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Nah, Cho, and Choi: Association of Homocysteine Levels with Subclinical Coronary Atherosclerosis in Asymptomatic Subjects

Abstract

Background

Progression of atherosclerotic plaques is known to be correlated with elevated circulating homocysteine (Hcy). However, whether the level of Hcy is related with coronary atherosclerosis in the subclinical state is unclear. Therefore, we performed this study to investigate the relationship between blood Hcy levels and subclinical atherosclerosis in asymptomatic self-referred subjects.

Methods

We retrospectively enrolled 2,968 self-referred asymptomatic subjects (1,374 men, 1,594 women) who had undergone both coronary CT angiography (CCTA) and coronary artery calcium scoring. The relationships between atherosclerosis, Hcy, and other clinical factors were assessed.

Results

Higher levels of Hcy were related with age, male gender, body mass index (BMI), waist circumference, blood pressure, high density lipoprotein (HDL), triglyceride, blood glucose, HbA1c, hsCRP, and coronary artery calcium score (CACS). Coronary plaque was more frequently found in higher Hcy quartile groups (21.3%, 28.8%, 34.4%, and 34.3%, P<0.001). Significant coronary artery stenosis (stenosis>50%) was also more frequent in higher Hcy quartile groups (1.8%, 5.4%, 5.0%, and 6.6%, P<0.001). The factors associated with CACS included age, male gender, levels of HbA1c, Hcy and hsCRP. Logistic regression analysis adjusted for gender and confounding factors showed that the third- and fourth-quartile Hcy groups had higher odds ratios [odd ratio (OR) 3.980 (1.723-9.194), P=0.001, 7.355 (3.291-16.439), P<0.001, respectively] for high CACS (CACS >400) than the first quartile group.

Conclusions

Blood Hcy levels were associated with an increased risk of the presence and extent of subclinical atherosclerosis in asymptomatic subjects.

Figures and Tables

Fig. 1

Presence of coronary plaque and significant coronary artery disease (CAD) based on homocysteine quartile groups.

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Table 1

Clinical and laboratory characteristics in the subjects based on the homocysteine quartile group

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Q1 (N = 784) Q2 (N = 709) Q3 (N = 780) Q4 (N = 708) P value
Hcy (μmol/L) 6.6 ± 0.8a 8.3 ± 0.4b 9.9 ± 0.5c 13.8 ± 4.3d < 0.001
Age (yr) 56.6 ± 8.4a 57.8 ± 9.5a 59.4 ± 9.5b 60.3 ± 10.4b < 0.001
Male (%) 15.8 38.7 58.2 74.9 < 0.001
WC (cm) 79.6 ± 8.4a 82.2 ± 8.8b 83.5 ± 8.3c 85 ± 8.7d < 0.001
BMI 24.1 ± 3.0a 24.7 ± 3.1b 24.8 ± 3.0b 24.8 ± 3.1b < 0.001
SBP (mmHg) 121.6 ± 14.0a 123.4 ± 13.6a,b 124.8 ± 13.3a,b 126.7 ± 14.0b < 0.001
DBP (mmHg) 73.5 ± 9.1a 74.6 ± 9.0a,b 75.3 ± 8.5a,b 76.2 ± 9.4b < 0.001
TC 206.6 ± 36.8a,b 209.0 ± 37.3b 203.3 ± 37.3a,b 199.6 ± 39.9a < 0.001
TG 121 ± 101.2a 118.6 69.3a 122.1 ± 74.7a,b 135.1 ± 110.2b 0.003
HDL 58.9 ± 14.4b 57.9 ± 14.9b 54.7 ± 12.5a 53 ± 13.4a < 0.001
LDL 119.2 ± 38.0a,b 123.2 ± 39.9b 121.2 ± 38a,b 115.8 40.2a 0.003
FBS 101 ± 17.8a 103.2 18.8a 103.6 ± 18.8a,b 106 ± 22.3b < 0.001
HbA1c 5.7 ± 0.7a 5.8 ± 0.7a,b 5.8 ± 0.8a,b 5.9 ± 0.8b 0.010
hs-CRP 0.14 ± 0.3a 0.19 ± 0.5a,b 0.16 ± 0.3a,b 0.21 ± 0.5b 0.006
CACS 17.5 ± 79.5a 35.6 ± 159.8a,b 56.5 ± 208b 95.8 ± 279.1c < 0.001
presence of coronary plaque (%) 21.3 28.8 34.4 34.3 < 0.001
Significant CAD (%) 1.8 5.4 5.0 6.6 < 0.001
Severe CAD (%) 0.5 1.7 1.8 2.4 < 0.001

