemiologic studies, but compared to Doppler, do not constitute an advantage regarding time requirement and accuracy of ABI assessment. Since PPG-based ABI values are inflated compared to Doppler, it will be necessary to adjust Doppler-based cut-offs for risk stratification.
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Índice Tobillo Braquial/normas , Fotopletismografía/normas , Ultrasonografía Doppler/normas , Anciano , Índice Tobillo Braquial/métodos , Automatización , Femenino , Humanos , Masculino , Variaciones Dependientes del Observador , Proyectos PilotoRESUMEN
Aging increases the risk to develop Alzheimer's disease. Cardiovascular diseases might accelerate this process. Our study aimed at investigating the impact of heart failure on brain connectivity using functional magnetic resonance imaging at resting state. Here we show brain connectivity alterations related to heart failure and cognitive performance. Heart failure decreases brain connectivity in the precuneus. Precuneus dysconnectivity was associated with biomarkers of heart failure-left ventricular ejection fraction and N-terminal prohormone of brain natriuretic peptide-and cognitive performance, predominantly executive function. Meta-analytical data-mining approaches-conducted in the BrainMap and Neurosynth databases-revealed that social and executive cognitive functions are mainly associated with those neural networks. Remarkably, the precuneus, as identified in our study in a mid-life cohort, represents one central functional hub affected by Alzheimer's disease. A long-term follow-up investigation in our cohort after approximately nine years revealed more severe cognitive impairment in the group with heart failure than controls, where social cognition was the cognitive domain mainly affected, and not memory such as in Alzheimer's disease. In sum, our results indicate consistently an association between heart failure and decoupling of the precuneus from other brain regions being associated with social and executive functions. Further longitudinal studies are warranted elucidating etiopathological mechanisms.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Insuficiencia Cardíaca , Humanos , Función Ejecutiva , Cognición Social , Volumen Sistólico , Función Ventricular Izquierda , Encéfalo , Cognición , Mapeo Encefálico , Lóbulo Parietal , Imagen por Resonancia MagnéticaRESUMEN
Structural brain damage associated with heart failure is well described; however, little is known about associated changes in various specific brain functions that bear immediate clinical relevance. A satisfactory pathophysiological link between heart failure and decline in cognitive function is still missing. In the present study, we aim to detect functional correlates of heart failure in terms of alterations in functional brain connectivity (quantified by functional magnetic resonance imaging) related to cognitive performance assessed by neuropsychological testing. Eighty patients were post hoc grouped into subjects with and without coronary artery disease. The coronary artery disease patients were further grouped as presenting with or without heart failure according to the guidelines of the European Society of Cardiology. On the basis of resting-state functional magnetic resonance imaging, brain connectivity was investigated using network centrality as well as seed-based correlation. Statistical analysis aimed at specifying centrality group differences and potential correlations between centrality and heart failure-related measures including left ventricular ejection fraction and serum concentrations of N-terminal fragment of the pro-hormone brain-type natriuretic peptide. The resulting correlation maps were then analysed using a flexible factorial model with the factors 'heart failure' and 'cognitive performance'. Our core findings are: (i) A statistically significant network centrality decrease was found to be associated with heart failure primarily in the precuneus, i.e. we show a positive correlation between centrality and left ventricular ejection fraction as well as a negative correlation between centrality and N-terminal fragment of the pro-hormone brain-type natriuretic peptide. (ii) Seed-based correlation analysis showed a significant interaction between heart failure and cognitive performance related to a significant decrease of precuneus connectivity to other brain regions. We obtained these results by different analysis approaches indicating the robustness of the findings we report here. Our results suggest that the precuneus is a brain region involved in connectivity decline in patients with heart failure, possibly primarily or already at an early stage. Current models of Alzheimer's disease-having pathophysiological risk factors in common with cerebrovascular disorders-also consider reduced precuneus connectivity as a marker of brain degeneration. Consequently, we propose that heart failure and Alzheimer's disease exhibit partly overlapping pathophysiological paths or have common endpoints associated with a more or less severe decrease in brain connectivity. This is further supported by specific functional connectivity alterations between the precuneus and widely distributed cortical regions, particularly in patients showing reduced cognitive performance.
