Publications by authors named "Marcus Kleber"

Introduction: The processes of atherosclerosis, inflammation, and carbamylation are closely linked in cardiovascular (CV) disease, but the potential of carbamylation burden as a CV mortality predictor is unclear, especially in patients with no or mild chronic kidney disease (CKD). This study aimed to investigate whether elevated carbamylated albumin (C-Alb), as a surrogate marker for carbamylation burden, is associated with mortality and arterial stiffness/atherosclerotic burden in patients with no or mild CKD, using pulse pressure (PP) as a marker for arterial stiffness.

Methods: We measured C-Alb in 3,193 participants of the Ludwigshafen Risk and Cardiovascular Health study who had been referred for coronary angiography and followed up for 10 years.

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Background: Arterial hypertension is a significant risk factor for cardiovascular (CV) morbidity and mortality. Although central blood pressure (BP) evaluation is considered the gold standard, the reliability of non-invasive measurements remains unclear. Therefore, we compared the predictive value of invasively measured central BP with non-invasively measured brachial BP and analyzed pulse pressure (PP) amplification (delta-PP; difference between central and peripheral PP) as an independent predictor of mortality.

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Purpose: It has been assumed that magnesium (Mg) status may interact with vitamin D status. We therefore aimed at investigating the association between Mg and vitamin D status in a large cohort of adult individuals with a high prevalence of deficient/insufficient vitamin D and Mg status.

Methods: We used data from the Ludwigshafen Risk and Cardiovascular Health Study (n = 2,286) to analyze differences according to serum Mg status in circulating 25-hydroxyvitamin D [25(OH)D] (primary endpoint), 24,25-dihydroxyvitamin D [24,25(OH)D], vitamin D metabolite ratio and calcitriol, and odds ratios for deficient or insufficient 25(OH)D (secondary endpoints).

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  • The study examined how serum levels of minerals and phosphate relate to overall and cardiovascular death rates, especially in patients with varying kidney functions.
  • Low levels of sodium and iron were linked to worse kidney performance and higher death risks, while higher zinc levels correlated with lower risks.
  • Those with kidney functions below 60 mL/min faced a fourfold increase in mortality risk, emphasizing the need for regular monitoring of serum minerals and kidney health in cardiovascular patients.
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  • - This study aimed to assess the predictive power of coronary artery calcification (CAC) genetic risk scores (GRSs) for coronary artery disease (CAD), suggesting existing GRSs may overlook important genetic factors related to intermediate phenotypes like CAC.
  • - Researchers analyzed data from three different studies involving a total of 3,535 participants, comparing CAC GRSs to traditional cardiovascular disease (CVD) risk factors and a broader CAD GRS constructed from 1.7 million genetic variants.
  • - Results indicated that CAC GRS is significantly linked to CAD across multiple cohorts and provides additional predictive value beyond traditional risk factors, enhancing risk assessment and precision in predicting CAD.
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  • Factor V (FV) is crucial for the blood coagulation process, and its plasma levels are linked to various health issues like blood clots and diabetes.
  • The researchers used a specific statistical method called the Brown-Forsythe methodology to analyze genetic factors affecting FV levels in 4505 individuals from four different studies.
  • They identified a significant genetic variant (rs75463553) associated with the variability in FV plasma levels, highlighting the interaction between neutrophil-related genes and FV biology.
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  • ANGPTL3/4/8 proteins regulate lipoprotein lipase (LPL) activity, with ANGPTL8 forming complexes that influence ANGPTL4's function; however, their association with cardiovascular outcomes is under-researched.
  • This study involved measuring various ANGPTL proteins and complexes in two large population studies (LURIC and getABI) focusing on cardiovascular health and outcomes over several years.
  • Findings showed that while ANGPTL3/8 inhibited LPL activity and correlated with increased LDL-C and triglycerides, they did not predict cardiovascular death; however, ANGPTL4/8 and CD-ANGPTL4 were linked to higher diabetes prevalence and increased cardiovascular mortality risk.
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  • Genetic studies have highlighted the need for more diverse research on plasma fibrinogen levels, as previous studies largely focused on Europeans, leading to gaps in understanding and missing heritability.
  • By analyzing data from whole-genome sequencing and genotype data from large cohorts, researchers identified 18 genetic loci related to fibrinogen levels, some of which are more common in African populations and include variants that may impact protein function.
  • The study's findings indicate a connection between fibrinogen levels and various health conditions, emphasizing the importance of whole-genome sequencing in discovering genetic factors in diverse populations and enhancing knowledge about fibrinogen regulation.
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Eastern and Western Finns show a striking difference in coronary heart disease-related mortality; genetics is a known contributor for this discrepancy. Here, we discuss the potential role of DNA methylation in mediating the discrepancy in cardiometabolic disease-risk phenotypes between the sub-populations. We used data from the Young Finns Study ( = 969) to compare the genome-wide DNA methylation levels of East- and West-originating Finns.

