The Association Between Homocysteine Levels and Cardiovascular Disease Risk Among Middle-Aged and Elderly Adults in Taiwan

doi:10.21203/rs.3.rs-120665/v1

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Research article

The Association Between Homocysteine Levels and Cardiovascular Disease Risk Among Middle-Aged and Elderly Adults in Taiwan

https://doi.org/10.21203/rs.3.rs-120665/v1

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published 20 Apr, 2021

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Background

Our study aimed to determine the association between homocysteine levels and cardiovascular disease (CVD) risk in middle-aged and elderly adults in a community in northern Taiwan.

Methods

Participants in our study included adults aged 50 to 85 years old during community health examinations on 2019. A total of 396 people were enrolled. We divided participants according to tertiles of homocysteine level (low, middle and high groups). The CVD risk was calculated by the Framingham cardiovascular risk score (FRS). An FRS ≥ 20% indicated high CVD risk. Pearson correlation coefficients were calculated between homocysteine level and other cardio-metabolic risk factors while adjusting for age. High CVD risk in the middle and high homocysteine groups was compared with that in the low homocysteine group by multivariate logistic regression with adjustments for age, sex, smoking, hypertension (HTN), diabetes mellitus (DM), body mass index (BMI) and hyperlipidemia. The Youden index and receiver operating characteristic (ROC) curves were performed to determine the optimized cut-off value.

Results

There were 396 people enrolled for analysis; 41.4% of participants were male, and the average age was 63.72 (±8.76). In our study, we showed a positive correlation of homocysteine with FRS. In the logistic regression models, the prevalence of high CVD risk was increased as homocysteine increased. The odds ratio (OR) and 95% confidence interval for high CVD risk was 2.851 (1.402 to 5.801) in the high homocysteine level group compared with the low homocysteine group after adjusting for traditional CVD risk factors (P=0.004). The area under the ROC curve was 0.67, and a homocysteine cut-off value of 12.15 µmol/L was determined.

Conclusions

Middle-aged and elderly people with increased homocysteine levels were associated with higher FRSs in this Taiwan community. Furthermore, homocysteine was an independent risk factor for high CVD risk in this study.

Cardiac & Cardiovascular Systems

Cardiothoracic Surgery

homocysteine

cardiovascular disease

middle-aged and elderly

Framingham risk score

Despite progress in medicine, the National Center for Health Statistics revealed that heart disease is still the leading cause of death in the United States [1]. The World Health Organization has also indicated that cardiovascular diseases (CVDs) are the number one cause of death globally [2], causing great loss and heavy burden in society [3]. Several CVD risk prediction models have been developed, and the Framingham Heart Study has been the most famous system for developing these prediction models [4]. Health care providers are always interested in finding reliable biomarkers for CVD.

Endothelial damage and inflammation initiate the series of steps in CVD development [5], and many biomarkers related to those steps have been investigated. C-reactive protein (CRP) has emerged as a potential useful marker for CVD, and chronic vessel inflammation suggests the possibility that subclinical states can be identified by an increasing CRP level as an indicator of circulating markers of inflammation before acute events occur [6]. The erythrocyte sedimentation rate (ESR) is another potentially novel biomarker to predict CVD, and a study showed that the ESR was mostly prolonged in patients with coronary heart disease [7].

Homocysteine is a nonproteinogenic α-amino acid in the human body and cannot be obtained from the diet. Instead, homocysteine is synthesized from methionine via multiple biochemical steps. Homocysteine can be transformed into L-cysteine or back into L-methionine. Bacteria and plants have different pathways to produce homocysteine.

An elevated homocysteine level was considered to be a risk factor for CVD in recent studies [8]. It has been believed that homocysteine disrupts endothelial function, leading to vessel damage and, ultimately, to CVD [9] [10].

Previous studies focused on mechanisms and relationships, but in our study, we wanted to know whether homocysteine is an independent risk factor for CVD. We collected many parameters related to CVD, including the traditional cardio-metabolic risk factors, in this study. After the sophisticated analysis, the results revealed that homocysteine was an independent risk factor for high CVD risk.

