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Background/objective: Prolonged heart rate-corrected QT interval (QTc) on the electrocardiogram (ECG) is maybe associated with the occurrence of cardiovascular diseases (CVD), but the evidence is inconsistent. Therefore, we investigated whether baseline prolongation of the QTc interval is associated with CVD morbidity and mortality and its subtypes and whether glucose tolerance modifies this association in a population-based cohort study with a mean follow-up of 10.8 years., Methods: We analyzed a glucose tolerance stratified sample (N = 487) from the longitudinal population-based Hoorn Study cohort (age 64 ± 7 years, 48% female). Cox regression was used to investigate the association between sex-specific baseline QTc quartiles and CVD morbidity and mortality. The risk was also estimated per 10 ms increase in QTc. All analyses were adjusted for age, sex, smoking status, systolic blood pressure, prevalent CVD, glucose tolerance status, hypertension and total cholesterol. In addition, stratified analyses were conducted for glucose tolerance status., Results: During a mean follow-up of 10.8 years, 351 CVD events were observed. The adjusted hazard ratios (95% CI) for each 10 ms increase in QTc interval were 1.06 (95% CI: 1.02-1.10) for CVD, 1.06 (95% CI: 0.97-1.15) for acute myocardial infarction, 1.07 (95% CI: 1.01-1.13) for stroke, 1.12 (95% CI: 1.06-1.19) for heart failure, 1.04 (95% CI: 0.96-1.12) for peripheral arterial disease and 1.01 (95% CI:0.95-1.08) for coronary heart disease. Glucose tolerance status did not modify the association (P > 0.2)., Conclusion/interpretation: Prolongation of the QTc interval is associated with morbidity and mortality due to general CVD. Glucose tolerance status did not modify these associations., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: To investigate the association of (changes in) electrocardiogram (ECG) abnormalities with incident major adverse cardiac events (MACE) in people with Type 2 diabetes (T2D) without pre-existing cardiovascular disease (CVD)., Methods and Results: A prospective longitudinal study of 11 993 people with T2D without known CVD from the Hoorn Diabetes Care System cohort. Annually repeated measurements (1998-2018), included cardiovascular risk factors, over 70 000 ECG, and self-reported cardiovascular events. ECG abnormalities were classified according to the Minnesota Classification as prolonged PR duration, prolonged QRS duration, left QRS-axis, QS pattern, ST-segment/T-wave abnormalities, or tall R-wave. The association of ECG abnormalities with MACEs was assessed using time-dependent Cox-regression models, adjusted for time-varying cardiovascular risk factors, and medication use [hazard ratios (HRs) with 95% confidence intervals (CIs)]. During a median follow-up of 6.6 (IQR, 3.1-10.7) years, 5445 (45.4%) of the participants had an ECG abnormality (prevalent or incident) at any of the median 6 (IQR, 3-10) annual ECG recordings, and 905 people (7.5%) had a MACE (529 coronary heart disease (CHD), 250 heart failure (HF), and 126 sudden cardiac arrest (SCA)). After adjustment, most ECG abnormalities were associated with HF: prolonged QRS duration [HR, 4.01 (95% CI, 2.67-6.03)], QS pattern [2.68 (0.85-8.49)], ST-segment/T-wave abnormalities [4.26 (2.67-6.80)], and tall R-wave [2.23 (1.33-3.76)]. Only QS pattern [2.69 (1.20-6.03)] and ST-segment/T-wave abnormalities [2.11 (1.48-3.02)] were associated with CHD. These associations were robust across age, sex, hypertension, or estimated CVD risk subgroups., Conclusion: In people with T2D without pre-existing CVD, ECG abnormalities related to decelerated conduction, ischaemia, and hypertrophy are predominantly early signs of emerging HF, while only abnormalities related to ischaemic disorders are signs of CHD., Competing Interests: Conflicts of interest: The authors had complete autonomy in the design, conduct, and reporting of the manuscript. The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims/hypothesis: Both manifestations of kidney disease in diabetes, reduced eGFR (ml/min per 1.73 m 2 ) and increased urinary albumin/creatinine ratio (UACR, mg/mmol), may increase the risk of specific CVD subtypes in adults with diabetes., Methods: We assessed the prospective association between annually recorded measures of eGFR and UACR and the occurrence of myocardial infarction (MI), CHD, stroke, heart failure (HF) and cardiovascular mortality in 13,657 individuals with diabetes (53.6% male, age 62.3±12.1 years) from the Hoorn Diabetes Care System cohort, using data obtained between 1998 and 2018. Multivariate time-dependent Cox regression models adjusted for cardiovascular risk factors were used to