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Investigating the cross talk of different omics layers is crucial to understand molecular pathomechanisms of metabolic diseases like obesity. Here, we present a large-scale association meta-analysis of genome-wide whole blood and peripheral blood mononuclear cell (PBMC) gene expressions profiled with Illumina HT12v4 microarrays and metabolite measurements from dried blood spots (DBS) characterized by targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) in three large German cohort studies with up to 7706 samples. We found 37,295 associations comprising 72 amino acids (AA) and acylcarnitine (AC) metabolites (including ratios) and 8579 transcripts. We applied this catalogue of associations to investigate the impact of associating transcript-metabolite pairs on body mass index (BMI) as an example metabolic trait. This is achieved by conducting a comprehensive mediation analysis considering metabolites as mediators of gene expression effects and vice versa. We discovered large mediation networks comprising 27,023 potential mediation effects within 20,507 transcript-metabolite pairs. Resulting networks of highly connected (hub) transcripts and metabolites were leveraged to gain mechanistic insights into metabolic signaling pathways. In conclusion, here, we present the largest available multi-omics integration of genome-wide transcriptome data and metabolite data of amino acid and fatty acid metabolism and further leverage these findings to characterize potential mediation effects towards BMI proposing candidate mechanisms of obesity and related metabolic diseases. KEY MESSAGES: Thousands of associations of 72 amino acid and acylcarnitine metabolites and 8579 genes expand the knowledge of metabolome-transcriptome associations. A mediation analysis of effects on body mass index revealed large mediation networks of thousands of obesity-related gene-metabolite pairs. Highly connected, potentially mediating hub genes and metabolites enabled insight into obesity and related metabolic disease pathomechanisms.
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Leucocitos Mononucleares , Enfermedades Metabólicas , Humanos , Índice de Masa Corporal , Leucocitos Mononucleares/metabolismo , Cromatografía Liquida , Espectrometría de Masas en Tándem , Aminoácidos , Obesidad/genética , Transcriptoma , Metabolómica/métodosRESUMEN
AIMS: Physical activity (PA) is a mainstay of cardiovascular prevention. This study aimed to identify metabolic mediators of PA that protect against the development of atherosclerosis. METHODS AND RESULTS: A total of 2160 participants in the LIFE heart study were analysed with data on PA and vascular phenotyping. In a targeted metabolomic approach, 61 metabolites (amino acids and acylcarnitines) were measured using liquid chromatography-tandem mass spectrometry. We investigated the interactions between PA, metabolites and markers of atherosclerosis in order to uncover possible mediation effects. Intended sports activity, but no daily PA, was associated with a lower degree of atherosclerosis, odds ratio (OR) for total atherosclerotic burden of 0.76 (95% confidence interval 0.62-0.94), carotid artery plaque OR 0.79 (0.66-0.96), and peripheral artery disease OR 0.74 (0.56-0.98). Twelve amino acids, free carnitine, five acylcarnitines were associated with sports activity. Of these, eight metabolites were also associated with the degree of atherosclerosis. In the mediation analyses, a cluster of amino acids (arginine, glutamine, pipecolic acid, taurine) were considered as possible mediators of atheroprotection. In contrast, a group of members of the carnitine metabolism (free carnitine, acetyl carnitine, octadecenoyl carnitine) were associated with inactivity and higher atherosclerotic burden. CONCLUSION: Our metabolomic approach, which is integrated into a mediation model, provides transformative insights into the complex metabolic processes involved in atheroprotection. Metabolites with antioxidant and endothelial active properties are believed to be possible mediators of atheroprotection. The metabolomic mediation approach can support the understanding of complex diseases in order to identify targets for prevention and therapy.
