What does it mean to have a family history of a specific disease or illness? Is it simply an indicator of risk that merits close medical attention over time? Or does this information warrant something more? A referral to specialized care? A diagnosis of a potential genetic disorder? Additional health screenings for close relatives and younger generations? How should patients and their families navigate these difficult questions, particularly when the burden of their condition is high, public awareness is low, and the research still evolving? While our family has thought about these questions a great deal, we have only recently been able to start answering them. It is an incredible privilege to share part of our family’s story with the support of my father, Eugene Mszar, and to offer a few viewpoints that other families may relate to.

High cholesterol and cardiovascular disease have impacted our family for generations. My paternal grandfather underwent a coronary artery bypass graft procedure in his mid- to late-50s and later suffered a fatal heart attack in his 60s. One of my uncles, also on my father’s side, had a stent placed in one of his coronary arteries in his 40s. My father, his father, and both of my paternal uncles all had moderate or severe hypercholesterolemia. In my father’s early 30s, his low-density lipoprotein cholesterol (LDL-C) levels were already >200 mg/dL (Figure). Despite his severe hypercholesterolemia and family history, he received recurring instructions to focus solely on lifestyle modifications to lower his cholesterol levels, starting when he received his first lipid panel through a workplace wellness program in the early 1990s. Given his general understanding at the time that high cholesterol ran in the family, he was already cognizant of the importance of eating nutritious foods and exercising regularly. To him, this advice did not seem to fully account for his cardiovascular risk. After receiving these same recommendations over the course of several years without any discernible improvements in his lipid profile, he decided it was time to get a second opinion on the additional steps he could take to decrease his cholesterol levels reduce his risk.

Figure. Timeline (≈30 y) of prior lipid panel results, along with approximate dates of key clinical, treatment, and cardiac event milestones. Dates presented across the timeline represent previous lipid panels and are not spaced evenly. FH indicates familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; and TIMI, Thrombolysis in Myocardial Infarction.

Upon meeting with a primary care physician close to our home, our family history finally started gaining the close attention it required. After only half an hour, my father left with a prescription for a low-dose statin in hand, along with another lipid panel and follow-up appointment already scheduled. Though the road ahead would prove difficult, my parents were optimistic given that their concerns were now being taken more seriously. While every reduction in his LDL-C levels, though relatively small at first, brought my father a sense of relief, it was clear that more aggressive treatment was necessary. In the span of just a few years taking a high-intensity statin, his LDL-C levels were nearly cut in half.

Despite these long-awaited improvements, in April of 2002 (a few years into taking a high-intensity statin), my father began experiencing a dull pain in his jaw, which progressively evolved into a tightness sensation that spread to his chest and increased with exertion. He was 45 years old at the time. Following several periods of this chest pain and tightness, it was clear that he needed urgent medical care. A prompt coronary angiogram revealed 4 different areas of significant occlusion in his coronary arteries, which required immediate revascularization through a coronary artery bypass graft operation, the same procedure his father underwent. As I was just entering the first grade at the time, I could not even begin to grasp the full extent of this kind of procedure.

Years later, while conducting undergraduate research in Maine, I began learning about a genetic lipid disorder—familial hypercholesterolemia (FH)—that increases individuals’ risk of high cholesterol and premature cardiovascular disease, a condition that is even more prevalent in certain ethnic groups, including French Canadians and Franco-Americans, due to the presence of a founder effect.^1,2 While our family’s roots are neither French nor Canadian, it was not difficult to begin drawing comparisons to our family’s risk factors and medical history.³ It has now been >20 years since my father’s quadruple bypass surgery but only 4 years since we were finally able to identify FH as the potential culprit behind our family’s history of high cholesterol and early heart disease. The first time a physician told my father that he had FH did not take place in an outpatient clinic or hospital waiting room, but rather on a college campus in a large atrium filled with hundreds of students and faculty. I was presenting my thesis research on FH to a few classmates and professors when one of my mentors, a cardiologist and public health practitioner, began talking to my father about his condition off to the side. Before I even finished my presentation, my mentor had provided this FH diagnosis, discussed current and future treatment approaches, and asked whether my father had any questions.

