International Journal of Cardiology 167 (2013) 1825–1834

Contents lists available at ScienceDirect

International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Review

Acute myocardial infarction — Historical notes

Rogério Teixeira a, b,⁎, Lino Gonçalves a, b, Bernard Gersh c
a
Serviço de Cardiologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
b
Faculdade de Medicina Universidade de Coimbra, Coimbra, Portugal
c
Division of Cardiovascular Disease and Internal Medicine Mayo Clinic, Rochester, USA

a r t i c l e i n f o a b s t r a c t

Article history: For the time being, acute myocardial infarction represents a history of success concerning diagnose, manage-
Received 5 September 2012 ment and treatment, whereas it was considered a fatal disease in the beginning of the 1900s. The present
Received in revised form 5 December 2012 paper is aimed at reviewing the landmarks of acute myocardial infarction, as key historical concepts are an
Accepted 25 December 2012
important tool for understanding disease management, the daily dilemmas and future perspectives.
Available online 20 January 2013
© 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords:
Acute myocardial infarction
History
Landmarks

1. Introduction
Although description of clinical cases compatible with an acute
myocardial infarction (AMI) was reported by William Harvey in the
XXVII century literature, the initial recognition of AMI in a living
patient was later attributed to Dock, in his paper, “Notes on the coro-
nary arteries”, published in 1896 [1]. In 1899, an American pathologist,
Ludwing Hektoen, also contributed to the understanding of this pathol-
ogy by stating “… while cardiac infarction may be caused by embolism,
it caused much more frequently by thrombosis, and thrombosis again is
usually secondary to sclerotic changes in the coronaries” [1]. Another
pathologist, Osler, has, for the first time published a correlation between
clinical and pathological findings of coronary thrombosis [2]. Based
upon a number of cases from his private practice, he gave a thorough
discussion of practically every aspect of angina pectoris reporting sev-
eral cases of coronary thrombosis. He concluded that a blockage of
one of the coronaries by a thrombus or an embolus led to a condition
which was known as anemic necrosis, or white infarct [2].
In the beginning of the twentieth century, acute coronary artery
thrombosis was not considered as a major health problem even though
it was always fatal when it occurred [3]. The whole work of Krehl in
1901, the reports of Obrastzov and Strazhesko in 1910 and the ones of
James Herrick in 1912 challenged the paradigm of the inevitable fatality
of AMI [4–6]. Their observations described the relationship of symp-
toms with the sudden or gradual arterial occlusion, the identification
of complications of an AMI, such as ventricular aneurysm formation
⁎ Corresponding author at: Serviço de Cardiologia, Hospitais da Universidade de Coimbra,
Av. Bissaya Barreto—Praceta Prof. Mota Pinto, 300-050 Coimbra, Portugal. Tel.: +351
936740242.
E-mail address: rogeriopteixeira@gmail.com (R. Teixeira).
and myocardial rupture, and also established AMI as a clinical entity dis-
tinct from angina pectoris [3].
Joseph Wearn, from the Peter Bent Brigham Hospital, Boston
Massachusetts, published the first series of 19 patients with a clinical
diagnosis of AMI, confirmed at necropsy. After an exhaustive clinical
and etiological description, Wearn concluded that an AMI was caused,
most likely, by a thrombus in an atherosclerotic left anterior descend-
ing coronary artery, mostly affecting fifty-year-old male patients,
with sudden chest pain in the heart region. The attack was typically
severe and could be associated with other symptoms, such as acute
dyspnea. Physical examination usually revealed “signs of the failing
circulation, such as pale and cold skin, lung crackles, enlarged heart,
pericardial rub and irregular rhythm”. Regarding management, a crit-
ical concept, noted by Wearn, was that the outcome of the patient
would depend upon the extent of the damage in the cardiac muscle
and in the conduction system. Treatment should be based upon abso-
lute bed rest, in order to spare the heart and prevent sudden cardiac
death. It was also emphasized that in patients with pulmonary rales,
fluid intake should be restricted and digitalis given, as this appeared
to result in an improvement in symptoms, perfusion, and diuresis.
Among the 19 patients, in no case did nitrates relieved chest pain,
and usually large doses of morphine were required. Also, he added:
“… in very critical times, when blood pressure dropped and patients
showed other signs of collapse” caffeine and camphor should be
used, as they seemed to provide an almost immediate relief [2].
In 1929, Samuel Levine, from Boston, published another important
clinical series of AMI patients. In his book, entitled “Coronary throm-
bosis: its various clinical features”, he presented the concept of cardiac
risk factors, namely heredity, male gender, obesity, diabetes and hy-
pertension, as they predisposed to coronary thrombosis. Levine also
drew attention to the adverse impact of cardiac arrhythmias during

0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijcard.2012.12.066
1826 R. Teixeira et al. / International Journal of Cardiology 167 (2013) 1825–1834
an AMI, addressing, probably for the first time, the concept of patient
monitoring. He suggested that trained nurses should carefully follow
the rate and rhythm of the apex beat, so as to identify and promptly
treat arrhythmias. He also noted the use of quinidine for ventricular
tachycardia, and adrenaline for AV block [1].
