Cardiovascular Research 2002 56(3):332-338; doi:10.1016/S0008-6363(02)00643-0
© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Personal reflections on efforts to reduce ischemic myocardial damage
Eugene Braunwald*
Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
* Tel.: +1-617-732-8989; fax: +1-617-975-0955. ebraunwald{at}partners.org
Received 14 August 2002; accepted 20 August 2002
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1 Background
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In the second half of the 19th Century, physiologists observed
that ligation of a major coronary artery in the dog was immediately
fatal. During that era, pathologists occasionally encountered
thrombosis of such vessels and acute myocardial infarction (AMI)
at autopsy, and considered this combination of findings to be
quite uncommon and uniformly fatal. At the dawn of the twentieth
century, Krehl, a Viennese physician, challenged these beliefs
and reported that coronary thrombosis was actually compatible
with survival
[1]. In 1910, Obrastov and Strazheske
[2], two
Russian physicians, and in 1912, Herrick, a Chicago physician
[3], described the clinical features of AMI, related them to
the pathologic findings and distinguished AMI from angina pectoris.
Herrick also adapted the then new technique of electrocardiography
to the premorbid diagnosis of AMI, considered at the time to
be a very uncommon condition.
By the middle of the 20th Century, during my clinical training in internal medicine and cardiology at New York University, New York's Mount Sinai Hospital, and Johns Hopkins, it was clear that rather than being a curiosity, AMI was, in fact, the most common cause of death in the United States and western Europe. Arrhythmias and pump failure were the two major reasons for both the very high early (approximately 30% in 30 days) and late (approximately 50% in 1 year) mortality in patients who reached the hospital. The development of the coronary care unit in the early 1960s with continuous electrocardiographic monitoring and prompt external defibrillation by a trained team eliminated almost all early arrhythmic deaths in patients treated in such units, thereby reducing the early mortality by half [4], leaving pump failure associated with large infarction as a major challenge in cardiology.
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2 Early research
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In 1951, as a medical student at New York University and Bellevue
Hospital, I was introduced to cardiovascular research in the
hemodynamic laboratory of Ludwig Eichna, a pioneer in the study
of human heart failure. I participated in some of the earliest
measurement of cardiac output in patients with cardiogenic shock
secondary to AMI. During a postdoctoral fellowship in the Nobel
Prize winning laboratory of Professors Andre Cournand and Dickinson
Richards in 1954–55, on the Columbia University Service
of Bellevue Hospital, we studied patients with chronic congestive
heart failure, many of whom had previously suffered a MI. Therefore,
by the time that I began my second postdoctoral fellowship with
Stanley Sarnoff in the newly created Laboratory of Cardiovascular
Physiology in the intramural research program of the then National
Heart Institute (now the National Heart, Lung and Blood Institute)
in 1955, I was aware that myocardial ischemic injury plays a
central role in both acute and chronic heart failure and that
ischemic heart failure was a major problem in cardiology. Since
myocardial ischemia was, by definition, secondary to an imbalance
between myocardial oxygen supply and demand, I welcomed the
opportunity to investigate the hemodynamic determinants of one
side of this balance, i.e. O
2 demand, as reflected in myocardial
O
2 consumption (MVO
2). Over the course of the next two years
we identified myocardial tension development and heart rate
as two important determinants of both MVO
2 [5] and coronary
blood flow
[6]. In the early 1960s, and now working in my own
laboratory at NIH in collaboration with Ross, Sonnenblick, and
Covell, it became clear that tension development and heart rate
could not be the
only important determinants of MVO
2, since
stimulation of the cardiac adrenergic nerves or the administration
of sympathomimetic amines increased MVO
2 without altering, indeed
while often reducing, the product of developed tension and heart
rate. We identified myocardial contractility, as expressed by
the maximum velocity of myocardial shortening of unloaded muscle,
i.e.
Vmax, as the third major determinant of MVO
2 [7]. It was
our distinct honor to publish the first paper in the first volume
of
Cardiovascular Research on the relation between two of the
three determinants of MVO
2, i.e. heart rate and contractility
[8].
