Analysis of the Correlation between Non-high Density Lipoprotein Cholesterol and Coronary Heart Disease in Elderly Chinese

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1 ORIGINAL ARTICLE Analysis of the Correlation between Non-high Density Lipoprotein Cholesterol and Coronary Heart Disease in Elderly Chinese Dazhi Ke, Qingwei Chen, Qing Wu, Xingsheng Li, Zhiqin Wu, Guiqiong Li, Wei Deng and Xiangang Mo Abstract Objective In the aged population, serum cholesterol is directly correlated with coronary heart disease (CHD) risk. We aimed to investigate the correlation between non-high density lipoprotein cholesterol (non- HDL-C) level and CHD and coronary lesions in an aged population. Methods 1,272 cases of old patients who were more than 65 years old and accepted for coronary angiography were analyzed retrospectively. Based on the result of coronary angiography, the patients were divided into control group and CHD group. Further, 767 CHD patients were divided into subgroups according to the number of branches with pathological changes and Gensini score. Serum TC, HDL-C, LDL-C and TG were assayed to measure the level of non-hdl-c. The differences in non-hdl-c among groups were compared, and the correlation between non-hdl-c and coronary artery disease degree was also analyzed. Results The non-hdl-c level in the CHD group was significantly higher than that in the control group (p< 0.01). Further, the serum non-hdl-c showed an increasing tendency accompanied by the increase in branches with lesions. Compared with patients with single or double coronary artery branches lesions, the non-hdl-c in those with multiple lesions in branches was significantly increased (p<0.01, p<0.05). With the aggravation of coronary artery stenosis, the serum non-hdl-c level was gradually increased. The most significant increase was observed in the group with Gensini score of more than 40. There was a significant difference between Gensini score >40 group and Gensini score of group and Gensini score <20 group, respectively (p<0.05, p<0.01). Meanwhile, there were significant positive correlations between the serum non-hdl-c level and coronary lesions area and severity (r=0.147, p<0.01; r=0.152, p<0.01). Conclusion In conclusion, serum non-hdl-c was closely associated with development of CHD and coronary artery lesions severity. Key words: non-high density lipoprotein cholesterol, coronary heart disease, coronary angiography () () Introduction Blood lipid disorder is one of the main risk factors for coronary heart disease (CHD). In the aged population, serum cholesterol is directly correlated with cardiovascular disease risk. Low density lipoprotein cholesterol (LDL-C) is constantly regarded as a key factor for atherosclerosis and a primary target of lipid-lowering therapy for cardiovascular diseases (1). Recently the role of non-high density lipoprotein cholesterol (non-hdl-c) in atherosclerosis has been widely focused upon. It was confirmed that non-hdl-c not LDL-C was a preferential index to predict CHD risk (2, 3). Non-HDL-C was defined as the second lipid target of therapy in the 2001 National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII), which includes low-density lipoprotein cholesterol (LDL-C), very lowdensity lipoprotein cholesterol (VLDL-C), intermediate den- Department of Geriatrics Cardiology, the Second Affiliated Hospital of Chongqing Medical University, PR China Received for publication December 12, 2010; Accepted for publication February 20, 2011 Correspondence to Dr. Qingwei Chen, chenqwcq@yahoo.com.cn 1279