estimate HRs and 95% CI. Associations of eGFR were adjusted for UACR values and vice versa. Effect modification by sex was investigated for all associations., Results: After a mean follow-up period of 7 years, event rates per 1000 person-years were 3.08 for MI, 3.72 for CHD, 1.12 for HF, 0.84 for stroke and 6.25 for cardiovascular mortality. Mildly reduced eGFR (60-90 ml/min per 1.73 m 2 ) and moderately to severely reduced eGFR (<59 ml/min per 1.73 m 2 ) were associated with higher risks of MI (HR 1.52; 95% CI 1.10, 2.12 and HR 1.69; 95% CI 1.09, 2.64) and CHD (HR 1.67; 95% CI 1.23, 2.26 and HR 2.01; 95% CI 1.34, 3.02) compared with normal eGFR (>90 ml/min per 1.73 m 2 ). Mildly reduced eGFR was associated with a higher risk of stroke (HR 2.53; 95% CI 1.27, 5.03). Moderately increased UACR (3-30 mg/mmol) and severely increased UACR (>30 mg/mmol) were prospectively associated with a higher cardiovascular mortality risk in men and women (HR 1.87; 95% CI 1.41, 2.47 and HR 2.78; 95% CI 1.78, 4.34) compared with normal UACR (<3 mg/mmol). Significant effect modification by sex was observed for the association between UACR and HF. Because there were a limited number of HF events within the category of UACR >30 mg/mmol, categories were combined into UACR <3.0 and >3.0 mg/mmol in the stratified analysis. Women but not men with UACR >3.0 mg/mmol had a significantly higher risk of HF compared with normal UACR (HR 2.79; 95% CI 1.47, 5.28)., Conclusions/interpretation: This study showed differential and independent prospective associations between manifestations of early kidney damage in diabetes and several CVD subtypes, suggesting that regular monitoring of both kidney function measures may help to identify individuals at higher risk of specific cardiovascular events., (© 2022. The Author(s).)

Background: Conflicting findings have described the association between prolonged heart rate-corrected QT interval (QTc) and cardiovascular disease., Aims: To identify articles investigating the association between QTc and cardiovascular disease morbidity and mortality, and to summarize the available evidence for the general and type 2 diabetes populations., Methods: A systematic search was performed in PubMed and Embase in May 2022 to identify studies that investigated the association between QTc prolongation and cardiovascular disease in both the general and type 2 diabetes populations. Screening, full-text assessment, data extraction and risk of bias assessment were performed independently by two reviewers. Effect estimates were pooled across studies using random-effect models., Results: Of the 59 studies included, 36 qualified for meta-analysis. Meta-analysis of the general population studies showed a significant association for: overall cardiovascular disease (fatal and non-fatal) (hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.33-2.12; I 2 =69%); coronary heart disease (fatal and non-fatal) in women (HR 1.27, 95% CI 1.08-1.50; I 2 =38%; coronary heart disease (fatal and non-fatal) in men (HR 2.07, 95% CI 1.26-3.39; I 2 =78%); stroke (HR 1.59, 95% CI 1.29-1.96; I 2 =45%); sudden cardiac death (HR 1.60, 95% CI 1.14-2.25; I 2 =68%); and atrial fibrillation (HR 1.55, 95% CI 1.31-1.83; I 2 =0.0%). No significant association was found for cardiovascular disease in the type 2 diabetes population., Conclusion: QTc prolongation was associated with risk of cardiovascular disease in the general population, but not in the type 2 diabetes population., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Although associations of total plasma N- glycome (TPNG) with type 2 diabetes have been reported, little is known on the role of TPNG in type 2 diabetes complications, a major cause of type 2 diabetes-related morbidity and mortality. Here, we assessed TPNG in relation to type 2 diabetes complications in subsamples of two Dutch cohorts using mass spectrometry (n=1815 in DiaGene and n=1518 in Hoorn Diabetes Care System)., Research Design and Methods: Blood plasma samples and technical replicates were pipetted into 96-well plates in a randomized manner. Peptide:N-glycosidase F (PNGase F) was used to release N- glycans, whereafter sialic acids were derivatized for stabilization and linkage differentiation. After total area normalization, 68 individual glycan compositions were quantified in total and were used to calculate 45 derived traits which reflect structural features of glycosylation. Associations of glycan features with prevalent and incident microvascular or macrovascular complications were tested in logistic and Cox regression in both independent cohorts and the results were meta-analyzed., Results: Our results demonstrated similarities between incident and prevalent complications. The