本文深入探讨了家族性高胆固醇血症（FH），这是一种由基因引起的疾病，会导致血液中低密度脂蛋白胆固醇（LDL-C）水平升高，从而增加患心脏病的风险。文章详细介绍了FH的定义、遗传基础和临床表现，并探讨了预防和治疗心血管疾病的各种方法，包括CETP抑制剂的历史和最新进展。此外，文章还揭示了APOE基因在阿尔茨海默病和心血管疾病中的作用，以及未来针对高危患者的靶向治疗前景。

🧬 家族性高胆固醇血症（FH）是一种遗传性疾病，其特征是血液中LDL-C水平升高，从而增加过早发生动脉粥样硬化性心血管疾病（ASCVD）的风险。文章详细阐述了FH的定义、遗传学基础以及临床识别方法。

🩺 诊断FH需要综合考虑表型和基因型。虽然FH患者通常表现出高胆固醇血症，但具体表现和严重程度可能因个体而异。文章解释了FH相关基因突变的病理生理学，以及临床表现、体征和诊断方法。

💊 治疗和预防FH涉及多种方法。文章探讨了针对FH患者的治疗方案，包括药物治疗和生活方式干预，旨在降低LDL-C水平，从而降低心血管疾病的风险。文章还探讨了CETP抑制剂在治疗中的应用及其历史。

🧠 APOE基因在阿尔茨海默病和心血管疾病中扮演着重要角色。APOE4等位基因会增加患阿尔茨海默病和心血管疾病的风险。文章解释了APOE在脂质代谢中的作用，以及APOE4与这两种疾病之间的关联。

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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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