2 sity lipoprotein cholesterol (IDL-C), and cholesterol in lipoprotein a [Lp(a)]. Thus, non-hdl-c is a sum total of all potential lipoprotein cholesterols which can cause atherosclerosis except for HDL-C (4). Non-HDL-C could efficiently predict the occurrence of cardiovascular diseases in patients with diabetes and renal failure (5, 6). During a long-term follow-up in a general population, the CHD risk was increased by 50% when non-hdl-c was increased by 1.11 mmol/l (43 mg/dl) (7). A recent joint consensus report by the American Diabetes Association (ADA) and the American College of Cardiology (ACC) Foundation concluded that non-hdl-c was a better index for identifying high risk patients with multiple cardiometabolic risk factors (8). Over the past decades, numerous population-based and intervention studies have identified non-hdl-c as a key risk factor for CHD (9-11). However, few studies have reported on the correlation between non-hdl-c and CHD in the aged, especially in southwest China. Because of lifestyles changing, published data regarding the prevalence of CHD in the elderly in southwest China, and others in general, are not available. In view of this, we retrospectively analyzed the lipid data of 1,272 old people who accept coronary angiography and investigated the value of non-hdl-c in CHD risk evaluation in the aged to investigate the correlation between non-hdl-c level and CHD and coronary lesion degree in the aged population. Clinical data Materials and Methods From January 2002 to December 2009, 1,272 elderly patients (age older than 65 years old) who underwent coronary angiography in the department geriatric cardiology of our hospital were selected for the present study. The case number of complications such as hypertension, diabetes, hyperlipidemia, and cerebral ischemic stroke was 825, 368, 447, and 252, respectively. Meanwhile, severe infection, wound, tumor, rheumatism, hypothyroidism, severe hepatic and renal dysfunction were excluded. Subjects Based on the coronary angiography results, the subjects were selected and divided into control group and CHD group. There were 505 and 767 cases in the control group and the CHD group, respectively. The 767 CHD patients were classified into single, double, and multiple branch lesions according to the number of impaired branches. Among these, lesions in the anterior descending branch, left circumflex branch or right coronary artery were deemed as single branch lesions and lesions in the left main stem were regarded as double branch lesion. The patients were again separated into three groups: slight (Gensini score <20), moderate (Gensini score 20-40), and severe (Gensini score > 40) lesion groups. Specimen collection and analysis Prior to coronary angiography, a 3 ml venous blood sample was obtained from each patient. Total cholesterol (TC) and triglyceride (TG) were assayed by enzyme method. HDL-C and LDL-C were measured by direct method. All analyses were performed using a 7,600 automatic analyzer (Hitachi, Tokyo, Japan). Non-HDL-C was simply calculated by subtracting HDL-C from total cholesterol. Coronary angiography examination Coronary angiography examination was done using an INNOVA 2000 cardioangiography machine (GE Medical Systems, Hermosa Beach, CA, USA). Judkin s method was employed in the visualization at multiple positions. Quantitative coronary analysis (QCA) analysis system was used to analyze the coronary stenosis degree quantitatively. The standard for CHD diagnosis is an internal diameter stenosis degree of at least one vessel, such as left main stem, left anterior descending branch, left circumflex branch, right coronary artery or its main branches, which is equal to or more than 50% of stenosis degree. Otherwise, it is negative. Gensini Gensini score scale (12) According to the coronary stenosis degree, the score is 1, 2, 4, 8, l6, and 32 when coronary stenosis degree is 25%, 26%-50%, 51%-75%, 76%-90%, 91%-99%, and 100%, respectively. Score coefficient was calculated according to the lesion position as follows: left main stem lesions (5); left anterior descending branch: proximal lesions (2.5), middle lesions (1.5), distal lesions (1.0), the first diagonal branch lesions (1.0), the second diagonal branch lesions (0.5); left circumflex branch: proximal branch lesions (2.5), margo obtusus branch lesions (1.0), distal middle lesion lesions (1.0); lesions in proximal, middle, and distal section of right coronary artery (1.0). The product of is the score for the lesions in this position. Statistical analysis All the data were expressed as mean ± standard deviation. SPSS16.0 software was used in the present study. T-test and one-way ANOVA were employed to analyze the differences between and among groups. Correlation was determined by Spearman analysis. Correlation between serum lipid parameters and coronary artery lesions was examined by multiple regression analysis. Logistic regression analysis was used to show which lipid has the closest association with the presence of CHD. A p value of less than 0.05 was considered significant. Results Among the 1,272 subjects participating in the study, males constituted 44.58% of the total sample population, compared with females constituting 55.42% (Table 1). The age of the total sample population was 74.7±5.4 years. The 1280