strongest association for prevalent cardiovascular disease was a high level of bisection on a group of diantennary glycans (A2FS0B; OR=1.38, p=1.34×10 -11 ), while for prevalent nephropathy the increase in 2,6-sialylation on triantennary glycans was most pronounced (A3E; OR=1.28, p=9.70×10 -6 ). Several other TPNG features, including fucosylation, galactosylation, and sialylation, firmly demonstrated associations with prevalent and incident complications of type 2 diabetes., Conclusions: These findings may provide a glance on how TPNG patterns change before complications emerge, paving the way for future studies on prediction biomarkers and potentially disease mechanisms., Competing Interests: Competing interests: MW is inventor on a patent application on sialic acid derivatization by ethyl esterification. EM is employed by Genos. VD currently works at BioTherapeutics Analytical Development, Janssen Biologics BV. No other potential conflicts of interest relevant to this article were reported., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Aims: The American Diabetes Association, and the joint European Society of Cardiology and European Association for the Study of Diabetes guidelines recommend a resting ECG in people with type 2 diabetes with hypertension or suspected cardiovascular disease (CVD). However, knowledge on the prevalence of ECG abnormalities is incomplete. We aimed to analyse the prevalence of ECG abnormalities and their cross-sectional associations with cardiovascular risk factors in people with type 2 diabetes., Methods: We used data of the Diabetes Care System cohort obtained in 2018. ECG abnormalities were defined using the Minnesota Classification and categorised into types of abnormalities. The prevalence was calculated for the total population (n = 8068) and the subgroup of people without a history of CVD (n = 6494). Logistic regression models were used to asses cross-sectional associations., Results: Approximately one-third of the total population had minor (16.0%) or major (13.1%) ECG abnormalities. Of the participants without a CVD history, approximately one-quarter had minor (14.9%) or major (9.1%) ECG abnormalities, and for those with hypertension or very high CVD risk, the prevalence was 27.5% and 39.6%, respectively. ECG abnormalities were significantly and consistently associated with established CVD risk factors., Conclusions: Resting ECG abnormalities are common in all people with type 2 diabetes (29.1%), including those without a history of CVD (24.0%), and their prevalence is related to traditional cardiovascular risk factors such as older age, male sex, hypertension, lower HDL cholesterol, higher BMI, and smoking behaviour., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: A low vitamin D and K status has been associated with increased cardiovascular disease (CVD) risk but the evidence of their combined effect on cardiovascular health is limited., Objectives: Our study aimed to investigate the prospective association of vitamin D and K status with subclinical measures of cardiovascular health and all-cause mortality among a population of Dutch Caucasians., Methods: We performed an observational prospective study on 601 participants of the Hoorn Study (mean ± SD age: 70 ± 6 y, 50.4% women, BMI: 27.2 ± 4.0 kg/m2), of whom 321 underwent an echocardiogram in 2000-2001 and 2007-2009. Vitamin D and K status was assessed at baseline by serum 25-hydroxyvitamin D [25(OH)D] and plasma desphospho-uncarboxylated matrix-gla protein (dp-ucMGP)-high concentrations indicate low vitamin K status. Vital status was assessed from baseline until 2018. We studied the association of categories of 25(OH)D (stratified by the clinical cutoff of 50 mmol/L) and dp-ucMGP (stratified by the median value of 568 pmol/L) with echocardiographic measures using linear regression and with all-cause mortality using Cox regression, adjusted for confounders., Results: Compared with markers of normal vitamin D and K status, markers of low vitamin D and K status were prospectively associated with increased left ventricular mass index (5.9 g/m2.7; 95% CI: 1.8, 10.0 g/m2.7). Participants with low vitamin D and K status were also at increased risk of all-cause mortality with an HR of 1.64 (95% CI: 1.12, 2.39) compared with normal vitamin D and K status., Conclusions: A combination of low vitamin D and K status is associated with adverse cardiac remodeling and increased risk of all-cause mortality in men and women. Future studies should investigate whether vitamin D and K supplementation could help to improve cardiovascular health and to decrease CVD risk., (© The Author(s) 2020. Published by Oxford University Press on behalf of American Society for Nutrition.)

