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      Serum Acylcarnitines and Risk of Cardiovascular Death and Acute Myocardial Infarction in Patients With Stable Angina Pectoris

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          Abstract

          Background

          Excess levels of serum acylcarnitines, which are intermediate products in metabolism, have been observed in metabolic diseases such as type 2 diabetes mellitus. However, it is not known whether acylcarnitines may prospectively predict risk of cardiovascular death or acute myocardial infarction in patients with stable angina pectoris.

          Methods and Results

          This study included 4164 patients (median age, 62 years; 72% men). Baseline serum acetyl‐, octanoyl‐, palmitoyl‐, propionyl‐, and (iso)valerylcarnitine were measured using liquid chromatography/tandem mass spectrometry. Hazard ratios ( HRs) and 95% CIs for quartile 4 versus quartile 1 are reported. The multivariable model included age, sex, body mass index, fasting status, current smoking, diabetes mellitus, apolipoprotein A1, apolipoprotein B, creatinine, left ventricular ejection fraction, extent of coronary artery disease, study center, and intervention with folic acid or vitamin B6. During median 10.2 years of follow‐up, 10.0% of the patients died of cardiovascular disease and 12.8% suffered a fatal or nonfatal acute myocardial infarction. Higher levels of the even‐chained acetyl‐, octanoyl‐, and palmitoyl‐carnitines were significantly associated with elevated risk of cardiovascular death, also after multivariable adjustments ( HR [95% CI]: 1.52 [1.12, 2.06]; P=0.007; 1.73 [1.23, 2.44]; P=0.002; and 1.61 [1.18, 2.21]; P=0.003, respectively), whereas their associations with acute myocardial infarction were less consistent.

          Conclusions

          Among patients with suspected stable angina pectoris, elevated serum even‐chained acylcarnitines were associated with increased risk of cardiovascular death and, to a lesser degree with acute myocardial infarction, independent of traditional risk factors.

          Clinical Trial Registration

          URL: http://www.clinicaltrials.gov. Unique identifier: NCT00354081.

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          Most cited references 29

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          Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity.

          Dysregulation of fatty acid oxidation (FAO) is recognized as important in the pathophysiology of obesity and insulin resistance (IR). However, demonstrating FAO defects in vivo in humans has entailed complex and invasive methodologies. Recently, the identification of genetic blocks in FAO has been vastly simplified by using tandem mass spectrometry (MS/MS) of dried bloodspots to specify acylcarnitine (AcylCN) alterations characteristic for each disorder. This technology has recently been applied to examine FAO alterations in human and animal models of obesity and type 2 diabetes mellitus (T2DM). This study focused on characterizing AcylCN profiles in human plasma from individuals with obesity and T2DM during fasting and insulin-stimulated conditions. Following an overnight fast, plasma was obtained from lean (n = 12), obese nondiabetic (n = 14), and T2DM (n = 10) participants and analyzed for AcylCN using MS/MS. Plasma samples were also obtained at the end of a 4-h insulin-stimulated euglycemic clamp. In obesity and T2DM, long-chain AcylCNs were similarly significantly increased in the fasted state; free-CN levels were also elevated. Additionally, T2DM subjects of comparable BMI had increased short- and medium-chain AcylCNs, both saturated and hydroxy, as well as increased C(4)-dicarboxylcarnitine (C(4)DC-CN) that correlated with an index of poor glycemic control (HbA(1c); r = 0.74; P < 0.0001). Insulin infusion reduced all species of plasma AcylCN but this reduction was blunted in T2DM. Plasma long-chain AcylCN species are increased in obesity and T2DM, suggesting that more fatty acids can enter mitochondria. In T2DM, many shorter species accumulate, suggesting that they have a generalized complex oxidation defect.
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            A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders.

            We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor alpha (PPARalpha), plays a pivotal role in the cellular metabolic response to fasting. Short-term starvation caused hepatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPARalpha (PPARalpha-/-), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPARalpha+/+ mice, fasting induced the hepatic and cardiac expression of PPARalpha target genes encoding key mitochondrial (medium-chain acyl-CoA dehydrogenase, carnitine palmitoyltransferase I) and extramitochondrial (acyl-CoA oxidase, cytochrome P450 4A3) enzymes. In striking contrast, the hepatic and cardiac expression of most PPARalpha target genes was not induced by fasting in PPARalpha-/- mice. These results define a critical role for PPARalpha in a transcriptional regulatory response to fasting and identify the PPARalpha-/- mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization.
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              Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance.

              Lipid infusion or ingestion of a high-fat diet results in insulin resistance, but the mechanism underlying this phenomenon remains unclear. Here we show that, in rats fed a high-fat diet, whole-animal, muscle and liver insulin resistance is ameliorated following hepatic overexpression of malonyl-coenzyme A (CoA) decarboxylase (MCD), an enzyme that affects lipid partitioning. MCD overexpression decreased circulating free fatty acid (FFA) and liver triglyceride content. In skeletal muscle, levels of triglyceride and long-chain acyl-CoA (LC-CoA)-two candidate mediators of insulin resistance-were either increased or unchanged. Metabolic profiling of 36 acylcarnitine species by tandem mass spectrometry revealed a unique decrease in the concentration of one lipid-derived metabolite, beta-OH-butyrate, in muscle of MCD-overexpressing animals. The best explanation for our findings is that hepatic expression of MCD lowered circulating FFA levels, which led to lowering of muscle beta-OH-butyrate levels and improvement of insulin sensitivity.
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                Author and article information

                Contributors
                elin.strand@uib.no
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                03 February 2017
                February 2017
                : 6
                : 2 ( doiID: 10.1002/jah3.2017.6.issue-2 )
                Affiliations
                [ 1 ] Department of Clinical Science University of Bergen Norway
                [ 2 ] Department of Clinical Medicine University of Bergen Norway
                [ 3 ] Department of Global Public Health and Primary Care University of Bergen Norway
                [ 4 ] KG Jebsen Center for Diabetes Research University of Bergen Norway
                [ 5 ] Department of Nutrition University of Oslo Norway
                [ 6 ] Department of Pediatrics Haukeland University Hospital Bergen Norway
                [ 7 ] Department of Heart Disease Haukeland University Hospital Bergen Norway
                [ 8 ] Hormone Laboratory Haukeland University Hospital Bergen Norway
                [ 9 ] Division for Health Data and Digitalisation Norwegian Institute of Public Health Bergen Norway
                Author notes
                [* ] Correspondence to: Elin Strand, PhD, Department of Clinical Science, University of Bergen, Laboratory Building, 8th floor, Haukeland University Hospital, Jonas Lies veg 87, Bergen N‐5021, Norway. E‐mail: elin.strand@ 123456uib.no
                Article
                JAH31997
                10.1161/JAHA.116.003620
                5523736
                28159823
                © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 3, Tables: 4, Pages: 27, Words: 8184
                Product
                Funding
                Funded by: Advanced Research Program and Research Council of Norway
                Funded by: Department of Heart Disease at Haukeland University Hospital
                Funded by: Norwegian Foundation for Health and Rehabilitation
                Funded by: Norwegian Heart and Lung Patient Organization
                Funded by: Norwegian Ministry of Health and Care Services
                Funded by: Western Norway Regional Health Authority
                Funded by: University of Bergen
                Categories
                Original Research
                Original Research
                Preventive Cardiology
                Custom metadata
                2.0
                jah31997
                February 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.3 mode:remove_FC converted:11.07.2017

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