本期节目深入探讨了遗传性高胆固醇血症（FH），这是一种由血液中低密度脂蛋白胆固醇水平升高导致的遗传性疾病，会增加患心脏病的风险。节目涵盖了FH的定义、遗传基础和临床识别，并探讨了预防和治疗心血管疾病的治疗方案，包括对CETP抑制剂的历史回顾。节目还阐述了APOE在其中的作用，解释了为什么APOE4等位基因编码的蛋白质会显著增加患阿尔茨海默病和心血管疾病的风险。

👨‍⚕️ **遗传性高胆固醇血症（FH）**：FH是一种由血液中低密度脂蛋白胆固醇水平升高导致的遗传性疾病，会增加患心脏病的风险。FH的遗传基础是由于LDLR基因的突变导致的，该基因负责编码低密度脂蛋白受体，低密度脂蛋白受体是肝脏细胞表面的一种蛋白质，负责从血液中清除低密度脂蛋白胆固醇。FH患者的低密度脂蛋白受体功能受损，导致血液中低密度脂蛋白胆固醇水平升高，从而增加患动脉粥样硬化性心血管疾病的风险。FH的临床表现多种多样，包括高胆固醇血症、冠心病、早发性冠心病、心肌梗塞、脑卒中等。

🧪 **CETP抑制剂**：CETP抑制剂是一种新型药物，通过抑制胆固醇酯转移蛋白（CETP）的活性来降低血液中低密度脂蛋白胆固醇水平。CETP是一种在肝脏和血液中表达的酶，负责将高密度脂蛋白胆固醇（HDL）中的胆固醇酯转移到低密度脂蛋白胆固醇（LDL）中。CETP抑制剂通过抑制CETP的活性，减少了HDL向LDL的胆固醇酯转移，从而降低了血液中LDL的水平，提高了HDL的水平。CETP抑制剂的最新研究表明，它不仅对心血管疾病有益，而且对阿尔茨海默病和2型糖尿病等其他疾病也具有潜在的治疗价值。

🧬 **APOE基因**：APOE基因编码一种叫做载脂蛋白E的蛋白质，这种蛋白质参与脂质代谢和胆固醇转运。APOE基因有多个等位基因，其中APOE4等位基因被认为与阿尔茨海默病和心血管疾病风险增加有关。APOE4等位基因编码的蛋白质会影响脂质代谢，导致血液中胆固醇水平升高，增加患阿尔茨海默病和心血管疾病的风险。APOE4等位基因与心血管疾病风险增加的关联机制尚不清楚，但可能与它对脂质代谢的影响以及对动脉粥样硬化的促进作用有关。

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John Kastelein is a renowned expert in lipoprotein metabolism and atherosclerotic cardiovascular disease (ASCVD) research. In this discussion, John delves deep into familial hypercholesterolemia (FH), a genetic disorder characterized by high levels of LDL cholesterol in the blood that increases the risk of developing heart disease. He covers its definition, genetic underpinnings, and clinical identification. He then explores the therapeutic options available for the prevention and treatment of cardiovascular disease, including the captivating history of CETP inhibitors. He explains the past shortcomings of previous CETP inhibitors before underscoring the compelling potential of the latest iterations, not only for cardiovascular disease but also for conditions like Alzheimer's disease and type 2 diabetes. Moreover, he unveils the intricate role of APOE, shedding light on why the APOE4 isoform codes for a protein that significantly increases the risk of Alzheimer's disease and cardiovascular disease. Concluding the discussion, John shares a profound sense of optimism, envisioning the possibility of targeted therapeutic interventions for high-risk patients in the near future.

We discuss:

Familial hypercholesterolemia (FH): a genetic condition [4:30]; Differentiating between phenotype and genotype when it comes to FH [9:45]; The pathophysiology related to mutations of FH [15:30]; Clinical presentations, physical manifestations, and diagnosis of FH [22:00]; Why a small fraction of people with FH do not develop premature ASCVD [34:15]; Treatment and prevention for those with FH [39:45]; Addressing the assertion by some that elevated LDL is not casual in cardiovascular disease [52:45]; The history of CETP inhibitors, and the role of the CETP protein [55:45]; The thrifty gene hypothesis and why genes underlying FH may have been preserved [1:09:00]; The compelling potential of the latest CETP inhibitor (obicetrapib) [1:13:00]; Promising results from phase 3 trials exploring obicetrapib [1:27:45]; Why the APOE4 allele increases the risk of Alzheimer’s disease, and the connection to blood lipids [1:41:30]; The role of APOE in cardiovascular disease [1:51:45]; Takeaways and looking ahead [1:57:00]; and More.

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