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Aminoácidos , Metabolómica , Biomarcadores , Ejercicio Físico , Humanos , Espectrometría de Masas , Metabolómica/métodosRESUMEN
BACKGROUND: For many drugs, mechanisms of action with regard to desired effects and/or unwanted side effects are only incompletely understood. To investigate possible pleiotropic effects and respective molecular mechanisms, we describe here a catalogue of commonly used drugs and their impact on the blood transcriptome. METHODS AND RESULTS: From a population-based cohort in Germany (LIFE-Adult), we collected genome-wide gene-expression data in whole blood using in Illumina HT12v4 micro-arrays (n = 3,378; 19,974 gene expression probes per individual). Expression profiles were correlated with the intake of active substances as assessed by participants' medication. This resulted in a catalogue of fourteen substances that were identified as associated with differential gene expression for a total of 534 genes. As an independent replication cohort, an observational study of patients with suspected or confirmed stable coronary artery disease (CAD) or myocardial infarction (LIFE-Heart, n = 3,008, 19,966 gene expression probes per individual) was employed. Notably, we were able to replicate differential gene expression for three active substances affecting 80 genes in peripheral blood mononuclear cells (carvedilol: 25; prednisolone: 17; timolol: 38). Additionally, using gene ontology enrichment analysis, we demonstrated for timolol a significant enrichment in 23 pathways, 19 of them including either GPER1 or PDE4B. In the case of carvedilol, we showed that, beside genes with well-established association with hypertension (GPER1, PDE4B and TNFAIP3), the drug also affects genes that are only indirectly linked to hypertension due to their effects on artery walls or their role in lipid biosynthesis. CONCLUSIONS: Our developed catalogue of blood gene expressions profiles affected by medication can be used to support both, drug repurposing and the identification of possible off-target effects.
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Hipertensión , Transcriptoma , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Carvedilol/uso terapéutico , Humanos , Hipertensión/tratamiento farmacológico , Leucocitos Mononucleares , TimololRESUMEN
Knowledge about cardiac and inflammatory biomarkers in patients with stable coronary artery disease (CAD) is limited. To address this, we analyzed 3072 patients (36% female) with a median follow-up of 10 years in the Leipzig LIFE Heart Study with suspected CAD with coronary angiography. Selected biomarkers included troponin T (hsTNT), N-terminal pro B-type natriuretic peptide (NT-proBNP), copeptin, C-reactive protein (hsCRP), and interleukin-6 (IL-6). Patients were stratified by CAD severity: CAD0 (no sclerosis), CAD1 (non-obstructive, i.e., stenosis < 50%), and CAD2 (≥one stenosis ≥ 50%). Group comparison (GC) included GC1: CAD0 + 1 vs. CAD2; GC2: CAD0 vs. CAD1 + 2. CAD0, CAD1, and CAD2 were apparent in 1271, 631, and 1170 patients, respectively. Adjusted for classical risk factors, hs-cTnT, NT-proBNP, and IL-6 differed significantly in both GC and hsCRP only in GC2. After multivariate analysis, hs-cTnT, NT-proBNP, and IL-6 remained significant in GC1. In GC2, hs-cTnT (p < 0.001) and copeptin (p = 0.014) reached significance. Ten-year survival in groups CAD0, CAD1, and CAD2 was 88.3%, 77.3%, and 72.4%. Incorporation of hs-cTnT, NT-proBNP, copeptin, and IL-6 improved risk prediction (p < 0.001). The studied cardiac and inflammatory biomarkers enable fast and precise non-invasive identification of mortality risk in CAD patients, allowing the tailoring of primary and secondary CAD prevention.
