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Background: Vascular calcification is a known risk factor for cardiovascular events and mortality in patients with chronic kidney disease (CKD). However, since there is a lack of studies examining several arterial regions at a time, we aimed to evaluate the risk of major adverse cardiovascular events (MACE) and all-cause mortality according to calcium scores in five major arterial sites., Methods: This was a prospective study of 580 patients from the Copenhagen CKD Cohort. Multidetector computed tomography of the coronary and carotid arteries, the thoracic aorta, the abdominal aorta and the iliac arteries was used to determine vascular calcification at baseline. Calcium scores were divided into categories: 0, 1-100, 101-400 and >400., Results: During the follow-up period of 4.1 years a total of 59 cardiovascular events and 64 all-cause deaths occurred. In Cox proportional hazards models adjusted for age, sex, estimated glomerular filtration rate, hypertension, diabetes mellitus, hypercholesterolemia and smoking, only the coronary and carotid arteries, and the thoracic aorta were independent predictors of the designated endpoints. When examining the potential of calcification in the five arterial sites for predicting MACE, the difference in C-statistic was also most pronounced in these three sites, at 0.21 [95% confidence interval (CI) 0.16%-0.26%, P < .001], 0.26 (95% CI 0.22%-0.3%, P < .001) and 0.20 (95% CI 0.16%-0.24%, P < .001), respectively. This trend also applied to all-cause mortality., Conclusions: The overall results, including data on specificity, suggest that calcium scores of the coronary and carotid arteries have the most potential for identifying patients with CKD at high cardiovascular risk and for evaluating new therapies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Significance Statement: Magnesium prevents vascular calcification in animals with CKD. In addition, lower serum magnesium is associated with higher risk of cardiovascular events in CKD. In a randomized, double-blinded, placebo-controlled trial, the authors investigated the effects of magnesium supplementation versus placebo on vascular calcification in patients with predialysis CKD. Despite significant increases in plasma magnesium among study participants who received magnesium compared with those who received placebo, magnesium supplementation did not slow the progression of vascular calcification in study participants. In addition, the findings showed a higher incidence of serious adverse events in the group treated with magnesium. Magnesium supplementation alone was not sufficient to delay progression of vascular calcification, and other therapeutic strategies might be necessary to reduce the risk of cardiovascular disease in CKD., Background: Elevated levels of serum magnesium are associated with lower risk of cardiovascular events in patients with CKD. Magnesium also prevents vascular calcification in animal models of CKD., Methods: To investigate whether oral magnesium supplementation would slow the progression of vascular calcification in CKD, we conducted a randomized, double-blinded, placebo-controlled, parallel-group, clinical trial. We enrolled 148 subjects with an eGFR between 15 and 45 ml/min and randomly assigned them to receive oral magnesium hydroxide 15 mmol twice daily or matching placebo for 12 months. The primary end point was the between-groups difference in coronary artery calcification (CAC) score after 12 months adjusted for baseline CAC score, age, and diabetes mellitus., Results: A total of 75 subjects received magnesium and 73 received placebo. Median eGFR was 25 ml/min at baseline, and median baseline CAC scores were 413 and 274 in the magnesium and placebo groups, respectively. Despite plasma magnesium increasing significantly during the trial in the magnesium group, the baseline-adjusted CAC scores did not differ significantly between the two groups after 12 months. Prespecified subgroup analyses according to CAC>0 at baseline, diabetes mellitus, or tertiles of serum calcification propensity did not significantly alter the main results. Among subjects who experienced gastrointestinal adverse effects, 35 were in the group receiving magnesium treatment versus nine in the placebo group. Five deaths and six cardiovascular events occurred in the magnesium group compared with two deaths and no cardiovascular events in the placebo group., Conclusions: Magnesium supplementation for 12 months did not slow the progression of vascular calcification in CKD, despite a significant increase in plasma magnesium., Clinical Trials Registration: www.clinicaltrials.gov ( NCT02542319 )., (Copyright © 2023 by the American Society of Nephrology.)

