今日共读
A Half-Century of Progress in Health: The National Academy of Medicine at 50
半个世纪的健康进步:50岁的国家医学研究院
Conquering Atherosclerotic Cardiovascular Disease — 50 Years of Progress
征服动脉粥样硬化性心血管疾病- 50年的进展
Gary H. Gibbons, M.D., Christine E. Seidman, M.D., and Eric J. Topol, M.D.
翻译：猫，校对：叮当丸子麻
One of the most important 最重要的因素之一biomedical success stories of the past half-century in the United States has been a 50% reduction in cardiovascular mortality. This progress reflects the power of a system that facilitates the cross-disciplinary interchange of scientific ideas and catalyzes the integration of basic science, translational research, technological innovation, evidence-based public policy, and public health practice.
过去半个世纪美国生物医学领域最重要的成功案例之一就是心血管疾病死亡率降低了50%。这一进展反映了一个系统的力量，该系统促进了科学思想的跨学科交流，并促进了基础科学、转化研究、技术创新、循证公共政策和公共卫生实践的整合。
During the first half of the 20th century, advances in science and public health led to a dramatic decline in infectious diseases传染病. This achievement provided a backdrop for为···提供背景 the gradual emergence of cardiovascular disease as the new leading cause of death in the United States. As the death toll from cardiovascular disease climbed to a peak in the mid1960s, findings from clinical and epidemiologic research began to elucidate sex-specific differences in its natural history. After launching in 1948, the Framingham Heart Study — the first largescale, multigenerational study of cardiovascular risk in the United States — led to the identification of major risk factors 最主要的风险因素for cardiovascular disease, including smoking, high cholesterol, hypertension, physical inactivity, and diabetes. The rapid translation of these findings into public policy and public health campaigns resulted in a substantial reduction in exposure to tobacco smoke and in hypertension treatments that accelerated the decrease in deaths from cardiovascular disease. Support from public and private investments and initiatives, such as the Dietary Reference Intakes series published by the Institute of Medicine, now called the National Academy of Medicine (NAM), have bolstered this progress by serving a foundational role in federal and state food and nutrition programs and policies. This process of translating discovery science into public health benefits established a model of primary prevention of cardiovascular disease based on risk stratification风险层分层 — a cornerstone基石 of biomedical research and public health practice.
在20世纪50年代，科学和公共卫生的进步促进了传染病的急剧减少。这一成就为心血管疾病逐渐成为美国新的主要死亡原因提供了背景。随着心血管疾病死亡人数在20世纪60年代中期攀升至高峰，临床和流行病学研究的发现开始阐明其自然史上的性别差异。1948年启动的弗雷明汉心脏研究——美国第一个大规模的、多代人的心血管风险研究——确定了心血管疾病的主要危险因素，包括吸烟、高胆固醇、高血压、缺乏运动和糖尿病。这些发现迅速转化为公共政策和公共卫生运动，导致吸烟暴露和高血压治疗大幅减少，从而加速了心血管疾病死亡人数的减少。来自公共和私人投资和倡议的支持，如由医学研究所(现在称为国家医学研究院(NAM))发布的膳食参考摄入量系列，通过在联邦和州的食品和营养项目和政策中发挥基础性作用，推动了这一进展。这个将发现科学转化为公共卫生利益的过程建立了一个基于风险分层的心血管疾病一级预防模型——生物医学研究和公共卫生实践的基石。
Biomedical progress against infectious diseases was driven by the paradigm of Koch’s postulates, which established that identifying a disease’s causative agent is an important prerequisite for developing therapeutic interventions. Yet the causative factors involved in chronic, age-related disorders such as cardiovascular disease remained poorly understood. It’s in this context that key mechanistic insights were gained through the lens of molecular genetics分子遗传学. Early insights were gleaned from the study of familial clusters of dyslipidemias and people with extreme phenotypes, such as children with myocardial infarctions心梗. The characterization of heritable forms of early-onset cardiovascular disease enabled Michael Brown, Joseph Goldstein, and others to elucidate the causal role of low-density lipoprotein (LDL)低密度脂蛋白 cholesterol metabolism in the development of atherosclerosis动脉粥样硬化 (see timeline). Their Nobel Prize–winning work characterizing the LDL receptor and Akira Endo’s identification of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase as an amenable drug target were an important chapter in the cardiovascular disease success story.这是···的重要一章
对抗传染病的生物医学进展受到科赫法则的推动，该法则确立了识别疾病病原体的原则是发展治疗干预的重要前提。然而，慢性、年龄相关疾病(如心血管疾病)的致病因素仍然不为人所知。正是在这样的背景下，我们通过分子遗传学的视角获得了关键的机制洞见。早期的见解来自对血脂异常的家族聚集和极端表型人群(如患有心肌梗死的儿童)的研究。早发性心血管疾病遗传形式的表征使Michael Brown、Joseph Goldstein等人阐明了低密度脂蛋白(LDL)胆固醇代谢在动脉粥样硬化发展中的因果作用(见时间线)。他们获得诺贝尔奖的工作描述了低密度脂蛋白受体和Akira Endo鉴定3-羟基-3-甲基戊二酰辅酶A (HMG-CoA)还原酶作为一种依从性药物靶点，是心血管疾病成功故事的重要章节。
The gradual bench-to-bedside translation 从实验室到临床of these findings involved a robust portfolio of largescale, randomized clinical trials, something the field of cardiology widely embraced, years before other scientific fields did so. The results of these trials collectively provided definitive evidence that reducing LDL cholesterol levels prevents myocardial infarctions, thereby closing the causal loop of Koch’s postulates for the LDL cholesterol hypothesis.1 This milestone里程碑, which led to the development of multiple effective cholesterol-lowering drugs, illustrates the power of collaboration between public and private entities to link discovery science with clinical practice. This group of molecular-genetics studies, basic biochemical investigations, cohort studies (e.g., the Dallas Heart Study), and clinical trials also collectively identified the PCSK9 gene as another molecular mediator of LDL cholesterol metabolism and determined that PCSK9 inhibition significantly reduces rates of myocardial infarctions and strokes.