2. Angina pectoris
It is believed that the first description of angina pectoris dates
back to 1550BC. In the Ebers Papyrus, Egyptians reported a classic
and dramatic description of coronary ischemia: “if thou examinest a
man for illness in his cardia and he has pains in his arms, and in his
breast and in one side of his cardia… it is death threatening him” —
Fig. 1 [7]. More than 3000 years later, in 1768, William Heberden, an
English physician, published a clinical description of angina pectoris
associated with adverse prognosis and sudden death. The pathophys-
iologic correlation between angina and coronary artery disease was
established only a few years later, in 1786, by Edward Jenner, who
witnessed three patients' autopsies with history of anginal attacks,
and reported “…a kind of firm fleshy tube, formed within the coronary
vessel, with a considerable quantity of ossific matter dispersed irregu-
larly through it…” [1]. Almost a century later, in 1856, Rudolph
Virchow, Professor of Pathology at the University of Berlin, was the
first to describe the characteristics of the coronary vessel wall in
patients with atherosclerosis. He proposed that injury to the inner
wall of the blood vessel, possibly caused by fat, might lead to inflam-
mation and secondary plaque formation, a very close notion to present
day theory [8]. In 1867, a Scottish physician, Thomas Brunton, intro-
duced the use of nitrates (inhaled amyl nitrate) for the treatment of
Fig. 1. The Ebers papyrus. In 1862, the Ebers Papyrus was purchased by Edwin Smith, an
American adventurer living in Cairo. He kept the papyrus in his possession until 1869
when he placed it on sale. In 1872, the papyrus was purchased by the Egyptologist
Georg Ebers, for whom the papyrus is named. The papyrus is 110 pages long, making
it the largest medical papyrus discovered ever. The exact date when the papyrus was
composed is open to some debate but it probably dates back to around 1534 BCE. The
papyrus refers to a myriad of medical spells, treatments, surgeries and diseases that
afflicted the ancient Egyptians. In: A small dose of toxicology. The Health effects of com-
mon chemicals. Steven Gilbert, 2nd edition, Healthy World Press, 2012 [151].
the angina crises, for he believed that angina was caused by a derange-
ment of the vasomotor system [1].
3. Clinical and electrocardiographic correlations
The origin of modern cardiac electrophysiology dates back to
1840. At that time, an Italian physicist, Carlo Matteucci identified an
electrical current that accompanied each cardiac contraction. A few
years later, Emil DuBois, a German physiologist, confirmed the dis-
covery of electrical activity in the frog heart. French physicist Gabriel
Lippmann devised a capillary electrometer in the early 1870s, that the
following British physiologists, John Burdon Sanderson and Frederick
Page, used to record the heart's electrical current. In 1878, they
reported that each cardiac contraction was accompanied by a two-
phase electrical variation, which was the very first description of ven-
tricular depolarization and repolarization. A few years later, Burdon
Sanderson and Page published several tracings of the heart's electrical
activity recorded with a capillary electrometer. The undulations they
registered were later termed as the QRS complex and the T wave.
Right about this time, Augustus Waller began a series of experiments,
at St. Mary's Hospital Medical School, in London, which culminated in
his recording of the first human electrocardiogram. By connecting
electrodes attached to the front and back of a man's chest to a capil-
lary electrometer, Waller showed that each heartbeat was “accompa-
nied by an electrical variation” [9].
After attending an international physiology meeting, Einthoven
began to explore the use of the capillary electrometer to record min-
ute electrical currents and, in 1895, he was able to detect recognizable
waves, which he labeled “P, Q, R, S, and T”. Probably one of the most
important advances made by Einthoven was the invention of the
string galvanometer, in 1903. This device was much more sensitive
than both the capillary electrometer previously used by Waller and
the string galvanometer that had been invented separately, in 1897,
by the French engineer Clément Ader. Rather than using today's
self-adhesive electrodes, Einthoven's subjects would immerse each
of their limbs into containers of salt solutions from which the electro-
cardiogram was recorded. With this new technique, he standardized
the tracings and formulated the concept of “Einthoven's triangle” by
mathematically relating the three leads (Lead III = Lead II − Lead I).
He described bigeminy, complete heart block, “P mitrale,” right and
left and ventricular hypertrophy, atrial fibrillation and flutter, the
U wave, and examples of various heart diseases [9,10].
A physician from Chicago, Fred Smith, documented the electrocar-
diographic changes associated with coronary artery ligation in dogs,
and Bousfield described, in 1918, the electrocardiogram during an
episode of angina [11]. These findings set the stage for other clini-
cians, such as Harold Pardee in New York, by the 1920s, to describe
the electrocardiographic changes associated with AMI in human be-
ings. He gave rise to the entity of ST-segment elevation myocardial
infarction, by describing the electrocardiographic changes of acute
coronary occlusion as the takeoff of the T-wave from the descending
R-wave [12] — Fig. 2. Thus, by the early of the 20th century, physi-
cians were armed with knowledge on the fundamental clinical and
electrocardiographic features of myocardial infarction (MI) and with
the belief that sudden coronary thrombosis was the most common
immediate precipitant [13].
4. The “Boston chair” treatment of AMI
Until the mid-1950s absolute bed rest deemed essential. Care was
largely palliative: to relieve chest pain, to prevent deep vein thrombosis
and to ease the breathlessness and edema caused by the falling heart.
Patients were confined to strict bed rest for four to six weeks; not
allowed to turn from side to side without assistance, and they were
even isolated, as well as deprived from trivial activities such as listening
to the radio or reading a newspaper. The concept was based upon the
 R. Teixeira et al. / International Journal of Cardiology 167 (2013) 1825–1834 1827

A) B) C)

Fig. 2. By 1920 physicians were armed with knowledge of the fundamental clinical and electrocardiographic features of AMI. This paper, published in 1920, by Pardee, was a report of
a 38 year-old male with sudden onset of chest pain that radiated to the left chest. “On admission to the hospital 2 h later the heart rate was 44 per minute and the rhythm was noted
to be regular”. He was discharged from the hospital, and returned to his work as a chauffeur. He died suddenly after a day of driving in automobile. By that time, ST elevation was
recognized as an electrocardiographic marker of acute myocardial infarction. In Pardee H: An electrocardiographic sign of artery obstruction. Arch Intern Med 26: 244, 1920 [12].

therapeutic principle of the need to rest a diseased body part, such as in a
bone fracture [14].