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Enfermedad de la Arteria Coronaria , Biomarcadores , Proteína C-Reactiva , Constricción Patológica , Femenino , Humanos , Interleucina-6 , Masculino , Péptido Natriurético Encefálico , Fragmentos de Péptidos , PronósticoRESUMEN
Apolipoprotein E (apoE) occurs on the majority of plasma lipoproteins and plays a major role in the lipid metabolism in the periphery and in the central nervous system. ApoE is a polymorphic protein with three common isoforms, apoE2, apoE3 and apoE4, derived from respective alleles ε2, ε3 and ε4. The aim of this study was to develop a sample pretreatment protocol combined with rapid mass spectrometry (MS)-based assay for simultaneous apolipoprotein profiling and apoE phenotype identification. This assay was validated in 481 samples from patients with stable atherosclerotic cardiovascular disease (ASCVD) and applied to study association with mild cognitive impairment (MCI) in the LIFE Adult study, including overall 690 study subjects. Simultaneous quantification of 8−12 major apolipoproteins including apoA-I, apoB-100 and apoE could be performed within 6.5 min. Phenotyping determined with the developed MS assay had good agreement with the genotyping by real-time fluorescence PCR (97.5%). ApoE2 isoform was associated with the highest total apoE concentration compared to apoE3 and apoE4 (p < 0.001). In the subgroup of diabetic atherosclerotic cardiovascular disease (ASCVD) patients, apoE2 isoform was related to higher apoC-I levels (apoE2 vs. apoE3, p < 0.05), while in the subgroup of ASCVD patients under statin therapy apoE2 was related to lower apoB-100 levels (apoE2 vs. apoE3/apoE4, p < 0.05). A significant difference in apoE concentration observed between mild cognitive impairment (MCI) subjects and controls was confirmed for each apoE phenotype. In conclusion, this study provides evidence for the successful implementation of an MS-based apoE phenotyping assay, which can be used to assess phenotype effects on plasma lipid and apolipoprotein levels.
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Enfermedades Cardiovasculares , Disfunción Cognitiva , Apolipoproteína B-100 , Apolipoproteína E2/genética , Apolipoproteína E3/genética , Apolipoproteína E4 , Apolipoproteínas E/metabolismo , Humanos , Espectrometría de Masas , Isoformas de ProteínasRESUMEN
Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
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Diabetes Mellitus , Nefropatías Diabéticas , Creatinina , Nefropatías Diabéticas/genética , Estudio de Asociación del Genoma Completo , Tasa de Filtración Glomerular/genética , Humanos , RiñónRESUMEN
BACKGROUND AND AIMS: The association of plasma trimethylamine N-oxide (TMAO) with atherosclerotic cardiovascular disease (ASCVD), diabetes mellitus (DM) and its determinants, as well as the role of TMAO as a predictor for short and long-term mortality, is still under discussion. We investigated associations between four plasma metabolites of the TMAO pathway and different clinical manifestations of atherosclerosis, diabetes determinants, and risk of short and long-term mortality in patients with stable ASCVD, acute myocardial infarction (AMI), cardiogenic shock (CS), and DM in three independent cohorts. METHODS: TMAO and its dietary precursors were simultaneously quantified by liquid chromatography-tandem mass spectrometry in a total of 2655 participants of the German Leipzig Research Center for Civilization Diseases (LIFE)-Heart study, LIFE-Adult study, and the European Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) multicenter trial. Associations with ASCVD manifestations, metabolic syndrome, 30-day mortality of patients with AMI and CS, and long-term mortality of subjects with suspected coronary artery disease (CAD) were analyzed. RESULTS: TMAO plasma levels were not independently associated with stable ASCVD. Elevated TMAO plasma concentrations were independently associated with obesity (odds ratio, 1.23; p < 0.01) and DM (odds ratio, 1.37; p < 0.001) in LIFE-Heart. The latter association was confirmed in LIFE-Adult. We found no association of TMAO plasma levels with short-term mortality in patients with AMI and CS. However, TMAO plasma levels were independent predictors of long-term mortality in patients with suspected CAD (hazard ratio, 1.24; p < 0.05). CONCLUSIONS: Potential proatherogenic mechanisms of TMAO seem to have no short-term effect in AMI. Presented associations with diabetes mellitus and obesity suggest that TMAO might have a functional role in metabolic syndrome.
