Lower extremity peripheral artery disease (PAD) affects between 116 and 230 million people worldwide.¹ Manifestations of PAD range from asymptomatic, in which patients report no exertional leg symptoms, to chronic limb-threatening ischemia (CLTI), defined by lower-limb rest pain, gangrene, or ulceration.² Compared with age-matched people without PAD, those with PAD have significantly higher rates of cardiovascular events and major adverse limb events (MALEs), defined as severe lower-extremity ischemia requiring prompt revascularization or amputation. PAD is characterized by walking disability, and even people with asymptomatic PAD have significantly greater walking impairment than people without PAD.³ This perspective summarizes advances in the diagnosis and treatment of PAD over the past century and identifies opportunities to improve outcomes in the next century.

In the past 50 years, randomized clinical trials demonstrated benefits of intensive low-density lipoprotein–lowering therapy for people with cardiovascular disease, including in those with PAD. Among patients in the Heart Protection Study, simvastatin lowered low-density lipoprotein cholesterol to less than ≈80 mg/dL and significantly reduced cardiovascular events and mortality, including in the 6487 patients with PAD, compared with placebo. In the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), adding the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab to statin therapy lowered low-density lipoprotein cholesterol to a median of 31 mg/dL and further reduced cardiovascular events and MALEs, including in the 3642 patients with PAD, compared with statins alone.³ Rivaroxaban combined with aspirin was also shown to reduce cardiovascular events in people with PAD. In the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), low-dose rivaroxaban (2.5 mg twice daily) combined with aspirin 81 mg significantly reduced cardiovascular events and MALEs compared with aspirin alone in 6391 people with PAD. The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) similarly demonstrated benefits of rivaroxaban with aspirin compared with aspirin alone after lower-extremity revascularization. The discovery of thrombosis as a prominent component of lower-extremity atherosclerosis may explain the benefits of these antithrombotic therapies in people with PAD.

PAD is underdiagnosed.³ The high prevalence of asymptomatic PAD and variability in leg symptoms reported by people with PAD likely contribute to the underdiagnosis of PAD. In the mid-20th century, the ankle-brachial index (ABI) was discovered as a simple, noninvasive diagnostic test for PAD. An ABI <0.90 is 57% to 79% sensitive and 83% to 99% specific for PAD.³ In a multicenter study conducted in medical practices in the United States with the goal of establishing the prevalence of PAD among patients ≥70 years of age or 50 to 69 years of age with history of diabetes or smoking, 44% of 1865 patients were found to have ABI <0.90, but had not been previously diagnosed with PAD.³ Partially on the basis of these findings, the American Heart Association and the American College of Cardiology recommend that people ≥70 years of age or 50 to 69 years of age with diabetes or smoking history should be tested with the ABI to identify people with PAD who may benefit from interventions that prevent cardiovascular events and MALEs.

PAD is characterized by significantly impaired walking endurance and progressively greater declines in mobility and walking ability compared with no PAD.³ Guidelines recommend both lower-extremity revascularization and supervised exercise as first-line treatments for walking impairment in PAD.³ In May 2017, the Centers for Medicare & Medicaid Services began covering 12 weeks (36 sessions) of supervised exercise for PAD. However, as of December 2018, only 1.3% of 129 699 patients with PAD covered by Medicare had attended ≥1 Centers for Medicare & Medicaid Services–covered supervised exercise sessions, and only 87 of these PAD patients had completed all 36 sessions of exercise covered by Medicare.

Home-based exercise has the potential to overcome limitations of supervised exercise, including lack of available facilities meeting Medicare reimbursement requirements and the difficulty of traveling 3 times weekly to participate in center-based exercise. At least 5 randomized clinical trials have reported significant and meaningful benefits of structured home-based walking exercise, defined by walking exercise in or near the home without the presence of an exercise physiologist or nurse, for PAD.³ However, not all home-based exercise interventions were effective, contributing to uncertainty and confusion about the benefits of home-based exercise for PAD. Future studies should identify the most effective home-based exercise interventions for PAD and secure insurance coverage for these exercise interventions.