Changes in the paradigm begin with an encounter between a
patient and Samuel Levine, from Harvard Medical School. His patient
had an AMI and developed congestive heart failure refractory to stan-
dard therapies such as digitalis, diuretics and oxygen. According
to Bernard Lown's description, Dr. Levine “ordered the patient into
a chair for 2 h daily” believing that gravity would shift the excess
fluid from lungs to extremities. The patient actually improved re-
markably and went on to recover. This was the basis of a landmark
paper published by Levine and Lown a few years later in the Journal
of the American Medical Association (JAMA): “Armchair” treatment
of acute coronary thrombosis. This study of 81 consecutive patients
who were placed into a comfortable chair for increasing durations on
succeeding days, showed improvements in a number of clinical end-
points and a 9% reduction in 30 day mortality [15]. Interestingly, the
trial was apparently very difficult to initiate as many deemed such a
“radical” approach to be unethical and comparisons were drawn with
medical experiments in the Nazi's concentration camps [14]!
Although the sample size was small, the data were by and large
anecdotal, and there was no simultaneous matched control popula-
tion, the results were considered to be convincing and no other stud-
ies of the “armchair approach” were ever conducted. The reaction of
the medical community to the paper was severe, according to Lown's
description “… there were grumblings from some senior physicians.
I overheard one leading academic joke that the proper name for this
new radical management should be the Boston electric chair treat-
ment for heart attacks…” But the remarkable benefits of their land-
mark paper were later recognized: the duration of hospitalization
was reduced by half, walking was allowed earlier, the bedpan was
abandoned, and hospital mortality was reduced by about a third
(perhaps due to a reduction in deep vein thrombosis, pulmonary
embolism, debility and frailty), rehabilitation was hastened and re-
turn to work accelerated [14].
An interesting description of the management of AMI during the
1950s was the one related to US President Dwight Eisenhower AMI. In
September 24th 1995 President Eisenhower had his first (left anterior)
myocardial infarction while playing golf at the Cherry Hills Country
Club outside Denver. He was transported by car to Fitzsimmons
Veterans Hospital, placed in an oxygen tent and treated with intrave-
nous heparin [16]. A curious aspect of Eisenhower' first AMI was the
remarkably aggressive recovery pace for that time, prescribed by his
Cardiologist Paul White. By October 22nd, he was allowed to sit on a
chair for a few hours each day, holding daily conferences about his pres-
idential duties. By November 7th he began walking and climbing stairs,
and 6 months after, Eisenhower announced he was running for a second
term [17]. Regarding Eisenhower's long-term treatment, it included
coumadin 35 mg/week, a low fat diet, and maintenance of weight
at 175 lb. He righteously followed this treatment until his death. It
was only suspended to undergo a bowel obstruction procedure and a
cholecystectomy. Unfortunately, the treatment would not protect him
against further heart attacks and a stroke, highlighting the concept of
re-infarction, which, at that time, was almost inevitable [16].
5. The history of oxygen therapy
Soon after the recognition of AMI as a distinct clinical entity, it
was accepted that AMI was synonymous of 100% high flow oxygen
therapy regardless of arterial hypoxia. It was believed that hiperoxia
was associated with a higher oxygen delivery to myocardial cells, a
reduction in infarct size and a relief of angina [18]. The first challenge
to this unproven theory came in 1950, with a paper published in the
JAMA, where it was observed that 100% oxygen via a face mask led to
more pronounced and longer duration of the electrocardiographic
manifestations of myocardial ischemia and failed to prevent the
onset or influence the duration of anginal pain [19]. This controversial
topic continued to be studied in the 1960s and 70s with reports
documenting adverse hemodynamic effects of high flow oxygen in
the setting of AMI [20,21]. It was also proved that hypoxia did not
affect the availability of oxygen for myocardial metabolism in normal
subjects until the oxygen saturation fell to about 50%, although coro-
nary artery disease anaerobic metabolism indicative of myocardial
ischemia was observed in some patients with saturations between
70 and 85% [22]. The most prominent studies were collected in a
Cochrane review, which assessed three trials of 387 patients with
presumed AMI who were randomly assigned to supplemental oxygen
or room air. No significant difference in mortality was found [23]. This
data supported the concept that routine oxygen administration is
of no benefit, but in the presence of hypoxemia its use is logical, al-
though exceptionally, high flow rates are of no added benefit, from
an evidence-based standpoint [18].
1828 R. Teixeira et al. / International Journal of Cardiology 167 (2013) 1825–1834
6. The development of coronary care units
The concept of the coronary care unit (CCU) was introduced in
July 1961, in a paper presented to the Thoracic Society of Great Britain
by Desmond Julian and promptly published in The Lancet [24].
According to Eugene Braunwald, it was the single most important
advance in the treatment of AMI and within 5 years, CCUs became
the standard of care worldwide [3].
The rationale for the CCU concept was driven to some extent by
developments in the field of closed chest cardiopulmonary resuscita-
tion, the use of external defibrillators, the continuous telemetry mon-
itor with an alarm system, and in the postulated relationship between
“warning” ventricular arrhythmias and subsequent sudden arrhyth-
mic death, a concept first described by Samuel Levine in 1920 [25].
The landmark paper, regarding the potential of the CCU to im-
prove survival after an AMI, was published in 1967, by Thomas Killip
and John Kimball [26]. Killip and Kimball described the course of 250
patients with an AMI, defined by electrocardiographic and laboratory
findings, treated either in a regular ward, or in a specialized coronary
unit. After some protocol changes a clear improvement in mortality
was observed. Those modifications were delegation of some medical
authority to trained nurses, allowing them to apply a precordial shock
whenever a physician was not available, and the creation of a protocol
for treatment of CCU patients by the senior physician. The rate de-
creased from 26% in patients treated in a regular ward, to 7% among
those treated in the CCU. This paper also highlighted the extremely
high mortality of cardiogenic shock and the lack of any CCU impact on
mortality in cardiogenic shock in these “early days” preceding the re-
perfusion era [26]. Another important contribution from these authors
and one that has stood the test of time was the heart failure (or severity)
index. The original paper subdivided the study population according to
the severity of cardiac failure and the status of systemic perfusion, also
known as the Killip classification [27].
