Publications by authors named "Robin P F Dullaart"

294 Publications

High Plasma Levels of Betaine, a Trimethylamine N-Oxide Related Metabolite, are Associated with Severity of Cirrhosis.

Liver Int 2022 May 18. Epub 2022 May 18.

Department of Endocrinology, University of Groningen, University Medical Center Groningen, The Netherlands.

Background And Aims: The gut microbiome-related metabolites betaine and trimethylamine N-oxide (TMAO) affect major health issues. In cirrhosis, betaine metabolism may be diminished due to impaired hepatic betaine homocysteine methyltransferase activity, whereas TMAO generation from trimethylamine may be altered due to impaired hepatic flavin monooxygenase expression. Here we determined plasma betaine and TMAO levels in patients with end-stage liver disease and assessed their relationships with liver disease severity.

Methods: Plasma betaine and TMAO concentrations were measured by nuclear magnetic resonance spectroscopy in 129 cirrhotic patients (TransplantLines cohort study; NCT03272841) and compared with levels from 4,837 participants of the PREVEND cohort study. Disease severity was assessed by Child-Pugh-Turcotte (CPT) classification and Model for End-stage Liver Disease (MELD) score.

Results: Plasma betaine was on average 60% higher (P<0.001), whereas TMAO was not significantly lower in cirrhotic patients vs. PREVEND population (P=0.44). After liver transplantation (n=13), betaine decreased (P=0.017; P=0.36 vs. PREVEND population), whereas TMAO levels tended to increase (P=0.085) to higher levels than in the PREVEND population (P=0.003). Betaine levels were positively associated with CPT stage and MELD score (both P<0.001). The association with MELD score remained in fully adjusted analysis (P<0.001). The association of TMAO with MELD score did not reach significance (P=0.11). Neither betaine, nor TMAO levels were associated with mortality on the waiting list for liver transplantation (adjusted P=0.78 and P=0.44, respectively).

Conclusion: Plasma betaine levels are elevated in cirrhotic patients in parallel with disease severity, and decrease after liver transplantation.
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http://dx.doi.org/10.1111/liv.15310DOI Listing
May 2022

Nuclear Magnetic Resonance-Measured Ionized Magnesium Is Inversely Associated with Type 2 Diabetes in the Insulin Resistance Atherosclerosis Study.

Nutrients 2022 Apr 25;14(9). Epub 2022 Apr 25.

Laboratory Corporation of America Holdings (Labcorp), Morrisville, NC 27560, USA.

The aims were to optimize a nuclear magnetic resonance (NMR)-based assay for quantifying ionized or free magnesium and investigate its association with type 2 diabetes (T2D). A high-throughput, ionized magnesium assay was optimized and evaluated. Plasma magnesium was quantified, and associations with T2D were ascertained in Insulin Resistance Atherosclerosis Study (IRAS) participants. Coefficients of variation for the ionized magnesium assay ranged from 0.7-1.5% for intra-assay and 4.2-4.7% for inter-assay precision. In IRAS (n = 1342), ionized magnesium was significantly lower in subjects with prediabetes and T2D than in normoglycemic subjects, and lower in participants with T2D than those with prediabetes ( < 0.0001). Cross-sectional regression analyses revealed that magnesium was associated with T2D at baseline in models adjusted for multiple clinical risk factors ( = 0.032). This association appeared to be modified by sex, in such a way that the associations were present in women (OR = 0.54 (95% CI 0.37-0.79), = 0.0015) and not in men (OR = 0.98 (95% CI 0.71-1.35), = 0.90). Longitudinal regression analyses revealed an inverse association between magnesium and future T2D in the total population ( = 0.035) that was attenuated by LP-IR ( = 0.22). No interactions were detected between magnesium and age, race, BMI, glucose, insulin, triglycerides, or LPIR for the prospective association with future T2D. However, a significant interaction between magnesium and sex was present, now with a trend for an association in men (OR = 0.75 (95% CI 0.55-1.02), = 0.065 and absence of an association in women (OR = 1.01 (0.76-1.33), = 0.97). Conclusions: lower ionized magnesium, as measured by an NMR-based assay optimized for accuracy and precision, was associated cross-sectionally with T2D at baseline and longitudinally with incident T2D in IRAS.
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http://dx.doi.org/10.3390/nu14091792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103587PMC
April 2022

Lipoprotein Z, an abnormal LDL-like lipoprotein, independently predicts mortality in cirrhosis.

Eur J Intern Med 2022 Apr 1. Epub 2022 Apr 1.

Department of Internal Medicine, Division of Endocrinology, University Medical Center Groningen, University of Groningen, the Netherlands.

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http://dx.doi.org/10.1016/j.ejim.2022.03.030DOI Listing
April 2022

Remnant lipoprotein cholesterol is associated with incident new onset diabetes after transplantation (NODAT) in renal transplant recipients: results of the TransplantLines Biobank and cohort Studies.

Cardiovasc Diabetol 2022 03 16;21(1):41. Epub 2022 Mar 16.

Division of Clinical Chemistry, Department of Laboratory Medicine (LABMED), H5, Alfred Nobels Alle 8, Karolinska Institutet, 141 83, Stockholm, Sweden.

Background: New onset diabetes after transplantation (NODAT) is a frequent and serious complication of renal transplantation resulting in worse graft and patient outcomes. The pathophysiology of NODAT is incompletely understood, and no prospective biomarkers have been established to predict NODAT risk in renal transplant recipients (RTR). The present work aimed to determine whether remnant lipoprotein (RLP) cholesterol could serve as such a biomarker that would also provide a novel target for therapeutic intervention.

Methods: This longitudinal cohort study included 480 RTR free of diabetes at baseline. 53 patients (11%) were diagnosed with NODAT during a median [interquartile range, IQR] follow-up of 5.2 [4.1-5.8] years. RLP cholesterol was calculated by subtracting HDL and LDL cholesterol from total cholesterol values (all directly measured).

Results: Baseline remnant cholesterol values were significantly higher in RTR who subsequently developed NODAT (0.9 [0.5-1.2] mmol/L vs. 0.6 [0.4-0.9] mmol/L, p = 0.001). Kaplan-Meier analysis showed that higher RLP cholesterol values were associated with an increased risk of incident NODAT (log rank test, p < 0.001). Cox regression demonstrated a significant longitudinal association between baseline RLP cholesterol levels and NODAT (HR, 2.27 [1.64-3.14] per 1 SD increase, p < 0.001) that remained after adjusting for plasma glucose and HbA1c (p = 0.002), HDL and LDL cholesterol (p = 0.008) and use of immunosuppressive medication (p < 0.001), among others. Adding baseline remnant cholesterol to the Framingham Diabetes Risk Score significantly improved NODAT prediction (change in C-statistic, p = 0.01).

