脂蛋白(a)水平与钙化性主动脉瓣狭窄患者瓣膜钙化体积及进展的研究

An Analysis of the Relationship between Lipoprotein (a) Levels and the Variation of Calcification Volume in Patients with Calcific Aortic Stenosis

摘要: 目的：本文旨在描述钙化性主动脉瓣狭窄患者的临床特征，揭示疾病进展的个体差异，分析评价脂蛋白(a) [Lp(a), lipoprotein (a)]在该疾病病变程度及病情进展中的作用。方法：本研究类型为回顾性的病例对照研究及自身前后对照研究。选取2017年9月至2023年9月我院158例钙化性主动脉瓣狭窄接受主动脉瓣置换术患者，在大致为1年的研究时间窗内，根据主动脉瓣狭窄、钙化程度区组比较Lp(a)水平，根据Lp(a)水平以300 mg/l为截断值分为病例组及对照组比较进展。在研究时间窗终点，患者自身的主动脉瓣年化增长钙化体积(mm³/y)、主动脉瓣年化增长瓣口峰值流速(m∙s⁻¹/y)作为衡量钙化、狭窄的具体进展指标。收缩期主动脉瓣口峰值流速是评估瓣膜狭窄程度的重要血流动力学指标，其来源于超声医师的经胸二维超声心动图报告。应用计算机断层显像(CT, Computerized Tomography)评估进行主动脉瓣的钙化程度，由影像学医师带领研究生使用GE Healthcare后处理医学图像软件6.0版本中的测量工具勾画心脏CT中的病灶区域得出钙化体积。Lp(a)测定主要采用透射比浊法。统计学结果由R语言3.5版本运行获得。结果：1) 158例患者中，男性、谷丙转氨酶、Lp(a)、高脂血症家族病史对主动脉瓣钙化的影响具有统计学意义；Lp(a)与主动脉瓣钙化体积呈正相关(r = 0.19, P = 0.0154)；主动脉瓣钙化体积与主动脉瓣瓣口最大流速呈正相关(r = 0.32, P < 0.001)；Lp(a)与主动脉瓣瓣口最大流速无明显相关关系(P = 0.80)。2) 92例主动脉瓣重度钙化组Lp(a)高于66例轻度钙化组(163.7比152.4 mg/l，P = 0.032)；120例主动脉瓣重度狭窄组Lp(a)高于38例中度狭窄组(192.3比135.3 mg/l，P = 0.028)。42例对照组与20例高Lp(a)组的年化增长主动脉瓣瓣口最大流速差异无统计学意义(0.33比0.29 m∙s⁻¹/y，P = 0.76 > 0.05)；17例高Lp(a)组年化增长主动脉瓣钙化体积高于45例对照组(86.1比50.8 mm³/y，P = 0.018)。3) 62例患者Lp(a)、低密度脂蛋白胆固醇(LDL-C, low-density lipoprotein cholesterol)、高密度脂蛋白胆固醇(HDL-C, high-density lipoprotein cholesterol)等血脂成分作为标志物绘制接受者操作特征曲线(ROC, Receiver Operating Characteristic)曲线，曲线下面积(AUC, area under curve) Lp(a) = 0.70 (95% CI 0.57~0.84)且最大，AUCHDL-C = 0.49 (95% CI 0.34~0.64)且最小，AUC Lp(a)/AUC HDL-C曲线比较差异有统计学意义(P = 0.0469)，可以认为两者判断钙化进展效能不同；53例患者中，主动脉瓣钙化体积进展对主动脉瓣口最大血流速度进展的影响有统计学意义，Lp(a)对主动脉瓣口最大血流速度进展的影响无统计学意义。4) 158例患者中，113例对照组与45例高Lp(a)病例组生存曲线的比较差异无统计学意义(P = 0.85)。结论：在钙化性主动脉瓣狭窄患者中，Lp(a)与主动脉瓣瓣膜钙化体积相关，而与疾病进展无关。

Abstract: Objective: To describe the clinical features of patients with calcified aortic stenosis, reveal individual differences in disease progression, and evaluate the role of lipoprotein (a) [Lp(a)] in the severity and progression of the disease. Methods: A retrospective case-control and self-control study was conducted on 158 patients with calcified aortic stenosis who received aortic valve replacement in our hospital from September 2017 to September 2023. Within approximately one year of the study time window, according to the degree of aortic stenosis and calcification, the patients were divided into case and control groups to compare Lp(a) levels. According to the Lp(a) level with 300 mg/l as the cut-off value, the patients were divided into a case group and a control group to compare their progress. At the end of the study time window, patients’ annualized increase in aortic valve calcification volume (mm³/y) and maximum aortic valve flow velocity (m∙s⁻¹/y) were used as specific calcification and stenosis progression indicators. Systolic peak aortic orifice velocity is an essential hemodynamic index to evaluate the degree of valve stenosis, which is derived from the two-dimensional transthoracic echocardiography. The degree of aortic valve calcification is evaluated using Computed Tomography (CT). The imaging technician used the measurement tool in GE Healthcare post-processing imaging software version 6.0 to map the lesion area in the cardiac CT to obtain the calcification volume. Lp(a) was determined by transmission turbidimetry. The statistical results were obtained by running R 3.5 version. Results: 1) Among the 158 patients, the effects of male, alanine aminotransferase, Lp(a), and history of hyperlipidemia on the aortic valve calcification volume were statistically significant. No statistically significant correlation existed between Lp(a) and the maximum aortic valve flow velocity (P = 0.80). However, Lp(a) was positively correlated with aortic valve calcification volume (r = 0.19, P = 0.0154), and aortic valve calcification volume was positively correlated with the maximum aortic valve flow velocity (r = 0.32, P < 0.001). 2) Lp(a) in the severe aortic valve calcification group was higher than in the mild aortic valve calcification group (92 vs. 66 cases, 163.7 vs. 152.4 mg/l, P = 0.032). Lp(a) in the severe aortic stenosis group was higher than in the moderate stenosis group (120 vs. 38 cases, 192.3 vs. 135.3 mg/l, P = 0.028). There was no statistically significant difference in terms of the annualized increase of the maximum aortic valve flow velocity between the control group and the abnormal Lp(a) group (42 vs. 20 cases, 0.33 vs. 0.29 m∙s⁻¹/y, P = 0.76 > 0.05). The annualized increase of aortic valve calcification volume was higher in the group with abnormal Lp(a) than in the control group (17 vs. 45 cases, 86.1 vs. 50.8 mm³/y, P = 0.018). 3) Among the 62 patients, the Lp(a), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were selected as markers to plot the Receiver Operating Characteristic (ROC) curve. The area under the curve (AUC) Lp(a) was 0.70 (95% CI 0.57~0.84), which is the largest, so it is considered to be the best in diagnosing calcification progression, and the AUCHDL-C was 0.49 (95% CI 0.34~0.64) which is supposed to have the reverse predictive value of calcification progression. In 53 patients, the effect of calcification volume variation, instead of Lp(a), on the progression of the maximum aortic valve flow velocity is statistically significant. 4) Among the 158 patients, there was no significant difference in survival curve between the control group and the abnormal Lp(a) group (113 vs. 45 cases, P = 0.85). Conclusion: In patients with calcific aortic valve stenosis, Lp(a) was associated with aortic valve calcification volume but not with disease progression.