Background: Chronic cardiometabolic diseases, including cardiovascular disease (CVD), type 2 diabetes (T2D) and chronic kidney disease (CKD), share many modifiable risk factors and can be prevented using combined prevention programs. Valid risk prediction tools are needed to accurately identify individuals at risk., Objective: We aimed to validate a previously developed non-invasive risk prediction tool for predicting the combined 7-year-risk for chronic cardiometabolic diseases., Design: The previously developed tool is stratified for sex and contains the predictors age, BMI, waist circumference, use of antihypertensives, smoking, family history of myocardial infarction/stroke, and family history of diabetes. This tool was externally validated, evaluating model performance using area under the receiver operating characteristic curve (AUC)-assessing discrimination-and Hosmer-Lemeshow goodness-of-fit (HL) statistics-assessing calibration. The intercept was recalibrated to improve calibration performance., Participants: The risk prediction tool was validated in 3544 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab)., Key Results: Discrimination was acceptable, with an AUC of 0.78 (95% CI 0.75-0.81) in men and 0.78 (95% CI 0.74-0.81) in women. Calibration was poor (HL statistic: p < 0.001), but improved considerably after intercept recalibration. Examination of individual outcomes showed that in men, AUC was highest for CKD (0.85 [95% CI 0.78-0.91]) and lowest for T2D (0.69 [95% CI 0.65-0.74]). In women, AUC was highest for CVD (0.88 [95% CI 0.83-0.94)]) and lowest for T2D (0.71 [95% CI 0.66-0.75])., Conclusions: Validation of our previously developed tool showed robust discriminative performance across populations. Model recalibration is recommended to account for different disease rates. Our risk prediction tool can be useful in large-scale prevention programs for identifying those in need of further risk profiling because of their increased risk for chronic cardiometabolic diseases.

Objective: To investigate risk of a recurrent cardiovascular event and its predictors in a population-based cohort., Research Design and Methods: Participants of the Hoorn Study who had experienced a first cardiovascular event after baseline (n = 336) were followed with respect to a recurrent event. Absolute risk of a recurrent event was calculated for individuals with normal glucose metabolism, intermediate hyperglycemia, and type 2 diabetes. Cox regression models were used to investigate which variables, measured before the first vascular event, predicted a recurrent event using the stepwise backward procedure., Results: During a median follow-up of 4.1 years, 44% (n = 148) of the population developed a recurrent vascular event. The rate of recurrent events per 100 person-years was 7.2 (95% CI 5.8-8.7) in individuals with normal glucose metabolism, compared with 9.8 (6.6-14.0) in individuals with intermediate hyperglycemia and 12.5 (8.5-17.6) in individuals with type 2 diabetes. Higher age (hazard ratio 1.02 [95% CI 1.00-1.04]), male sex (1.56 [1.08-2.25]), waist circumference (1.02 [1.02-1.03]), higher systolic blood pressure (1.01 [1.01-1.02]), higher HbA1c (%, 1.13 [0.97-1.31]/ mmol/mol, 1.01 [1.00-1.03]), and family history of myocardial infarction (1.38 [0.96-2.00]) predicted a recurrent cardiovascular event., Conclusions: Individuals with type 2 diabetes, but not individuals with intermediate hyperglycemia, are at increased risk for a recurrent vascular event compared with individuals with normal glucose metabolism. In people with a history of cardiovascular disease, people at increased risk of a recurrent event can be identified based on the patient's risk profile before the first event.

Background: Chronic cardiometabolic diseases, including cardiovascular disease (CVD), type 2 diabetes (T2D) and chronic kidney disease (CKD), share many modifiable risk factors and can be prevented using combined prevention programs. Valid risk prediction tools are needed to accurately identify individuals at risk.Objective: We aimed to validate a previously developed non-invasive risk prediction tool for predicting the combined 7-year-risk for chronic cardiometabolic diseases.Design: The previously developed tool is stratified for sex and contains the predictors age, BMI, waist circumference, use of antihypertensives, smoking, family history of myocardial infarction/stroke, and family history of diabetes. This tool was externally validated, evaluating model performance using area under the receiver operating characteristic curve (AUC)-assessing discrimination-and Hosmer-Lemeshow goodness-of-fit (HL) statistics-assessing calibration. The intercept was recalibrated to improve calibration performance.Participants: The risk prediction tool was validated in 3544 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab).Key Results: Discrimination was acceptable, with an AUC of 0.78 (95% CI 0.75-0.81) in men and 0.78 (95% CI 0.74-0.81) in women. Calibration was poor (HL statistic: p < 0.001), but improved considerably after intercept recalibration. Examination of individual outcomes showed that in men, AUC was highest for CKD (0.85 [95% CI 0.78-0.91]) and lowest for T2D (0.69 [95% CI 0.65-0.74]). In women, AUC was highest for CVD (0.88 [95% CI 0.83-0.94)]) and lowest for T2D (0.71 [95% CI 0.66-0.75]).Conclusions: Validation of our previously developed tool showed robust discriminative performance across populations. Model recalibration is recommended to account for different disease rates. Our risk prediction tool can be useful in large-scale prevention programs for identifying those in need of further risk profiling because of their increased risk for chronic cardiometabolic diseases. [ABSTRACT FROM AUTHOR]