第一部分 早发冠心病三支病变患者脂蛋白（a）与冠状动脉钙化的相关性研究

背景：研究显示，随着冠状动脉钙化程度增加，冠心病患者的不良预后及心血管事件风险增加。虽然有研究显示脂蛋白（a）与主动脉瓣钙化之间存在相关性，但脂蛋白（a）增高是否会增加冠状动脉钙化风险仍具有争议。

目的：探讨脂蛋白（a）是否与早发冠心病三支病变患者的冠状动脉钙化相关。

方法：本研究为单中心、前瞻性、观察性队列研究。连续纳入于2013年1月至2013年12月在阜外医院接受经皮冠状动脉介入术的患者10724例，并从中选取早发冠心病三支病变患者（男性≤50岁，女性≤60岁，所有主要三支冠状动脉血管造影提示狭窄均≥50%）进行分析。根据冠状动脉造影结果判断冠状动脉钙化程度，并将患者分为冠状动脉低度钙化组（n=904）和冠状动脉高度钙化组（n=227）。采用多因素Logistic回归分析脂蛋白（a）是否是冠状动脉高度钙化的独立危险因素。

结果：共计1131例同时具有脂蛋白（a）和冠状动脉钙化结果的早发冠心病三支病变患者（平均年龄：47.88±6.30岁；男性占比：74.0%）最终纳入分析。高水平脂蛋白（a）（≥30mg/dl）在冠状动脉高度钙化组中更为常见（43.6% vs. 36.5%，P=0.048）。多因素Logistic回归分析显示，脂蛋白（a）水平升高（≥30mg/dl）与冠状动脉高度钙化独立相关（OR=1.391, 95% CI: 1.030-1.880, P=0.031）。同时，糖尿病（OR=1.645，95% CI=1.216-2.224，P=0.001）和高血压（OR=1.466，95% CI=1.065-2.020，P=0.019）也是冠状动脉高度钙化的独立相关影响因素。

结论：本研究显示在早发冠心病三支病变患者中，脂蛋白（a）是一种新型的冠状动脉高度钙化的独立危险因素，提示在早发冠心病三支病变患者中可用脂蛋白（a）水平对冠状动脉钙化风险进行早期评估。

第二部分 冠心病合并糖尿病或糖尿病前期患者糖脂代谢标记物甘油三酯-葡萄糖指数与冠状动脉钙化的相关性研究

背景：冠状动脉钙化是一种高度特异的动脉粥样硬化标志，且冠状动脉钙化越严重，冠心病预后越差。甘油三酯-葡萄糖指数（Triglyceride-glucose index，TyG指数）是糖脂代谢和胰岛素抵抗的重要指标，与冠状动脉病变严重程度和不良心血管结局密切相关。但TyG指数与冠状动脉钙化之间的相关性尚不明确。

目的：探讨TyG指数与冠心病合并糖尿病或糖尿病前期患者冠状动脉钙化的相关性。

方法：本研究为一项单中心、前瞻性、观察性队列研究。连续纳入于2013年1月至2013年12月在阜外医院接受经皮冠状动脉介入术的冠心病患者10724例，并从中选取合并糖尿病或糖尿病前期的患者进行分析。根据冠状动脉造影结果判断冠状动脉钙化的严重程度，并将患者分为冠状动脉高度钙化组（n=6405）和冠状动脉低度钙化组（n=1481）。根据TyG指数对冠状动脉高度钙化预测的最佳截断值，我们选择TyG指数≥8.951作为本研究的最佳截断值。采用多因素Logistic回归分析TyG指数是否是冠状动脉高度钙化的独立危险因素。

结果：共计7782例冠心病合并糖尿病或糖尿病前期并同时具有TyG指数和冠状动脉钙化结果（平均年龄：58.24±10.80岁；男性占比：76.8%）的患者最终纳入分析。多因素Logistic回归分析显示，TyG指数升高是冠状动脉高度钙化的独立影响因素（OR=1.147, 95% CI: 1.017-1.294, P=0.025），年龄（OR=1.018，95% CI=1.011-1.024，P<0.001）、糖尿病（OR=1.137，95% CI=1.008-1.283，P=0.036）和既往冠状动脉旁路移植史（OR=1.411，95% CI=1.069-1.862，P=0.015）也与冠状动脉高度钙化独立相关。进一步的亚组分析显示，在糖尿病患者中，TyG指数与冠状动脉高度钙化的相关性较高（OR=1.303, 95% CI: 1.075-1.579），而在糖尿病前期患者中，TyG指数与冠状动脉高度钙化的相关性无显著性差异（交互作用P=0.042）。

结论：本研究显示在冠心病合并糖尿病或糖尿病前期的患者中，高TyG指数是冠状动脉高度钙化的独立影响因素；进一步亚组分析，在糖尿病患者中，TyG指数与冠状动脉高度钙化的相关性较高，但在糖尿病前期患者中，TyG指数未见与冠状动脉高度钙化明显相关。