其他科学领域也是如此。这些试验的结果共同提供了降低低密度脂蛋白胆固醇水平可防止心肌梗死的明确证据，从而闭合了低密度脂蛋白胆固醇假说的科赫假设的因果循环。这一里程碑式的成就导致了多种有效的降胆固醇药物的开发，说明了公共和私人实体之间的合作将发现科学与临床实践联系起来的力量。这组分子遗传学研究、基础生化调查、队列研究(如达拉斯心脏研究)和临床试验也共同确定了PCSK9基因作为LDL胆固醇代谢的另一个分子中介，并确定PCSK9抑制显著降低心肌梗死和中风的发生率。
Although cardiovascular disease is often conceptualized as affecting the elderly, it has become increasingly clear that the antecedents of atherosclerosis begin in utero子宫 and evolve throughout the lifespan, depending on genetic predisposition and, to a larger extent, behavioral factors and exposures. Ongoing progress in molecular genetics has led to the creation of polygenic risk scores that capture the collective effects of many heritable inputs that portend a high-risk trajectory高风险轨迹 for cardiovascular disease. Combining this increased understanding of risk with the long history of research on the advantages of controlling hypertension and the development of drugs开发药物 for this purpose permits preemption先发制人 and prevention of disease.
虽然心血管疾病常被认为影响老年人，但越来越清楚的是，动脉粥样硬化的先兆始于子宫，并在整个生命周期中演变，这取决于遗传易感，更大程度上取决于行为因素和暴露。分子遗传学的不断进展导致了多基因风险评分的产生，该评分捕捉了预示心血管疾病高风险轨迹的许多遗传输入的集体效应。对风险的认识的增加，加上长期以来对控制高血压的好处的研究，以及为此目的开发的药物，使预防和预防疾病成为可能。
Advances in vascular biology have further informed the LDL cholesterol hypothesis by defining critical interactions between the immune system免疫系统 and vascular cells that create a complex molecular environment复杂的分子环境 during atherosclerotic plaque斑块 progression. The multiple molecular networks activated by oxidized lipids, proinflammatory cytokines促炎因子, and prothrombotic factors can induce important changes in the plaque (e.g., rupture or erosion) that trigger acute coronary syndromes急性冠脉综合征.A key component of the cardiovascular disease success story has involved the progressive development of treatments for acute coronary syndromes, including fibrinolytic and antiplatelet agents 纤溶抗板药and percutaneous coronary interventionPCI经皮冠脉介入治疗; diagnostic tools that permit direct imaging of the vasculature, such as intravascular ultrasound technology血管内超声技术; interventions that alter the vasculature, such as coronary bypass surgery and stents冠状动脉旁路手术和支架; and therapeutics that selectively modulate the prothrombotic and proinflammatory plaque milieu.
血管生物学的进展通过定义免疫系统和血管细胞之间在动脉粥样硬化斑块进程中创造复杂分子环境的关键相互作用，进一步证实了LDL胆固醇假说。氧化脂质、促炎细胞因子和促血栓形成因子激活的多重分子网络可以诱导斑块发生重要变化(如破裂或侵蚀)，从而引发急性冠脉综合征。心血管疾病成功故事的一个关键组成部分涉及急性冠脉综合征治疗的逐步发展，包括纤溶蛋白和抗血小板药物以及经皮冠状动脉介入治疗;允许血管系统直接成像的诊断工具，如血管内超声技术;改变血管系统的干预措施，如冠状动脉搭桥手术和支架;选择性调节促血栓形成和促炎症斑块环境的疗法。
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