The clinical syndrome of heart failure (HF), encompassing a constellation of signs and symptoms, has been recognized for more than a century. The incremental steps over the past 100 years—discoveries from basic research, the use of investigational drugs, pivotal clinical trials—often have been indiscernible. Nevertheless, the century has witnessed a reduction in morbidity and mortality rates for this large group of patients. Indeed, recent reviews have estimated that optimal use of therapies for HF with reduced ejection fraction (HFrEF) can add 2 to 8 years free from cardiovascular death or a HF hospital admission, depending on the age of the patient at onset of the disease.

In 1924, Willem Einthoven won the Nobel Prize in Medicine for the development of the electrocardiograph, ushering in the discipline of cardiology. The most common cause of HFrEF—coronary artery disease—was appearing as a scourge of modernity. Werner Forssman, a urologist, performed the first cardiac catheterization in 1929—on himself. The procedure was developed as a routine measure by André Frédéric Cournand and Dickinson W. Richards in the years thereafter (all 3 men received a Nobel Prize in 1956). It was not until 1953, however, that the original description of M-mode echocardiography by Inge Edler and Hellmuth Hertz marked the beginning of the development of a critical noninvasive technique in HF.

Charles A. Chidsey, Donald C. Harrison, and Eugene Braunwald described the augmented catecholamine response to exercise in patients with HF in publications from 1962 and 1963. They and others demonstrated the key role of the sympathetic nervous system in the pathogenesis of the HF syndrome, a prelude to the early clinical trials of β-blockade by Finn Waagstein and colleagues in Sweden, reported in 1975. Braunwald, John Ross Jr, and Edmund H. Sonnenblick published a 5-part series in the New England Journal of Medicine on the mechanisms of contraction of the normal and failing heart in 1967. Chatterjee et al¹ wrote a landmark study in 1973 titled “Hemodynamic and metabolic responses to vasodilator therapy in acute myocardial infarction.” This novel therapeutic approach to the patient with acute HF secondary to myocardial infarction was the mainstay of treatment until thrombolysis became routine.

In 1977, Cohn and Franciosa² outlined the rationale for vasodilator therapy of HFrEF in a 2-part series, followed by the initiation of the first multicenter trial in chronic HF in 1980: V-HeFT I (Vasodilator–Heart Failure Trial). This trial showed a 23% reduction in mortality rate for patients on hydralazine and isosorbide dinitrate (H-I) compared with placebo at 3 years, marking the beginning of hope for successful treatment of HF. Although race and ethnicity were not originally described for the 630 patients, 29% of the participants were Black, and had more hypertension and less coronary disease than their White counterparts. Mortality rate did not differ between the Black and White participants on placebo. Only Black patients on H-I showed a reduction in mortality rate; White patients showed no difference versus placebo.³ This remarkable observation was not reported until 1999 and underscores the critical need for diversity in clinical trial populations. Had all the patients in the trial been White, the concept of chronic vasodilator therapy for HFrEF might have been discounted.

Dzau and colleagues⁴ summarized the role of the renin-angiotensin-aldosterone system in HF in 1981, and by 1985, CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study) was enrolling patients, as was SOLVD (Studies of Left Ventricular Dysfunction) for patients with symptomatic HF in 1986. Both trials were evaluating the role of angiotensin-converting enzyme (ACE) inhibitors, a class of drugs initially used for hypertension. At the same time, the role of β-blockade in chronic HF was explored in several trials with long-acting metoprolol or carvedilol, beginning in 1993.

The combination of ACE inhibitors and β-blockers was so successful in decreasing morbidity and mortality rates, and the incidence of sudden cardiac death, that clinicians could not conceive that a generic drug such as spironolactone could meaningfully provide more clinical benefit. The unbridled aldosterone system in HF was addressed by several mineralocorticoid receptor antagonists, most notably illustrated in RALES (Randomized Aldactone Evaluation Study), which began enrolling patients in 1995, and showed a stunning reduction in mortality rate and sudden death incidence. By the end of the 20th century, the treatment of chronic HFrEF was firmly established to include ACE inhibitors (or angiotensin receptor blockers), β-blockers, and mineralocorticoid receptor antagonists.