第三部分 早发冠心病三支病变患者血脂代谢相关基因NPC1L1及HMGCR基因多态性与冠状动脉钙化的相关性研究

背景：冠状动脉钙化是一种高度特异的动脉粥样硬化标志。Niemann-Pick C1-like 1蛋白 （NPC1L1）和3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）分别是依折麦布和他汀类药物的治疗靶点，它们的基因多态性对动脉粥样硬化的发生和发展具有重要作用，但冠状动脉钙化与上述基因的遗传易感性尚不清楚。

目的：探讨NPC1L1及HMGCR基因多态性是否与早发冠心病三支病变患者的冠状动脉钙化具有相关性。

方法：本研究为一项单中心、前瞻性、观察性队列研究。纳入872例于2004年4月至2011年2月在阜外医院住院的早发冠心病三支病变（男性≤50岁，女性≤60岁，所有三条主要冠状动脉血管造影提示狭窄均≥50%）患者进行分析。对NPC1L1基因的4个单核苷酸多态性（rs11763759、rs4720470、rs2072183和rs2073547）和HMGCR基因的3个单核苷酸多态性（rs12916、rs2303151和rs4629571）进行分析。根据冠状动脉造影结果判断冠状动脉钙化的严重程度，并将患者分为冠状动脉低度钙化组（n=699）和冠状动脉高度钙化组（n=173）。采用多因素logistic回归分析NPC1L1及HMGCR基因多态性是否是冠状动脉高度钙化的独立危险因素。

结果：共计872例早发冠心病三支病变患者（平均年龄：47.71±6.12岁；男性：72.8%）最终纳入分析。多因素Logistic回归分析显示，NPC1L1和HMGCR基因多态性与冠状动脉高度钙化之间无显著相关性（P>0.05）。进一步的性别亚组分析显示，NPC1L1基因的rs4720470变异基因型仅在男性患者中与冠状动脉高度钙化风险增加相关（OR=1.505, 95% CI: 1.008-2.249, P=0.046)，而在女性患者中无统计学差异（P>0.05），且NPC1L1基因的其他单核苷酸多态性以及HMGCR基因的单核苷酸多态性与冠状动脉高度钙化之间无明显相关性(P>0.05)。

结论：本研究显示NPC1L1基因的rs4720470变异基因型与早发冠心病三支病变男性患者的冠状动脉高度钙化相关。检测NPC1L1基因的rs4720470变异基因型有助于早期识别冠脉钙化严重的男性冠心病患者。

Part 1  Association of Lipoprotein (a) with Coronary Artery Calcification in Patients with Premature Triple-vessel Coronary Disease

Background: Studies have shown that as the severity of coronary artery calcification (CAC) increases, the risk of adverse prognosis and cardiovascular events increases in patients with coronary heart disease. Although studies have shown a correlation between lipoprotein (a) [lp(a)] and aortic valve calcification, whether elevated Lp(a) increases the risk of CAC remains controversial.

Objective: To investigate whether Lp(a) was associated CAC in patients with premature triple-vessel coronary disease (PTVD).

Methods: This was a single-center, prospective and observational cohort study. 10,724 consecutive patients who were admitted to Fuwai Hospital and underwent percutaneous coronary intervention were enrolled form January 2013 to December 2013, from which we selected PTVD patients (male ≤ 50 years old and female ≤ 60 years old; angiographic stenosis of ≥50% in all three main coronary arteries) for analysis. The degree of CAC was determined according to the coronary angiography results, and patients were divided into low-degree CAC group (n=904) and high-degree CAC group (n=227). Multivariate Logistic regression was used to analyze whether Lp(a) was an independent risk factor for high-degree CAC.

Results: A total of 1,131 PTVD patients (mean age, 47.88 ± 6.30 years; male, 74.0%) who had both Lp(a) and CAC results were finally enrolled for analysis. High level Lp(a) (≥30mg/dl) was more common in the high-degree CAC group (43.6% vs. 36.5%, P=0.048). Multivariate Logistic regression analysis showed that elevated Lp(a) level (≥30mg/dl) was independently associated with high-degree CAC (odds ratio [OR]=1.391, 95% confidence interval [CI]: 1.030-1.880, P=0.031). Moreover, diabetes（OR=1.645，95% CI=1.216-2.224，P=0.001） and hypertension （OR=1.466，95% CI=1.065-2.020，P=0.019） were also independent and relevant influencing factors of high-degree CAC (all P<0.05).

Conclusion: This study showed that Lp(a) was a novel independent risk factor for high-degree CAC in patients with PTVD, suggesting that Lp(a) levels could be used for early assessment of CAC risk in patients with PTVD.

