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The early history and development of thrombolysis in acute myocardial infarction

2004; Elsevier BV; Volume: 2; Issue: 11 Linguagem: Inglês

10.1111/j.1538-7836.2004.00881.x

1538-7933

Anjli Maroo, Eric J. Topol,

Cardiac Imaging and Diagnostics

Fibrinolytic therapy has been a major advance in the treatment of acute myocardial infarction (AMI), leading to improved early survival, less heart failure, less ventricular remodeling, and fewer arrhythmias [1]. The thrombolytic era was founded on a fundamental concept: that most cases of AMI are the result of sudden obstruction of an epicardial coronary artery by intracoronary thrombus superimposed on a ruptured or fissured atherosclerotic plaque. Physicians trained after the advent of thrombolytic therapy may find it difficult to believe that this concept was one of the most intensely debated pathophysiologic tenets of the 20th century. Yet, the development of thrombolytic agents for treatment of AMI remained a tortuous and stuttering process until this concept achieved widespread acceptance. We will review the interesting history of coronary artery thrombosis and its foundation of the thrombolytic era. In the late 19th century, great confusion existed with respect to the pathophysiologic basis of AMI. During this time, several leading pathologists, including J. F. Payne and E.F.A. Vulpian, reported postmortem findings of clot obstructing coronary arteries. However, antemortem clinical correlation between coronary thrombosis and AMI was sorely needed. A pathologist, Ludwig Hektoen, and two internists, Sir William Osler and George Dock, helped to establish this link in their writings. In an 1899 editorial entitled Infarction of the Heart, Hektoen wrote: 'While cardiac infarction may be caused by embolism, it is caused much more frequently by thrombosis, and thrombosis again is usually secondary to sclerotic changes in the coronaries'[2]. Osler was even more specific: 'The blocking of one of these vessels by a thrombus or an embolus leads to a condition which is known as anaemic necrosis, or white infarct. This is most commonly seen in the left ventricle and in the septum, in the territory of distribution of the anterior coronary artery.'[3] Dock was one of the first physicians to describe the diagnosis of myocardial infarction in a live patient in his paper, 'Notes on the coronary arteries', published in 1896 [2]. Interestingly, during the late 19th century, many physicians believed that coronary thrombosis inevitably led to sudden death. This concept was challenged in 1910 by two Russian physicians, Obraztsov and Strazhesko, who described the clinical features of patients who suffered non-fatal MI [4]. Soon afterwards, in a presentation to the Association of American Physicians in 1912, James Herrick described the classic signs and symptoms of acute coronary artery occlusion [5]. Although Herrick's work is now recognized as a landmark synthesis of the clinical and pathophysiologic bases of AMI, his initial presentation did not generate much attention from his peers. An updated version of his work, presented to the same society in 1918, produced a more favorable response and made the term 'coronary thrombosis' almost synonymous with AMI. Importantly, Herrick refuted the idea that coronary thrombosis was uniformly fatal: 'I have been surprised at the preservation of bodily strength that is often manifested. Patients occasionally walk about within a few hours after such a seizure and within a few days may be out of doors trying to attend to business… As in so many other conditions the first essential is to think of this condition as a possibility and to rid the mind of the notion that such a diagnosis is only possible at autopsy.'[5]. This important clinical observation was the spark that led many future physicians and scientists to seek out novel therapies for AMI. With Herrick's encouragement, Fred Smith documented the electrocardiographic (ECG) changes associated with coronary artery ligation in dogs. These findings set the stage for other clinicians, such as Pardee, to describe the ECG changes associated with AMI in human beings. Thus, by the early 20th century, physicians were armed with knowledge of the fundamental clinical and electrocardiographic features of MI and with the belief that sudden coronary thrombosis was the most common immediate precipitant. However, the available therapeutic repertoire for AMI was strikingly limited, and the mortality from an acute event remained as high as 30%. In order to advance treatment further, physicians had yet to develop another fundamental concept, the 'open-artery hypothesis': that early restoration of infarct artery patency and of perfusion to the downstream myocardium can improve left ventricular function and overall survival. The development of the open-artery hypothesis and the application of thrombolytic agents to AMI were delayed for several decades by a heated controversy that ensued from the 1930s to the 1980s over the exact role of coronary thrombosis in the pathogenesis of AMI. The controversy began with the publication of a paper entitled 'Acute myocardial infarction not due to coronary obstruction', in 1939 by Friedberg and Horn [6]. The authors found evidence of coronary thrombosis in only 31% of patients who had evidence of myocardial necrosis on autopsy. They also noted that some patients with classic clinical and electrocardiographic signs of MI had evidence of coronary thrombosis, while others did not. Improved identification of patients with subendocardial infarction contributed, in part, to the variability of these findings. In 