Simultaneously, in another section of the laboratory, we were studying cardiovascular control by the carotid sinuses and learned that stimulation of the carotid sinus nerves causes reflex venodilatation, thereby reducing ventricular preload [9] and we confirmed earlier observations that such stimulation also reflexly lowers heart rate, ventricular wall tension and myocardial contractility. Thus, stimulation of the carotid sinus nerves reflexly reduces all of the determinants of MVO2 that we had previously elucidated. Dr Samuel Levine, one of the fathers of American cardiology and an eminent cardiologist at the Harvard Medical School and the former Peter Bent Brigham (now Brigham and Women's) Hospital, had many years earlier described a clinical maneuver to distinguish angina pectoris from non-anginal chest pain. When external massage of the neck in the region of the bifurcation of the carotid artery relieved ongoing chest pain it was very likely to have been angina pectoris; when it failed it usually was not.
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3 The reduction of ischemia by carotid nerve stimulation
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I did not put these various pieces together until early in 1967
when I served as a Visiting Professor at the University of Rochester,
NY. There I met a young Assistant Professor of Surgery, Seymour
Schwartz, who later served for many years as the Chair of the
Department at Rochester. Schwartz showed me how he controlled
blood pressure in dogs with renal hypertension by continuously
stimulating both carotid sinus nerves with a modified cardiac
pacemaker implanted into the chest wall. On the flight back
to Washington it occurred to me that patient-activated electrical
stimulation of the carotid sinus nerves might relieve intractable
angina. In collaboration with my late first wife, Nina Starr
Braunwald, who was a cardiac surgeon at the Institute, as well
as with Glick, Epstein and Wechsler, we set about to implant
radiofrequency pacemakers which stimulated the carotid sinus
nerves. It took just 10 weeks from the development of the idea
to its clinical execution and we were gratified that severe
angina could be readily relieved
[10]. Nina and I continued
this work at the University of California, San Diego in 1968
after we moved there to help start a new medical school. Indeed,
we were preparing to conduct a large Phase III trial on this
approach, when Favolaro and Effler described a new operation—coronary
artery bypass grafting—which was very successful in restoring
the balance between myocardial O
2 supply and demand by directly
increasing supply. This operation immediately made our more
indirect approach obsolete. However, our efforts had not been
a waste of time since they had provided us with a unique opportunity
to study reflex control of the circulation in conscious humans
[11]. Much more important, however, had been an observation
on one of our patients with an implanted carotid sinus nerve
stimulator who had returned to the hospital because of an AMI.
Contrary to our instructions, he maintained the stimulator in
the active mode despite severe and prolonged chest pain. I turned
the stimulator off but after I left the coronary care unit he
had the good sense to turn it on again until I returned to turn
it off once more. Later, inspection of his electrocardiogram
showed that his precordial ST segments rose each time I turned
the stimulator off and they became isoelectric when he reactivated
it.
Before considering the interpretation of this observation, it is useful to place it into context. Simply put, it was widely assumed in the 1960s that myocardium perfused by a vessel which became acutely occluded was irreversibly injured. However, two important early papers had suggested that perhaps some opportunity existed for salvaging infarcting myocardium. In the first of these, Tennant and Wiggers in 1935 temporarily occluded a major coronary artery and observed that dyskinetic contraction of the ischemic myocardium commenced within seconds. When the duration of ischemia was brief, i.e. less than 20 min, normal myocardial contraction returned after reperfusion, but when it was longer, dyskinesis continued [12]. In 1941, Blumgart et al. [13] reported pathologic observations, also in the dog, that extensive infarction occurred when coronary occlusion was maintained for 40 min or longer, while occlusions of 5–20 min did not result in infarction. With occlusions of intermediate duration, the extent of necrosis depended on the time to reperfusion.
In 1967, I speculated that techniques which augment O2 delivery to the infarcting myocardium while reducing its O2 needs might be beneficial in patients with acute MI [14]. Thus, the observation in 1968 that ST segment elevations were reduced in our patient undergoing an AMI when his myocardial O2 demands were lowered by carotid sinus nerve stimulation, supported the suggestion that myocardial ischemic injury was not necessarily irreversible in this situation.