P value derived from one-way ANOVA and χ2 test was used for intergroup comparison.

a, b, c, d: The same letters indicate a non-significant difference between groups based on Scheffe's multiple comparison test.

Abbreviations: Q, quartile; Hcy, homocysteine; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; FBS, fasting blood sugar; HbA1c, hemoglobin A1c; hsCRP, high sensitivity C-reactive protein; CACS, coronary artery calcium score; CAD, coronary artery disease.

Table 2

Characteristics of subjects with/without coronary plaque

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Plaque (−)
(N=2,099)
Plaque (+)
(N=882)
P value
Hcy (μmol/L) 9.4±3.2 10.0±3.8 <0.001
Age (yr) 57.1±9.8 61.8±8.1 <0.001
Male (%) 42 56.7 <0.001
WC (cm) 81.7±8.8 84.5±8.3 <0.001
BMI 24.4±3.1 25.1±3.1 <0.001
SBP (mmHg) 122.8±13.9 127.1±13.2 <0.001
DBP (mmHg) 74.4±9.2 76.0±8.5 <0.001
TC 206.4±37.5 200.5±38.7 <0.001
TG 123.4±95.3 125.6±78 0.554
HDL 56.5±14.4 55.2±13.1 0.024
LDL 121.6±37.9 115.6±41.6 <0.001
FBS 101.7±18.7 107.6±20.8 <0.001
HbA1c 5.7±0.7 5.9±0.8 <0.001
hs-CRP 0.17±0.4 0.18±0.4 0.424
CACS 21±139.3 121.1±276.5 <0.001
Significant CAD (%) 1.3 28 <0.001
Severe CAD (%) 0.1 10.2 <0.001

P value derived from Student's t-test and χ2 test was used for comparing subjects with/without coronary artery plaques.

Abbreviations: Hcy, homocysteine; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; FBS, fasting blood sugar; HbA1c, hemoglobin A1c; hsCRP, high sensitivity C-reactive protein; CACS, coronary artery calcium score; CAD, coronary artery disease.

Table 3

Logistic regression analysis for the variables affecting the presence of coronary plaque

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Variables OR (95% CI) P value
Age 1.051 (1.039–1.064) < 0.001
Male 1.800 (1.454–2.227) < 0.001
WC 1.018 (1.006–1.030) 0.004
SBP 1.012 (1.005–1.020) < 0.001
FBS 1.006 (1.002–1.011) 0.010
Hcy 0.972 (0.942–1.003) 0.080
CACS 1.002 (1.001–1.003) < 0.001

This model was adjusted for age, sex, body mass index, waist circumference, blood pressure, blood lipid, fasting blood glucose and HbA1c level.

Abbreviations: OR, odds ratio; CI, confidence interval; WC, waist circumference; SBP, systolic blood pressure; FBS, fasting blood sugar; Hcy, homocysteine; CACS, coronary artery calcium score.