Study design and participants

This was a cross-sectional and community-based study with participants from a community health survey project conducted in 2019 in northern Taiwan. The inclusion criteria were as follows: (1) aged 50 years and below 85 years; (2) ability to complete a questionnaire; (3) living in the community and ability to walk to the clinic; (4) completion of all examinations. The exclusion criteria were (1) a history of heart disease or (2) missing or incomplete data (Fig. 1). Finally, 396 subjects were enrolled in this study and eligible for analysis. Each participant completed a questionnaire including personal information and medical history during face-to-face interviews. The total 396 participants were divided into three groups based on homocysteine level (low, middle, and high). This study was approved by the Institutional Review Board (IRB) of Linkou Chang Gung Memorial Hospital, and all participants were informed and gave their consent before enrollment. All the participants signed consent form before entering the study.

Data collection and measurements

The content of the questionnaire included sex, age, alcohol drinking status (no drinking, occasional drinking, drinking ≥ 3 days/week, or former drinker) and current smoking (self-reported current smoker, former smoker or nonsmoker). The health survey collected vegetarian diet, hypertension (HTN), diabetes mellitus (DM), and dyslipidemia data. Resting systolic and diastolic blood pressure (BP, mmHg) were measured at least two times at rest. The following biochemical laboratory parameters were analyzed at the Roche® model lab at Taiwan E&Q Clinical Laboratory: fasting sugar (AC sugar), homocysteine, low-density lipoprotein (LDL-C, mg/dl), high-density lipoprotein (HDL-C, mg/dl), total cholesterol (TC, mg/dl), triglyceride level (TG, mg/dl), alanine transaminase (ALT, mg/dl), creatinine (mg/dl), fasting plasma glucose (FPG, mg/dl), and uric acid (mg/dl). Waist circumference (WC, cm) was measured at the midpoint between the inferior margin of the last rib and the iliac crest in a horizontal plane while the individual was in an upright position. Body mass index (BMI) was calculated as the person's weight in kilograms divided by the square of height in meters.

Definition of CVD risk and other variables

In this study, the CVD risk was defined according to the 2008 general CVD risk model from the Framingham Heart Study, which included age, sex, systolic blood pressure (SBP), anti-HTN medication, current smoking, DM, TC, and HDL-C [13]. Then, participants were divided into a low-risk group (Framingham Risk Score [FRS] < 10%), a middle-risk group (10% ≤ FRS < 20%), and a high-risk group (FRS ≥ 20%). DM was defined as an FPG ≥ 126 mg/dL or the use of oral hypoglycemic agents or insulin therapy. HTN was defined as SBP ≥ 140 mmHg, diastolic blood pressure (DBP) ≥ 90 mmHg, or the use of treatment for HTN. Dyslipidemia was defined as LDL-C ≥ 130 mg/dL, HDL-C < 40 mg/dL in males or < 50 mg/dL in females, TG ≥ 150 mg/dL, TC ≥ 200 mg/dL, or the use of lipid-lowering medication.

Statistical analysis

Participants were divided into three groups according to homocysteine level: low homocysteine level (homocysteine concentration < 11.1 µmol/L), middle homocysteine level (11.1 < µmol/L homocysteine concentration ≤ 14.3), and high homocysteine level (14.3 < µmol/L homocysteine concentration). For laboratory and clinical data within each group, continuous variables were expressed as the mean ± SD and analyzed by one-way Analysis of variance (ANOVA); categorical variables were expressed as n (%) and analyzed by chi-square test. Pearson’s correlation coefficient was used to analyze correlations between homocysteine and age, CVD risk, AC sugar, TG, HDL-C, LDL-C, uric acid, WC, SBP, DBP and BMI; the Pearson’s correlation was adjusted by age. In addition, we further calculated the prevalence of high CVD risk according to the three levels of homocysteine. Finally, a multiple logistic regression was performed to evaluate the association between homocysteine and high CVD risk after adjusting for sex, age, WC, HTN, DM, and hyperlipidemia in each group. In our study, a p-value of < 0.05 was considered statistically significant. Youden index and receiver operating characteristic (ROC) curves were performed to determine the optimized homocysteine cut-off value to determine high CVD risk. All statistical analyses were performed using SPSS for Windows (IBM Corp. Released 2011. IBM SPSS Statistics, version 25.0. Armonk, NY: IBM Corp.)

