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

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

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

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 Angiographic Characteristics of the 309 Coronary Lesions (from n = 183 patients).

<p>For continuous variables, mean and standard deviation within each group is calculated. Student's T-test was used to compare the two groups. For categorical variables, number and percentage is presentend and a Chi square test used to compare the two groups. Fisher's exact test was used when appropriate. ). FA, folic acid (0.8 mg); B₁₂, vitamin B₁₂ (0.4 mg); B₆, vitamin B₆ (40 mg); LMS, left main stem artery; LAD, left anterior descending artery; CX; circumflex artery; RCA, right coronary artery; mm, millimeters.</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

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

Asymmetric dimethylarginine and trimethyllysine before and after supplementation with folic acid/vitamin B₁₂.

<p>The graph shows empirical cumulative distribution frequencies for asymmetric dimethylarginine on the left and trimethyllysine on the right. Patients receiving folic acid/B₁₂ are displayed on the top, while patients receiving placebo or B₆ on the bottom. Time of measurement is shown as baseline (solid line) and follow-up (dashed line) after a median of 10.5 month.</p

Asymmetric dimethylarginine, trimethyllysine and angiographic progression of coronary artery disease.

<p>The graph shows the regression line from a linear quantile mixed model. The two left panels show the relation between the asymmetric dimethylarginine (ADMA) and DS measured at follow-up, whereas the two right panels show the relation between trimethyllysine (TML) and DS at follow-up. The bivariate models (adjusted for baseline DS measurement) are on the top and the multivariate (adjusted for age, sex, folic acid/B₁₂ intervention status, follow-up time, diabetes, smoking, systolic blood pressure, body mass index, estimated glomerular filtration rate (eGFR), apolipoprotein B100, C-reactive protein, ADMA or TML) at the bottom. The plasma level of either ADMA or TML is shown on the x-axis, with DS at follow-up on the y-axis. The solid line represents the regression line for the effect on median DS, while the others are displayed according to the legend.</p