Gaining a more tailored understanding of the issue that has impacted so many members of our family provided my father with some long-awaited peace of mind. Perhaps more importantly, he also came away with an appreciation that he was not at fault for the sequence of events that led up to his quadruple bypass procedure. For years, it seemed that regardless of his behavioral changes, his cholesterol levels remained stubbornly high. Even when his LDL-C levels began to plummet after initiating a high-intensity statin, feelings of frustration and guilt were promptly replaced by confusion and cynicism when these improvements were unable to prevent his chest pain and subsequent procedure. However, it was later explained to him that atherosclerotic plaque had been building up in his coronary arteries over the course of decades and that it was the prolonged exposure to atherogenic lipid particles that ultimately caused his cardiovascular event.

Though certain aspects of our family’s full health history remain elusive, all indications point to a probable FH diagnosis based on frequently used clinical criteria that consider one’s personal and familial medical histories, LDL-C levels, and other clinical features. Since the use of statins has increased substantially over the last several decades and current clinical practice guidelines now have access to a larger body of evidence pointing to the cardiovascular benefits of statins and other lipid-lowering therapies, critiquing the clinical decisions made >20 years ago is a complex and messy endeavor. Despite these points, one thing remains clear: the needs of individuals with FH have been largely unmet and under-recognized, with many patients and their loved ones falling through the cracks. Even today, the vast majority of individuals with FH remain undiagnosed and undertreated for their condition.^4,5 Given the earlier age of onset of atherosclerosis and the increased risk of cardiovascular events in those with FH, it is now well established that this population requires early and aggressive care with ≥1 lipid-lowering therapies.⁶

This new knowledge surrounding the basis of my father’s condition produced several key takeaways. First, it validated and legitimized many preconceptions about our family’s medical history, along with my father’s minimal physiological response to lifestyle modifications alone. Second, it empowered him to use this information to gain greater control of his health, including speaking with his primary care physician about adding nonstatin therapies like ezetimibe to his current treatment regimen. Third, it connected our whole family to evidence-based resources, tailored support, and a community of individuals with strikingly similar stories and experiences, particularly through engaging with the Family Heart Foundation. Finally, it made clear the importance of engaging in cascade screening to check my own cholesterol levels and remain mindful of other key cardiovascular risk factors.

A diagnosis can mean very different things to different people. For our family, knowledge has truly been power. For countless families, however, this knowledge can come too late and at a significant cost. Early screening, diagnosis, and treatment are all critical steps in reducing one’s cholesterol levels and, thus, their risk of experiencing a cardiovascular event. We feel extremely fortunate that my father’s bypass procedure saved his life decades ago, and that his current medication regimen and lifestyle modifications have reduced his LDL-C levels to <55 mg/dL, which is well under the treatment targets for someone with his cardiovascular risk. Through our family’s determination to search for answers that coincide with our lived experiences, our ability to seek out and learn from thoughtful clinician researchers and patient advocacy organizations, as well as a degree of luck in meeting the right people at the right time, we have finally started to gain the autonomy we have long sought to prevent FH from continuing to define the trajectory of our lives.

The authors thank the Family Heart Foundation (https://familyheart.org/) for their continued pursuit of research and advocacy for all those impacted by familial hypercholesterolemia, as well as elevated lipoprotein(a).

None.

Disclosures None.

The articles published in Viewpoints reflect the opinions of the authors and do not reflect the policy or position of the American Heart Association, and the American Heart Association provides no warranty as to their accuracy or reliability.

For Sources of Funding and Disclosures, see page 303.

