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. 2022 May;24(2):224-235.
doi: 10.5853/jos.2021.02152. Epub 2022 May 31.

Association of Lipids, Lipoproteins, and Apolipoproteins with Stroke Subtypes in an International Case Control Study (INTERSTROKE)

Martin J O'Donnell  1   2 , Matthew McQueen  1 , Allan Sniderman  3 , Guillaume Pare  1 , Xingyu Wang  4 , Graeme J Hankey  5 , Sumathy Rangarajan  1 , Siu Lim Chin  1 , Purnima Rao-Melacini  1 , John Ferguson  2 , Denis Xavier  6 , Liu Lisheng  4 , Hongye Zhang  7 , Prem Pais  6 , Patricio Lopez-Jaramillo  8 , Albertino Damasceno  9 , Peter Langhorne  10 , Annika Rosengren  11 , Antonio L Dans  12 , Ahmed Elsayed  13 , Alvaro Avezum  14 , Charles Mondo  15 , Conor Judge  2 , Hans-Christoph Diener  16 , Danuta Ryglewicz  17 , Anna Czlonkowska  18 , Nana Pogosova  19 , Christian Weimar  16 , Romana Iqbal  20 , Rafael Diaz  21 , Khalid Yusoff  22 , Afzalhussein Yusufali  23 , Aytekin Oguz  24 , Ernesto Penaherrera  25 , Fernando Lanas  26 , Okechukwu S Ogah  27 , Adesola Ogunniyi  28 , Helle K Iversen  29 , German Malaga  30 , Zvonko Rumboldt  31 , Shahram Oveisgharan  32 , Fawaz Al Hussain  33 , Yongchai Nilanont  34 , Salim Yusuf  1 ; INTERSTROKE Investigators
Affiliations

Association of Lipids, Lipoproteins, and Apolipoproteins with Stroke Subtypes in an International Case Control Study (INTERSTROKE)

Martin J O'Donnell et al. J Stroke. 2022 May.

Abstract

Background and purpose: The association of dyslipidemia with stroke has been inconsistent, which may be due to differing associations within etiological stroke subtypes. We sought to determine the association of lipoproteins and apolipoproteins within stroke subtypes.

Methods: Standardized incident case-control STROKE study in 32 countries. Cases were patients with acute hospitalized first stroke, and matched by age, sex and site to controls. Concentrations of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1), and apoB were measured. Non-HDL-C was calculated. We estimated multivariable odds ratio (OR) and population attributable risk percentage (PAR%). Outcome measures were all stroke, ischemic stroke (and subtypes), and intracerebral hemorrhage (ICH).

Results: Our analysis included 11,898 matched case-control pairs; 77.3% with ischemic stroke and 22.7% with ICH. Increasing apoB (OR, 1.10; 95% confidence interval [CI], 1.06 to 1.14 per standard deviation [SD]) and LDL-C (OR, 1.06; 95% CI, 1.02 to 1.10 per SD) were associated with an increase in risk of ischemic stroke, but a reduced risk of ICH. Increased apoB was significantly associated with large vessel stroke (PAR 13.4%; 95% CI, 5.6 to 28.4) and stroke of undetermined cause. Higher HDL-C (OR, 0.75; 95% CI, 0.72 to 0.78 per SD) and apoA1 (OR, 0.63; 95% CI, 0.61 to 0.66 per SD) were associated with ischemic stroke (and subtypes). While increasing HDL-C was associated with an increased risk of ICH (OR, 1.20; 95% CI, 1.14 to 1.27 per SD), apoA1 was associated with a reduced risk (OR, 0.80; 95% CI, 0.75 to 0.85 per SD). ApoB/A1 (OR, 1.38; 95% CI, 1.32 to 1.44 per SD) had a stronger magnitude of association than the ratio of LDL-C/HDL-C (OR, 1.26; 95% CI, 1.21 to 1.31 per SD) with ischemic stroke (P<0.0001).

Conclusions: The pattern and magnitude of association of lipoproteins and apolipoproteins with stroke varies by etiological stroke subtype. While the directions of association for LDL, HDL, and apoB were opposing for ischemic stroke and ICH, apoA1 was associated with a reduction in both ischemic stroke and ICH. The ratio of apoB/A1 was the best lipid predictor of ischemic stroke risk.

Keywords: Apolipoproteins; Case-control; Dyslipidemia; Lipoproteins; Risk factor; Stroke.

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Figures

Figure 1.
Figure 1.
Association of total cholesterol, lipoproteins and apolipoprotein (Apo), and stroke. Forest plot for association of total cholesterol, non-high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), HDL-C, non-HDL/HDL ratio, LDL/HDL ratio, apoB, apoA1, and apoB/A1 ratio, and ischemic stroke, ischemic stroke subtypes, and intracerebral hemorrhage. Odd ratio and 95% confidence interval (CI) per standard deviation (SD) change.
Figure 2.
Figure 2.
(A) Association of lipoproteins with ischemic stroke and intracerebral hemorrhage (ICH). (B) Association of apolipoproteins with ischemic stroke and ICH. Restricted cubic spline plot of association of (A) lipoproteins (low-density lipoprotein cholesterol [LDL-C] and high-density lipoprotein cholesterol [HDL-C]) (X-axis) and (B) apolipoproteins (apoB and apoA1) (X-axis) with ischemic stroke and ICH. Spline curve truncated at highest and lowest 2% of values. All splines adjusted for age, sex, geographic region, and potential confounders (smoking, diabetes mellitus, physical activity, diet risk score, psychosocial factors, waist-to-hip ratio, pre-admission statin, and alcohol intake).
Figure 3.
Figure 3.
Association of (A) low-density lipoprotein cholesterol (LDL-C), (B) high-density lipoprotein cholesterol (HDL-C), (C) apolipoprotein B (apoB), (D) apoA1 by ischemic stroke subtype. Restricted cubic spline plot of association of (A) LDL-C (X-axis), (B) HDL-C (X-axis), (C) apoB (X-axis), (D) apoA1 (X-axis) with ischemic stroke subtypes. Spline curve truncated at highest and lowest 2% of values. All splines adjusted for age, sex, geographic region, and potential confounders (smoking, diabetes mellitus, physical activity, diet, psychosocial factors, waist-to-hip ratio, pre-admission statin, and alcohol intake).
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