3 Table 1. Background of Research Participants Subject CHD Control Cases Age 74.9± ±5.4 Male/ female 405/ /194 BMI (kg/m 2 ) 22 ±3.6 21±2.4 Complications Hypertension 825 (64.86%) 512(66.75%) 313(61.98%) SBPmmHg ± ±20.25 Diabetes 368(28.93%) DBPmmHg) 92.00± ± (34.55%) 103(20.40%) HbA1c(%) 6.78± ±0.54 FBG(mmol/L) 5.70± ±1.20 2hPBG(mmol/L) 9.20± ±3.40 Cerebral ischemic stroke 252 (19.81%) 156(20.34%) 96(19.01%) users of statin(%) 322(41.98%) 102(20.20%) degree of achievement to treatment goals in lipid (%) 284(37.03%) 153(30.30%) CHD, coronary heart disease. SBP, Systolic blood pressure. DBP, diastolic blood pressure. BMI, body mass index. HbA1c, Hemoglobin A1c. FBG, fasting plasma glucose. 2hPBG, plasma glucose of two hours after meal The criteria for diagnosis of hypertension is SBP 140 mmhg or DBP 90 mmhg or taking antihypertensive medication [Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) 2003]. The criteria for diagnosis of dyslipidemia is TC 5.18 mmol/l or TG 1.70 mmol/l or LDL-C 3.37 mmol/l or HDL-C<1.04 mmol/l [National Cholesterol Education Program (NCEP) Adult Treatment Panel III(ATPIII), 2001]. The criteria for diagnosis of diabetes is FBG 7.0 mmol/l or 2hPBG during an oral glucose tolerance test (OGTT) 11.1 mmol/l or a random BG 11.1 mmol/l or HbA1c 6.5% [Standards of Medical Care in Diabetes, American Diabetes Association (ADA),2010]. The criteria for diagnosis of cerebral ischemic stroke is brain infarcts may be visible with MRI or CT [Guidelines for the Prevention of Stroke in Patients With Stroke or Transient Ischemic Attack, American Heart Association (AHA)/American Stroke Association(ASA), 2010]. percent of cases with complications such as hypertension, diabetes, hyperlipidemia, and cerebral ischemic stroke was 64.86%, 28.93%, 35.14% and 19.81%, respectively. Meanwhile, severe infection, wound, tumor, rheumatism, hypothyroidism, sever hepatic and renal dysfunction were excluded. Based on the coronary angiography results, the subjects were divided into control group and CHD group. There were 505 (311 males/194 females) and 767 (405 males/362 females) cases in the control group and the CHD group, respectively. The mean age was 74.3±5.4 and 74.9±5.4 in the control group and the CHD group, respectively. Assay of blood lipid Serum cholesterol levels were measured for all subjects and the results are also summarized in Table 2. Mean non- HDL-C concentrations were 3.42±0.44 and 5.04±0.19 mmol/l for control and CHD group, respectively. Compared with the control group, the non-hdl-c, LDL-C, and TC in the CHD group was significantly increased respectively (p< 0.01, p<0.05, p<0.05). And, HDL in the CHD group was markedly decreased (p<0.05). However, there was no obvious difference in TG between the two groups (p>0.05). Blood lipid in CHD patients with different impaired branches and different Gensini score Table 3 presents levels of blood lipid in CHD patients with a different number of impaired branches and a different Gensini score. Increasing lipid levels were associated with increased CHD risk. The non-hdl-c level was increased most significantly in CHD patients with multiple branches lesions. There were significant differences between multiple branch lesions and single, double branch lesions (p<0.01, p< 0.05). The non-hdl-c was increased most significantly in the CHD patients with a Gensini score of more than 40 (Ta- 1281