In 1970 Swan and Ganz reported the development of the flow-
directed, balloon-tipped (Swan-Ganz) catheter which allowed online
monitoring of ventricular function in the CCU, and the performance of
specific hemodymically directed therapies based upon measurements
of filling pressures, cardiac output and systemic vascular resistance
[28]. These consisted in the intravenous administration of fluid or
diuretics to optimize ventricular preload, vasopressors or vasodilators
to optimize systemic vascular resistance and left ventricular afterload,
and positive inotropic agents (cardiac glycosides, beta adrenoceptor
agonists) for “pump” failure [3].
7. Pre hospital care
By 1963 it was known that among casualties from coronary artery
disease in people aged 50 or younger, 63% occurred within 1 h after
the onset of symptoms and despite the development of the CCU, the
majority of the fatalities occurred before hospital admission [29]. It
was also understood that the majority of those casualties, during an
early phase of an AMI, were due to ventricular fibrillation and not
“pump failure”, and that ventricular fibrillation could be corrected.
This was based on the seminal papers of Beck in 1947 regarding the
first successful internal cardiac defibrillation [30], and of Zoll's in
1956, that used alternating current (later changed to direct current)
across the chest to successfully treat ventricular fibrillation [31].
Also, by the late 1960s, the concept of cardiopulmonary resuscitation
(CPR) was known, as Kouwenhoven demonstrated that blood flow to
vital organs could be maintained simply by compressing the lower
end of the sternum [32].
In Belfast, Northern Ireland, in the late 1960s it was urged to de-
crease pre-hospital coronary mortality. Physicians, technicians and
nurses managed to create a communication network, and with the
use of a local constructed portable defibrillator started the Belfast
Coronary Care Scheme, or Cardiac Ambulance service on January
1st, 1966 [33]. A year later, the initial experience was published in
The Lancet. No death occurred in transit within a fifteen-month peri-
od and, most importantly, ten cases of successful resuscitation outside
hospital were reported. Five of those patients survived to hospital dis-
charge, and the potential of out of hospital resuscitation from cardiac
arrest was established [34].
The paper led to the acceptance of the concept of pre-hospital
coronary care, subsequently implemented both in the United States
of America (USA) and Australia. The USA experience began in New
York, in 1968, with William Grace, staffed by medical personnel.
Other experiences were accomplished in Miami, Seattle, Portland
and Columbus using paramedic personnel — defibrillation by emer-
gency medical technicians (EMT) without the presence of physicians
[34]. Another important program was initiated in 1968, in Seattle,
aimed at training citizens in CPR [34]. It was even broadcast on the
United States national TV, due to its importance and, above all, man-
aged to increase survival of a coronary attack with ventricular fibrilla-
tion in Seattle, when comparing to New York or Chicago regions [25].
The Seattle model also pointed out that there was an inverse rela-
tionship between the duration of ventricular fibrillation and long-
term survival. Pantridge, in trying to solve that problem, suggested
that if small cheap defibrillators had a fail-safe mechanism like the
safety catch on a pistol, then the lay public could perform defibrilla-
tion. It was reasonable to assume that anyone capable of performing
CPR could use a fail-safe defibrillator [33]. By 1970 Mirowski, based
upon an animal model, developed the automatic implantable defibril-
lator which was capable of picking up the cardiac rhythm from the tip
of a catheter in the right ventricle [35]. In the 1970s, several proto-
types of automated external defibrillators (AEDs) were developed
and tested in the Portland area. The first to be tested was a portable,
automatic resuscitator that recognized respiratory signals and electro-
cardiogram of a victim in cardiac arrest through an intrapharyngeal
sensor and a lingual — epigastric skin pathway. The testing of the
device in 21 patients with ventricular fibrillation resulted in 35 suc-
cessful conversions to sinus rhythm and one long-term survivor [36].
Pre hospital trials began in Brighton, England 1980, and later in 1982
the United States Food and Drug Administration (FDA) gave approval
for EMT automated defibrillators clinical trials. In the early 1990s
police officers and other first responders completed AED training
and later use by lay personnel was approved by the FDA. Automated
external defibrillator training was included in the American Red
Cross basic CRP course, beginning in March 1999. A few years later,
FDA allowed home AED prescriptions and its use in high risk populat-
ed areas [37]. Since 2000s different studies showed an improved sur-
vival and neurological outcomes for AEDs use by laypersons prior
to EMT, located in places such as public transit facilities, shopping
malls, public sports venues, industrial sites, golf courses, casinos, dial-
ysis centers, and fitness centers — a concept referred to as “public
access defibrillation” [38–40]. Moreover, it was also realized that the
majority of patients admitted to intensive care units after out of hospi-
tal cardiac arrest, died from neurological injury [41]. Lowering brain
temperature, to 32 to 34 °C, during the first few hours after cardiac
arrest, reduced the risk of neurologic injury and improved prognosis.
It was therefore considered a major breakthrough in the management
of post cardiac arrest patients [42]. Despite advances in the treatment
of heart disease, the outcome of patients experiencing sudden cardiac
death remains poor, as recent reports conclude for a 17% survival to
hospital discharge [43]. On the contrary, the long-term outcome
among patients who survive until hospital discharge is improving
[44], as in a recent community based study of 200 out of hospital car-
diac arrest patients over 70% survived until hospital admission, and
40% of these were discharged with mild or absent neurological dam-
age [45].
The time elapsed prior to resuscitation efforts appeared to be the
most critical element in prognosis. There are several ways to decrease
the time to the onset of resuscitative efforts resumed previously: a
 R. Teixeira et al. / International Journal of Cardiology 167 (2013) 1825–1834
rapid emergency medical system response, bystander CPR and early
defibrillation with the use of AEDs.
8. Cardiac biomarkers
As early as the 1920s, it was known that AMI was usually accom-
panied by laboratory evidence of tissue damage, such as leukocytosis.