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Aterosclerosis , Enfermedades Cardiovasculares , Síndrome Metabólico , Intervención Coronaria Percutánea , Adulto , Aterosclerosis/diagnóstico , Biomarcadores , Humanos , Síndrome Metabólico/diagnóstico , Metilaminas , Factores de RiesgoRESUMEN
BACKGROUND: Coronary artery disease (CAD) is a significant risk factor for atrial fibrillation (AF). Experimental studies demonstrated that atrial ischemia induced by right coronary artery (RCA) stenosis promote AF triggers and development of electro-anatomical substrate for AF. AIM: To analyze the association between AF prevalence and coronary arteries status in the LIFE-Heart Study. METHODS: This analysis included patients with available coronary catheterization data recruited between 2006 and 2014. Patients with acute myocardial infarction were excluded. CAD was defined as stenosis ≥75%, while coronary artery sclerosis (CAS) was defined as non-critical plaque(s) <75%. RESULTS: In total, 3.458 patients (median age 63 years, 34% women) were included into analysis. AF was diagnosed in 238 (6.7%) patients. There were 681 (19.7%) patients with CAS and 1.411 (40.8%) with CAD (27.5% with single, 32.4% with double, and 40.1% with triple vessel CAD). In multivariable analysis, there was a significant association between prevalent AF and coronary artery status (OR 0.64, 95% CI 0.53-0.78, Ptrend < .001). Similarly, AF risk was lower in patients with higher CAD extent (OR 0.54, 95%CI 0.35-0.83, Ptrend = .005). Compared to single vessel CAD, the risk of AF was lower in double (OR 0.42, 95%CI 0.19-0.95, P = .037) and triple CAD (OR 0.31, 95%CI 0.13-0.71, P = .006). Finally, no association was found between AF prevalence and CAD origin among patients with single vessel CAD. CONCLUSION: In the LIFE-Heart Study, CAS but not CAD was associated with increased risk of AF.
Asunto(s)
Fibrilación Atrial/epidemiología , Enfermedad de la Arteria Coronaria/complicaciones , Vasos Coronarios/diagnóstico por imagen , Electrocardiografía , Anciano , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/etiología , Cateterismo Cardíaco , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/fisiopatología , Femenino , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Background: Patients with cardiac complaints but without confirmed diagnosis of coronary heart disease by angiography frequently develop cardiac events in the following years. This follow-up study investigated the frequency of cardiac symptoms and cardiovascular events (CVE) 5 years after initial angiography of patients with nonobstructive coronary artery disease (NobCAD, LIFE Heart study), with the aim to identify gender-specific indicators for CVE. Methods: In 2014/2015, 1462 women and men with NobCAD, defined as no or non-relevant obstructive coronary artery disease were identified among 2660 subjects participating in the observational angiographic LIFE Heart study. Questionnaires of 820 responding patients were analyzed. Results: The median observation time was 55 months. Cardiac symptoms were found in 53.6% of all patients, significantly more often in women than in men (59.4% vs. 48.8%; p = 0.002). CVE occurred in 46.1% of all participants (n = 378/820). Patients with cardiac symptoms had a 2.94 time higher risk for CVE than those without cardiac symptoms (p < 0.001). Men with no cardiac symptoms had significantly more CVE (p = 0.042) than women. Common risk factors for CVE comprised cardiac symptoms, atrial fibrillation, and age. Sex-specific risk factors comprised body mass index (BMI) ≥25 kg/m2 for women and anxiety for men. Conclusions: Patients with cardiac symptoms have about three times higher risk for CVE within 5 years than patients without cardiac symptoms. Sex differences exist in patients without symptoms where men were at higher risk for CVE. Atrial fibrillation was the strongest indicator for CVE, whereas anxiety was an indicator only in men and BMI ≥25 kg/m2 only in women, suggesting sex- and gender-specific phenotypic profiles.