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4 Early efforts to reduce ischemic damage
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Working with Maroko, a talented post-doctoral fellow, as well
as with Ross, Sobel and Covell who had accompanied me from Bethesda
to La Jolla, and with Libby, a promising medical student, we
obtained evidence to support this hypothesis. We employed epicardial
ST segment elevation as an indicator of ischemic injury in the
open-chest anesthetized dog and extended the Tennant and Wiggers
observations by finding that ST segment elevations rapidly became
isoelectric when reperfusion was carried out within 20 min following
coronary artery occlusion
[15–17]. However, our new finding
was that the extent and severity of ischemic injury—which
correlated closely with the size of the evolving MI—could
be expanded by increasing myocardial O
2 demands (e.g. by beta-adrenergic
stimulation) or by reducing further the O
2 delivery to the border
of the ischemic zone (e.g. by lowering arterial pressure). More
importantly, ischemic injury produced by coronary occlusion
could be reduced by lowering myocardial O
2 demands by beta adrenergic
blockade (
Fig. 1), increasing O
2 supply by reperfusion
[17–19] (
Fig. 2) or by simultaneously increasing myocardial O
2 supply
and reducing O
2 demands with intra-aortic balloon counterpulsation.
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Fig. 1 Results of an experiment demonstrating the effectiveness of the beta-adrenergic receptor blocker practolol on the severity and extent of ischemic injury in the open chest dog. Two consecutive 20 min coronary occlusions were carried out separated by an interval of 1 h. Left panel: average ST segment elevation in all sites (ST) at various times after occlusion, control occlusion (solid line), occlusion after practolol (dashed line). Right panel: diagram of the heart showing the site of occlusion (occ). The solid dots indicate the sites of placement of the epicardial electrodes. The area with ST segment elevation 15 min after the control occlusion is shown by the diagonal lines and in the occlusion after practolol by the dots. LA=left atrial appendage; LAD=left anterior descending coronary artery. In other studies, a close correlation was demonstrated between the elevation of the ST segment and the extent of necrosis in the subjacent myocardium. Reproduced with permission from Libby et al. (Cardiovasc Res 1973;7:167).
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Fig. 2 Relation between ST-segment elevation 15 min after occlusion and log creatine phosphokinase (CPK) activity 24 h later in the same myocardial sites in experimental canine studies. Lower line: control (untreated) group. Middle line: administration of glucose–insulin–potassium (GIK) and of propranolol starting 3 h after occlusion. Upper line: reperfusion of coronary arteries 3 h after occlusion. The slope of the three lines is statistically different from one another, signifying that glucose–insulin–potassium and propranolol administration reduced myocardial damage compared to control; in turn, reperfusion resulted in even greater tissue salvage than pharmacotherapy. Reproduced with permission from Maroko and Braunwald (Ann Intern Med 1973;79:720–733) [17].
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After moving to Harvard and the Brigham in 1972, Maroko and
I were joined by Muller and Kloner and our efforts were extended
in two directions. We sought methods more precise than epicardial
ST segment mapping to assess the effect of interventions on
ischemic injury. We employed pathological techniques to measure
the area at risk, i.e. the portion of the myocardium perfused
by the occluded artery, and assessed the fraction that became
necrotic. Simultaneously, we assessed ischemic injury in patients
with evolving AMI using a 35-lead precordial electrode system
[20].
While we were aware from the aforementioned studies by Tennant and Wiggers in the 1930s [12], of Blumgart et al. in the 1940s [13], and of course our own group's observations in the early 1970s [17–19] and of the elegant work of Reimer and Jennings [21] in the late 1970s that timely reperfusion could limit damage during evolving MI, it remained for others to develop techniques for myocardial reperfusion in patients.
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5 Clinical myocardial reperfusion
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In 1933, Tillett and Garner showed that hemolytic streptococci
could liquify clotted human plasma
[22]. The fibrinolytic substance
produced by the streptococcus, named streptokinase, was purified
and administered to patients with various thrombotic disorders.
Indeed, Tillett was chair of the department of Medicine when
I attended the New York University School of Medicine and I
recall observing some of the earliest administrations of streptokinase
to patients at Bellevue Hospital in 1950. At the time, streptokinase
had not yet been well purified and frequently caused severe
febrile reactions. In 1976, Chazov et al.
[23] reported the
successful lysis of coronary thrombi in patients with AMI with
intracoronary streptokinase. Two years later, Rentrop et al.