有特定疾病或疾病的家族史意味着什么？它只是一个值得长期密切关注的风险指标吗？或者这些信息是否有更多的依据？转介至专门护理？潜在遗传性疾病的诊断？对近亲和年轻一代进行额外的健康检查？患者及其家人应该如何解决这些难题，特别是当他们的病情负担很高、公众意识较低且研究仍在不断发展时？虽然我们的家人对这些问题思考了很多，但我们直到最近才开始回答这些问题。在我父亲尤金·姆扎尔（Eugene Mszar）的支持下，我非常荣幸能够分享我们家庭的部分故事，并提供一些其他家庭可能感兴趣的观点。

高胆固醇和心血管疾病影响了我们家族几代人。我的祖父在 50 多岁的时候接受了冠状动脉搭桥手术，后来在 60 多岁时遭遇了致命的心脏病发作。我的一位叔叔，也是我父亲的家族，在 40 多岁的时候在他的一根冠状动脉中放置了支架。我的父亲、他的父亲和我的两个叔叔都患有中度或重度高胆固醇血症。我父亲 30 岁出头时，他的低密度脂蛋白胆固醇 (LDL-C) 水平已经 >200 mg/dL（图）。尽管他有严重的高胆固醇血症和家族史，但从 20 世纪 90 年代初通过工作场所健康计划接受第一次血脂检查开始，他反复收到指示，要求他仅关注生活方式的改变，以降低胆固醇水平。鉴于他当时普遍认为家里有高胆固醇，他已经认识到吃营养食物和定期锻炼的重要性。对他来说，这个建议似乎并没有完全解释他的心血管风险。几年来，他收到了这些相同的建议，但他的血脂状况没有任何明显的改善，他决定是时候就他可以采取的额外措施征求第二意见，以降低胆固醇水平，从而降低风险。

数字。 先前血脂小组结果的时间线（约 30 年），以及关键临床、治疗和心脏事件里程碑的大致日期。时间线上显示的日期代表之前的脂质面板，并且间隔不均匀。 FH表示家族性高胆固醇血症； HDL-C，高密度脂蛋白胆固醇； LDL-C，低密度脂蛋白胆固醇；和 TIMI，心肌梗塞溶栓。

在与我们家附近的一位初级保健医生会面后，我们的家族史终于开始获得所需的密切关注。仅仅半小时后，我父亲就离开了，手里拿着一张低剂量他汀类药物的处方，还有另一项血脂检查和已经安排好的后续预约。尽管前进的道路会很困难，但我的父母很乐观，因为他们的担忧现在得到了更认真的对待。虽然 LDL-C 水平的每一次降低（虽然一开始相对较小）都给我父亲带来了一种如释重负的感觉，但很明显，更积极的治疗是必要的。在服用高强度他汀类药物的短短几年内，他的低密度脂蛋白胆固醇水平几乎降低了一半。

尽管有了这些期待已久的改善，但在 2002 年 4 月（服用高强度他汀类药物几年后），我父亲开始感到下巴隐隐作痛，逐渐演变成一种紧绷感，这种感觉蔓延到胸部，并随着时间的推移而加剧。用力。当时他45岁。经过几次胸痛和胸闷，很明显他需要紧急医疗护理。及时的冠状动脉造影显示他的冠状动脉有 4 个不同的区域明显闭塞，需要立即通过冠状动脉旁路移植手术进行血运重建，这与他父亲所经历的手术相同。由于我当时刚刚进入一年级，我什至无法开始掌握这种程序的全部内容。

几年后，在缅因州进行本科研究时，我开始了解一种遗传性脂质紊乱——家族性高胆固醇血症（FH）——它会增加个体患高胆固醇和早发心血管疾病的风险，这种疾病在某些种族群体中更为普遍。由于创始人效应的存在，包括法裔加拿大人和法裔美国人。^1,2虽然我们家族的血统既不是法国人也不是加拿大人，但开始与我们家族的风险因素和病史进行比较并不困难。³距离我父亲的四重搭桥手术已经过去了 20 年多，但距离我们最终能够确定 FH 是我们家族高胆固醇和早期心脏病史的潜在罪魁祸首仅 4 年。医生第一次告诉我父亲他患有 FH 并不是在门诊诊所或医院候诊室，而是在大学校园的一个大中庭里，里面有数百名学生和教职员工。当我向几位同学和教授展示我的关于 FH 的论文研究时，我的一位导师，一位心脏病专家和公共卫生从业者，开始在一边与我父亲谈论他的病情。在我完成演讲之前，我的导师就给出了 FH 的诊断，讨论了当前和未来的治疗方法，并询问我父亲是否有任何问题。