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Background: Metabolic clusters can stratify subgroups of individuals at risk for type 2 diabetes mellitus and related complications. Since obesity and insulin resistance are closely linked to alterations in hemostasis, we investigated the association between plasmatic coagulation and metabolic clusters including the impact on survival.

Methods: Utilizing data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, we assigned 917 participants without diabetes to prediabetes clusters, using oGTT-derived glucose and insulin, high-density lipoprotein cholesterol, triglycerides, and anthropometric data.

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Aims: Inflammation accompanies heart failure (HF) and elevated levels of inflammatory biomarkers are linked to new onset of HF. However, whether the prognostic relevance of inflammatory biomarkers is different in HF with reduced (HFrEF) and preserved ejection fraction (HFpEF) is unclear. The aim of the current study is to explore the role of inflammation on the mortality risk in patients with HF.

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Background: Severe hypertriglyceridemia (HTG) has predominantly multifactorial causes (MCS). Yet a small subset of patients have the monogenetic form (FCS). It remains a challenge to distinguish patients clinically, since decompensated MCS might mimic FCS´s severity.

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Objectives: The role of vitamin D deficiency in cardiovascular disease (CVD) is controversial. Inherent biological and analytical limitations compromise the specificity of widely used 25-hydroxyvitamin D [25(OH)D] cut-offs. Simultaneous determination of 25(OH)D and 24,25-dihydroxyvitamin D [24,25(OH)D] permits a functional assessment of vitamin D metabolism.

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  • PCSK9 is important in lipid metabolism, with higher levels in women throughout their lives, and statin treatment influences these levels with potential genetic variances affecting results by sex.* -
  • The study involved meta-analyses of PCSK9 levels in over 14,000 individuals, analyzing the effects of both sex and statin treatment on genetic associations related to PCSK9 and LDL cholesterol levels.* -
  • Results highlighted 11 genetic loci linked to PCSK9, with some showing different effects based on sex and statin status, including novel associations for specific groups; this suggests distinct genetic influences on cholesterol levels based on gender and medication use.*
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  • * Discovery of 7 new genetic loci associated with FVIII and 1 new locus for VWF, supporting their roles in thrombotic outcomes via Mendelian randomization.
  • * Functional testing revealed that silencing genes like B3GNT2 and CD36 impacted FVIII and VWF release from endothelial cells, indicating their potential regulatory roles.
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X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1.

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Aims: To investigate the prevalence of familial hypercholesterolaemia (FH) and compare the performance of clinical criteria and genetic testing in patients undergoing coronary angiography.

Methods And Results: The prevalence of FH was determined with the Dutch Lipid Clinical Network (DLCN), US 'Make Early Diagnosis to Prevent Early Death' (US-MEDPED), Simon Broome (SB) criteria, the 'familial hypercholesterolaemia case ascertainment tool' (FAMCAT), and a clinical algorithm. Genetic screening was conducted with a custom array from Affymetrix (CARRENAL array) harbouring 944 FH mutations.