In contrast to the relatively poor uptake of supervised exercise for PAD, lower-extremity revascularization procedures are common and increasing. Endovascular treatments for PAD rapidly evolved during the 21st century.² Compared with open surgery, endovascular revascularization treatments have lower risk.² Although patients with acute limb ischemia and CLTI typically require urgent lower-extremity revascularization, most lower-extremity revascularization procedures in the United States are performed for patients with PAD without acute limb ischemia or CLTI. Few randomized clinical trials have been performed to identify optimal timing or optimal endovascular procedures for patients with PAD. Although the magnitude of benefit of lower-extremity endovascular revascularization is comparable to that of walking exercise, lower-extremity revascularization procedures increase the risk for MALEs, particularly during the first year after revascularization.^2,3

Approximately 11% of people with PAD will develop CLTI, which typically requires revascularization to prevent limb loss.² In 2005, the UK BASIL randomized clinical trial (Bypass vs. Angioplasty in Severe Ischemia of the Leg) reported that among 452 patients with infrainguinal atherosclerosis and CLTI, lower-extremity surgical revascularization and endovascular balloon angioplasty had similar benefits for the outcome of amputation-free survival.² In 2022, the BEST-CLI randomized trial (Best Endovascular vs Best Surgical Therapy in Patients With CLTI) reported that among 1830 patients with CLTI, surgical revascularization significantly lowered the primary outcome of MALEs or death compared with endovascular procedures.⁴ In addition to informing clinical practice, the BEST-CLI trial demonstrated the feasibility of large randomized clinical trials of revascularization for patients with PAD.

Since its discovery, PAD has been underappreciated. In the early 21st century, US physicians were significantly more likely to be aware of the importance of antiplatelet therapy or cholesterol-lowering therapy for a patient with coronary artery disease than for a patient with PAD. More recently, inequities in diagnosis and treatment by race, geography, and socioeconomic status have been identified among people with PAD.⁵ In the United States, Black people have an ≈2-fold higher prevalence of PAD compared with White people, and Black patients with PAD have more adverse outcomes, including higher amputation rates, compared with White patients with PAD.⁵

Cilostazol is the only drug recommended by guidelines to improve walking performance in PAD, but its effects are modest.³ No new drugs have been approved by the US Food and Drug Administration for PAD-related walking impairment since 1999. Therapies intended to stimulate lower-extremity angiogenesis, including locally administered hypoxia inducible factor-α1 and systemically administered granulocyte colony-stimulating factor or granulocyte macrophage colony-stimulating factor, did not significantly improve walking performance in PAD compared with placebo. Recent evidence has identified some promising therapeutic effects for PAD-related walking impairment in oral therapies that reduce oxidative stress and increase nitric oxide bioavailability. Consistent with these findings, preliminary evidence suggested that the beneficial effects of supervised exercise in PAD may be mediated by increases in endothelial nitric oxide synthase activity and nitric oxide. Because PAD is characterized by both lower-extremity skeletal muscle abnormalities and impaired perfusion, treatments for PAD that improve both perfusion and lower-extremity skeletal muscle health are likely to be most effective. An improved understanding of the specific skeletal muscle pathology contributing to walking impairment and the biological processes mediating the benefits of walking exercise in PAD are needed to identify targets for new PAD therapies.

None.

Disclosures Dr McDermott has received research funding from Helixmith. She has received other research support from ArtAssist, Mars, ChromaDex, ReserveAge, and Helixmith. She has received funding from the National Institute on Aging, the National Heart Lung and Blood Institute, and the American Heart Association.

The American Heart Association celebrates its 100^th anniversary in 2024. This article is part of a series across the entire AHA Journal portfolio written by international thought leaders on the past, present, and future of cardiovascular and cerebrovascular research and care. To explore the full Centennial Collection, visit https://www.ahajournals.org/centennial

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

For Sources of Funding and Disclosures, see pages 1152–1153.