Conclusions: This study demonstrates that baseline RLP cholesterol levels strongly associate with incident NODAT independent of several other recognized risk factors.
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http://dx.doi.org/10.1186/s12933-022-01475-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8925054PMC
March 2022

Incorporating Baseline Outcome Data in Individual Participant Data Meta-Analysis of Non-randomized Studies.

Front Psychiatry 2022 22;13:774251. Epub 2022 Feb 22.

Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland.

Background: In non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC).

Methods: For the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA.

Results: Ten of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score.

Conclusion: ANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.
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http://dx.doi.org/10.3389/fpsyt.2022.774251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8902696PMC
February 2022

Profoundly Disturbed Lipoproteins in Cirrhotic Patients: Role of Lipoprotein-Z, a Hepatotoxic LDL-like Lipoprotein.

J Clin Med 2022 Feb 24;11(5). Epub 2022 Feb 24.

Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

Detailed information regarding lipoprotein concentrations and subfractions in cirrhotic patients before and after orthotopic liver transplantation (OLT) is lacking. Lipoprotein-Z (LP-Z) is a recently characterised abnormal, hepatotoxic free cholesterol-rich low-density lipoprotein (LDL)-like lipoprotein. We determined the lipoprotein profiles, including LP-Z, in cirrhotic patients and OLT recipients and assessed the prognostic significance of LP-Z on the OLT waiting list. We performed analyses in cirrhotic transplant candidates and non-cirrhotic OLT recipients. A population-based cohort was used as reference. The setting was a University hospital. Lipoprotein particle concentrations and subfractions were measured by nuclear magnetic resonance spectroscopy. In the cirrhotic patients (N = 130), most measures of triglyceride-rich lipoproteins (TRL), LDL, and high-density lipoproteins (HDL) were much lower compared to the OLT recipients (N = 372) and controls (N = 6027) ( < 0.01). In the OLT recipients, many lipoprotein variables were modestly lower, but HDL-cholesterol, triglycerides, and TRL and HDL size were greater vs. the control population. LP-Z was measurable in 40 cirrhotic patients and 3 OLT recipients (30.8% vs. 0.8%, < 0.001). The cirrhotic patients with measurable LP-Z levels had profoundly lower HDL-cholesterol and particle concentrations ( < 0.001), and worse Child Pugh Turcotte classifications and MELD scores. The presence of LP-Z (adjusted for age, sex, and MELD score) predicted worse survival in cirrhotic patients (HR per 1 LnSD increment: 1.11, 95%CI 1.03-1.19, = 0.003). In conclusion, cirrhotic patients have considerably lower plasma concentrations of all major lipoprotein classes with changes in lipoprotein subfraction distribution. After OLT, these lipoprotein abnormalities are in part reversed. LP-Z is associated with cirrhosis. Its presence may translate in disturbed HDL metabolism and worse survival.
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http://dx.doi.org/10.3390/jcm11051223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8910943PMC
February 2022

Branched chain amino acids are associated with metabolic complications in liver transplant recipients.

Clin Biochem 2022 Apr 7;102:26-33. Epub 2022 Feb 7.

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, The Netherlands. Electronic address:

Background: Obesity, dyslipidemia and type 2 diabetes (T2D) contribute substantially to increased cardiovascular morbidity and mortality in patients after orthotopic liver transplantation (OLTx). Elevated plasma branched chain amino acids (BCAA) are linked to metabolic disturbances and cardiovascular disease (CVD) risk profiles in several non-OLTx populations.

Methods: Cross-sectional analysis of liver transplant recipients from TransplantLines, a single-center biobank and cohort study. BCAA plasma levels were measured by means of nuclear-magnetic resonance spectroscopy. CVD and cardiometabolic factors were collected by using data from electronic patient records. Associations were determined between BCAA plasma levels and T2D, Metabolic Syndrome (MetS), CVD as well as mTOR inhibition in liver transplant recipients.

Results: 336 Patients were divided into sex-stratified tertiles of total BCAA. MetS (P < 0.001) and T2D (P = 0.002) were significantly more frequent in subjects in the highest BCAA tertile. In logistic regression analyses, the multivariable adjusted odds ratio (OR) per 1 standard deviation increase in BCAA was 1.68 (95%CI: 1.18-2.20, P = 0.003) for MetS and 1.60 (95%CI: 1.14-2.23, P = 0.006) for T2D. Use of Sirolimus (mTOR inhibitor) was significantly associated with higher BCAA plasma levels, independent of age, sex, time after OLTx, MetS and other immunosuppressive medication (adjusted P = 0.002).

Conclusion: Elevated BCAA plasma levels are associated with T2D, MetS and use of Sirolimus in liver transplant recipients. BCAA plasma levels may represent a valuable biomarker for cardiometabolic complications after OLTx.
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http://dx.doi.org/10.1016/j.clinbiochem.2022.01.009DOI Listing
April 2022

Higher Free Triiodothyronine Is Associated With Higher HDL Particle Concentration and Smaller HDL Particle Size.

J Clin Endocrinol Metab 2022 Apr;107(5):e1807-e1815

Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

Context: Thyroid function status has effects on the development of atherosclerotic cardiovascular disease by affecting lipid metabolism, but associations of high-density lipoprotein (HDL) particle concentrations and subfractions with thyroid hormone levels within the reference range remain elusive.

Objective: The aim of the present study was to determine the associations of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels with HDL particle characteristics in euthyroid individuals.

Methods: This cross-sectional study on the associations of thyroid hormones with HDL particle concentrations, HDL subfractions, and HDL particle size included 5844 euthyroid individuals (FT3, FT4, and TSH levels within the reference range and no medication use affecting thyroid function), participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. HDL particles and subfractions were measured by nuclear magnetic resonance using an optimized version of the NMR LipoProfile Test (LP4).

Results: In multivariable linear regression analyses, FT3 was positively associated with total HDL particle concentration (std.β = 0.14; P < 0.001) and with small (std.β = 0.13; P < 0.001) and medium-sized HDL particles (std.β = 0.05; P = 0.001). Conversely, FT3 was inversely associated with large HDL particles (std.β = -0.07; P < 0.001) and with HDL particle size (std.β = -0.08; P < 0.001). Such associations with FT4 or reciprocally with TSH were less pronounced or nonsignificant.