Also, another nonspecific laboratorial finding proved that there was
an abnormal urinary sediment, with a high rate of hyaline and gran-
ular casts [2]. These inflammatory changes were occasionally helpful
but the most definitive diagnostic aid was the ECG [46]. The sensitiv-
ity of the diagnosis of AMI improved considerably in 1956 when
LaDue and Wroblewski showed a rise in the levels of serum glutamic
oxaloacetic transaminases (GOT) during an AMI [47]. This was
followed by the work of Stewart and Warburton in 1961, regarding
the usefulness of serum lactic dehydrogenase in addition to serum
GOT to diagnose AMI [48]. In 1965, Warburton and Wright concluded
that serum creatine phosphokinase (CPK) levels at 48 from onset
were diagnostic of AMI in a patient with typical symptoms [49]. A
year later, Van der Veen identified the different isoenzymes of CPK
[50] and by the 1970s it became evident that MBCK was to be the
standard of care for diagnosis and quantitative assessment of AMI
[46]. The next step, in the 1980s, the use of monoclonal antibodies
to detect biomarkers in the plasma [46] which increased the specific-
ity and the speed of the assay took place [51]. Nonetheless, the spec-
ificity of these assays was limited, as many patients without apparent
cardiac disease were found to have elevations of MBCK, usually sec-
ondary to skeletal muscle injury [52]. In the late 1980s, troponin
was introduced as a marker of cardiac injury, by Cummins [53]. At
the same time, the assay for myosin light chain, later identified as tro-
ponin T was developed [54]. David Silva, a postdoctoral fellow at
Washington University School of Medicine, developed a two-site im-
munoassay for myoglobin, widely used nowadays. [55]. It was found
that troponin I was specific for cardiac injury in acute muscle disease,
chronic muscle disease, chronic renal failure, and even after a mara-
thon run [56]. A number of studies to assess its value in identifying
cardiac damage in different settings were performed and included
perioperative myocardial infarction, cardiac contusion, myocarditis,
unstable angina, and non-cardiac critically ill patients [57]. It was also
concluded that troponin had a prolonged elevation after an AMI, and
therefore, it was more useful than lactate dehydrogenase isoenzymes
for detecting cardiac damage in patients with late presentations [57].
The importance of the troponin assay (third generation, highly sensitiv-
ity troponins) was clearly noted in the 2007 consensus document
published in agreement with the European Society of Cardiology, the
American College of Cardiology, and the World Heart Federation, as
the guideline redefined myocardial infarction diagnosis to a troponin
standard [58].
9. Changing concepts of AMI pathophysiology
In 1856, Rudolf Virchow's starting point of describing coronary
vessels in a patient with atherosclerosis, pioneered the understanding
of coronary artery disease and acute coronary thrombosis [1]. During
the 1930s, studies of the blood concentration of cholesterol began,
and, in 1950, John Gofman, from the University of California, identified
both low and high-density lipoprotein cholesterol using the ultracen-
trifuge technique. In addition, it was found that 101 of 104 men with
AMI had elevated LDL cholesterol molecules [59]. Constantinides, in
1966, had previously described plaque fissuring and hypothesized
that ruptures in the lining of the atherosclerotic coronary arteries
were the precipitating cause of coronary thrombosis [60]. Ten years
later, Maseri, reported observations of dynamic coronary artery ob-
struction and the role of coronary vasospasm [61]. Davies and Thomas,
in 1985, as well as Falk, in 1983, in post-mortem studies, observed that
vulnerable plaques had thin fibrous caps over a lipid core, containing
1829
inflammatory cells, and, more importantly, these plaques were the
cause of AMI, sudden ischemic death, and crescendo angina. Falk
also proved that embolization from plaque rupture might result in
micro-infarctions. In 1999, Russell Ross, proposed in a New England
Journal of Medicine publication that coronary artery disease was an in-
flammatory process which has, since then, remained a focus of intense
investigation [8].
A major pathophysiologic paradigm, lasting almost until the
1980s, was whether AMI was the consequence of thrombosis or was
thrombosis itself a secondary phenomenon [13]. The controversy
started with a JAMA paper in 1939, entitled “Acute myocardial infarc-
tion not due to coronary obstruction”. In this article, Friedberg and
Horn published a case series of autopsy findings of AMI and found
evidence of coronary thrombosis in only 31% of the patients who
had myocardial necrosis [62]. In fact, even as late as 1976, thrombosis
was believed to be the consequence and not the cause of myocardial
infarction, …“although it may play a 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 the myocardial necrosis comes first and that coronary
thrombosis is secondary”, William Roberts published in Seminars in
Thrombosis and Hemostasis [63]. He identified generalized coronary
atherosclerosis with severe luminal narrowing, at least in two of
the three major coronary arteries as the main precipitant of fatal
AMI [63]. Philip Oliva challenged this theory in 1979 [64] and the
work of Marcus De Wood, in the 1980s, contributed decisively to
the change in paradigm. He performed coronary angiography within
24 h of presentation, challenging, at that time, the risk of fatal ar-
rhythmia or hemodynamic compromise. Of a total of 126 patients
studied, coronary occlusion was identified in 87% of patients, with an-
giographic evidence of thrombus in 59 patients. Moreover, he proved
that thrombus formation declined over the first 24 h from symptoms
onset, supporting the concept that thrombus was the cause and not
the consequence of an AMI [65].
10. The fibrinolytic era
The 1970s and 80s witnessed the start of the reperfusion era and
a dramatic breakthrough that transformed the management of AMI
[13]. The concept of reperfusion after coronary obstruction dates
back to the late 1980s, but the genesis of pharmacologic fibrinolysis
began in 1933 with the isolation of a fibrinolytic substance from
Lancefield Group A beta hemolytic streptococci [66]. Christensen
and Macleod were able to describe the entire mechanism of strepto-
coccal fibrinolysis in 1945, by demonstrating that human plasma
contained the precursor of an enzyme system, called plasminogen,
and that the streptococcal fibrinolysin, which they had named as
streptokinase, was an activator able to convert plasminogen into the
proteolytic enzyme plasmin [67]. Later, in 1947, the first partially
purified preparation of streptokinase was clinically used to treat
hemothorax, empyema and abscess cavities [68,69]. The story contin-
ued and, in 1952, Johnson and Tillet achieved thrombolysis of exper-
imental thrombi in rabbit ear veins, with streptokinase, through a
peripheral vein [70]. In 1957, purified preparations of intravenous
streptokinase were made available by the Lederle Laboratories®,
and after the work by Sherry's group, regarding the pharmacokinetics
of streptokinase [71], in 1958, the first human study of intravenously
administered streptokinase for the treatment of AMI took place [72].