[24] achieved patency of acutely occluded coronary arteries
by disrupting coronary thrombi with a guide wire passed through
a catheter. These two seminal papers were the forerunners of
modern reperfusion therapy of AMI, i.e. thrombolysis and primary
percutaneous coronary intervention (PCI).
In 1981, we utilized myocardial thallium-201 imaging to demonstrate that early opening of the infarct-related artery indeed salvages substantial quantities of myocardium in patients with ST segment elevation MI (STEMI) [25]. In 1984, the National Heart, Lung and Blood Institute invited me to chair the first Thrombolysis in Myocardial Infarction (TIMI) trial. In this multicenter trial, we compared intravenous streptokinase with the then new thrombolytic agent, tissue plasminogen activator (t-PA), and learned that: (1) t-PA was superior to streptokinase in opening totally occluded coronary arteries [26,27]; and (2) that one year survival was greater in STEMI patients in whom the infarct related artery was open (irrespective of how that opening was achieved) than in those in whom it remained occluded [28]. Subsequently, in a much larger trial, the GUSTO investigators demonstrated that t-PA treatment was associated with a lower mortality than treatment with streptokinase [29].
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6 The TIMI trials
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I have had the privilege of chairing the TIMI Study Group since
its inception. As many as 800 hospitals in 32 countries on five
continents have been involved in 20 completed trials; ten additional
trials are ongoing or in the late planning stages. McCabe, Antman
and Cannon are three of the many talented collaborators in these
trials. Among the observations made on patients with STEMI,
the TIMI Study Group has: (1) developed and championed the ‘open
infarct-artery’ theory, which holds that early reperfusion
of the infarct-related artery results in myocardial salvage
which preserves ventricular function, which in turn improves
survival
[30,31]; however, while the benefits of reperfusion
diminish with time from the onset of symptoms
[32], even late
revascularization may be beneficial
[30]; (2) demonstrated reductions
in death and recurrent infarction with beta-blockers in STEMI
patients who received early t-PA
[33]; (3) developed a system
for describing epicardial coronary flow on angiography (the
TIMI Flow Grade)
[26], a system that has been universally adopted,
and M. Gibson, a member of the group described quantitative
angiographic assessments for measuring both epicardial and myocardial
blood flow in patients with STEMI
[34,35]. Taken together, these
techniques have allowed comparisons of the state of myocardial
perfusion between patients, treatment arms, and even laboratories;
(4) showed the ability of the surface electrocardiogram to predict
survival and coronary patency in STEMI patients
[36]; (5) characterized
the efficacy and safety of TNK–tPA, which is likely to
become the most widely used thrombolytic
[37]; (6) reported
that thrombolytic therapy can be safely administered in the
ambulance, thereby reducing further the time between the onset
of symptoms and reperfusion
[38]; and (7) showed that platelet
inhibition with a glycoprotein IIb/IIIa inhibitor can enhance
early myocardial reperfusion with t-PA
[39].
The combination of early reperfusion, combined with aspirin and anticoagulant therapy, has reduced the early mortality of STEMI by one-third, from about 15 to 10%. However, there clearly is still room for additional progress. We are now studying a carefully blended combination of therapies that has been termed ‘facilitated PCI.’ In the ADVANCE MI trial (TIMI-26) we are testing the efficacy and safety of a reduced dose of TNK–tPA, eptifibatide, a platelet glycoprotein IIb/IIIa inhibitor, aspirin, and low molecular weight heparin as a ‘holding maneuver,’ and then transporting the patient to a facility where immediate PCI can be carried out. It is likely that some combination of pharmacologic management and PCI will become the standard of care for reducing myocardial ischemic injury in STEMI.