Aims: People with type 1 diabetes have increased risk of cardiovascular (CV) and kidney disease. A 24-hour ambulatory blood pressure (BP) measurement (ABPM) examines diurnal variations in BP. We aimed to determine the prognostic significance of blunted decrease in nocturnal systolic BP of <10 % (non-dipping of nocturnal BP) for CV- and kidney disease and all-cause mortality in type 1 diabetes., Methods: From 2009 to 2011, at Steno Diabetes Center Copenhagen, 654 participants with type 1 diabetes had 24-hour ABPM obtained with a tonometric wrist-watch device (BPro, HealthStats, Singapore). In 2017, outcomes (composite CV endpoint; all-cause mortality; decline in estimated glomerular filtration rate (eGFR) ≥30 %; end-stage kidney disease (ESKD); and a composite kidney endpoint including decline in eGFR ≥30 %, ESKD and all-cause mortality) were registered. Hazard Ratios (HR) were calculated using Cox regressions., Results: Participants were mean ± SD 55 ± 13 years old and had median (IQR) 35 (24-44) years diabetes duration. Mean daytime and nocturnal systolic BP were 133 ± 16 and 121 ± 16 mmHg while 337 (52 %) participants demonstrated non-dipping. After CV risk factor adjustments, non-dipping was associated with all-cause mortality (HR 2.12 (1.09-4.11), p = 0.03) and the composite kidney endpoint (HR 1.92 (1.23-3.00), p = 0.004)., Conclusions: Non-dipping entailed increased risk of all-cause mortality and kidney disease in type 1 diabetes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Chronic kidney disease accelerates both atherosclerosis and arterial calcification. The aim of the present study was to explore whether maximal carotid plaque thickness (cPTmax) was increased in patients with chronic kidney disease compared to controls and associated with cardiovascular disease and severity of calcification in the carotid and coronary arteries., Methods: The study group consisted of 200 patients with chronic kidney disease stage 3 from the Copenhagen Chronic Kidney Disease Cohort and 121 age- and sex-matched controls. cPTmax was assessed by ultrasound and arterial calcification by computed tomography scanning., Results: Carotid plaques were present in 58% of patients (n = 115) compared with 40% of controls (n = 48), p = 0.002. Among participants with plaques, cPTmax (median, interquartile range) was significantly higher in patients compared with controls (1.9 (1.4-2.3) versus 1.5 (1.2-1.8) mm), p = 0.001. Cardiovascular disease was present in 9% of patients without plaques (n = 85), 23% of patients with cPTmax 1.0-1.9 mm (n = 69) and 35% of patients with cPTmax >1.9 mm (n = 46), p = 0.001. Carotid and coronary calcium scores >400 were present in 0% and 4%, respectively, of patients with no carotid plaques, in 19% and 24% of patients with cPTmax 1.0-1.9 mm, and in 48% and 53% of patients with cPTmax >1.9 mm, p<0.001., Conclusions: This is the first study showing that cPTmax is increased in patients with chronic kidney disease stage 3 compared to controls and closely associated with prevalent cardiovascular disease and severity of calcification in both the carotid and coronary arteries., Competing Interests: I have read the journal´s policy and the authors of this manuscript have the following competing interests: BFR reports research grants from The NovoNordisk Foundation (Steno Collaborative Grant), HS reports research grants from Philips Ultrasound and Bayer and honoraria from Bayer, Novo Nordisk, Bracco and Philips Ultrasound, TBS reports research grants from Sanofi Pasteur and GE Healthcare, the Lundbeck Foundation and the Novo Nordisk Foundation during the conduct of the study. All other authors: no competing interests.

Background: Patients with chronic kidney disease (CKD) and arterial calcification are considered at increased risk of adverse cardiovascular outcomes. However, the optimal site for measurement of arterial calcification has not been determined. The primary aim of this study was to examine the pattern of arterial calcification in different stages of CKD., Methods: This was an observational, cross-sectional study that included 580 individuals with CKD stages 1-5 (no dialysis) from the Copenhagen CKD Cohort. Calcification of the carotid, coronary and iliac arteries, thoracic and abdominal aorta was assessed using non-contrast multidetector computed tomography scans and quantified according to the Agatston method. Based on the distribution of Agatston scores in the selected arterial region, the subjects were divided into calcium score categories of 0 (no calcification), 1-100, 101-400 and > 400., Results: Participants with CKD stages 3-5 had the highest prevalence of calcification and the highest frequency of calcium scores > 400 in all arterial sites. Calcification in at least one arterial site was present in > 90% of patients with CKD stage 3. In all five CKD stages prevalence of calcification was greatest in both the thoracic and abdominal aorta, and in the iliac arteries. These arterial sites also showed the highest calcium scores. High calcium scores (> 400) in all five arterial regions were independently associated with prevalent cardiovascular disease. In multivariable analyses, after adjusting for cardiovascular risk factors, declining creatinine clearance was associated with increasing calcification of the coronary arteries (p = 0.012) and the thoracic aorta (p = 0.037) only., Conclusions: Arterial calcification is highly prevalent throughout all five CKD stages and is most prominent in both the thoracic and abdominal aorta, and in the iliac arteries. Follow-up studies are needed to explore the potential of extracardiac calcification sites in prediction of cardiovascular events in the CKD population.