The 1980s heralded the first randomized controlled trial (RCT) of
intravenous and intracoronary fibrinolytic therapy culminating in the
Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico
(GISSI) trial that achieved an impressive and unequivocal survival
benefit for intravenous streptokinase over placebo [73]. An important
concept brought about by the GISSI trial was the need of antiplatelet
therapy (namely aspirin) in addition to streptokinase, to promote a
more significant mortality reduction during an AMI [74].
1830 R. Teixeira et al. / International Journal of Cardiology 167 (2013) 1825–1834
The discovery of tissue plasminogen activator (t-PA) was made in
the early 1980s, in Belgium, by Rijken and Collen [75]. They managed
to purify a substance called human extrinsic plasminogen activator,
from a melanoma cell line, later renamed tissue plasminogen activa-
tor (t-PA). Scientists from Genetech® started working with the
Belgian group, that led to the successful cloning and expression of
the t-PA gene, using a Chinese hamster ovary cell line [13].
Eric Topol went on to conduct a randomized myocardial reperfu-
sion trial, The Global Utilization of Streptokinase and Tissue Plasminogen
Activator for Occluded Coronary Arteries (GUSTO-1). The trial showed
afterwards a higher rate of vessel patency at 90 min after treatment
with intravenous t-PA versus streptokinase representing a 15% reduc-
tion in mortality. The trial also concluded that the elapsed time
between the onset of pain and the administration of thrombolytic
therapy was extremely important, not depending on the agent used,
and obliging the concept of short door-to-needle to become a top pri-
ority regarding treatment procedures [76]. Several new plasminogen
activators were designed after the validation of the benefits of early
reperfusion, including reteplase (r-PA), and tenecteplase (TNK) [13].
These drugs had shorter plasma half-life, on the one hand, and were
administered in a bolus, proving to be associated with less bleeding
complications afterwards [77].
Thrombolytic therapy of AMI has become one of the most widely
studied therapies of any life-threatening illnesses with well over
250,000 patients enrolled in prospective randomized trials to date
[3]. It has improved survival, heart failure rate, and ventricular
remodeling. The need to understand the delicate balance between
ischemic and bleeding endpoints led to multiple trials which have
been conducted to compare different lytic agents in order to assess
different combinations of adjunctive anticoagulant therapies and to
compare lytic therapy with catheter-based reperfusion [78].
11. Primary angioplasty
The history of primary angioplasty dates back to 1929s Forssmann
work [79], to André Cournand and Dickinson Richards [10] and to
Seldinger in 1953 [80]. They all contributed towards the development
of a percutaneous technique for both right and left heart catheteriza-
tion. In the early 1950s, the visualization of the coronary arteries was
still a challenge and papers were published regarding different tech-
niques for a non-selective coronary identification [81,82]. In 1958,
Mason Sones, from the Cleveland Clinic, and his colleagues, devel-
oped selective coronary angiography, during an aortic root angiogra-
phy in a patient with rheumatic and aortic valvular disease and
published it as an abstract in Circulation [83]. An important contribu-
tion to the technique was introduced by Melvin Judkins, who de-
scribed the percutaneous transfemoral approach with the Seldinger
technique, in 1967, (with Mason Sones coronary angiograms were
performed by a brachial arteriotomy) and introduced a series of spe-
cialized catheters to perfect the transfemoral approach [84].
Charles Dotter is generally credited with developing a new medi-
cal specialty, interventional radiology. He was a pioneer concerning
the flow-directed balloon catheterization development, the double-
lumen balloon catheter, the safety guidewire and percutaneous arte-
rial stenting. In 1963, he was the first to perform a percutaneous
transluminal angioplasty of an occluded right iliac artery that marked
a new era in the treatment of peripheral atherosclerotic lesions [85].
An import boost to the technique happened with a Zurich Cardiologist,
Andreas Gruentzig, who substituted a balloon-tipped catheter for the
rigid dilator and performed the first peripheral balloon angioplasty
in a human being [86]. After animal experiments, in 1977, Gruntzig
performed the first coronary balloon angioplasty in a 37 year-old
awoken businessmen, admitted for unstable angina, with an isolated
lesion in the left anterior descending artery, who consented to angio-
plasty instead of an unavoidable bypass operation, even after being
informed that he would be the first patient to be treated by that
technique [87]. In 1979, Gruentzig published, in the New England
Journal Medicine, his experience with 50 patients submitted to percu-
taneous balloon transluminal coronary angioplasty with a significant
successful result in 32 on them [88]. Another important evolutionary
step for the treatment of coronary artery disease happened in 1986
with the report of the first stent implantation in Toulouse, France by
Jacques Puel [89] and a first clinical series was presented later that
year in a joint publication from Toulouse, and Lausanne [90].
Focusing on the population with an AMI in 1982, Meyer showed
the feasibility of recanalization by angioplasty of the acutely occluded
coronary artery during the initial stage of myocardial infarction, in
case of failure of intracoronary streptokinase infusion [91]. Hartzler
introduced, in 1983, the technique of coronary artery recanalization
by primary balloon angioplasty [92] and its potential advantages over
thrombolytic therapy were recognized, even in the early experience
[93]. Randomized controlled trials and later meta-analyses comparing
balloon primary angioplasty and intravenous fibrinolysis successfully
proved the superiority of the invasive approach [94–96]. Later studies
concluded that primary angioplasty with a stent was significantly
more effective than with a balloon, namely in the reduction of target
vessel revascularization [97,98]. Moreover, primary angioplasty with a
stent also improved survival when compared to lytic therapy if both
therapies were administered within the same time period [99].