Conclusion: In euthyroid individuals, higher FT3 is cross-sectionally associated with higher total HDL particle concentration and with lower HDL particle size. These associations may be relevant to better understand the role of HDL in thyroid function-associated atherosclerotic cardiovascular disease.
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http://dx.doi.org/10.1210/clinem/dgac044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9016450PMC
April 2022

Association of diuretic use with increased risk for long-term post-transplantation diabetes mellitus in kidney transplant recipients.

Nephrol Dial Transplant 2022 Jan 29. Epub 2022 Jan 29.

Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Post-transplantation diabetes mellitus (PTDM) is a major clinical problem in kidney transplant recipients (KTRs). Diuretic-induced hyperglycemia and diabetes have been described in the general population. We aimed to investigate whether diuretics also increase PTDM risk in KTRs.

Methods: We included 486 stable outpatient KTRs (with a functioning graft ≥ 1 year) without diabetes from a prospective cohort study. Participants were classified as diuretic users and non-users based on their medication use verified by medical records.

Results: At current baseline study, 168 (35%) KTRs used a diuretic (thiazide, n = 74; loop diuretic, n = 76; others, n = 18) and 318 KTRs did not use a diuretic. After 5.2 (IQR, 4.0‒5.9) years of follow up, 54 (11%) KTRs developed PTDM. In Cox regression analyses, diuretic use was associated with incident PTDM, independent of age, sex, fasting plasma glucose (FPG), and HbA1c (hazard ratio[HR] 3.28, 95% CI 1.84-5.83; P < 0.001). Further adjustment for potential confounders, including lifestyle, family history of cardiovascular disease, use of other medication, kidney function, transplantation-specific parameters, BMI, lipids, and blood pressure did not materially change the association. Moreover, in Cox regression analyses, both thiazide and loop diuretics associated with the development of PTDM, independent of age, sex, FPG, and HbA1c ([HR 2.70, 95% CI 1.24-5.29; P = 0.012], and [HR 5.08, 95% CI 2.49-10.34; P < 0.001], respectively).

Conclusions: This study demonstrates that diuretics overall are associated with increased risk of developing PTDM in KTRs, independent of established risk factors for PTDM development. The association was present both for thiazide and loop diuretics.
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http://dx.doi.org/10.1093/ndt/gfac012DOI Listing
January 2022

Low Detection Rates of Genetic FH in Cohort of Patients With Severe Hypercholesterolemia in the United Arabic Emirates.

Front Genet 2021 3;12:809256. Epub 2022 Jan 3.

Imperial College London Diabetes Centre, Abu Dhabi, United Arab Emirates.

Programs to screen for Familial hypercholesterolemia (FH) are conducted worldwide. In Western societies, these programs have been shown to be cost-effective with hit/detection rates of 1 in 217-250. Thus far, there is no published data on genetic FH in the Gulf region. Using United Arab Emirates as a proxy for the Gulf region, we assessed the prevalence of genetically confirmed FH in the Emirati population sample. We recruited 229 patients with LDL-C >95 percentile and employed a customized next generation sequencing pipeline to screen canonical FH genes (). Participants were characterized by mean total cholesterol and low-density lipoprotein cholesterol (LDL-c) of 6.3 ± 1.1 and 4.7 ± 1.1 mmol/L respectively. Ninety-six percent of the participants were using lipid-lowering medication with mean corrected LDL-c values of 10.0 ± 3.0 mmol/L 15 out of 229 participants were found to suffer from genetically confirmed FH. Carriers of causal genetic variants for FH had higher on-treatment LDL-c compared to those without causal variants (5.7 ± 1.5 vs 4.7 ± 1.0; = 3.7E-04). The groups did not differ regarding high-density lipoprotein cholesterol, triglycerides, body mass index, blood pressure, glucose, and glycated haemoglobin. This study reveals a low 7% prevalence of genetic FH in Emiratis with marked hypercholesterolemia as determined by correcting LDL-c for the use of lipid-lowering treatment. The portfolio of mutations identified is, to a large extent, unique and includes gene duplications. Our findings warrant further studies into origins of hypercholesterolemia in these patients. This is further supported by the fact that these patients are also characterized by high prevalence of type 2 diabetes (42% in the current study cohort) which already puts them at an increased risk of atherosclerotic cardiovascular disease. These results may also be useful in public health initiatives for FH cascade screening programs in the UAE and maybe the Gulf region.
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http://dx.doi.org/10.3389/fgene.2021.809256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8762259PMC
January 2022

Temporal Course of Plasma Trimethylamine N-Oxide (TMAO) Levels in ST-Elevation Myocardial Infarction.

J Clin Med 2021 Dec 1;10(23). Epub 2021 Dec 1.

Department of Cardiology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.

The gut metabolite trimethylamine N-oxide (TMAO) at admission has a prognostic value in ST-elevation myocardial infarction (STEMI) patients. However, its sequential changes and relationship with long-term infarct-related outcomes after primary percutaneous coronary intervention (PCI) remain elusive. We delineated the temporal course of TMAO and its relationship with infarct size and left ventricular ejection fraction (LVEF) post-PCI, adjusting for the estimated glomerular filtration rate (eGFR). We measured TMAO levels at admission, 24 h and 4 months post-PCI in 379 STEMI patients. Infarct size and LVEF were determined by cardiac magnetic resonance 4 months after PCI. TMAO levels decreased from admission (4.13 ± 4.37 μM) to 24 h (3.41 ± 5.84 μM, = 0.001) and increased from 24 h to 4 months (3.70 ± 3.86 μM, = 0.026). Higher TMAO values at 24 h were correlated to smaller infarct sizes (rho = -0.16, = 0.024). Larger declines between admission and 4 months suggestively correlated with smaller infarct size, and larger TMAO increases between 24 h and 4 months were associated with larger infarct size (rho = -0.19, = 0.008 and rho = -0.18, = 0.019, respectively). Upon eGFR stratification using 90 mL/min/1.73 m as a cut-off, significant associations between TMAO and infarct size were only noted in subjects with impaired renal function. In conclusion, TMAO levels in post-PCI STEMI patients are prone to fluctuations, and these fluctuations could be prognostic for infarct size, particularly in patients with impaired renal function.
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http://dx.doi.org/10.3390/jcm10235677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658331PMC
December 2021

Lipoprotein particle sizes and incident type 2 diabetes: the PREVEND cohort study.

Diabetologia 2022 02 20;65(2):402-405. Epub 2021 Nov 20.

Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

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http://dx.doi.org/10.1007/s00125-021-05603-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741709PMC
February 2022

Association of Circulating Ketone Bodies With Functional Outcomes After ST-Segment Elevation Myocardial Infarction.