Asunto(s)
Fibrilación Atrial/epidemiología , Dolor en el Pecho/epidemiología , Enfermedad de la Arteria Coronaria/epidemiología , Anciano , Enfermedades Cardiovasculares/epidemiología , Angiografía Coronaria , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de Riesgo , Caracteres Sexuales , Factores Sexuales , Encuestas y CuestionariosRESUMEN
BACKGROUND: The pathophysiology of arterial stiffness is not completely understood. Pulse wave velocity (PWV) is an established marker for arterial stiffness. We compare genetics of three PWV modes, namely carotid-femoral PWV (cfPWV), brachial-ankle (baPWV) and brachial-femoral (bfPWV), reflecting different vascular segments to analyse association with genetic variants, heritability and genetic correlation with other biological traits. Furthermore we searched for shared genetic architecture concerning PWV, blood pressure (BP) and coronary artery disease (CAD) and examined the causal relationship between PWV and BP. METHODS AND RESULTS: We performed a genome-wide association study (GWAS) for cfPWV, baPWV and bfPWV in LIFE-Adult (N = 3,643-6,734). We analysed the overlap of detected genetic loci with those of BP and CAD and performed genetic correlation analyses. By bidirectional Mendelian Randomization, we assessed the causal relationships between PWV and BP. For cfPWV we identified a new locus with genome-wide significance near SLC4A7 on cytoband 3p24.1 (lead SNP rs939834: p = 2.05x10-8). We replicated a known PWV locus on cytoband 14q32.2 near RP11-61O1.1 (lead SNPs: rs17773233, p = 1.38x10-4; rs1381289, p = 1.91x10-4) For baPWV we estimated a heritability of 28% and significant genetic correlation with hypertension (rg = 0.27, p = 6.65x10-8). We showed a positive causal effect of systolic blood pressure on PWV modes (cfPWV: p = 1.51x10-4; bfPWV: p = 1.45x10-3; baPWV: p = 6.82x10-15). CONCLUSIONS: We identified a new locus for arterial stiffness and successfully replicated an earlier proposed locus. PWV shares common genetic architecture with BP and CAD. BP causally affects PWV. Larger studies are required to further unravel the genetic determinants and effects of PWV.
Asunto(s)
Presión Sanguínea , Hipertensión/genética , Rigidez Vascular , Anciano , Femenino , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Análisis de la Onda del Pulso , Simportadores de Sodio-Bicarbonato/genéticaRESUMEN
BACKGROUND AND AIMS: Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). As key regulators of lipoprotein metabolism, apolipoproteins (apos) are discussed as vascular risk factors. This study aimed to analyze associations of major plasma apos with coronary artery disease (CAD), peripheral artery disease (PAD) and carotid artery plaque (CAP) to elucidate their diagnostic potential in risk assessment. METHODS: ApoA-I, apoA-II, apoA-IV, apoB-100, apoC-I, apoC-III, apoE, and apoJ were simultaneously quantified in 3⯵L EDTA-plasma by LC-MS/MS in a case-control subgroup of the Leipziger LIFE-Heart Study (Nâ¯=â¯911). Confounder analysis with demographic, clinical covariates and serum lipids, cardiac, inflammatory, and hepatic markers were performed. Apos were associated with CAD, CAP, and PAD in a multivariate regression model. RESULTS: Fasting and statin therapy showed strongest effects on apo concentrations. Inverse correlations of HDL-related apos A-I, A-II, A-IV, and C-I were observed for troponin T and interleukin 6. Concentrations of apos A-II, B-100, C-I, and E were decreased under statin therapy. After adjustment for influencing factors and related lipids, only apoB-100 (odds ratio per one SD [OR], 1.39; 95% confidence interval [CI], 1.05-1.84) was independently associated with CAD while apoA-IV (OR, 0.74; 95% CI 0.58-0.95) indicated PAD. ApoB-100 (OR, 1.55; 95% CI, 1.18-2.04), apoC-III (OR, 1.30; 95% CI, 1.06-1.58), and apoE (OR, 1.34; 95% CI, 1.13-1.58) were associated with CAP. CONCLUSIONS: Triglyceride rich lipoproteins (TRLs) associated apos A-IV, B-100, C-III, and E are independently associated with stable ASCVD, providing further evidence for a potential role of TRLs in atherogenesis.