Many practical concepts arrived from the evidence regarding
myocardial revascularization, such as the importance of the time var-
iable, risk stratification, sub group analysis and new endpoints to clas-
sify a therapy, such as the bleeding results.
12. Unstable angina and non-ST elevation AMI
Heberden was probably the first to describe crescendo angina in
1772 [8] but only during the 1930's was it realized that severe angina
could be a precursor of impeding acute coronary occlusion [100]. In
the 1940s an oral anticoagulant was tested with success, supporting
the concept that “efforts should be made to improve coronary blood”
in patients with coronary insufficiency [8], as was later confirmed in
1960 with the work of Beamish and Storie [101]. In 1971 Fowler was
the first to use the term ‘unstable angina’ to describe the complex clin-
ical condition [102], known today as non-ST elevation acute coronary
syndromes, usually with biochemical evidence of some myonecrosis
and obstructive coronary artery disease.
During the 1970s the natural history of unstable angina was clarified
[103], and the prognostic significance of electrocardiographic ischemic
abnormalities was described [104]. With the advent of coronary artery
bypass surgery [105] and of coronary care units [24], urgent surgery
was tested in the earliest revascularization RCT [106]. Later with the
advent of coronary angioplasty [86] and with the lack of evidence of
thrombolytic therapy in patients without classic electrocardiographic
findings of transmural infarction [107], the so-called invasive strategy
started to be used with success in patients with intermediate-to-high
ischemic risk [108]. Immediate reperfusion is not needed for the major-
ity of patients with a non-ST elevation acute coronary syndrome but the
timing of the invasive strategy has also been investigated in most con-
temporary trials [109,110]. Supporting both the conservative and the
invasive strategy, evidence was collected for the use of dual antiplatelet
therapy [111,112], and anti-thrombotic agents [113]. Patients with
non-ST elevation acute coronary syndromes now outnumber those
with ST-segment elevation AMI by about 3 to 1 and account for about
1 million hospital admissions yearly in the USA [114].
13. Acute myocardial infarction systems of care
Unfortunately data from several registries showed that reperfu-
sion therapy has been insufficiently implemented, and a large propor-
tion of patients with ST elevation AMI do not receive any reperfusion
therapy for a wide variety of reasons, despite its availability [115].
 R. Teixeira et al. / International Journal of Cardiology 167 (2013) 1825–1834
Primary angioplasty becomes more challenging when the activities of
diagnosis and reperfusion span multiple, loosely connected hospitals
and emergency medical services (EMS) [116]. In addition, one of the
major delays in patients receiving rapid reperfusion is the delay in
the patient seeking care and arrival at the emergency department
[117].
Based on the impressive results from the Danish Multicenter
Randomized Study on Thrombolytic Therapy versus Acute Coronary
Angioplasty in Acute Myocardial Infarction (DANAMI 2) and the PRimary
Angioplasty in patients transferred from General community hospitals
to specialized PTCA Units with or without Emergency thrombolysis
(PRAGUE) trials [118,119], Europeans have been pioneers in the iden-
tification of a need to establish a network of reperfusion at a regional
and national level, implying a close collaboration between all the
actors involved in reperfusion, namely hospitals, departments of car-
diology, primary angioplasty centers, and EMS [115]. The concept was
adopted in the USA and in 2005 the first ST elevation AMI network
started in Michigan and was shown to be highly effective in achieving
treatment goals and reducing mortality [120]. Soon a number of local
systems were developed and recently a statewide ST elevation net-
work was developed in North Carolina, evolving 119 hospitals, a pop-
ulation of 9.4 million residents, and an area of 53,000 mile 2, with
impressive results [116]. During the past decade it was possible to
develop networks of care based on standardized protocols and order
sets designed by the use of guideline based therapies. The system
requires a prearranged and individualized reperfusion and transfer
plan for each community, which necessitates leadership and team-
work to optimize communication and referral status, evaluate out-
comes, and to promote quality improvement [121].
Another important contribution to AMI network treatment has
been telemedicine in the form of 12-lead standard electrocardiogram
(ECG) recording, from the pre-hospital setting to a receiving hospital
[122]. The first tracings transmitted over the phone line occurred in
the early 1960s, but it was after the introduction of lytic therapy in
the 1980s that several studies used pre-hospital 12-lead ECG to diag-
nose AMI and administer fibrinolysis [123]. The concept was later
studied in the context of primary angioplasty not only to promote an
earlier activation of the cardiac catheterization laboratory, but also
to reroute patients to hospitals with the capability to perform the
invasive procedure [124,125]. Telemedicine in the form of 12 lead
ECG has been a major contributor to improved organization and col-
laboration between the EMS and the cardiology community, as the
ability to provide a diagnostic pre hospital ECG to health care profes-
sionals with decision-making power has proven pivotal for reduction
treatment delays with respect to diagnosis, triage, and initiation of
reperfusion therapy [122].
14. Secondary prevention
With respect to the management of post AMI survivors, evidence
has been gathered for the past 20 years regarding medical therapy
and lifestyle modifications that significantly increase prognosis. This
is the case for beta blockers [126], angiotensin converting enzyme
(ACE) inhibitors [127,128], angiotensin receptor blockers [129], anti-
platelet therapy [74,130,131] and of aggressive risk factor reduction,
such as statin therapy [132].
Preventive measures were a critical advance in coronary artery
disease management, as declines in smoking, in saturated fat intake
and increased blood pressure control, correlated with a decreased
rate of death from cardiac causes [133]. Regarding risk factor reduc-
tion, a landmark dates back to the 1960s with the Framingham
Heart Study that identified the importance of blood cholesterol and
elevation in blood pressure as risk factors for coronary artery disease
[134]. It was demonstrated that the risk of developing clinically sig-
nificant coronary artery disease was a continuous curvilinear function
of blood cholesterol levels [135]. During the 1950s and 1960s, many
1831
cholesterol-lowering agents were introduced into clinical use, includ-
ing nicotinic acid, cholestyramine, clofibrate, and plant sterols. A
Japanese microbiologist Akira Endo discovered statins a decade later,
and the first to reach clinical practice was mevalonate (later called
lovastatin). In 1985, the National Heart Lung and Blood Institute
established the National Cholesterol Education Program, to educate
both physicians and patients about the importance of treating hyper-
cholesterolemia and high blood pressure, and the first guidelines were
published in 1988 [136]. A number of trials for primary and secondary
prevention of coronary artery disease have been published since the
1990s, leading to a widespread use of statins in general daily practice.