J Am Coll Cardiol 2021 10;78(14):1421-1432

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: Circulating ketone bodies (KBs) are increased in patients with heart failure (HF), corresponding with increased cardiac KB metabolism and HF severity. However, the role of circulating KBs in ischemia/reperfusion remains unknown.

Objectives: This study sought to investigate longitudinal changes of KBs and their associations with functional outcomes in patients presenting with ST-segment elevation myocardial infarction (STEMI).

Methods: KBs were measured in 369 participants from a randomized trial on early metformin therapy after STEMI. Nonfasting plasma concentrations of KBs (β-hydroxybutyrate, acetoacetate, and acetone) were measured by nuclear magnetic resonance spectroscopy at presentation, at 24 hours, and after 4 months. Myocardial infarct size and left ventricular ejection fraction (LVEF) were determined by cardiac magnetic resonance imaging at 4 months. Associations of circulating KBs with infarct size and LVEF were determined using multivariable linear regression analyses.

Results: Circulating KBs were high at presentation with STEMI (median total KBs: 520 μmol/L; interquartile range [IQR]: 315-997 μmol/L). At 24 hours after reperfusion, KBs were still high compared with levels at 4-month follow-up (206 μmol/L [IQR: 174-246] vs 166 μmol/L [IQR: 143-201], respectively; P < 0.001). Increased KB concentrations at 24 hours were independently associated with larger myocardial infarct size (total KBs, per 100 μmol/L: β = 1.56; 95% confidence interval: 0.29-2.83; P = 0.016) and lower LVEF (β = -1.78; 95% CI: (-3.17 to -0.39; P = 0.012).

Conclusions: Circulating KBs are increased in patients presenting with STEMI. Higher KBs at 24 hours are associated with functional outcomes after STEMI, which suggests a potential role for ketone metabolism in response to myocardial ischemia. (Metabolic Modulation With Metformin to Reduce Heart Failure After Acute Myocardial Infarction: Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III): a Randomized Controlled Trial; NCT01217307).
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http://dx.doi.org/10.1016/j.jacc.2021.07.054DOI Listing
October 2021

Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.

JAMA Intern Med 2021 11;181(11):1440-1450

Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea.

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings.

Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia.

Design, Setting, And Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021.

Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values.

Main Outcomes And Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated.

Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia.

Conclusions And Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.
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http://dx.doi.org/10.1001/jamainternmed.2021.5078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424529PMC
November 2021

Mahalanobis distance, a novel statistical proxy of homeostasis loss is longitudinally associated with risk of type 2 diabetes.

EBioMedicine 2021 Sep 20;71:103550. Epub 2021 Aug 20.

Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen 9713 GZ, the Netherlands.

Background: The potential role of individual plasma biomarkers in the pathogenesis of type 2 diabetes (T2D) has been broadly studied, but the impact of biomarkers interaction remains underexplored. Recently, the Mahalanobis distance (MD) of plasma biomarkers has been proposed as a proxy of physiological dysregulation. Here we aimed to investigate whether the MD calculated from circulating biomarkers is prospectively associated with development of T2D.

Methods: We calculated the MD of the Principal Components (PCs) integrating the information of 32 circulating biomarkers (comprising inflammation, glycemic, lipid, microbiome and one-carbon metabolism) measured in 6247 participants of the PREVEND study without T2D at baseline. Cox proportional-hazards regression analyses were performed to study the association of MD with T2D development.

Findings: After a median follow-up of 7·3 years, 312 subjects developed T2D. The overall MD (mean (SD)) was higher in subjects who developed T2D compared to those who did not: 35·65 (26·67) and 30.75 (27·57), respectively (P = 0·002). The highest hazard ratio (HR) was obtained using the MD calculated from the first 31 PCs (per 1 log-unit increment) (1·72 (95% CI 1·42,2·07), P < 0·001). Such associations remained after the adjustment for age, sex, plasma glucose, parental history of T2D, lipids, blood pressure medication, and BMI (HR 1·37 (95% CI 1·11,1·70), P = 0·004).

Interpretation: Our results are in line with the premise that MD represents an estimate of homeostasis loss. This study suggests that MD is able to provide information about physiological dysregulation also in the pathogenesis of T2D.

Funding: The Dutch Kidney Foundation (Grant E.033).
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http://dx.doi.org/10.1016/j.ebiom.2021.103550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379628PMC
September 2021

Plasma creatine concentration is associated with incident hypertension in a cohort enriched for the presence of high urinary albumin concentration: the Prevention of Renal and Vascular Endstage Disease study.

J Hypertens 2022 02;40(2):229-239

Department of Internal Medicine.

Objective: : Hypertension is a major risk factor for cardiovascular disease, kidney disease, and premature death. Increased levels of creatine kinase are associated with development of hypertension. However, it is unknown if creatine, a substrate of CK, is associated with the development of hypertension. We therefore, aimed to investigate the association between plasma creatine concentration and incident hypertension.

Methods: We measured fasting plasma creatine concentrations by nuclear magnetic resonance spectroscopy in participants of the population-based PREVEND study. The study outcome was incident hypertension, defined as either a SBP of at least 140 mmHg, a DBP of at least 90 mmHg, or the new usage of antihypertensive drugs. Participants with hypertension at baseline were excluded.

Results: We included 3135 participants (46% men) aged 49 ± 10 years. Mean plasma creatine concentrations were 36.2 ± 17.5 μmol/l, with higher concentrations in women than in men (42.2 ± 17.6 versus 29.2 ± 17.6 μmol/l; P < 0.001). During a median of 7.1 [interquartile range: 3.6-7.6] years of follow-up, 927 participants developed incident hypertension. Higher plasma creatine concentrations were associated with an increased risk of incident hypertension [HR per doubling of plasma creatine: 1.21 (95% confidence interval: 1.10-1.34); P < 0.001], which remained significant after adjustment for potential confounders. Sex-stratified analyses demonstrated higher plasma creatine that was independently associated with an increased risk of incident hypertension in men [hazard ratio: 1.26 (95% CI 1.11-1.44); P < 0.001], but not in women (hazard ratio: 1.13 (95% CI 0.96-1.33); P = 0.14]. Causal pathway analyses demonstrate that the association was not explained by sodium or protein intake.

Conclusion: Higher plasma creatine is associated with an increased risk of hypertension in men. Future studies are warranted to determine the underlying mechanisms.
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http://dx.doi.org/10.1097/HJH.0000000000002996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728759PMC
February 2022

A metabolomic index based on lipoprotein subfractions and branched chain amino acids is associated with incident hypertension.

Eur J Intern Med 2021 Dec 25;94:56-63. Epub 2021 Jul 25.