Data from middle-aged and elderly people from communities in northern Taiwan were analyzed in this study. A total of 396 individuals, including 164 men (41.4%) and 232 women (58.6%) with a mean age of 63.72 ± 8.76 years, were enrolled for analysis. Table 1 summarizes the demographic and clinical characteristics of the study subjects. The enrolled patients were categorized into three subgroups according to their homocysteine level group. There were no statistically significant differences in age, TG concentration, LDL-C concentration, ALT concentration, alcohol drinking, prevalence of hyperlipidemia, or vegetarian diet between the low, middle and high homocysteine level groups. The participants in the high homocysteine group were more likely to be male and have a higher AC sugar level, Framingham CVD risk, uric acid concentration, creatinine concentration, waist circumference, SBP, DBP, BMI, smoking rate, prevalence of HTN, and prevalence of DM than those in the low homocysteine group. In addition, HDL-C was lower among participants in the high homocysteine group.

Table 2 demonstrates the correlations between homocysteine level and various cardiovascular risk factors. Homocysteine level was positively correlated with CVD risk, LDL-C concentration, uric acid concentration, waist circumference, SBP, DBP, and BMI; homocysteine level was negatively correlated with HDL-C concentration. All of these associations were statistically significant, even after adjusting for age. Age, AC sugar and TG were not significantly associated with homocysteine. Figure 1 shows a scatterplot of CVD risk by homocysteine level. The Pearson’s correlation was 0.360 with a p-value < 0.001.

In Table 3, Participants were divided into three groups according to homocysteine level: low homocysteine level (homocysteine concentration < 11.1 µmol/L), middle homocysteine level (11.1 < µmol/L homocysteine concentration ≤ 14.3), and high homocysteine level (14.3 < µmol/L homocysteine concentration). Multiple logistic regression models were used to calculate the odds ratio (OR) of homocysteine levels with high CVD risk after adjustment for other risk factors. The high and middle homocysteine groups were compared with the low homocysteine group in all three models. Model 1 was unadjusted; Model 2 was adjusted for age and sex; Model 3 was adjusted for age, sex, smoking, DM, HTN, hyperlipidemia and BMI. When we considered more factors in the multiple logistic regression model, all the ORs were decreased, but all the p-values were increased. All variables in the logistic regression remained statistically significant even after adjusting. The OR for high CVD risk was 2.851 (1.402 to 5.801) in the high homocysteine group compared with the low homocysteine group in model 3. Figure 2 shows the ROC curve for homocysteine level as a biomarker of CVD risk. The area under the ROC curve was 0.67; the homocysteine cut-off value of 12.15 µmol/L with a sensitivity of 0.75 and a specificity of 0.51 (Table 4).

CVD has been a worldwide healthcare burden for a long time, and medical providers are always interested in finding reliable biomarkers for CVD and CVD risk factors. In this community-based study, we investigated homocysteine levels in association with high CVD risk in middle-aged and elderly people in northern Taiwan. Looking at three homocysteine tertiles (Table 1), there was a rising proportion of males, HTN, smoking status, and SBP as the homocysteine level increased. These results correspond with previous studies, [11] [12] [13] [14] but HDL had an inverse relationship with homocysteine, which was also noted in a previous study [15]. According to the Framingham risk score, male sex, HTN, smoking status, and SBP are risk factors for CVD, but HDL serve as a protective factor against CVD. [16] Meanwhile, an increase in plasma homocysteine is directly associated with increases in Framingham CVD risk. In Fig. 3, the prevalence of high CVD risk was significantly greater in the higher tertiles of homocysteine. These findings led us to speculate that an association exists between homocysteine levels and Framingham CVD risk.

In Table 2, we found a positive correlation between homocysteine levels and Framingham CVD risk, along with other traditional CVD risk factors such as BMI and waist circumference. All the correlations reached statistical significance even after adjustment for age. The Pearson’s correlation between homocysteine and CVD risk was 0.360 with a p value < 0.001, which corresponds with a previous study that homocysteine can be a risk factor for CVD [7] [17]. All the previous results raise the question of whether homocysteine can be an important risk factor for predicting high CVD risk. Hence, we wanted to know whether homocysteine can be an independent risk factor for high CVD risk or not.

In the logistic regression models (Table 3), the middle and high homocysteine groups were compared with the low homocysteine group, and the prevalence of high CVD risk increased as homocysteine increased. After adjusting for age, sex, smoking, DM, HTN, hyperlipidemia, and BMI, the odds ratio (OR) and 95% confidence interval for high CVD risk was 2.851 (1.402 to 5.801) in the high homocysteine group compared with the low homocysteine group. This result confirmed that homocysteine was an independent risk factor for high CVD risk. Figure 2 shows the ROC curve for homocysteine as a biomarker for high CVD risk. The AUC was 0.667. The optimized cut-off value for homocysteine was 12.15 µmol/L with a sensitivity of 0.75 and a specificity of 0.51.