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  • - The study utilized a tree-like graph structure to represent the diverse characteristics of type 2 diabetes, analyzing 927 participants with recent-onset diabetes to identify key health factors and complications over time.
  • - Participants were evaluated on clinical and laboratory measures, including insulin sensitivity and secretion, and factors such as hepatic lipid content and inflammatory biomarkers were linked to different progression outcomes in diabetes.
  • - Findings revealed that lower insulin sensitivity correlated with higher liver fat, inflammation, and cardiovascular risk, while lower insulin secretion was associated with greater need for insulin therapy and increased chance of diabetic neuropathy.
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Lower extremity amputation and requirement of peripheral artery revascularization are common outcomes of undiagnosed peripheral artery disease patients. In the current work, prediction models for the need of amputation or peripheral revascularization focused on hypertensive patients within seven years follow up are employed. We applied machine learning (ML) models using classifiers such as Extreme Gradient Boost (XGBoost), Random Forest (RF) and Adaptive Boost (AdaBoost), that will allow clinicians to identify the patients at risk of these two endpoints using simple clinical data.

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Clinically, disorders of lipid metabolism often remain without symptoms. Typical skin lesions, however, can be indicative. Secondary hyperlipoproteinemias (HLP) are more common than primary hyperlipoproteinemias; they can (partially) be improved by treating the underlying disease.

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Introduction: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) are risk factors for cardiovascular mortality (CVM). Pulse pressure (PP) is an easily available parameter of vascular stiffness, but its impact on CVM in chronic dialysis patients with diabetes is unclear.

Methods: Therefore, we have examined the predictive value of baseline, predialytic PP, SBP, DBP, and MAP in the German Diabetes and Dialysis (4D) study, a prospective, randomized, double-blind trial enrolling 1,255 patients with type 2 diabetes on hemodialysis in 178 German dialysis centers.

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Background: Determining serum 25-hydroxyvitamin D [25(OH)D], 24,25-dihydroxyvitamin D [24,25(OH)2D] and the vitamin D metabolite ratio (VMR) allows the identification of individuals with a low vitamin D metabolite profile. Here, we evaluated if such a functional approach provides superior diagnostic information to serum 25(OH)D alone.

Methods: 25(OH)D, 24,25(OH)2D, and the VMR were determined in participants of the DESIRE (Desirable Vitamin D Concentrations, n = 2010) and the LURIC (Ludwigshafen Risk and Cardiovascular Health, n = 2456) studies.

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Background: Heterogeneous metabolic clusters have been identified in diabetic and prediabetic states. It is not known whether such pathophysiologic clusters impact survival in at-risk persons being evaluated for coronary heart disease.

Methods: The LURIC Study recruited patients referred for coronary angiography at a median age of 63 (IQR 56-70) with a follow-up of 16.

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  • This study examines the relationship between resting heart rate and cardiovascular diseases, identifying 493 genetic variants linked to this trait through a large-scale analysis of 835,465 individuals.
  • It highlights the significance of higher genetically predicted resting heart rates, which are associated with an increased risk of dilated cardiomyopathy but lower risk for conditions like atrial fibrillation and ischemic strokes.
  • The study also challenges previous findings on resting heart rate and all-cause mortality, suggesting earlier results may have been influenced by biases, ultimately enhancing our understanding of the biological implications of resting heart rate in cardiovascular health.
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Background: Different observations have suggested that patients with depression have a higher risk for a number of comorbidities and mortality. The underlying causes have not been fully understood yet.

Aims: The aim of our study was to investigate the association of a genetic depression risk score (GDRS) with mortality [all-cause and cardiovascular (CV)] and markers of depression (including intake of antidepressants and a history of depression) in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study involving 3,316 patients who had been referred for coronary angiography.

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