Circulation is available at www.ahajournals.org/journal/circ

下肢外周动脉疾病 (PAD) 影响着全球 116 至 2.3 亿人。¹ PAD 的表现包括无症状（患者报告没有腿部用力症状）到慢性肢体威胁性缺血 (CLTI)（定义为下肢静息痛、坏疽或溃疡）。²与年龄匹配的未患 PAD 的人相比，患有 PAD 的人心血管事件和主要不良肢体事件 (MALE) 的发生率显着较高，主要不良肢体事件 (MALE) 定义为需要立即进行血运重建或截肢的严重下肢缺血。 PAD 的特点是行走障碍，即使是无症状 PAD 的人，其行走障碍也明显比没有 PAD 的人严重。³这一观点总结了过去一个世纪 PAD 诊断和治疗方面的进展，并确定了下个世纪改善结果的机会。

在过去 50 年中，随机临床试验证明了强化低密度脂蛋白降低治疗对心血管疾病患者（包括外周动脉疾病患者）的益处。在心脏保护研究的患者中，与安慰剂相比，辛伐他汀将低密度脂蛋白胆固醇降低至约 80 mg/dL 以下，并显着降低心血管事件和死亡率，包括 6487 名 PAD 患者。在 FOURIER 试验（高风险受试者中抑制 PCSK9 的进一步心血管结果研究）中，在他汀类药物治疗中添加前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型抑制剂 evolocumab 可将低密度脂蛋白胆固醇中位值降低至 31 mg/dL，并进一步降低与单独使用他汀类药物相比，心血管事件和 MALE（包括 3642 名 PAD 患者）。³利伐沙班联合阿司匹林也被证明可以减少 PAD 患者的心血管事件。在 COMPASS 试验（使用抗凝策略的患者的心血管结果）中，在 6391 名 PAD 患者中，低剂量利伐沙班（2.5 毫克，每天两次）联合阿司匹林 81 毫克，与单用阿司匹林相比，显着减少了心血管事件和 MALE。 VOYAGER PAD 试验（ASA 与利伐沙班在 PAD 血管内或外科肢体血运重建中的血管结果研究）同样证明了下肢血运重建后，与单独使用阿司匹林相比，利伐沙班联合阿司匹林具有益处。血栓形成是下肢动脉粥样硬化的一个重要组成部分，这一发现可能解释了这些抗血栓治疗对 PAD 患者的益处。

PAD 诊断不足。³无症状 PAD 的高患病率以及 PAD 患者报告的腿部症状的变异性可能导致 PAD 诊断不足。 20 世纪中叶，踝臂指数 (ABI) 被发现是一种简单、无创的 PAD 诊断测试。 ABI <0.90 对 PAD 的敏感性为 57% 至 79%，特异性为 83% 至 99%。³在美国医疗实践中进行的一项多中心研究旨在确定 70 岁以上或 50 至 69 岁有糖尿病或吸烟史的患者中 PAD 的患病率，结果发现 1865 名患者中有 44% ABI <0.90，但之前未诊断出患有 PAD。³部分基于这些发现，美国心脏协会和美国心脏病学会建议，≥70 岁或 50 至 69 岁有糖尿病或吸烟史的人应接受 ABI 测试，以识别患有 PAD 的人谁可能受益于预防心血管事件和男性的干预措施。

与没有 PAD 的患者相比，PAD 的特点是步行耐力显着受损，活动能力和步行能力逐渐下降。³指南建议将下肢血运重建和监督运动作为 PAD 步行障碍的一线治疗方法。³ 2017 年 5 月，医疗保险和医疗补助服务中心开始为 PAD 提供为期 12 周（36 次）的监督锻炼。然而，截至 2018 年 12 月，在 Medicare 承保的 129 699 名 PAD 患者中，只有 1.3% 参加过 ≥ 1 个 Medicare 和 Medicaid 服务中心承保的监督锻炼课程，其中只有 87 名 PAD 患者完成了承保的全部 36 次锻炼通过医疗保险。

家庭锻炼有可能克服监督锻炼的局限性，包括缺乏满足医疗保险报销要求的可用设施以及每周 3 次旅行参加中心锻炼的困难。至少 5 项随机临床试验报告了结构化家庭步行锻炼对 PAD 的显着且有意义的益处，这种锻炼的定义是在家中或家附近进行步行锻炼，而无需运动生理学家或护士在场。³然而，并非所有家庭锻炼干预措施都有效，导致人们对家庭锻炼对 PAD 的益处产生不确定性和困惑。未来的研究应该确定针对 PAD 的最有效的家庭运动干预措施，并确保这些运动干预措施的保险范围。