A variety of drug classes have been assessed in the past 2 decades, including some oral inotropes. Debate about the therapeutic efficacy of digitalis, and other inotropes, continues. A new class of drug that inhibited endopeptidases was unveiled and tested in a trial using omapatrilat, published in 2002. The results were not promising. Omapatrilat blocked 3 pathways that break down bradykinin, leading to high rates of angioedema. However, by 2014, the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) was published, showing astonishing efficacy of a combination drug, sacubitril and valsartan (later known as an angiotensin receptor/neprilysin inhibitor), in HFrEF compared with an ACE inhibitor. This drug offered the benefit of concurrent blockade of the renin-angiotensin-aldosterone system and the inhibition of neprilysin while minimizing the occurrence of angioedema.

In 1967, the first successful human heart transplant was performed. Dr Sharon Hunt was a medical student in 1968, when the first transplant was done at her institution, Stanford University. She and her colleagues would subsequently develop and define the discipline of caring for the patient before and after heart transplant. In 2010, the first certifying examination was held for the cardiology secondary specialty of advanced HF and transplant cardiology.

The first definitive electronic pacemaker was implanted by Rune Senning and Åke Elmqvist in Sweden in 1958 using a thoracotomy approach. In 1980, Dr Michel Mirowski and his team inserted the first implantable cardioverter defibrillator in a patient. An understanding of fundamental pathophysiologic mechanisms in electrophysiology were incrementally crafted because of the high incidence of sudden cardiac death in patients with HFrEF. The first successful implantation of a left ventricular assist device was completed by Dr Michael E. DeBakey in 1966; 35 years later, in 2001, the REMATCH trial (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) results were published comparing left ventricular assist device treatment with medical therapy. The 1- and 2-year survival in the medical group of patients with severe HF was 25% and 8%, respectively; in contrast, the device arm survival rate was 52% and 23%.

The US Agency for Health Care Policy and Research published one of the earliest clinical practice guidelines for the care and evaluation of patients with HFrEF in 1994. A table of commonly used drugs listed 9 diuretics, including spironolactone, 4 ACE inhibitors, digoxin, and H-I. The first American Heart Association/American College of Cardiology joint clinical practice guideline on HF appeared in 1995. The document covered both HFrEF and “diastolic HF,” and urged the use of ACE inhibitors in all patients with HFrEF (H-I was the alternative for ACE inhibitor–intolerant patients) and the cautious use of β-blockers after myocardial infarction. Heart transplantation was discussed as an option, and HF in infants and children was covered, as was the role of myocarditis, and a long outline of the management of acute HF was included. The entire length of the guideline was 55 pages.

Today, guideline-directed therapy for HFrEF includes quadruple therapy (β-blockade, ACE inhibitor or angiotensin receptor/neprilysin inhibitor, mineralocorticoid receptor antagonist, and SGLT2 inhibitor). Recommendations include consideration for an implantable cardioverter defibrillator or cardiac resynchronization therapy, a multidisciplinary HF clinic, or remote monitoring techniques. Patients with nonischemic cardiomyopathy are now evaluated with a battery of genetic analytics. Even end-of-life considerations in HFrEF have improved.

Twenty years ago, I coauthored a review of HF.⁵ Some common clinical problems cited there have been resolved. Many have not, including how to identify patients with familial cardiomyopathy at an earlier stage, how to identify patients with greatest risk of sudden death, how to determine who will best be served by mechanical cardiac support devices, and how to afford optimal care for the growing number of patients with HF. An important challenge—that of making intense efforts to control hypertension and vascular risk factors to prevent the HF syndrome—has made little progress.

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The American Heart Association celebrates its 100th 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 page 901.