Department of Internal Medicine, Division of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Objective: The present study aims to evaluate the performance of the Diabetes Risk Index (DRI), a metabolomic index based on lipoprotein particles and branched chain amino acids, on the incidence of newly developed hypertension in a large community dwelling cohort.

Methods: The DRI was calculated by combining 6 lipoprotein parameters [sizes of very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), concentrations of large VLDL, small LDL, and large HDL particles], and the concentrations of valine and leucine. DRI scores were estimated in 4169 participants from the PREVEND prospective cohort. Cox proportional hazards regression was used to evaluate the association of DRI scores with incident hypertension.

Results: During a median follow-up of 8.6 years, 924 new hypertension cases were ascertained. In analyses adjusted for age and sex, there was a significant association between DRI and incident hypertension with a hazard ratio (HR) per 1 SD increase of 1.45 (95% CI 1.36,1.54; p < 0.001). After additional adjustment for traditional risk factors, the HR remained significant (HR 1.21, 95% CI 1.10, 1.33, p <0.001). Likewise, subjects in the top quartile of DRI presented with a higher risk of hypertension (HR 1.64, 95% CI 1.28, 2.10, p <0.001). Furthermore, the net reclassification improvement assessment improved after the addition of DRI to a traditional risk model (p <0.001), allowing proper reclassification of 34% of the participants.

Conclusion: Higher DRI scores were associated with an increased risk of incident hypertension. Such association was independent of traditional clinical risk factors for hypertension.
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http://dx.doi.org/10.1016/j.ejim.2021.07.002DOI Listing
December 2021

Triglyceride-rich lipoprotein and LDL particle subfractions and their association with incident type 2 diabetes: the PREVEND study.

Cardiovasc Diabetol 2021 07 28;20(1):156. Epub 2021 Jul 28.

Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Triglyceride-rich lipoproteins particles (TRLP) and low density lipoprotein particles (LDLP) vary in size. Their association with β-cell function is not well described. We determined associations of TRLP and LDLP subfractions with β-cell function, estimated as HOMA-β, and evaluated their associations with incident T2D in the general population.

Methods: We included 4818 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study without T2D at baseline. TRLP and LDLP subfraction concentrations and their average sizes were measured using the LP4 algorithm of the Vantera nuclear magnetic resonance platform. HOMA-IR was used as measure of insulin resistance. HOMA-β was used as a proxy of β-cell function.

Results: In subjects without T2D at baseline, very large TRLP, and LDL size were inversely associated with HOMA-β, whereas large TRLP were positively associated with HOMA-β when taking account of HOMA-IR. During a median follow-up of 7.3 years, 263 participants developed T2D. In multivariable-adjusted Cox regression models, higher concentrations of total, very large, large, and very small TRLP (reflecting remnants lipoproteins) and greater TRL size were associated with an increased T2D risk after adjustment for relevant covariates, including age, sex, BMI, HDL-C, HOMA-β, and HOMA-IR. On the contrary, higher concentrations of large LDLP and greater LDL size were associated with a lower risk of developing T2D.

Conclusions: Specific TRL and LDL particle characteristics are associated with β-cell function taking account of HOMA-IR. Moreover, TRL and LDL particle characteristics are differently associated with incident T2D, even when taking account of HOMA-β and HOMA-IR.
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http://dx.doi.org/10.1186/s12933-021-01348-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320057PMC
July 2021

Nonalcoholic fatty liver disease, circulating ketone bodies and all-cause mortality in a general population-based cohort.

Eur J Clin Invest 2021 Dec 13;51(12):e13627. Epub 2021 Jun 13.

Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent, paralleling the obesity epidemic. Ketone bodies are produced in the liver, but it is currently uncertain whether circulating ketone bodies are increased in the context of NAFLD. We investigated the association between NAFLD and circulating ketone bodies and determined the extent to which NAFLD and circulating ketone bodies are associated with all-cause mortality.

Methods: Plasma ketone bodies were measured by nuclear magnetic resonance spectroscopy in participants of the general population-based PREVEND study. A fatty liver index (FLI) ≥60 was regarded as a proxy of NAFLD. Associations of an elevated FLI and ketone bodies with all-cause mortality were investigated using Cox regression analyses.

Results: The study included 6,297 participants aged 54 ± 12 years, of whom 1,970 (31%) had elevated FLI. Participants with elevated FLI had higher total ketone bodies (194 [153-259] vs 170 [133-243] µmol/L; P < .001) than participants without elevated FLI. During 7.9 [7.8-8.9] years of follow-up, 387 (6%) participants died. An elevated FLI was independently associated with an increased risk of mortality (HR: 1.34 [1.06-1.70]; P = .02). Higher total ketone bodies were also associated with an increased mortality risk (HR per doubling: 1.29 [1.12-1.49]; P < .001). Mediation analysis suggested that the association of elevated FLI with all-cause mortality was in part mediated by ketone bodies (proportion mediated: 10%, P < .001).

Conclusion: Circulating ketone bodies were increased in participants with suspected NAFLD. Both suspected NAFLD and higher circulating ketone bodies are associated with an increased risk of all-cause mortality.
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http://dx.doi.org/10.1111/eci.13627DOI Listing
December 2021

Circulating Trimethylamine N-Oxide Is Associated with Increased Risk of Cardiovascular Mortality in Type-2 Diabetes: Results from a Dutch Diabetes Cohort (ZODIAC-59).

J Clin Med 2021 May 24;10(11). Epub 2021 May 24.

Department of Internal Medicine, Division of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

Trimethylamine N-oxide (TMAO), a novel cardiovascular (CV) disease and mortality risk marker, is a gut microbiota-derived metabolite as well. Recently, plasma concentrations of branched-chain amino acids (BCAA) have been reported to be affected by microbiota. The association of plasma TMAO with CV mortality in Type 2 Diabetes (T2D) and its determinants are still incompletely described. We evaluated the association between plasma BCAA and TMAO, and the association of TMAO with CV mortality in T2D individuals. We used data of 595 participants (mean age 69.5 years) from the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort were analyzed. Plasma TMAO and BCAA were measured with nuclear magnetic resonance spectroscopy. CV mortality risk was estimated using multivariable-adjusted Cox regression models. Cross-sectionally, TMAO was independently associated with BCAA standardized (Std) β = 0.18 (95% Confidence Interval (CI) 0.09; 0.27), <0.001. During a median follow-up of 10 years, 113 CV deaths were recorded. In Cox regression analyses, adjusted for multiple clinical and laboratory variables including BCAA, TMAO was independently associated with CV mortality: adjusted hazard ratio (HR) 1.93 (95% CI 1.11; 3.34), = 0.02 (for the highest vs. the lowest tertile of the TMAO distribution). The same was true for analyses with TMAO as continuous variable: HR 1.32 (95% CI 1.07; 1.63), = 0.01 (per 1 SD increase). In contrast, BCAAs were not associated with increased CV mortality. In conclusion, higher plasma TMAO but not BCAA concentrations are associated with an increased risk of CV mortality in individuals with T2D, independent of clinical and biochemical risk markers.
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http://dx.doi.org/10.3390/jcm10112269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197378PMC
May 2021

Self-reported alcohol consumption, carbohydrate deficient transferrin and risk of cardiovascular disease: The PREVEND prospective cohort study.