4 Table 2. Blood Lipid Assay in the Control and CHD Groups ( x±s, mmol/l) Group n non-hdl-c TC HDL-C LDL-C TG Control ± ± ± ± ±1.05 CHD ±0.19 ** 5.31±0.31 * 1.01±0.14 * 2.91±0.17 * 1.78±1.44 CHD, coronary heart disease; non-hdl-c, non-high density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride Data are presented as mean ± SD. *p<0.05, **p<0.01 as compared with control group. Table 3. Blood Lipid in CHD Patients with Different Impaired Branches ( x±s, mmol/l) Group n non-hdl-c TC HDL-C LDL-C TG Single branches ± ± ± ± ±0.26 lesions Double branches lesions ±0.41 * 4.74± ± ± ±0.33 Multiple 5.23±0.49 ** 5.53±0.46 * branches ± ±0.46* 1.85±0.28 lesions Gensini 289 score< ± ± ± ± ± <Gensini 258 score< ±0.46 * 4.76± ± ± ±0.20 Gensini ±0.37 ** 5.68±0.48 * 1.27± ±0.48* score> ±0.25 non-hdl-c, non-high density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride Data are presented as mean ± SD. *p<0.05, **p<0.01 as compared with Single branch lesion group or Gensini score<20 group; p<0.05 as compared with double branch lesion group or 20<Gensini score<40 group. ble 3). There was a significant difference between Gensini score >40 group and Gensini score <40 group, Gensini score group, respectively (p<0.01, p<0.05). Correlations between blood lipid and the number of impaired coronary artery branches and stenosis degree To evaluate each factor in Table 1, 2, simple logistic regression analysis was performed. The results of logistic regression analysis are shown in Table 4. Among these parameters, hyperlipidemia, hypertension, and diabetes mellitus were selected as the representative factors from their higher correlation with CHD. Correlation between blood lipids and the number of impaired coronary artery branches and stenosis degree were analyzed. The results showed that there were significant positive correlations between serum non- HDL-C and the number of impaired coronary artery branches and stenosis degree (r=0.147, p<0.01; r=0.152, p< 0.01) (Table 5). Discussion A large number of clinical studies have confirmed that decreased LDL-C level is helpful to reduce CHD mortality and the incidence of cardiovascular events. However, there were still some events could not be prevented even under the therapy of lowering LDL-C. We observed that among our study population in a cohort representative of a contemporary Chinese population, non-hdl-c was more strongly associated with the risk of future CHD than was LDL-C. Non-HDL-C reflects potential lipoprotein cholesterol that can cause atherosclerosis. In addition, LDL-C, VLDL-C, IDL-C, Lp (a) actually also involved in the process of atherosclerosis. IDL-C is a residuary particle in the conversion process from VLDL-C to LDL-C, and it readily enters macrophages and participates in the process of atherosclerosis (13-15). Lp (a) is a specific lipoprotein that is constituted by apoa and particles similar to LDL lipoprotein. It remaines in vascular endothelial cells and suppresses the activation of plasminogen, thereby delaying thrombolysis, which promotes foam cell formation and smooth muscle cell proliferation. After the oxidization modification, Lp (a) is changed to oxidative Lp(a) and then recognized and combined by scavenger receptor, which induces and stimulates monocyte differentiation and promotes further formation of macrophages (16). Thus, LDL is not an independent lipo- 1282

5 Table 4. Logistic Regression Analysis Simple Multiple Term Estimate SE p Estimate SE p age BMI < Sex male female Hypertension Diabetes Hyperlipidemia < < non-hdl-c < TC < HDL-C LDL-C < TG cerebral ischemic stroke Table 5. Correlations between Blood Lipid and Number of Coronary Artery Lesions and Stenosis Degree number of impaired Blood lipid coronary artery Stenosis degree branches r p value r p value non-hdl-c TC HDL-C LDL-C TG non-hdl-c, non-high density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride protein causing atherosclerosis. Compared with LDL-C, non-hdl-c is a more effective index which can reflect the effect of cholesterol-induced atherosclerosis (17). Now, many studies have already confirmed that non- HDL-C can predict cardiovascular diseases risk, and it is better than LDL-C (18-21). Clinical trial results also have shown that the decreased non-hdl-c level can predict decreased CHD risk in patients after single drug administration, and this predictive