对这个影响了我们许多家庭成员的问题有了更具体的了解，这让我父亲得到了期待已久的内心平静。也许更重要的是，他在离开时也认识到，他对导致四重搭桥手术的一系列事件并没有过错。多年来，尽管他的行为发生了变化，他的胆固醇水平似乎仍然居高不下。即使在开始使用高强度他汀类药物后，他的 LDL-C 水平开始直线下降，但当这些改善无法阻止他的胸痛和后续手术时，沮丧和内疚感很快就被困惑和愤世嫉俗所取代。然而，后来有人向他解释说，几十年来，动脉粥样硬化斑块一直在他的冠状动脉中积聚，而长期暴露于致动脉粥样硬化的脂质颗粒最终导致了他的心血管事件。

尽管我们家族完整健康史的某些方面仍然难以捉摸，但所有迹象都表明可能的 FH 诊断基于常用的临床标准，这些标准考虑了个人和家族病史、LDL-C 水平和其他临床特征。由于他汀类药物的使用在过去几十年中大幅增加，并且当前的临床实践指南现在可以获得更多证据，表明他汀类药物和其他降脂疗法对心血管有益，并对 20 年前做出的临床决策提出了批评是一项复杂而混乱的工作。尽管存在这些观点，但有一件事仍然很明确：FH 患者的需求在很大程度上没有得到满足，也没有得到充分认识，许多患者及其亲人被忽视。即使在今天，绝大多数 FH 患者仍未得到诊断且治疗不足。^4,5鉴于 FH 患者动脉粥样硬化发病年龄较早且心血管事件风险增加，目前已明确该人群需要早期积极护理并采用 ≥1 种降脂疗法。⁶

围绕我父亲病情基础的新知识得出了几个关键结论。首先，它验证了关于我们家族病史的许多先入之见，以及我父亲对生活方式改变的最小生理反应，并使其合理化。其次，它使他能够利用这些信息更好地控制自己的健康，包括与他的初级保健医生讨论在他目前的治疗方案中添加依折麦布等非他汀类药物疗法。第三，它将我们整个家庭与基于证据的资源、量身定制的支持以及具有惊人相似故事和经历的个人社区联系起来，特别是通过与家庭心脏基金会的合作。最后，它明确了进行级联筛查以检查我自己的胆固醇水平并保持注意其他关键心血管危险因素的重要性。

诊断对于不同的人来说可能意味着非常不同的事情。对于我们家庭来说，知识确实就是力量。然而，对于无数家庭来说，这些知识可能来得太晚，而且代价高昂。早期筛查、诊断和治疗都是降低胆固醇水平的关键步骤，从而降低发生心血管事件的风险。我们感到非常幸运，我父亲的搭桥手术在几十年前挽救了他的生命，并且他目前的治疗方案和生活方式的改变已将他的 LDL-C 水平降低至 <55 mg/dL，这远低于患有心血管疾病的人的治疗目标风险。通过我们的家人寻找与我们生活经历相符的答案的决心，我们向有思想的临床研究人员和患者倡导组织寻求并向他们学习的能力，以及在正确的时间遇到​​正确的人的一定程度的运气，我们已经终于开始获得我们长期以来寻求的自主权，以阻止 FH 继续定义我们的生活轨迹。

作者感谢家庭心脏基金会 (https://familyheart.org/) 为所有受家族性高胆固醇血症和高脂蛋白 (a) 影响的人们不断进行研究和宣传。

没有任何。

披露无。

Viewpoints 上发表的文章仅反映作者的观点，并不反映美国心脏协会的政策或立场，美国心脏协会对其准确性或可靠性不提供任何保证。

有关资金来源和披露信息，请参阅第 303 页。