Clin Chim Acta 2021 Sep 26;520:1-7. Epub 2021 May 26.

Department of Internal Medicine, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands.

Background: Self-reported alcohol consumption is an established risk factor for cardiovascular disease (CVD). Carbohydrate deficient transferrin (CDT) is an established objective marker of excessive alcohol consumption, but data on its prospective association with CVD are lacking. We aimed to evaluate the associations of self-reported alcohol consumption and CDT (expressed as %CDT, a more reliable marker than absolute CDT levels) with CVD risk.

Materials And Methods: In the PREVEND prospective study of 5,206 participants (mean age, 53 years; 47.7% males), alcohol consumption by self-reports, absolute CDT measured using the Siemens nephelometric assay and %CDT calculated as the percentage of total transferrin concentrations, were assessed at baseline. Alcohol consumption was classified into 5 categories: abstention (reference), light, light-moderate, moderate and heavy alcohol consumption.Hazard ratios (HRs) (95% confidence intervals [CI]) for first CVD events were estimated.

Results: Mean (SD) of %CDT was 1.59 (0.54) %. During a median follow-up of 8.3 years, 326 first CVD events were recorded. Compared with abstainers, the multivariable-adjusted HRs (95% CIs) of CVD for light, light-moderate, moderate and heavy alcohol consumption were 0.66 (0.46-0.95), 0.83 (0.62-1.11), 0.83 (0.61-1.14) and 0.80 (0.48-1.36), respectively. Light alcohol consumption was associated with reduced coronary heart disease risk 0.62 (0.40-0.96), whereas light-moderate alcohol consumption was associated with reduced stroke risk 0.45 (0.24-0.83). The association of %CDT with CVD risk was not significant.

Conclusions: Our findings confirm the established association between self-reported light to moderate alcohol consumption and reduced CVD risk. However, %CDT within the normal reference range may not be a risk indicator for CVD.
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http://dx.doi.org/10.1016/j.cca.2021.05.024DOI Listing
September 2021

Circulating trimethylamine-N-oxide is associated with all-cause mortality in subjects with nonalcoholic fatty liver disease.

Liver Int 2021 10 8;41(10):2371-2382. Epub 2021 Jun 8.

Department of Internal Medicine, Division of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background And Aims: Trimethylamine-N-oxide (TMAO), a gut microbiota-liver metabolite, has been associated with cardiometabolic disease. However, whether TMAO is associated with nonalcoholic fatty liver disease (NAFLD) and NAFLD-related health outcomes remains unclear. We aimed to investigate the association of TMAO with NAFLD and to assess the extent to which the association of TMAO with all-cause mortality is dependent on the presence of NAFLD in the general population.

Methods: We included 5292 participants enrolled in the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort study. Cox proportional-hazards regression analyses were performed to study the association of TMAO with all-cause mortality in subjects with and without a fatty liver index (FLI) ≥60, which was used as a proxy of NAFLD.

Results: During a median follow-up of 8.2 years, 307 subjects died, of whom 133 were classified with NAFLD. TMAO was positively and independently associated with baseline FLI (Std β 0.08, 95% CI 0.05, 0.11, P < .001). Higher TMAO was associated with increased risk of all-cause mortality in subjects with NAFLD, in crude analysis (hazard ratio [HR] per 1 SD, 2.55, 95% CI 1.60, 4.05, P < .001) and after full adjustment ( HR 1.90, 95% CI 1.18, 3.04, P = .008). Such an association was not present in subjects without NAFLD (crude HR 1.14, 95% CI 0.81, 1.71, P = .39; HR 0.95, 95% CI 0.65, 1.39, P = .78).

Conclusion: This prospective study revealed that plasma concentrations of TMAO were associated with all-cause mortality in subjects with NAFLD, independently of traditional risk factors.
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http://dx.doi.org/10.1111/liv.14963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518486PMC
October 2021

Sex Differences in Lipid Profile across the Life Span in Patients with Type 2 Diabetes: A Primary Care-Based Study.

J Clin Med 2021 Apr 19;10(8). Epub 2021 Apr 19.

Department of Internal Medicine, Martini Hospital, 9728NT Groningen, The Netherlands.

We assessed sex differences across the life span in the lipid profile of type 2 diabetes (T2D) patients treated and not treated with statins. We used the Groningen Initiative to ANalyze Type 2 diabetes Treatment database, which includes T2D patients from the north of the Netherlands. Patients with a full lipid profile determined between 2010 and 2012 were included. We excluded patients treated with other lipid-lowering drugs than statins. Sex differences in low- and high-density lipoprotein cholesterol (LDL-c and HDL-c) and triglyceride (TG) levels across 11 age groups stratified by statin treatment were assessed using linear regression. We included 26,849 patients (51% women, 55% treated with statins). Without statins, women had significantly lower LDL-c levels than men before the age of 45 years, similar levels between 45 and 49 years, and higher levels thereafter. With statins, similar LDL-c levels were shown up to the age of 55, and higher levels in women thereafter. Women had significantly higher HDL-c levels than men, regardless of age or statin treatment. Men had significantly higher TG levels up to the age of 55 and 60, depending on whether they did not take or took statins, respectively, and similar levels thereafter. When managing cardiovascular risk in patients with T2D, attention is needed for the menopausal status of women and for TG levels in younger men.
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http://dx.doi.org/10.3390/jcm10081775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072568PMC
April 2021

Plasma Vitamin C and Risk of Late Graft Failure in Kidney Transplant Recipients: Results of the TransplantLines Biobank and Cohort Study.

