Association between Body Mass Index, Asymmetric Dimethylarginine and Risk of Cardiovascular Events and Mortality in Norwegian Patients with Suspected Stable Angina Pectoris

<div><p>Background</p><p>Asymmetric dimethylarginine (ADMA) is associated with increased risk of atherosclerotic cardiovascular disease and mortality through inhibition of nitrogen oxide (NO) synthesis. As positive correlations between serum concentrations of NO and body mass index (BMI) have been observed, we aimed to explore whether the potential associations between plasma ADMA levels and the risk of acute myocardial infarction (AMI) and mortality were modified by BMI.</p><p>Methods</p><p>Multivariable Cox proportional hazard models were used to estimate the hazard ratios (HR) for AMI, cardiovascular death and all-cause mortality according to baseline plasma ADMA levels in 4122 patients with suspected stable angina pectoris. Analyses were subsequently repeated in patients with BMI below (low BMI) or above (high BMI) median.</p><p>Results</p><p>A total of 2982 patients (72%) were men. Median (range) age, plasma ADMA level and BMI were 62 (21–88) years, 0.54 (0.10–1.25) μmol/L and 26.3 (18.5–54.3) kg/m², respectively. During a mean (standard deviation) follow-up time of 4.7 (1.4) years, 337 (8%) patients suffered from an AMI, 300 (7%) died, whereof 165 (55%) due to cardiovascular disease. Each 0.1 μmol/L increment in plasma ADMA level was associated with an increased risk of AMI (HR (95% CI) 1.21 (1.08, 1.35) and cardiovascular death 1.30 (1.13, 1.49) in participants with low BMI only. Interactions were significant for AMI (<i>p</i> = 0.04) and CV death (<i>p</i> = 0.03). BMI did not modify the association between plasma ADMA levels and all-cause mortality.</p><p>Conclusion</p><p>Plasma ADMA levels were associated with risk of AMI and cardiovascular death among patients with low BMI only.</p></div

Additional file 2: Table S2. of Serum trans fatty acids, asymmetric dimethylarginine and risk of acute myocardial infarction and mortality in patients with suspected coronary heart disease: a prospective cohort study

Quartiles of trans 18:1 and risk of acute myocardial infarction, cardiovascular death and all-cause mortality. (DOCX 20 kb

Additional file 3: Table S3. of Serum trans fatty acids, asymmetric dimethylarginine and risk of acute myocardial infarction and mortality in patients with suspected coronary heart disease: a prospective cohort study

Quartiles of trans fatty acids and risk of acute myocardial infarction, cardiovascular death and all-cause mortality adjusted for plasma ADMA levels. (DOCX 20 kb

Baseline characteristics in the total population and according to patients with low and high BMI.

<p>Baseline characteristics in the total population and according to patients with low and high BMI.</p

Risk of acute myocardial infarction, cardiovascular death and all-cause mortality according to plasma ADMA levels in the total population and in patients with high or low BMI.

<p>Risk of acute myocardial infarction, cardiovascular death and all-cause mortality according to plasma ADMA levels in the total population and in patients with high or low BMI.</p

Diameter stenosis at follow-up according to plasma concentrations of asymmetric dimethylarginine and trimethyllysine^a.

<p>DS, Diameter Stenosis; ADMA, asymmetric dimethylarginine; TML, trimethyllysine.</p>a<p>Non-parametric linear quantile mixed-effects models of diameter stenosis at follow-up using Laplace distribution.</p>b<p>Effect estimate given as regression coefficient (95% confidence interval) and p-value for change in percentage point diameter stenosis.</p>c<p>The fixed effect in this model is ADMA and DS measured at baseline while the random effect is the clustering of arterial segments within a single patient. Estimates are presented as median (95% confidence interval). Standard error is estimated using bootstrapping.</p>d<p>The fixed effect in this model is TML and DS measured at baseline while the random effect is the clustering of arterial segments within a single patient. Estimates are presented as median (95% confidence interval). Standard error is estimated using bootstrapping.</p>e<p>The fixed effect in this model is DS measured at baseline, follow-up time in days, presence of diabetes, randomization (folic acid/B₁₂ vs no folic acid/B₁₂) status at baseline, plasma TML at baseline, smoking status, age, gender, plasma ADMA at baseline, systolic blood pressure, body mass index, kidney function, apolioprotein B100 and C-reactive protein while the random effect is the clustering of arterial segments within a single patient. Standard error is estimated using bootstrapping.</p

Fish Oil and the Pan-PPAR Agonist Tetradecylthioacetic Acid Affect the Amino Acid and Carnitine Metabolism in Rats