Part 2  Association of Triglyceride-glucose Index Related to Glycolipid Metabolism with Coronary Artery Calcification in Coronary Heart Disease Patients with Diabetes or Pre-diabetes

Background: Coronary artery calcification is a highly specific marker of atherosclerosis. As the severity of coronary artery calcification (CAC) increases, the prognosis is getting worse in patients with coronary heart disease (CHD). High triglyceride-glucose (TyG) index, a marker of glycolipid metabolism and insulin resistance, is closely associated with poor cardiovascular outcomes and severe coronary lesions. However, the relationship between TyG index and CAC is still unknown.

Objective: To investigate whether TyG index is associated with CAC in CHD patients with diabetes or pre-diabetes.

Methods: This was a single-center, prospective and observational cohort study. 10,724 consecutive patients with CHD undergoing percutaneous coronary intervention who were admitted to Fuwai Hospital were enrolled from January 2013 to December 2013, from which we selected those with diabetes or pre-diabetes. Patients were divided into low-degree CAC group (n=6,405) and high-degree CAC group (n=1,481) according to the coronary angiography results. According to the optimal cut-off value of TyG index for high-degree CAC prediction, we selected TyG index ≥8.951 as cut-off point. Multivariate Logistic regression was used to analyze whether TyG index was an independent risk factor for high-degree CAC.

Results: A total of 7,782 CHD patients with diabetes or pre-diabetes (mean age, 58.24 ± 10.80 years; male, 76.8%) who had both TyG Index and CAC results were finally enrolled for analysis. Multivariate Logistic regression analysis showed that higher TyG Index was independently associated with high-degree CAC (odds ratio [OR]=1.147, 95% confidence interval [CI]: 1.017-1.294, P=0.025). Age (OR=1.018, 95% CI =1.011-1.024, P<0.001), diabetes (OR=1.137, 95% CI =1.008-1.283, P=0.036) and previous history of coronary artery bypass grafting (OR=1.411, 95% CI=1.069-1.862, P=0.015) was also independently associated with high-degree CAC. Subgroup analysis revealed that the correlation between TyG index and CAC was higher in patients with diabetes (OR=1.303, 95% CI: 1.075-1.579), but no significant difference was found in patients with pre-diabetes (P _{for interaction}=0.042).

Conclusion: This study showed that in patients with CHD combined with diabetes or pre-diabetes, high TyG index was an independent risk factor for high-degree CAC. Further subgroup analysis showed that in diabetic patients, TyG index was highly correlated with high-degree CAC, but in patients with pre-diabetes, TyG index was not significantly associated with high-degree CAC.

Part 3  Association of NPC1L1 and HMGCR Gene Polymorphisms Related to Lipid Metabolism with Coronary Artery Calcification in Patients with Premature Triple-vessel Coronary Disease

Background: Coronary artery calcification (CAC) is a highly specific marker of atherosclerosis. Niemann-Pick C1-like 1 (NPC1L1) and 3–hydroxy–3– methylglutaryl - coenzyme A reductase (HMGCR) are the therapeutic targets of ezetimibe and statins, respectively, which are important for the progression of atherosclerosis, but CAC’s genetic susceptibility with above genes is still unknown.

Objective: To investigate the association of NPC1L1 and HMGCR gene polymorphisms with CAC in patients with premature triple-vessel coronary disease (PTVD).

Methods: This was a single-center, prospective and observational cohort study. Four single nucleotide polymorphisms (SNPs) (rs11763759, rs4720470, rs2072183, rs2073547) of NPC1L1, and three SNPs (rs12916, rs2303151, rs4629571) of HMGCR were genotyped in 872 PTVD patients (male ≤ 50 years old or female ≤ 60 years old, with angiographic stenosis of ≥50% in all three main coronary arteries) who were admitted to Fuwai Hospital from April 2004 to February 2011. According to the coronary angiography results, patients were divided into low-degree CAC group (n=699) and high-degree CAC group (n=173). Multivariate Logistic regression was used to analyze whether NPC1L1 and HMGCR gene polymorphisms were independent risk factors for high-degree CAC.

Results: A total of 872 PTVD patients (mean age, 47.71±6.12 years; male, 72.8%) were finally included for analysis. Multivariate Logistic regression analysis showed no significant difference between the SNPs of NPC1L1 and HMGCR genes and high-degree CAC in the total population (P>0.05). Further subgroup analysis by gender revealed that the variant genotype of rs4720470 on NPC1L1 gene was associated with increased risk for high-degree CAC in male patients only (odds ratio [OR]=1.505, 95% confidence interval [CI]: 1.008-2.249, P=0.046), but no significant difference was found in female population, other SNPs of NPC1L1 and HMGCR genes (all P>0.05).

Conclusion: This study showed that the variant genotype of rs4720470 on NPC1L1 gene was associated with high-degree CAC in male patients with PTVD. Early detection of variant genotype of rs4720470 on NPC1L1 gene is helpful for early identification of male PTVD patients with severe CAC.