There are many possible explanations for the relationship between homocysteine and CVD. Homocysteine is a sulfur-containing amino acid that is a metabolic precursor of methionine and cystathionine [18]. Elevated homocysteine levels are not only considered a risk factor for cardiovascular disease [8] [16] [18] but are also linked to various diseases, such as chronic kidney disease [19]. A previous animal study with cell culture showed that high homocysteine levels had toxic effects on the vasculature, with manifestations of medial remodeling, adventitial inflammation, and endothelial injury. The mechanisms include abnormal protein metabolism [20] and the production of reactive oxidative species [21] [22]. Homocysteine specifically damages the endothelial, medial and adventitial layers of the vessel wall [9], than vessel damage leads to atherosclerosis [23], hypertension [24], stroke [25], coronary artery disease [26], peripheral arterial disease [27], and aneurysm [28].

Many studies have pointed out the positive relationship between homocysteine and CVD, but most of them did not consider the influence of other traditional CVD risk factors on the relationship between homocysteine and CVD. In our study, we considered traditional CVD risk factors and other parameters, and the results revealed that homocysteine level may be an important independent predictor of high CVD risk. Our findings may have an impact on health screening among middle-aged and elderly populations. In addition to those traditional parameters of CVD, homocysteine level should be considered an important biomarker in health screening, and people with elevated homocysteine should be warned of higher CVD risk.

This study showed that increased homocysteine levels are associated with high CVD risk among middle-aged and elderly populations in Taiwan. After this observational study examining the cross-sectional relationship between homocysteine and CVD risk, further follow-up and cohort studies are required to determine the effect of homocysteine on CVD.

CVD : cardiovascular disease, FRS : Framingham cardiovascular risk score, HTN : hypertension, DM : diabetes mellitus, BMI : body mass index, ROC : receiver operating characteristic, OR : odds ratio, CVDs : cardiovascular diseases, CRP : C-reactive protein, ESR : erythrocyte sedimentation rate, IRB : Institutional Review Board, BP : blood pressure, AC sugar : fasting sugar, LDL-C : low-density lipoprotein, HDL-C : high-density lipoprotein, TC : total cholesterol, TG : triglyceride level, ALT : alanine transaminase, FPG : fasting plasma glucose, WC : Waist circumference, BMI : Body mass index, DBP : diastolic blood pressure, SBP : systolic blood pressure, ANOVA : Analysis of variance, AUC : areas under ROC curve.

Ethics approval and consent to participate

This study was approved by the Institutional Review Board (IRB) of Linkou Chang Gung Memorial Hospital (No.1901150007), all participants were informed and gave their consent before enrollment.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests

Funding

This study was supported by United Safety Medical Group (USGN2019001)

Authors' contributions

FC analyzed and interpreted the patient data regarding the hematological disease and the transplant. RH performed the histological examination of the kidney, and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Not applicable

Authors' information (optional)

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Table 1 General characteristics of the study population according to tertiles of homocysteine