Antioxidants (Basel) 2021 Apr 21;10(5). Epub 2021 Apr 21.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

Recent studies have shown that depletion of vitamin C is frequent in outpatient kidney transplant recipients (KTR) and that vitamin C is inversely associated with risk of death. Whether plasma vitamin C is associated with death-censored kidney graft failure remains unknown. We investigated KTR who participated in the TransplantLines Insulin Resistance and Inflammation Biobank and Cohort Study. The primary outcome was graft failure (restart of dialysis or re-transplantation). Overall and stratified ( < 0.1) multivariable-adjusted Cox regression analyses are presented here. Among 598 KTR (age 51 ± 12 years-old; 55% males), baseline median (IQR) plasma vitamin C was 44.0 (31.0-55.3) µmol/L. Through a median follow-up of 9.5 (IQR, 6.3‒10.2) years, 75 KTR developed graft failure (34, 26, and 15 events over increasing tertiles of vitamin C, log-rank < 0.001). Plasma vitamin C was inversely associated with risk of graft failure (HR per 1-SD increment, 0.69; 95% CI 0.54-0.89; = 0.004), particularly among KTR with triglycerides ≥1.9 mmol/L (HR 0.46; 95% CI 0.30-0.70; < 0.001; = 0.01) and among KTR with HDL cholesterol ≥0.91 mmol/L (HR 0.56; 95% CI 0.38-0.84; = 0.01; = 0.04). These findings remained materially unchanged in multivariable-adjusted analyses (donor, recipient, and transplant characteristics, including estimated glomerular filtration rate and proteinuria), were consistent in categorical analyses according to tertiles of plasma vitamin C, and robust after exclusion of outliers. Plasma vitamin C in outpatient KTR is inversely associated with risk of late graft failure. Whether plasma vitamin C‒targeted therapeutic strategies represent novel opportunities to ease important burden of graft failure necessitates further studies.
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http://dx.doi.org/10.3390/antiox10050631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143099PMC
April 2021

High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events.

Circulation 2021 05 12;143(20):1935-1945. Epub 2021 Apr 12.

Department of Pediatrics (C.J., J.L.C.A., U.J.F.T.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: The role of high-density lipoprotein (HDL) function in cardiovascular disease represents an important emerging concept. The present study investigated whether HDL anti-inflammatory capacity is prospectively associated with first cardiovascular events in the general population.

Methods: HDL anti-inflammatory capacity was determined as its ability to suppress TNFα (tumor necrosis factor α)-induced VCAM-1 (vascular cell adhesion molecule-1) mRNA expression in endothelial cells in vitro (results expressed as achieved percent reduction by individual HDL related to the maximum TNFα effect with no HDL present). In a nested case-control design of the PREVEND (Prevention of Renal and Vascular End Stage Disease) study, 369 cases experiencing a first cardiovascular event (combined end point of death from cardiovascular causes, ischemic heart disease, nonfatal myocardial infarction, and coronary revascularization) during a median of 10.5 years of follow-up were identified and individually matched to 369 controls with respect to age, sex, smoking status, and HDL cholesterol. Baseline samples were available in 340 cases and 340 matched controls.

Results: HDL anti-inflammatory capacity was not correlated with HDL cholesterol or hsCRP (high-sensitivity C-reactive protein). HDL anti-inflammatory capacity was significantly lower in cases compared with controls (31.6% [15.7-44.2] versus 27.0% [7.4-36.1]; <0.001) and was inversely associated with incident CVD in a fully adjusted model (odds ratio [OR] per 1 SD, 0.74 [CI, 0.61-0.90]; =0.002). Furthermore, this association was approximately similar with all individual components of the cardiovascular disease end point. The HDL anti-inflammatory was not correlated with cholesterol efflux capacity (=-0.02; >0.05). When combining these 2 HDL function metrics in 1 model, both were significantly and independently associated with incident cardiovascular disease in a fully adjusted model (efflux: OR per 1 SD, 0.74; =0.002; anti-inflammatory capacity: OR per 1 SD, 0.66; <0.001). Adding HDL anti-inflammatory capacity improved risk prediction by the Framingham risk score, with a model likelihood-ratio statistic increase from 10.50 to 20.40 (=0.002).

Conclusions: The HDL anti-inflammatory capacity, reflecting vascular protection against key steps in atherogenesis, was inversely associated with incident cardiovascular events in a general population cohort, independent of HDL cholesterol and HDL cholesterol efflux capacity. Adding HDL anti-inflammatory capacity to the Framingham risk score improves risk prediction.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050808DOI Listing
May 2021

Genome-Wide Association Study and Identification of a Protective Missense Variant on Lipoprotein(a) Concentration: Protective Missense Variant on Lipoprotein(a) Concentration-Brief Report.

Arterioscler Thromb Vasc Biol 2021 05 18;41(5):1792-1800. Epub 2021 Mar 18.

Department of Cardiology (M.A.S., M.W.Y., Y.J.v.d.V., J.W.B., L.E.J.-O., N.V., P.v.d.H.), University Medical Center Groningen, University of Groningen, the Netherlands.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.120.315300DOI Listing
May 2021

Association of beta-hydroxybutyrate with development of heart failure: Sex differences in a Dutch population cohort.

Eur J Clin Invest 2021 May 18;51(5):e13468. Epub 2020 Dec 18.

Department of Internal Medicine, Division of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: In the failing heart, energy metabolism is shifted towards increased ketone body oxidation. Nevertheless, the association of beta-hydroxybutyrate (β-OHB) with development of heart failure (HF) remains unclear. We investigated the association between plasma β-OHB and the risk of HF in a prospective population-based cohort.

Design: Plasma β-OHB concentrations were measured in 6134 participants of the PREVEND study. Risk of incident HF with reduced (HFrEF) or preserved (HFpEF) ejection fraction was estimated using multivariable-adjusted Cox regression models.

Results: During median follow-up for 8.2 years, 227 subjects were diagnosed with HF (137 with HFrEF; 90 with HFpEF). Cox regression analyses revealed a significant association of higher β-OHB concentrations with incident HF (HR per 1 standard deviation increase, 1.40 (95% CI: 1.21-1.63; P < .001), which was largely attributable to HFrEF. In women, the hazard ratio (HR) for HFrEF per 1 standard deviation increase in β-OHB was 1.73 (95% confidence interval (CI): 1.17-2.56, P = .005) in age, BMI, type 2 diabetes, hypertension, myocardial infarction, smoking, alcohol consumption, total cholesterol, HDL-C, triglycerides, glucose, eGFR and UAE adjusted analysis. In men, in the same fully adjusted analysis, the HR was 1.14 (CI: 0.86-1.53, P = .36) (P < .01 for sex interaction). In N-terminal pro-brain natriuretic peptide (NT-proBNP)-stratified analysis, the age-adjusted association with HF was significant in women with higher NT-proBNP levels (P = .008).