1951, R.D. Miller noted that subendocardial infarction is rarely associated with intracoronary thrombi [7]. Replication of these findings by other pathologists called into question the cause-and-effect relationship between coronary thrombsis and AMI. One of the most influential physicians to challenge the significance of coronary thrombi was William C. Roberts, the Section Chief of the Cardiac Pathology Heart Institute at the National Institutes of Health. Roberts strongly believed that coronary thrombosis was the result, rather than the cause, of myocardial necrosis: 'Although it may play a major role in causing atherosclerosis, coronary thrombosis may well play a minor role, or none at all, in precipitating a fatal coronary event… Evidence [has been] gathered suggesting that myocardial necrosis comes first and that coronary thrombosis is secondary'[8]. According to Roberts, necrotic myocardium was the nidus for thrombus formation, especially in situations where there was slow blood flow (e.g. AMI with cardiogenic shock or large transmural AMI). He identified 'diffuse generalized coronary atherosclerosis with severe (> 75%) luminal narrowing (at least 2 of the 3 major coronary arteries)' as the main precipitant of fatal AMI. Furthermore, he believed that atherosclerotic plaque was the result of slow organization of intracoronary thrombus into fibrous tissue, 'the density [of which] may be determined by the composition of the initial thrombus, i.e. whether platelets or fibrin predominated.' Roberts' belief that thrombosis was the consequence of MI led many of his contemporaries to search for alternative pathophysiologic mechanisms for AMI, such as supply demand mismatch and coronary spasm. In 1980, Marcus DeWood and his colleagues in Spokane, Washington, published a landmark paper that sent ripples throughout the cardiology community [9]. DeWood's group astutely recognized the inherent limitations of autopsy series for the study of AMI. So, instead, they set out to perform coronary angiography in live patients within 24 h of presentation with AMI. Although this practice is common today, at the time, such a proposition was incredible! It was thought that injection of contrast during AMI was deleterious and could result in fatal arrhythmia or hemodynamic compromise during the procedure. DeWood observed total coronary occlusion in 110 out of 126 patients (87%) presenting within 4 h of the onset of symptoms of AMI. Angiographic evidence of thrombus was present in 59 patients. Remarkably, DeWood was able to use a Fogarty catheter to retrieve the thrombus in 52 (88%) of these patients. These data definitively established coronary thrombosis and total coronary occlusion as the dominant pathophysiologic mechanism of AMI. DeWood's paper also lent credence to the concept of endogenous fibrinolysis during the evolution of AMI. Of the patients who underwent angiography 12–24 h after symptom onset, only 37 out of 57 (65%) had evidence of total coronary occlusion. DeWood concluded that during the late phases of AMI, either relief of coronary spasm or recanalization of thrombus was capable of alleviating total coronary obstruction. This observation paved the way for the application of thrombolytic therapy to AMI. The early development of thrombolytic agents proceeded somewhat independently of the raging debate over the pathophysiology of AMI. In 1933, Tillet and Garner reported that Lancefield Group A beta-hemolytic streptococci were capable of producing a fibrinolytic substance (later named streptokinase) [10]. L. Royal Christiansen, and C.M. MacLeod went on to discover that streptokinase was responsible for converting plasminogen to the active fibrinolytic enzyme plasmin, which, in turn, was capable of degrading fibrinogen and fibrin. In 1947, Christiansen provided Tillet, Sol Sherry, George Hazelhurst, and Alan Johnson with a partially purified preparation of streptokinase for clinical use. Their group used the preparations to treat hemothorax, empyema, and abscess cavities [11, 12]. However, their true interest lay in the clinical application of streptokinase to the treatment of acute coronary thrombosis. So, in 1952, Johnson and Tillet pursued and achieved thrombolysis of experimental thrombi in rabbit ear veins by administration of streptokinase through a peripheral vein. Once purified preparations of streptokinase were made available by Lederle Laboratories in 1957, Sherry, Tony Fletcher, and Norma Alkjaersig proposed a strategy for intravenous fibrinolysis involving a loading dose of streptokinase, followed by a continuous infusion. This proposal led to the first human study of intravenously administered streptokinase for the treatment of AMI. Interestingly, the authors noted that early administration of streptokinase (within 14 h of symptom onset) resulted in low in-hospital mortality, while the in-hospital mortality of those who received delayed treatment was similar to untreated patients [13]. The tremendous advances in the development of thrombolytic agents in the scientific community did not translate into widespread acceptance in the clinical area in the 1960s and 70 s. As Fletcher astutely pointed out, one key question remained unanswered: did restoration of blood flow to infarcted tissue have any clinical benefit? Several key investigators, such as Peter Maroko, Peter Libby, and Burt Sobel, worked to establish this link. In dog models, these investigators demonstrated that reperfusion of an occluded coronary artery resulted in a decrease in infarct size, and improvement in abnormal ventricular wall motion, and an overall improvement in cardiac function [14, 15]. Demonstration of the utility of early