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

Elin Strand, Eva R Pedersen, Gard F T Svingen, Thomas Olsen, Bodil Bjørndal, Therese Karlsson, Jutta Dierkes, Pål R Njølstad, Gunnar Mellgren, Grethe S Tell, Rolf K Berge, Asbjørn Svardal, Ottar Nygård, Elin Strand, Eva R Pedersen, Gard F T Svingen, Thomas Olsen, Bodil Bjørndal, Therese Karlsson, Jutta Dierkes, Pål R Njølstad, Gunnar Mellgren, Grethe S Tell, Rolf K Berge, Asbjørn Svardal, Ottar Nygård

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.

Keywords: acylcarnitines; angina pectoris; cardiovascular outcomes; metabolism.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Association between acylcarnitines and clinical relevant covariates. Spearman's rho of ranked values of the serum acylcarnitines, acetyl‐, octanoyl‐, palmitoyl‐, propionyl‐, and (iso)valerylcarnitine, with important covariates at baseline are illustrated. The model was adjusted for sex. ApoA1 indicates apolipoprotein A1; ApoB, apolipoprotein B; B‐cell act., β‐cell activity; BMI, body mass index; CAD, coronary artery disease; CRP, C‐reactive protein; eGFR, estimated glomerular filtration rate; HbA1c, glycosylated hemoglobin; HDL, high‐density lipoprotein cholesterol; Insulin res., insulin resistance; Insulin sens., insulin sensitivity; LDL, low‐density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; TG, triglycerides. *P<0.01; **P<0.001.
Figure 2
Figure 2
Association between serum even‐chained acylcarnitines and risk of cardiovascular death (A) and acute myocardial infarction (B). In this generalized additive model, the hazard ratios are represented by the solid lines, whereas the 95% CIs lie within the shaded areas. Density plots show the distribution of serum acylcarnitines in the study cohort, and the vertical lines denote the 10th, 25th, 50th, 75th, and 90th percentiles. Values along the x‐axis have been log‐transformed and the plot has been cut at the 2.5th and 97.5th percentiles, respectively. The model was adjusted for age, sex, body mass index, fasting status, current smoker, 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.
Figure 3
Figure 3
Forest‐plot showing risk associations in the upper versus lower quartile of circulating acylcarnitines based on nonfasting and fasting measurements. Risk of cardiovascular death (A) and acute myocardial infarction (B) was calculated using Cox proportional hazards modeling. Hazard ratios (95% CIs) for quartile 4 versus 1 of each acylcarnitine are illustrated in strata of fasting status as designated. Cox proportional hazards survival analyses were adjusted for age and sex.

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