Conclusions: This prospective study suggests that high plasma concentrations of β-OHB are associated with an increased risk of HFrEF, particularly in women. The mechanisms responsible for the sex differences of this association warrant further study.
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http://dx.doi.org/10.1111/eci.13468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244065PMC
May 2021

HDL Particle Subspecies and Their Association With Incident Type 2 Diabetes: The PREVEND Study.

J Clin Endocrinol Metab 2021 05;106(6):1761-1772

Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands.

Context: High-density lipoproteins (HDL) may be protective against type 2 diabetes (T2D) development, but HDL particles vary in size and function, which could lead to differential associations with incident T2D. A newly developed nuclear magnetic resonance (NMR)-derived algorithm provides concentrations for 7 HDL subspecies.

Objective: We aimed to investigate the association of HDL particle subspecies with incident T2D in the general population.

Methods: Among 4828 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study without T2D at baseline, HDL subspecies with increasing size from H1P to H7P were measured by NMR (LP4 algorithm of the Vantera NMR platform).

Results: A total of 265 individuals developed T2D (median follow-up of 7.3 years). In Cox regression models, HDL size and H4P (hazard ratio [HR] per 1 SD increase 0.83 [95% CI, 0.69-0.99] and 0.85 [95% CI, 0.75-0.95], respectively) were inversely associated with incident T2D, after adjustment for relevant covariates. In contrast, levels of H2P were positively associated with incident T2D (HR 1.15 [95% CI, 1.01-1.32]). In secondary analyses, associations with large HDL particles and H6P were modified by body mass index (BMI) in such a way that they were particularly associated with a lower risk of incident T2D, in subjects with BMI < 30 kg/m2.

Conclusion: Greater HDL size and lower levels of H4P were associated with a lower risk, whereas higher levels of H2P were associated with a higher risk of developing T2D. In addition, large HDL particles and H6P were inversely associated with T2D in nonobese subjects.
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http://dx.doi.org/10.1210/clinem/dgab075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118359PMC
May 2021

Association of Circulating Trimethylamine -Oxide and Its Dietary Determinants with the Risk of Kidney Graft Failure: Results of the TransplantLines Cohort Study.

Nutrients 2021 Jan 18;13(1). Epub 2021 Jan 18.

Department of Internal Medicine, Division of Endocrinology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.

Background: Due to the critical shortage of kidneys for transplantation, the identification of modifiable factors related to graft failure is highly desirable. The role of trimethylamine--oxide (TMAO) in graft failure remains undetermined. Here, we investigated the clinical utility of TMAO and its dietary determinants for graft failure prediction in renal transplant recipients (RTRs).

Methods: We included 448 RTRs who participated in the TransplantLines Cohort Study. Cox proportional-hazards regression analyses were performed to study the association of plasma TMAO with graft failure. Net Benefit, which is a decision analysis method, was performed to evaluate the clinical utility of TMAO and dietary information in the prediction of graft failure.

Results: Among RTRs (age 52.7 ± 13.1 years; 53% males), the baseline median TMAO was 5.6 (3.0-10.2) µmol/L. In multivariable regression analysis, the most important dietary determinants of TMAO were egg intake (Std. β = 0.09 [95%CI, 0.01; 0.18]; = 0.03), fiber intake (Std. β = -0.14 [95%CI, -0.22, -0.05]; = 0.002), and fish and seafood intake (Std. β = 0.12 [95%CI, 0.03,0.21]; = 0.01). After a median follow-up of 5.3 (4.5-6.0) years, graft failure was observed in 58 subjects. TMAO was associated with an increased risk of graft failure, independent of age, sex, the body mass index (BMI), blood pressure, lipids, albuminuria, and the Estimated Glomerular Filtration Rate (eGFR) (Hazard Ratio per 1-SD increase of TMAO, 1.62 (95% confidence interval (CI): 1.22; 2.14, < 0.001)). A TMAO and dietary enhanced prediction model offered approximately double the Net Benefit compared to a previously reported, validated prediction model for future graft failure, allowing the detection of 21 RTRs per 100 RTRs tested, with no false positives versus 10 RTRs, respectively.

Conclusions: A predictive model for graft failure, enriched with TMAO and its dietary determinants, yielded a higher Net Benefit compared with an already validated model. This study suggests that TMAO and its dietary determinants are associated with an increased risk of graft failure and that it is clinically meaningful.
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http://dx.doi.org/10.3390/nu13010262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831477PMC
January 2021

Plasma creatine and incident type 2 diabetes in a general population-based cohort: The PREVEND study.

Clin Endocrinol (Oxf) 2021 04 10;94(4):563-574. Epub 2021 Jan 10.

Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Type 2 diabetes is associated with both impaired insulin action at target tissues and impaired insulin secretion in pancreatic beta cells. Mitochondrial dysfunction may play a role in both insulin resistance and impaired insulin secretion. Plasma creatine has been proposed as a potential marker for mitochondrial dysfunction. We aimed to investigate the association between plasma creatine and incident type 2 diabetes.

Methods: We measured fasting plasma creatine concentrations by nuclear magnetic resonance spectroscopy in participants of the general population-based PREVEND study. The study outcome was incident type 2 diabetes, defined as a fasting plasma glucose ≥7.0 mmol/L (126 mg/dl); a random sample plasma glucose ≥11.1 mmol/L (200 mg/dl); self-report of a physician diagnosis or the use of glucose-lowering medications based on a central pharmacy registration. Associations of plasma creatine with type 2 diabetes were quantified using Cox proportional hazards models and were adjusted for potential confounders.

Results: We included 4735 participants aged 52 ± 11 years, of whom 49% were male. Mean plasma creatine concentrations were 36.7 ± 17.6 µmol/L, with lower concentrations in males than in females (30.4 ± 15.1 µmol/L vs. 42.7 ± 17.7 µmol/L; p for difference <.001). During 7.3 [6.2-7.7] years of follow-up, 235 (5.4%) participants developed type 2 diabetes. Higher plasma creatine concentrations were associated with an increased risk of incident type 2 diabetes (HR per SD change: 1.27 [95% CI: 1.11-1.44]; p < .001), independent of potential confounders. This association was strongly modified by sex (p interaction <.001). Higher plasma creatine was associated with an increased risk of incident type 2 diabetes in males (HR: 1.40 [1.17-1.67]; p < .001), but not in females (HR: 1.10 [0.90-1.34]; p = .37).

Conclusion: Fasting plasma creatine concentrations are lower in males than in females. Higher plasma creatine is associated with an increased risk of type 2 diabetes in males.
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http://dx.doi.org/10.1111/cen.14396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048485PMC
April 2021
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