reperfusion led Chazov et al. and later, Rentrop et al. to deliver intracoronary streptokinase after performing diagnostic angiography in patients with AMI [16, 17]. These pioneers demonstrated that coronary patency could be re-established during the acute setting, resulting in an improvement in the patients' symptoms and in resolution of ECG changes. The 1980s was an historic decade for cardiology that marked the beginning of the thrombolytic era. After DeWood's in vivo demonstration of coronary thrombosis during AMI, physicians and scientists were primed for the first large-scale randomized mortality trial using thrombolytic therapy. In 1986, GISSI-1 (First study of the Gruppo Italiano per lo studio della strepochinasi ell'infarto Miocardio) became the first large randomized trial that definitively showed that intravenous thrombolytic therapy with streptokinase improves survival. Similar to Fletcher's findings, GISSI-1 demonstrated that treatment with thrombolytics was most effective when given early after the onset of AMI. The survival benefit of intravenous streptokinase was maintained at 1-year follow-up [18]. The antigenicity and minimal fibrin specificity of streptokinase were undesireable properties of this otherwise revolutionary therapy that spurred interest in finding other potential thrombolytic agents. In Belgium, during the early 1980s, Drs Desire Collen and D.C. Rijken were able to purify a substance called HEPA (human extrinsic plasminogen activator) from melanoma cell lines [19]. HEPA was later renamed tissue plasminogen activator (t-PA). Scientists at a company called Genentech heard of Dr Collen's work and began a collaboration that led to the successful cloning and expression of the t-PA gene. They were able to produce large quantities of the recombinant t-PA using a Chinese hamster ovary cell line. Melanoma-derived t-PA was tested in 7 patients with acute MI in 1983 [20]. Six of the seven patients experienced prompt thrombolysis. This study was the springboard for a multicenter trial that began in February, 1984 [21]. At that time, Dr Eric Topol, one of the coauthors of this article, was in the early phases of his career. 'I recall my introduction to t-PA in a hematology journal club that I attended during my last year of residency at the University of California – San Franscisco. The discussion featured a paper by Dr Collen regarding the use of HEPA in dogs. By the end of the meeting, I was struck by the idea that HEPA could be used for acute MI. I inquired further and was told to contact Diane Pennica at Genentech. Busy with plans for starting cardiology fellowship at the Johns Hopkins Hospital, I forgot about HEPA until I was packing and found Diane Pennica's name scribbled on a slip of paper. I called her and was introduced to the members of the Genentech team. Although I moved to Baltimore to start my fellowship, I was soon contacted by Bob Swift at Genentech, and began a collaborative effort to use HEPA for acute MI. In February, 1984, my colleagues and I successfully treated the first patient with recombinant t-PA at the Johns Hopkins Hospital, a 57-year-old woman with an acute occlusion of her left anterior descending artery, with TPA.' Topol went on to conduct the largest randomized myocardial reperfusion trial, GUSTO-1 (Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries) [22]. This megatrial firmly established the importance of the 'open artery hypothesis' by demonstrating that achievement of greater vessel patency at 90 min after treatment with intravenous t-PA (vs. streptokinase) resulted in a 15% reduction in mortality. Since this landmark trial, the concept of short 'door-to-needle' times has become a priority in the treatment of acute MI in hospitals nationwide. Several new plasminogen activators were designed after the validation of the open artery hypothesis, including reteplase (r-PA), tenectaplase (TNK), and lanetoplase (n-PA), although no new therapy has exceeded t-PA's efficacy. During the past decade, intense research efforts have been directed at identifying the optimal reperfusion strategy. Multiple trials, involving thousands of patients, have been conducted to compare different lytic agents, to test different combinations of adjunctive anticoagulant therapies, and to compare lytic therapy with catheter-based reperfusion. The treatment of acute myocardial has evolved into an active, dynamic process, focused on the rapid restoration of perfusion to the affected myocardial bed. For those of us that practice cardiology today, the current tools available to treat AMI may lead us to feel empowered to dramatically change the natural history of coronary thrombosis. During the next century, as we continue to try to prevent MI altogether, we may find that several of the important lessons learned during the development of fibrinolytic therapy are applicable to our future efforts. Controversy over the mechanisms of disease was a principal instigator of fundamental changes in therapy. Greater understanding of the pathophysiology of the disease process was required before novel therapies could be introduced or accepted. Interchange of ideas and collaboration between clinicians and scientists from a variety of specialties and backgrounds was instrumental to the application of thrombolytic therapy to AMI. Information from randomized clinical trials challenged conventional wisdom and led to major changes in clinical practice. Finally, the innovative physicians and scientists who worked to develop thrombolytic therapy for the treatment of AMI were constantly faced with the existence of more questions than answers with respect to the optimal therapeutic strategy for AMI.