Aims: Type 1 diabetes entails increased cardiovascular morbidity and cardiac chamber sizes are associated with cardiovascular disease. The aim of this study was to compare cardiac chamber sizes in normoalbuminuric persons with type 1 diabetes to a background population without diabetes., Methods: In a cross-sectional study, we examined 71 normoalbuminuric persons with long-term type 1 diabetes without known cardiovascular disease using cardiac multi-detector computed tomography. Cardiac chamber sizes and left ventricular remodelling were compared to persons without diabetes from the Copenhagen General Population Study., Results: Participants were median (interquartile range) 54 (48-60) (type 1 diabetes) and 57 (50-64) (without diabetes) years old and 59% were men (both groups). Participants with type 1 diabetes had smaller left ventricular mass (-3.5 g/m 2 , 95% confidence interval -5.8 to -1.3) and left (-4.0 mL/m 2 , 95% confidence interval -6.9 to -1.0) and right (-11.7 mL/m 2 , 95% confidence interval -15.4 to -7.9) ventricular volumes in multivariable analyses (adjusted for age, sex, body composition, blood pressure and antihypertensive medication), but no differences in atrial volumes., Conclusion: Persons with long-term type 1 diabetes had smaller left ventricular mass and biventricular volumes, yet similar atrial sizes, compared to a background population without diabetes. These findings may reflect subclinical development of diabetic cardiomyopathy.

Aims: Type 1 diabetes is associated with increased cardiovascular (CV) morbidity and mortality, and cardiovascular autonomic neuropathy (CAN) is an important CV risk factor. The study aimed to explore associations between CAN and altered cardiac chamber sizes in persons with type 1 diabetes., Methods: This was a cross-sectional study of 71 asymptomatic, normoalbuminuric participants with long-term type 1 diabetes (39 with CAN, determined by >1 abnormal autonomic function test) examined with cardiac multi detector computed tomography scans, which allowed measurements of left ventricular mass and all four cardiac chamber volumes. Cardiac chambers were indexed according to body surface area (ml/m 2 or g/m 2 )., Results: Persons with and without CAN had mean ± SD age of 57 ± 7 and 50 ± 8 years (p < 0.001) and diabetes duration of 36 ± 11 and 32 ± 9 years (p < 0.05), respectively. Increasing autonomic dysfunction, evaluated by decrease in heart rate variability during deep breathing (in beats per minute), was associated with larger right (-0.5, 95% CI -1.0 to -0.0, p < 0.05) and trend towards larger left (-0.4, 95% CI -0.8-0.0, p < 0.1) ventricular volumes in multivariable linear regression., Conclusions: Our results suggest that impaired autonomic function may be associated with modest enlargement of ventricular volumes; this might be an early sign of progression towards heart failure., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Type 1 diabetes is associated with increased risk of cardiovascular disease and the diabetic complication cardiovascular autonomic neuropathy in itself entails increased cardiovascular risk by mechanisms not yet fully understood. Arterial calcification is an important predictor of cardiovascular events; the aim of this study was to investigate the level of generalised arterial calcification in patients with long-term, normoalbuminuric type 1 diabetes and the association with cardiovascular autonomic neuropathy, as these factors have not been investigated in type 1 diabetes., Methods: Participants were examined for calcification of coronary and carotid arteries through non-contrast multi-detector computed tomography scans. Generalised arterial calcification was defined as the presence of calcium in both the coronary and carotid arteries., Results: A total of 53 patients with type 1 diabetes were included. Coronary and carotid artery calcium scores were correlated ( r = 0.720, p < 0.0001). Cardiovascular autonomic neuropathy was associated with increased coronary ( p = 0.002) and carotid ( p = 0.001) artery calcium scores. Seventeen of 20 patients with cardiovascular autonomic neuropathy (85%) demonstrated generalised arterial calcification compared to 11 (33%) patients without cardiovascular autonomic neuropathy; patients with cardiovascular autonomic neuropathy had an odds ratio of 11.3 (95% confidence interval = 2.7-47.1, p < 0.001) for generalised arterial calcification., Conclusion: Cardiovascular autonomic neuropathy is associated with increased level of generalised arterial calcification in patients with normoalbuminuric, long-term type 1 diabetes.