Table 4

Clinical and laboratory characteristics based on the coronary artery calcium score group in subjects

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CACS<1
(N=1,934)
1 ≤ CACS < 101
(N = 715)
101 ≤ CACS < 401
(N = 229)
CACS ≥ 401
(N = 90)
P value
Hcy (μmol/L) 9.2 ± 3.3 10.1 ± 3.1 10.6 ± 3.9 12 ± 3.9 < 0.001
Age (yr) 56.3 ± 9.3a 61.8 ± 7.7b 65.1 ± 7.0c 67.2 ± 7.6c < 0.001
Male (%) 39.7 56.5 59.39 74.44 < 0.001
WC (cm) 81.6 ± 8.9a 83.8 ± 8.2a 86.2 ± 8.1b 83.8 ± 8.3a < 0.001
BMI 24.4 ± 3.1a 24.9 ± 3.0a,b 25.5 ± 3.0b 24.4 ± 2.8a < 0.001
SBP (mmHg) 122.6 ± 14.0a 126.2 ± 13.2a,b 129 ± 13.0b 127.5 ± 12.8b < 0.001
DBP (mmHg) 74.5 ± 9.2a 75.9 ± 8.9a 75.9 ± 8.3a 74.2 ± 8.2a 0.001
TC 207.6 ± 36.9b 201.6 ± 39.4a,b 194 ± 37.0a 194.9 ± 41.3a < 0.001
TG 124.4 ± 97.6 124 ± 75.4 127 ± 82.4 114.6 ± 62.1 0.761
HDL 56.9 ± 14.0a 54.6 ± 13.9a 54.6 ± 14.1a 54.7 ± 12.8a 0.001
LDL 122.1 ± 38.3b 118.9 ± 39.7a,b 108.9 39.3a 110.3 ± 44.3a < 0.001
FBS 101.2 ± 17.5a 106.6 ± 20.2b 108 ± 22.4b 116.1 ± 33.2c < 0.001
HbA1c 5.7 ± 0.7a 5.9 ± 0.7a,b 6 ± 0.9b 6.3 ± 1.2c < 0.001
hs-CRP 0.161 ± 0.306a 0.2 ± 0.523a 0.164 ± 0.252a 0.317 ± 0.989b 0.003
Number of plaque 0.1 ± 0.398a 1.484 ± 1.584b 3.672 ± 2.994c 4.933 ± 4.618d < 0.001

P value derived from one-way ANOVA and χ2 test was used for intergroup comparison.

a, b, c, d: The same letters indicate non-significant differences between groups based on Scheffe's multiple comparison test.

Abbreviations: Hcy, homocysteine; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; FBS, fasting blood sugar; HbA1c, hemoglobin A1c; hsCRP, high sensitivity C-reactive protein; CACS, coronary artery calcium score.

Table 5

Association of the coronary artery calcium score with metabolic and demographic variables

lmo-6-221-i005
Variables R2 B t P value
Age 0.0492 3.878 9.32 < 0.001
Male 0.0670 39.110 4.65 < 0.001
HbA1C 0.0788 28.364 5.43 < 0.001
Hcy 0.0857 4.783 4.08 < 0.001
hs CRP 0.0898 31.708 3.51 < 0.001
LDL 0.0922 −0.262 −2.37 0.018
HDL 0.0942 0.661 2.32 0.020

P value derived from multiple linear regression analysis.

Abbreviations: HbA1c, hemoglobin A1c; Hcy, homocysteine; hsCRP, high sensitivity C-reactive protein; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol.

Table 6

Multiple logistic regression analysis for the effect of homocysteine quartile on significant coronary disease (CACS > 400)

lmo-6-221-i006
Variables OR (95% CI) P value
Age 1.134 (1.096–1.173) < 0.001
Male 3.503 (1.964–6.248) < 0.001
HbA1c 1.565 (1.265–1.936) < 0.001
Hcy Quartile
 Q1 1
 Q2 2.073 (0.823–5.226) 0.122
 Q3 3.980 (1.723–9.194) 0.001
 Q4 7.355 (3.291–16.439) < 0.001

This model was adjusted for age, sex, body mass index, waist circumference, blood pressure, blood lipid, fasting blood glucose and HbA1c.

Abbreviations: OR, odds ratio; CI, confidence interval; HbA1c, hemoglobin A1c; Hcy, homocysteine; Q, quartile.

Notes

This article is available from http://www.labmedonline.org

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