<div><p>Peroxisome proliferator-activated receptors (PPARs) are important in the regulation of lipid and glucose metabolism. Recent studies have shown that PPARα-activation by WY 14,643 regulates the metabolism of amino acids. We investigated the effect of PPAR activation on plasma amino acid levels using two PPARα activators with different ligand binding properties, tetradecylthioacetic acid (TTA) and fish oil, where the pan-PPAR agonist TTA is a more potent ligand than omega-3 polyunsaturated fatty acids. In addition, plasma L-carnitine esters were investigated to reflect cellular fatty acid catabolism. Male Wistar rats (<i>Rattus norvegicus</i>) were fed a high-fat (25% w/w) diet including TTA (0.375%, w/w), fish oil (10%, w/w) or a combination of both. The rats were fed for 50 weeks, and although TTA and fish oil had hypotriglyceridemic effects in these animals, only TTA lowered the body weight gain compared to high fat control animals. Distinct dietary effects of fish oil and TTA were observed on plasma amino acid composition. Administration of TTA led to increased plasma levels of the majority of amino acids, except arginine and lysine, which were reduced. Fish oil however, increased plasma levels of only a few amino acids, and the combination showed an intermediate or TTA-dominated effect. On the other hand, TTA and fish oil additively reduced plasma levels of the L-carnitine precursor γ-butyrobetaine, as well as the carnitine esters acetylcarnitine, propionylcarnitine, valeryl/isovalerylcarnitine, and octanoylcarnitine. These data suggest that while both fish oil and TTA affect lipid metabolism, strong PPARα activation is required to obtain effects on amino acid plasma levels. TTA and fish oil may influence amino acid metabolism through different metabolic mechanisms.</p></div

Gene expression of selected genes in liver of rats after 50 weeks of diet administration¹.

<p>Abbreviations: TTA, tetradecylthioacetic acid; FO, fish oil; <i>Aldh9a1</i>, aldehyde dehydrogenase 9, subfamily A1; <i>Bbox1</i>, gamma-butyrobetaine hydroxylase 1; <i>Tmlhe</i>, trimethyllysine hydroxylase, epsilon; <i>Aox3</i>, aldehyde oxidase 3; <i>Clpx</i>, ClpX caseinolytic peptidase×homolog; <i>Cyp7b1</i>, cytochrome P450, family 7, subfamily B, polypeptide 1; <i>Aadat</i>, aminoadipate aminotransferase; <i>Glyctk</i>, glycerate kinase; <i>Cbs</i>, cystathionine beta synthase; <i>Shmt2</i>, serine hydroxymethyltransferase; <i>Hdc</i>, histidine decarboxylase; <i>Glul</i>, glutamate-ammonia ligase; <i>Glud1</i>, glutamate dehydrogenase 1; <i>Arg1</i>, arginase, liver; <i>Ass1</i>, argininosuccinate synthase 1; <i>Asl</i>, argininosuccinate lyase.</p>1<p>Relative to control diet.</p>2<p>Values are mean ± SD (n = 10).</p>3<p>P-values from two-way ANOVA.</p

Baseline Characteristics and Laboratory Findings in Patients with Angiographic Coronary Lesions (n = 183).

<p>For continuous variables, mean and standard deviation or median and interquartile range within each group is calculated. Student's T-test or Mann-Withney U-test was used to compare the two groups. For categorical variables, number and percentage is presentend and a Chi square test was used to compare the four groups. Fisher's exact test was used when appropriate. All biochemical parameteres are prestented as median (interquartile range). FA, folic acid (0.8 mg); B₁₂, vitamin B₁₂ (0.4 mg); B₆, vitamin B₆ (40 mg); PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft surgery; NSTACS, composite syndrom consisting of acute coronary syndrome including both ST-elevated and non-ST-elevated myocardial infarction; AMI, acute myocardial infarction; CHD, coronary heart disease; LMS, left main stem; LAD, left anterior descending artery; CX, circumflex branch; RCA, right coronary artery; ACE, Angiotensin I converting enzyme; LDL, low-density lipoprotein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate; ADMA, asymmetric dimethylarginine. Percentages may not add up due to rounding of numbers.</p>a<p>Ejection fraction was measured during ventriculography for the majority of the patients. When this was not performed, ultrasonic echocardiography was used.</p>b<p>A prior diagnosis of any peripheral or cerebrovascular disease.</p>c<p>Medication at discharge.</p>d<p>Including ARB - angiotensin receptor blockers.</p

Plasma levels of L-carnitine and acylcarnitines were affected by both TTA and fish oil.

<p>Male Wistar rats were fed high fat diets supplemented with 0.375% (w/w) tetradecylthioacetic acid (TTA), 10% (w/w) fish oil (FO) or a combination of TTA and FO (TTA+FO) for 50 weeks, and L-carnitine (A), L-carnitine precursors (B-C) and acylcarnitines (D-H) were measured in plasma. Values given are means ± SD (n = 10). Asterix indicates statistical significance of variance ratio and effects of TTA (long clamps) and FO (short clamps) analyzed by two-way ANOVA (*p<0.05; **p<0.01; ***p<0.001).</p