Lipids, Lipoproteins, and Metabolites and Risk of Myocardial Infarction and Stroke

Abstract

Background: Blood lipids are established risk factors for myocardial infarction (MI), but uncertainty persists about the relevance of lipids, lipoprotein particles, and circulating metabolites for MI and stroke subtypes.

Objectives: This study sought to investigate the associations of plasma metabolic markers with risks of incident MI, ischemic stroke (IS), and intracerebral hemorrhage (ICH).

Methods: In a nested case-control study (912 MI, 1,146 IS, and 1,138 ICH cases, and 1,466 common control subjects) 30 to 79 years of age in China Kadoorie Biobank, nuclear magnetic resonance spectroscopy measured 225 metabolic markers in baseline plasma samples. Logistic regression was used to estimate adjusted odds ratios (ORs) for a 1-SD higher metabolic marker.

Results: Very low-, intermediate-, and low-density lipoprotein particles were positively associated with MI and IS. High-density lipoprotein (HDL) particles were inversely associated with MI apart from small HDL. In contrast, no lipoprotein particles were associated with ICH. Cholesterol in large HDL was inversely associated with MI and IS (OR: 0.79 and 0.88, respectively), whereas cholesterol in small HDL was not (OR: 0.99 and 1.06, respectively). Triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI, with a similar pattern for IS. Glycoprotein acetyls, ketone bodies, glucose, and docosahexaenoic acid were associated with all 3 diseases. The 225 metabolic markers showed concordant associations between MI and IS, but not with ICH.

Conclusions: Lipoproteins and lipids showed similar associations with MI and IS, but not with ICH. Within HDL particles, cholesterol concentrations were inversely associated, whereas triglyceride concentrations were positively associated with MI. Glycoprotein acetyls and several non-lipid-related metabolites associated with all 3 diseases.

Keywords: epidemiology; etiology; intracerebral hemorrhage; ischemic stroke; metabolomics; myocardial infarction.

Graphical abstract

Figure 1

Adjusted OR (95% CI) of MI, IS, and ICH for Lipoprotein Particle Concentration, Cholesterol, and Triglycerides as Measured by Nuclear Magnetic Resonance Spectroscopy Estimates are odds ratios (ORs) per 1-SD higher metabolic marker. Models are adjusted for age, sex, fasting hours, region, smoking status, and educational attainment. Significance (Sig.): ∗∗∗p ≤ 0.0001, ∗∗p ≤ 0.01, ∗p ≤ 0.05, - p > 0.05 (false discovery rate [FDR]–adjusted p values). CI = confidence interval; HDL = high-density lipoprotein; ICH = intracerebral hemorrhage; IDL = intermediate-density lipoprotein; IS = ischemic stroke; LDL = low-density lipoprotein; MI = myocardial infarction; VLDL = very low-density lipoprotein.

Figure 2

Adjusted OR (95% CI) of MI, IS, and ICH for Mean Particle Diameter, Cholesterol, Triglycerides, and Apolipoproteins as Measured by Nuclear Magnetic Resonance Spectroscopy Estimates are ORs per 1-SD higher metabolic marker. Models are adjusted for age, sex, fasting hours, region, smoking status, and educational attainment. Significance: ∗∗∗p ≤ 0.0001, ∗∗p ≤ 0.01, ∗p ≤ 0.05, - p > 0.05 (FDR-adjusted p values). ApoA1 = apolipoprotein A1; ApoB = apolipoprotein B; other abbreviations as in Figure 1.

Figure 3

Adjusted OR (95% CI) of MI, IS, and ICH for Other Traits as Measured by NMR Spectroscopy Estimates are ORs per 1-SD higher metabolic marker. Models are adjusted for age, sex, fasting hours, region, smoking status, and educational attainment. Significance: ∗∗∗p ≤ 0.0001, ∗∗p ≤ 0.01, ∗p ≤ 0.05, - p > 0.05 (FDR-adjusted p values). Abbreviations as in Figure 1.

Figure 4

Comparison of Adjusted OR (95% CI) of 225 Metabolic Measures as Measured by Nuclear Magnetic Resonance Spectroscopy Comparison between IS and (A) MI and (B) ICH. Estimates are per 1-SD higher metabolic marker. Model adjustment as in Figure 1. Abbreviations as in Figure 1.

Central Illustration

Lipoprotein Lipids and Other Metabolic Markers With Risk of Incident MI, IS, and ICH We assessed the associations of metabolic markers measured by nuclear magnetic resonance (NMR) spectroscopy with risk of incident myocardial infarction (MI), ischemic stroke (IS), and intracerebral hemorrhage (ICH). The study demonstrated that lipoprotein subclasses and their lipid constituents shared associations with both risk of MI and IS, but not with risk of ICH. For MI and IS, cholesterol (orange squares and horizontal lines) and triglycerides (green squares and horizontal lines) in apolipoprotein B–containing lipoproteins (very low-density lipoprotein [VLDL], intermediate-density lipoprotein [IDL], and low-density lipoprotein [LDL]) were positively associated with risk of both diseases. In contrast, cholesterol in large and medium high-density lipoprotein (HDL) particles was inversely associated with risk of MI and IS, whereas triglycerides in HDL particles were positively associated with disease risk. Neither lipoproteins nor lipid constituents showed associations with risk of ICH. In contrast, glucose and the inflammation marker glycoprotein acetyls were both associated with higher risks of all 3 diseases. Thus, although lipids and lipoproteins appear to be less relevant to ICH than MI or IS, the association of some metabolites with MI, IS, and ICH indicates shared pathways for all 3 subtypes of vascular disease.