The TIMI Study Group has also focused attention on unstable angina–non ST segment elevation MI (UA/NSTEMI), very common ischemic conditions that are closely related to STEMI, and also usually caused by a coronary thrombus. Unlike STEMI, the thrombus in UA/NSTEMI usually causes a subtotal coronary occlusion. We have learned that: (1) surprisingly, the outcome in patients with UA/NSTEMI is not improved by thrombolytic therapy [40]; (2) low molecular weight heparin, with its anti-coagulation factor Xa (as well as anti-IIa) activity, is superior to unfractionated heparin [41]; (3) an invasive therapeutic approach with early mechanical revascularization is superior to a conservative approach [42]; (4) the management of patients with UA/NSTEMI can be facilitated by risk stratification, which can be accomplished by a combination of clinical assessment [43], measurement of serum troponin [44], C-reactive protein [45], and brain natriuretic peptide [46] and even more effectively by a combination of these three biomarkers [47]. Both ischemic damage and death in UA/NSTEMI have been declining in the last ten years.
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7 Stunning and hibernation
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In 1978, Heyndrickx et al.
[48], working in Vatner's laboratory,
noted in the conscious dog that after a brief (15–30 min)
period of severe ischemia followed by reperfusion, not long
enough to cause myocardial necrosis, the myocardial dysfunction
in the ischemic region persisted for hours following reperfusion.
We termed this condition
myocardial stunning [49] and were able
to identify its presence in many clinical situations, such as
post surgical cardiac ischemia, exercise induced ischemia, unstable
angina and following thrombolytic reperfusion of evolving AMI
[50]. We also proposed that chronic stunning, i.e. persistent
moderate ischemia—not sufficiently severe to cause myocardial
necrosis—could cause prolonged contractile impairment
of viable myocardium. This condition, which was aptly named
‘myocardial hibernation’
[51,52] has emerged as
an important cause of ischemic heart failure which can be reversed
by revascularization. Hibernating myocardium can be detected
by a variety of imaging techniques, and observational studies
suggest that surgical revascularization prolongs survival in
these patients. I am now chairing an NIH-supported randomized
controlled trial that is testing this hypothesis.
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8 ACE inhibitors and statins
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In the 1980s, working with Marc Pfeffer and the late Janice
Pfeffer, we observed late remodeling of the left ventricle in
rats with MI
[53]. There is not only stretching of the infarcted
tissue, but also expansion and hypertrophy of the remaining
viable myocardium
[54]. In 1980, we were fortunate to obtain
small quantities of captopril, the first angiotensin-converting
enzyme inhibitor, and found that its administration could greatly
reduce this remodeling
[55]. After confirming this observation
in patients with MI
[56], we conducted a large multicenter trial,
the SAVE trial, which demonstrated improved survival in patients
randomized to the ACE inhibitor
[57] (
Fig. 3). This observation,
also, has been amply confirmed in a number of clinical trials
involving more than one hundred thousand patients. ACE inhibition
is now standard therapy and appears to be very helpful in reducing
the myocardial consequences of ischemic injury for the majority
of patients recovering from AMI.
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Fig. 3 Results of the SAVE trial. A total of 2231 patients were randomized and maintained on placebo or captopril an average of 11 days following acute myocardial infarction. These patients were not in clinical heart failure but had left ventricular dysfunction Reproduced with permission from Pfeffer et al. (New Engl J Med 1992;327:669) [57].
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With the progressive reductions in mortality from AMI, we are
focusing attention on prevention of recurrent MI and improving
survival of post-MI patients using HmG-CoA reductase inhibitors.
We have reported in the CARE trial that post-MI patients with
average levels of LDL-cholesterol show an improved outcome with
statin therapy
[58], not only by lipid lowering, but perhaps
also by the statin's anti-inflammatory actions reflected in
its ability to reduce C-reactive protein
[59]. Currently, we
are examining in the A to Z (TIMI 21)
[60] and in the PROVE
IT (TIMI 22) trials
[61], whether commencement of statin therapy
within days of an acute coronary event improves clinical outcomes
further.
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9 Conclusions
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I have been especially fortunate in my professional life in
several respects. I have had outstanding mentors who taught
me to focus on significant clinical–scientific problems
and to use a variety of approaches and techniques to address
them, rather than to become a slave of a single technique. I
have selected for investigation an important problem—ischemic
impairment of myocardial function, its treatment and prevention.
I have worked in great institutions, including New York University,
NIH, Johns Hopkins, University of California, Harvard Medical
School and the Brigham Hospital—all of which have been
very supportive of my efforts. I have been most fortunate of
all to have had the opportunity to work closely with several
generations of extraordinarily talented colleagues and trainees.
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1 Background
2 Early research