variable	total	low	middle	high
		( ≦ 11.1)	(༞11.1, ≦1 4.3)	(༞14.3)
	(n = 396)	(n = 132)	(n = 130)	(n = 134)	P value for trend
Age (year)	63.72 ± 8.76	63.10 ± 8.49	64.28 ± 9.34	63.78 ± 8.45	0.524
gender(male), n(%)	164(41.4)	24(18.2)	52(40.0)	88(65.7)	< 0.001
AC sugar (mg/dL)	109.79 ± 35.65	102.89 ± 20.65	111.74 ± 41.87	114.68 ± 39.74	0.007
Framingham CVD risk (%)	16 ± 11	12 ± 7	16 ± 11	20 ± 12	< 0.001
Homocysteine (umol/L)	13.60 ± 4.90	9.37 ± 1.26	12.66 ± 0.90	18.69 ± 4.92	< 0.001
TG (mg/dL)	141.07 ± 110.00	137.95 ± 105.33	141.65 ± 130.97	143.59 ± 91.41	0.677
LDL-C (mg/dl)	109.69 ± 33.99	113.27 ± 32.46	108.09 ± 35.97	107.71 ± 33.46	0.183
HDL-C (mg/dl)	53.56 ± 14.51	56.99 ± 13.87	54.42 ± 14.30	49.34 ± 14.41	< 0.001
Uric Acid (mg/dL)	5.63 ± 1.52	5.13 ± 1.27	5.53 ± 1.35	6.23 ± 1.70	< 0.001
ALT (U/L)	27.16 ± 22.82	26.06 ± 25.70	28.15 ± 21.44	27.28 ± 21.18	0.665
Creatinine (mg/dl)	0.87 ± 0.43	0.73 ± 0.14	0.80 ± 0.19	1.07 ± 0.66	< 0.001
waist circumference (cm)	85.36 ± 10.83	81.01 ± 10.06	86.01 ± 10.55	89.00 ± 10.40	< 0.001
SBP (mmHg)	137.30 ± 17.49	134.28 ± 16.60	137.29 ± 18.17	140.29 ± 17.29	0.005
DBP (mmHg)	85.19 ± 10.98	83.61 ± 10.62	84.04 ± 10.35	87.86 ± 11.49	0.001
BMI (kg/m²)	25.59 ± 3.84	24.53 ± 3.38	25.49 ± 3.54	26.74 ± 4.23	< 0.001
Smoking, n(%)	50(12.6)	7(5.3)	14(10.8)	29(21.6)	< 0.001
Alcohol drinking, n(%)	28(7.1)	8(6.1)	9(6.9)	11(8.2)	0.495
HTN, n(%)	201(50.8)	55(41.7)	63(48.5)	83(61.9)	0.001
DM, n(%)	133(33.6)	29(22.0)	49(37.7)	55(41.0)	0.001
hyperlipidemia, n(%)	153(38.6)	49(37.1)	43(33.1)	61(45.5)	0.158
vegetarian, n(%)	12(3.0)	4(3.0)	3(2.3)	5(3.7)	0.737

Notes: Clinical characteristics are expressed as mean± SD for continuous variables and n(%) for categorical variables. P-value were derived from one-way analysis of variance (one-way ANOVA) for continuous variables and chi-square test for categorical variables.

Abbreviations: TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; ALT, alanine aminotransferase; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; HTN, hypertension; DM, diabetes mellitus; CVD, cardiovascular disease

Table 2 The Pearson Correlation between homocysteine and cardio-metabolic risk factors.

variable	homocysteine
	Unadjusted		Adjusted for age
	Correlation	P vale	Correlation	P vale
Age (year)	0.091	0.069	NA	NA
CVD risk (%)	.360	<0.001	0.355	<0.001
AC sugar (mg/dL)	0.091	0.069	0.094	0.063
TG (mg/dL)	0.024	0.627	0.033	0.513
HDL-C (mg/dl)	-.198	<0.001	-0.202	<0.001
LDL-C (mg/dl)	-0.072	0.150	-0.055	0.277
Uric Acid (mg/dL)	.360	<0.001	0.360	<0.001
waist circumference (cm)	.251	<0.001	0.248	<0.001
SBP (mmHg)	.139	0.006	0.122	0.015
DBP (mmHg)	.152	0.002	0.168	0.001
BMI (kg/m²)	.191	<0.001	0.198	<0.001

Abbreviations: TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index.

Table 3 association between homocysteine and high CVD risk

Model 1 : unadjusted

Model 2 :unadjusted for model 1 plus age and gander

Model 3 :adjusted for model 2 plus smoking, DM, HTN, hyperlipidemia and BMI

	Model 1			Model 2			Model 3
Variable	OR	(95% C.I.)	p value	OR	(95% C.I.)	p value	OR	(95% C.I.)	p value
Low	1.00	-	-	1.00	-	-	1.00	-	-
Middle	2.366	1.276 to 4.388	0.006	2.064	1.065 to 3.999	0.032	2.012	1.005 to 4.027	0.048
High	3.772	2.075 to 6.854	< 0.001	3.346	1.707 to 6.558	< 0.001	2.851	1.402 to 5.801	0.004

Abbreviations: DM, diabetes mellitus; HTN, hypertension; BMI, body mass index.

Table 4 The areas under ROC curve (AUC), sensitivity, specificity by the optimized cut-off points for homocysteine as a biomarker of high CVD risk.

Variable	Area	p-value	Cut-off point	sensitivity	Specificity
homocysteine	0.667(0.609–0.726)	< 0.000	12.15 umol/L	0.75	0.51

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The Association Between Homocysteine Levels and Cardiovascular Disease Risk Among Middle-Aged and Elderly Adults in Taiwan

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