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

心力衰竭 (HF) 的临床综合征包含一系列体征和症状，一个多世纪以来人们就已经认识到它。过去 100 年来的渐进步骤——基础研究的发现、研究药物的使用、关键临床试验——往往是难以察觉的。尽管如此，本世纪见证了这一大群患者的发病率和死亡率的下降。事实上，最近的评论估计，射血分数降低 (HFrEF) 心力衰竭治疗的最佳使用可以延长 2 至 8 年，避免心血管死亡或心力衰竭入院，具体时间取决于患者发病时的年龄。

1924年，威廉·埃因托芬因开发心电图仪而获得诺贝尔医学奖，开创了心脏病学学科。HFrEF 最常见的病因——冠状动脉疾病——被视为现代社会的祸害。1929 年，泌尿科医生沃纳·福斯曼 (Werner Forssman) 对自己进行了首次心导管插入术。此后几年，安德烈·弗雷德里克·库南德 (André Frédéric Cournand) 和迪金森·W·理查兹 (Dickinson W. Richards) 将这一程序开发为常规措施（三人均于 1956 年获得诺贝尔奖）。然而，直到 1953 年，Inge Edler 和 Hellmuth Hertz 对 M 型超声心动图的最初描述才标志着心力衰竭关键无创技术发展的开始。

Charles A. Chidsey、Donald C. Harrison 和 Eugene Braunwald 在 1962 年和 1963 年的出版物中描述了心力衰竭患者对运动的儿茶酚胺反应增强。他们和其他人证明了交感神经系统在心力衰竭综合征发病机制中的关键作用1975 年，Finn Waagstein 及其同事在瑞典报道了 β 受体阻滞剂早期临床试验的序幕。Braunwald、John Ross Jr 和 Edmund H. Sonnenblick 在《新英格兰医学杂志》上发表了一篇由 5 部分组成的系列文章，内容涉及1967 年，Chatterjee 等人^在1973 年发表了一项具有里程碑意义的研究，题为“急性心肌梗塞对血管扩张剂治疗的血流动力学和代谢反应”。这种针对心肌梗塞继发的急性心力衰竭患者的新颖治疗方法是溶栓治疗成为常规治疗之前的主要治疗方法。

1977 年，Cohn 和 Franciosa ²在一个由两部分组成的系列文章中概述了 HFrEF 血管扩张剂治疗的基本原理，随后于 1980 年启动了第一个慢性心力衰竭多中心试验：V-HeFT I（血管扩张剂-心力衰竭试验）。该试验显示，与安慰剂相比，使用肼屈嗪和硝酸异山梨酯 (HI) 的患者 3 年死亡率降低了 23%，标志着成功治疗 HF 的希望的开始。尽管最初没有描述 630 名患者的种族和民族，但 29% 的参与者是黑人，与白人相比，他们患有更多的高血压和更少的冠心病。服用安慰剂的黑人和白人参与者的死亡率没有差异。只有服用 HI 的黑人患者死亡率有所下降；白人患者与安慰剂相比没有表现出差异。³这一非凡的观察结果直到 1999 年才被报道，强调了临床试验人群多样性的迫切需要。如果试验中的所有患者都是白人，那么慢性血管扩张剂治疗 HFrEF 的概念可能会被忽视。

Dzau 及其同事⁴于 1981 年总结了肾素-血管紧张素-醛固酮系统在心力衰竭中的作用，到 1985 年，CONSENSUS（北斯堪的纳维亚依那普利合作生存研究）正在招募患者，SOLVD（左心室功能障碍研究）也开始招募患者1986 年的症状性心力衰竭。这两项试验都在评估血管紧张素转换酶 (ACE) 抑制剂的作用，血管紧张素转换酶 (ACE) 抑制剂是一类最初用于治疗高血压的药物。与此同时，从 1993 年开始，多项长效美托洛尔或卡维地洛试验探索了 β-受体阻滞剂在慢性心力衰竭中的作用。

ACE抑制剂和β受体阻滞剂的组合在降低发病率和死亡率以及心源性猝死的发生率方面如此成功，以至于临床医生无法想象螺内酯等仿制药可以有意义地提供更多的临床益处。心力衰竭中不受控制的醛固酮系统可通过几种盐皮质激素受体拮抗剂解决，最引人注目的是 RALES（随机醛内酯评估研究），该研究于 1995 年开始招募患者，结果显示死亡率和猝死发生率显着降低。到 20 世纪末，慢性 HFrEF 的治疗已牢固确立，包括 ACE 抑制剂（或血管紧张素受体阻滞剂）、β 阻滞剂和盐皮质激素受体拮抗剂。

