Ceramides as Risk Markers for Future Cardiovascular Events and All-Cause Mortality in Long-standing Type 1 Diabetes.

Ceramides are lipid molecules involved in inflammation-related signaling. Recent studies have shown that higher amounts of specific circulating ceramides and their ratios are associated with future development of cardiovascular (CV) disease (CVD). We examined the associations between serum ceramide levels with CVD, kidney failure, and all-cause mortality in individuals with long-standing type 1 diabetes (T1D). We included 662 participants with T1D and 6-year follow-up, with a mean age of 55 years and mean diabetes duration of 33 years. Baseline serum samples were analyzed using liquid chromatography-mass spectrometry. Six predefined ceramide levels were measured, and predefined ratios were calculated. Adjusted Cox regression analyses on ceramide levels in relation to future CV events (CVE), kidney failure, and all-cause mortality were performed, with and without adjustment for age, sex, BMI, LDL, triglycerides, systolic blood pressure, HbA1c, history of CVD, smoking status, statin use, estimated glomerular filtration rate (eGFR), and urinary albumin excretion rate (UAER). The ceramide ratio cer(d18:1/18:0)/cer(d18:1/24:0) was significantly associated with risk of CVE (hazard ratio [HR] = 1.33, P = 0.01) and all-cause mortality (HR = 1.48, P = 0.01) before and after adjustments. All five investigated ceramide ratios were associated with kidney failure, before adjusting for the kidney markers eGFR and UAER. In this study, we demonstrate specific ceramides and ratios associated with 6-year cardiovascular risk and all-cause mortality in a T1D cohort. This highlights the strength of ceramide association with vascular complications and presents a new potential tool for early risk assessment if validated in other cohorts. ARTICLE HIGHLIGHTS: Improved tools for assessing risk for diabetes complication before onset will help in complication prevention. We investigated a set of six predefined ceramides and their ratios versus 6-year outcomes of cardiovascular events, kidney failure, and all-cause mortality in people with long-standing type 1 diabetes, using Cox regression with and without adjustment for potential confounders. We found that several ceramides and ceramide ratios associated with cardiovascular events and all-cause mortality. The ratio of cer(d18:1/18:0)/cer(d18:1/24:0) was an especially robust marker. These finding show that ceramides can be biomarkers of cardiovascular disease and all-cause mortality in individuals with long-standing type 1 diabetes.

Circulating metabolites and molecular lipid species are associated with future cardiovascular morbidity and mortality in type 1 diabetes.

BACKGROUND: Cardiovascular disease remains the leading cause of mortality in individuals with diabetes and improved understanding of its pathophysiology is needed. We investigated the association of a large panel of metabolites and molecular lipid species with future cardiovascular events in type 1 diabetes. METHODS: The study included 669 individuals with type 1 diabetes. Non-targeted serum metabolomics and lipidomics analyses were performed using mass spectrometry. Data on cardiovascular events (cardiovascular mortality, coronary artery disease, stroke, and peripheral arterial interventions) were obtained from Danish Health registries and analyzed by Cox hazards models. Metabolites and molecular lipid species were analyzed in univariate models adjusted for false discovery rate (FDR). Metabolites and molecular lipid species fulfilling a pFDR < 0.05 were subsequently analyzed in adjusted models including age, sex, hemoglobin A1c, mean arterial pressure, smoking, body mass index, low-density lipoprotein cholesterol, estimated glomerular filtration rate, urinary albumin excretion rate and previous cardiovascular disease. Analyses of molecular lipid species were further adjusted for triglycerides and statin use. RESULTS: Of the included participants, 55% were male and mean age was 55 ± 13 years. Higher 4-hydroxyphenylacetic acid (HR 1.35, CI [1.01-1.80], p = 0.04) and lower threonine (HR 0.81, CI [0.67-0.98] p = 0.03) were associated with development of cardiovascular events (n = 95). In lipidomics analysis, higher levels of three different species, diacyl-phosphatidylcholines (PC)(36:2) (HR 0.82, CI [0.70-0.98], p = 0.02), alkyl-acyl-phosphatidylcholines (PC-O)(34:2) (HR 0.76, CI [0.59-0.98], p = 0.03) and (PC-O)(34:3) (HR 0.75, CI [0.58-0.97], p = 0.03), correlated with lower risk of cardiovascular events, whereas higher sphingomyelin (SM)(34:1) (HR 1.32, CI [1.04-1.68], p = 0.02), was associated with an increased risk. CONCLUSIONS: Circulating metabolites and molecular lipid species were associated with future cardiovascular events in type 1 diabetes. While the causal effect of these biomolecules on the cardiovascular system remains unknown, our findings support that omics-based technologies, although still in an early phase, may have the potential to unravel new pathways and biomarkers in the field of cardiovascular disease in type 1 diabetes.

Myocardial flow reserve assessed by cardiac 82Rb positron emission tomography/computed tomography is associated with albumin excretion in patients with Type 1 diabetes.

AIMS: To evaluate myocardial flow reserve (MFR) and coronary artery calcium (CAC) in persons with Type 1 diabetes with or without albuminuria and in non-diabetic controls. MFR reflects the function of large epicardial arteries and myocardial microcirculation. CAC represents structural aspects of atherosclerosis. In addition, we evaluated the association of MFR and CAC with retinopathy, another microvascular complication. METHODS AND RESULTS: Cross-sectional study in Type 1 diabetes, stratified by normoalbuminuria (NORMO; n = 30) and macroalbuminuria (MACRO; n = 30), and in non-diabetic controls (n = 30). MFR (pharmacological stress flow/rest flow) was evaluated by cardiac 82Rb positron emission tomography/computed tomography. MFR was similar in patients with NORMO and controls (3.1 ± 0.79 vs. 3.0 ± 0.79; P = 0.74). Patients with MACRO had lower (impaired) MFR when compared with NORMO (2.1 ± 0.92 vs. 3.1 ± 0.79; P < 0.0001). The CAC score [median (interquartile range)] was higher in NORMO when compared with controls [72 (22-247) vs. 0 (0-81), P = 0.03], and comparable between MACRO and NORMO. MFR was comparable in patients with diabetes and simplex or no retinopathy (n = 24 and n = 12, 2.8 ± 0.84 vs. 3.3 ± 0.77, P = 0.11), but lower in proliferative (n = 24) compared with simplex retinopathy (2.1 ± 0.97 vs. 2.8 ± 0.84, P = 0.02). The CAC score was comparable between groups of retinopathy. CONCLUSION: Myocardial microvascular function was comparable in non-diabetic controls and patients with Type 1 diabetes and NORMO; but impaired in the presence of microvascular complications (MACRO and proliferative retinopathy). Coronary calcification was elevated in diabetes, however, not explained by albuminuria.