与外周动脉疾病 (PAD) 监督运动的采用率相对较低相比，下肢血运重建手术却很常见，而且不断增加。 PAD 的血管内治疗在 21 世纪迅速发展。²与开放手术相比，血管内血运重建治疗的风险较低。²虽然急性肢体缺血和 CLTI 患者通常需要紧急下肢血运重建，但美国大多数下肢血运重建手术是针对没有急性肢体缺血或 CLTI 的 PAD 患者进行的。很少有随机临床试验来确定 PAD 患者的最佳时机或最佳血管内手术。尽管下肢血管内血运重建术的获益程度与步行锻炼相当，但下肢血运重建手术会增加 MALE 的风险，特别是在血运重建后的第一年。^2,3

大约 11% 的 PAD 患者会出现 CLTI，这通常需要血运重建以防止肢体丧失。² 2005年，英国BASIL随机临床试验（Bypass vs. Angioplasty in Severe Ischemia of the Leg）报告称，在452名患有腹股沟下动脉粥样硬化和CLTI的患者中，下肢手术血运重建术和血管内球囊血管成形术对截肢结果具有相似的益处-自由生存。² 2022 年，BEST-CLI 随机试验（CLTI 患者的最佳血管内治疗与最佳手术治疗）报告称，在 1830 名 CLTI 患者中，与血管内手术相比，手术血运重建显着降低了 MALE 或死亡的主要结局。⁴除了为临床实践提供信息外，BEST-CLI 试验还证明了针对 PAD 患者进行血运重建的大型随机临床试验的可行性。

自发现以来，PAD 一直未被重视。 21世纪初，美国医生比外周动脉疾病患者更有可能意识到抗血小板治疗或降胆固醇治疗对冠状动脉疾病患者的重要性。最近，人们发现 PAD 患者在诊断和治疗方面存在种族、地理和社会经济地位方面的不平等。⁵在美国，黑人 PAD 患病率比白人高约 2 倍，并且与白人 PAD 患者相比，黑人 PAD 患者的不良后果更多，包括更高的截肢率。⁵

西洛他唑是指南推荐的唯一一种改善 PAD 步行能力的药物，但其效果有限。³自 1999 年以来，美国食品和药物管理局尚未批准用于治疗 PAD 相关步行障碍的新药。旨在刺激下肢血管生成的疗法，包括局部给予缺氧诱导因子-α1 和全身给予粒细胞集落刺激因子或粒细胞与安慰剂相比，巨噬细胞集落刺激因子并没有显着改善 PAD 患者的步行能力。最近的证据表明，口服疗法对 PAD 相关步行障碍有一些有希望的治疗效果，可减少氧化应激并增加一氧化氮的生物利用度。与这些发现一致的是，初步证据表明，监督运动对 PAD 的有益作用可能是通过内皮一氧化氮合酶活性和一氧化氮的增加来介导的。由于 PAD 的特点是下肢骨骼肌异常和灌注受损，因此改善灌注和下肢骨骼肌健康的 PAD 治疗可能是最有效的。需要更好地了解导致步行障碍的特定骨骼肌病理学以及调节步行锻炼对 PAD 的益处的生物过程，以确定新的 PAD 疗法的目标。

没有任何。

披露McDermott 博士已获得 Helixmith 的研究资助。她还获得了 ArtAssist、Mars、ChromaDex、ReserveAge 和 Helixmith 的其他研究支持。她获得了美国国家老龄化研究所、国家心肺和血液研究所以及美国心脏协会的资助。

美国心脏协会将于 2024 年庆祝成立 100^周年。本文是国际思想领袖撰写的整个 AHA 期刊系列文章的一部分，内容涉及心脑血管研究和护理的过去、现在和未来。要探索完整的百年纪念收藏，请访问 https://www.ahajournals.org/centennial

本文表达的观点不一定代表编辑或美国心脏协会的观点。

有关资金来源和披露信息，请参阅第 1152-1153 页。

流通量可在 www.ahajournals.org/journal/circ 上获取