在过去的二十年里，人们对多种药物类别进行了评估，其中包括一些口服正性肌力药。关于洋地黄和其他正性肌力药的治疗功效的争论仍在继续。2002 年发表的一类抑制肽链内切酶的新型药物被发现并在一项使用 omapatrilat 的试验中进行了测试。结果并不乐观。奥马曲拉阻断了 3 条分解缓激肽的途径，导致血管性水肿发生率较高。然而，到 2014 年，PARADIGM-HF 试验（ARNI 与 ACEI 的前瞻性比较，以确定对心力衰竭全球死亡率和发病率的影响）发表，显示了联合药物沙库巴曲和缬沙坦（后来称为血管紧张素受体）的惊人功效/脑啡肽酶抑制剂），在 HFrEF 中与 ACE 抑制剂相比。该药物具有同时阻断肾素-血管紧张素-醛固酮系统和抑制脑啡肽酶的优点，同时最大限度地减少血管性水肿的发生。

1967年，第一例人类心脏移植手术获得成功。1968 年，Sharon Hunt 博士还是一名医科学生，当时她所在的斯坦福大学完成了第一例移植手术。她和她的同事随后制定并定义了心脏移植前后护理患者的纪律。2010年，举办了首届心脏病学二级专业高级心力衰竭和移植心脏病学认证考试。

1958 年，Rune Senning 和 Åke Elmqvist 在瑞典通过胸廓切开术植入了第一个决定性的电子起搏器。1980 年，米歇尔·米洛斯基 (Michel Mirowski) 博士和他的团队将第一台植入式心脏复律除颤器植入患者体内。由于 HFrEF 患者心源性猝死的发生率很高，人们逐渐了解电生理学的基本病理生理机制。1966 年，Michael E. DeBakey 博士完成了首次成功植入左心室辅助装置；35 年后的 2001 年，REMATCH 试验（充血性心力衰竭机械辅助治疗的随机评估）结果发表，比较了左心室辅助装置治疗与药物治疗。医疗组重度心力衰竭患者的 1 年和 2 年生存率分别为 25% 和 8%；相比之下，设备臂的存活率分别为52%和23%。

美国卫生保健政策与研究机构于 1994 年发布了最早的 HFrEF 患者护理和评估临床实践指南之一。常用药物表列出了 9 种利尿剂，包括螺内酯、4 种 ACE 抑制剂、地高辛和 HI 。第一个美国心脏协会/美国心脏病学会关于心力衰竭的联合临床实践指南于 1995 年出现。该文件涵盖了 HFrEF 和“舒张性心力衰竭”，并敦促所有 HFrEF 患者使用 ACE 抑制剂（HI 是 ACE 的替代品）抑制剂不耐受的患者）以及心肌梗塞后谨慎使用β受体阻滞剂。讨论了心脏移植作为一种选择，涵盖了婴儿和儿童的心力衰竭以及心肌炎的作用，还包括了急性心力衰竭治疗的长纲。该指南的总长度为 55 页。

如今，HFrEF 的指南指导治疗包括四联疗法（β-阻断、ACE 抑制剂或血管紧张素受体/脑啡肽酶抑制剂、盐皮质激素受体拮抗剂和 SGLT2 抑制剂）。建议包括考虑植入式心脏复律除颤器或心脏再同步治疗、多学科心力衰竭诊所或远程监测技术。现在，非缺血性心肌病患者可以通过一系列基因分析进行评估。甚至 HFrEF 的报废考虑也得到了改善。

二十年前，我与人合着了一篇关于 HF 的评论。⁵其中提到的一些常见临床问题已得到解决。许多人还没有，包括如何在早期阶段识别家族性心肌病患者，如何识别猝死风险最大的患者，如何确定谁最适合接受机械心脏支持装置，以及如何为患者提供最佳护理心衰患者数量不断增加。一个重要的挑战是大力控制高血压和血管危险因素以预防心力衰竭综合征，但进展甚微。

没有任何。

没有任何。

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 901 页。

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