Aims: Coronary artery calcium (CAC) is associated with cardiovascular (CV) disease and progression of CAC is an independent predictor of mortality. Type 1 diabetes is associated with increased CV risk, especially in persons with cardiovascular autonomic neuropathy (CAN). This study aimed to examine whether short-term progression of CAC is increased in persons with type 1 diabetes compared to matched controls and if CAN increases risk of CAC progression., Methods: Fifty-three normoalbuminuric persons with long-term type 1 diabetes (20 with CAN) were matched in a 1:2 ratio with 106 controls without diabetes according to age, sex and baseline CAC. All were examined twice with cardiac computed tomography scans. Progression of CAC was defined as a value ≥2.5 between the square root-transformed values of follow-up and baseline CAC volume scores., Results: The participants were examined median (interquartile range) of 25 (23-27) months (type 1 diabetes) and 29 (25-33) months (controls) apart. In multivariable logistic regression, participants with type 1 diabetes had an odds ratio of 3.3 (95% CI 1.3-8.2, p = 0.01) for CAC progression. CAN did not increase progression of CAC (p = 0.64)., Conclusions: Progression of CAC was increased in well-treated, normoalbuminuric persons with type 1 diabetes compared to matched controls without diabetes, suggesting that type 1 diabetes is a risk factor for short-term progression. This finding could explain some of the increased morbidity and mortality observed in persons with type 1 diabetes, but it does not specifically explain the increased CV risk in persons with CAN., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Cardiovascular autonomic neuropathy (CAN) and abnormal circadian blood pressure (BP) rhythm are independent cardiovascular risk factors in patients with diabetes and associations between CAN, non-dipping of nocturnal BP and coronary artery disease have been demonstrated. We aimed to test if bedtime dosing (BD) versus morning dosing (MD) of the ACE inhibitor enalapril would affect the 24-hour BP profile in patients with type 1 diabetes (T1D), CAN and non-dipping., Setting: Secondary healthcare unit in Copenhagen, Denmark., Participants: 24 normoalbuminuric patients with T1D with CAN and non-dipping were included, consisting of mixed gender and Caucasian origin. Mean±SD age, glycosylated haemoglobin and diabetes duration were 60±7 years, 7.9±0.7% (62±7 mmol/mol) and 36±11 years., Interventions: In this randomised, placebo-controlled, double-blind cross-over study, the patients were treated for 12 weeks with either MD (20 mg enalapril in the morning and placebo at bedtime) or BD (placebo in the morning and 20 mg enalapril at bedtime), followed by 12 weeks of switched treatment regimen., Primary and Secondary Outcome Measures: Primary outcome was altered dipping of nocturnal BP. Secondary outcomes included a measurable effect on other cardiovascular risk factors than BP, including left ventricular function (LVF)., Results: Systolic BP dipping increased 2.4% (0.03-4.9%; p=0.048) with BD compared to MD of enalapril. There was no increase in mean arterial pressure dipping (2.2% (-0.1% to 4.5%; p=0.07)). No difference was found on measures of LVF (p≥0.15). No adverse events were registered during the study., Conclusions: We demonstrated that patients with T1D with CAN and non-dipping can be treated with an ACE inhibitor at night as BD as opposed to MD increased BP dipping, thereby diminishing the abnormal BP profile. The potentially beneficial effect on long-term cardiovascular risk remains to be determined., Trial Registration Number: EudraCT2012-002136-90; Post-results., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Aim: Type 1 diabetes mellitus (T1DM) is associated with an increased risk of ischemic heart disease (IHD). The relative contribution of structural and functional abnormalities of the coronary circulation determining clinically manifested IHD remains unknown. The aim of this study was to assess potential differences in myocardial perfusion at rest and coronary atherosclerosis between asymptomatic T1DM patients and healthy controls., Methods: Left ventricular (LV) myocardial perfusion at rest measured as LV myocardial Attenuation Density/LV blood pool Attenuation Density (MyoAD-ratio) and coronary artery atherosclerosis were evaluated with 320-multidetector computed tomography angiography in 57 asymptomatic T1DM patients and 114 sex and age matched controls., Results: In both groups median age was 53 years (p5,p95: 42,67) and 59.6% were men. Median duration of diabetes in the T1DM group was 35 years (p5,p95: 17,49). Median coronary calcium score was higher in T1DM patients (51 vs. 2, p=0.037) compared with controls. However, a similar frequency of >50% stenosis in one or more coronary arteries was found in T1DM patients and controls (18% vs. 14%, p=0.49). LV myocardial perfusion at rest (MyoAD-ratio) was 18% higher in T1DM patients than controls (0.13 vs. 0.11, p<0.0001). This difference was noted throughout all the LV myocardial segments. In a multiple regression analysis including diabetes, sex, age, cardiovascular risk factors, heart rate, calcium score and coronary stenosis >50%, MyoAD-ratio remained significantly higher in T1DM patients (p=0.0001)., Conclusions: LV myocardial perfusion at rest is higher in T1DM patients compared with controls independent of coronary atherosclerosis and cardiovascular risk factors., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)