efficiency is twice as much as LDL- C (20). Analysis of TNT (Treating to New Targets) and IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trials comparison of atorvastatin 80 mg to pravastatin 40 mg and simvastatin 20 to 40 mg, respectively, the results confirmed that non-hdl-c was a superior risk predictor to LDL-C (19). Arsenault et al found that non-hdl-c could still predict the CHD risk even at a low LDL-C level (2). The findings supported the non-hdl-c as a key treatment goal (21, 22). The European Prospective Investigation Into Cancer and Nutrition (EPIC)-Norfolk study, included more than 21,000 men and women, aged years old, who were followed up for eleven years. When non-hdl-c was higher than LDL-C by 0.77 mmol/l, the predicted CHD risk was increased. When the LDL-C level was less than 2.6 mmol/l and the non-hdl-c level was more than 3.37 mmol/l, the CHD risk was 1.8-fold compared with that when non-hdl- C level was less than 3.37 mmol/l. Importantly, this analysis was not restricted in the population with mmol/l TG recommended by NCEP ATPIII. The elderly form a unique patient population and are a susceptible population of CHD. Although the previous studies which handled young or middle-aged subjects were well conducted and analyzed (22-24), their results cannot be extrapolated to populations of Southwest China, in which CHD is common in the aged people and it displays a young tendency. The aging trend has emerged in China. Our study adds to knowledge about the relationship between non- HDL-C and CHD in the elderly of Southwest China. In the present study, elderly patients aged >65 years old were selected as subjects. The incidence of dyslipidemia was 35.14%. Dyslipidemia remained a significant risk factor for CHD in the elderly. The results of logistic regression analysis showed that hyperlipidemia was selected as the representative factor from the high correlation with CHD among these parameters. Among parameters of hyperlipidemia, the non-hdl-c, LDL-C, TC level in the CHD group was significantly higher than that in the control group, respectively (p<0.01, p<0.01, p<0.05), while HDL-C level was markedly decreased (p<0.05), suggesting an important role of dyslipidemia in the progression of CHD in the elderly. The results showed that more serum non-hdl-c was present in the CHD patients with more impaired coronary arter- 1283

6 ies. The non-hdl-c was increased most significantly in the patients with multiple branch lesions. Further, the serum non-hdl-c level was increased along with the aggravation of coronary stenosis. The elevation was most significant in Gensini score >40 group. And it was significantly higher than that in Gensini score <20 group and Gensini score group, respectively (p<0.01, p<0.05). Spearman correlation analysis also suggested significant positive correlations between non-hdl-c level and the number of impaired coronary artery branches and stenosis degree (r=0.147, p< 0.01; r=0.152, p<0.01). The correlation was slightly stronger than that of LDL-C (r=0.115, p<0.01; r=0.138, p<0.01). The results above suggested that the non-hdl-c level is more useful to assess the severity of CHD (23). In view of the preferred role of non-hdl-c in predicting the CHD risk and benefit via reducing non-hdl-c, the American Diabetes Association (ADA) and the American College of Cardiology (ACC) Foundation concluded that the non-hdl-c treatment goal was 2.6 mmol/l in all CHD and diabetes patients complicated with one cardiovascular risk factor; The goal was 3.37 mmol/l in patients with cardiometabolic risk complicated with two main cardiovascular risk factors. In addition, the National Lipid Association also recognized the importance of non-hdl-c and recommended that the reports from all laboratories should include non- HDL-C values (25). In summary, serum non-hdl-c level was closely associated with the development of CHD in the elderly. It was a good index to assess the area and severity of CHD. For simplicity, reliability, and good compliance, non-hdl-c assessment for CHD risk has a good implication prospect in daily practice. 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