It is currently understood that statins should be used aggressively
after an AMI and initiated during the admission right after the diagno-
sis with an LDL target below 70 mg/dl. Furthermore, while LDL reduc-
tion has been considered the primary goal of lipid lowering therapy,
the pleiotropic effects of statins (plaque stabilization, reversal of endo-
thelial dysfunction, decreased, thrombogenicity, and reduced inflam-
mation) may also render additional benefit [132].
Another significant improvement in post AMI patient manage-
ment was the implementation of a cardiac rehabilitation program.
The concept was first used during the 1940s in the work classification
unit by the New York State Employment Service, aimed at assisting in
the evaluation of cardiac workers, to assess the level of activity the
cardiac patient was able to perform in safety [137]. By the late 1950s,
inpatient cardiac rehabilitation began, with emphasis not only upon
the post-acute MI phase at the step down unit, but also in the early
post-MI phase at the coronary care unit [138,139]. A decade later pro-
grams were extended to the outpatient setting, supporting the use of
supervised physical activity for the post-MI patient, first in hospital
and secondly, within the community [140]. Those studies were the
basis of the current three phases of comprehensive cardiac rehabilita-
tion program considered to be a safe and effective method of improving
physical, physiological and psychological wellbeing, enhancing quality
of life and patient survival [141].
There has been a general agreement that prognosis after an AMI
has improved over the past three decades. The mortality rates have
been lower in clinical trials in which patients were carefully selected
and therapy monitored. It has been proved that the increased use of
aspirin, beta-blockers, ACE inhibitors and reperfusion could explain
71% of the decrease in short-term mortality rate from 1975 to 1995
[142]. Nevertheless, despite the increasing usage of proven treatment
modalities, a somewhat higher in-hospital mortality has been recently
reported from a Scandinavian non-selected ST elevation AMI cohort
[143], highlighting the need of further clinical and mechanistic inves-
tigation to optimize patient management and prognosis — Fig. 3. Re-
garding long-term data, a recent large study of community-dwelling
elderly with AMI indicates that mortality from AMI after discharge
has improved significantly during the last decade. In addition, the
notorious decrease in mortality may be due to practice improvement
related to cardiovascular medications prescription after AMI [144].
This supports the concept that adherence to optimal medical therapy
is nowadays the most relevant contributor to the decrease in coronary
heart disease related mortality, as was used in contemporary trials
such as the Invasive versus Conservative Treatment in Unstable coronary
Syndromes (ICTUS) [145], the Occluded Artery Trial (OAT) [146] and
the Clinical Outcomes Utilizing Revascularization and Aggressive drug
Evaluation (COURAGE) [147] trials.
Several areas of investigation such as genomics, molecular targeting,
viral therapy, pharmacogenomics, stem cell and regenerative medicine
are promising in continuing to maintain the steady decline in cardiovas-
cular death rate over the late 20th and early 21st centuries [114]. On
the contrary, there is a concern regarding the increase in prevalence
of cardiovascular risk factors which may reverse this optimistic view,
in particular the case of obesity, which is expected to reach 42% of
adult Americans by the year 2050, according to a sophisticated mathe-
matical model derived from the Framingham Heart Study Network
1832 R. Teixeira et al. / International Journal of Cardiology 167 (2013) 1825–1834

Fig. 3. Collection of data from non-selected AMI (ST elevation acute coronary syndromes when applicable) cohorts, since the 1960s. According to previous authors, data from studies
performed before 1960 should not be included for comparison because during that period, enzymatic confirmation of myocardial infarction was not generally available. A steady
decline in hospital mortality for an AMI is noted, although a recent Scandinavian single center experience reported an alarming 9.3% in hospital mortality (in red). In black: data
from a meta-analysis of unselected studies published between 1960 and 1987 concerning mortality after AMI that included over 25,000 patients from around the world [152].
In yellow: data from 16,000 non-selected hospital admission for AMI in the Boston area between two periods: 1973/74 and 1978/79 [153]. In green: population based studies of
AMI patients between 1975 and 1995 [142]. In blue: data from 250,000 hospitalizations of non-selected AMI patients in New Jersey hospitals between 1986 and 2007 [154]. In
red: data form a single center Finish center over 1000 patients with AMI that report a 9.6% mortality rate for ST elevation ACS patients [143].

[148]. Moreover, the epidemic of cardiovascular diseases and AMI on
the developing world has global implications [149] and emphasizes
the pivotal importance of primary and secondary prevention.
15. Conclusions
The management of myocardial infarction during the last 50 years
represents one of the triumphs of contemporary cardiology and re-
perfusion therapy has been the dominant force. Declines in mortality
have been demonstrated in multiple registries from around the
world. As our societies age, new challenges arise by the increasing
numbers of AMI patients of advanced age among whom the mortality
remains high irrespectively of which therapeutic modality is employed
[150]. Future advances in the management of AMI will focus on systems
of care, particularly in regard to patients who present to non-PCI capa-
ble hospitals and their transfer as rapidly and expeditiously as possible
to PCI-capable centers. Nonetheless, for many patients with no access to
such facilities, the goal is the same, the provision of reperfusion therapy
to all who are eligible.
Acknowledgments
The authors would like to thank Maria Teixeira, TEFL for the copy-
editing service of the manuscript.
References
[1] Fye W. A historical perspective on atherosclerosis and coronary artery disease.
In: Fuster Valentin, Topol Eric J, Nabel Elizzabeth G, editors. Atherothrombosis
and Coronary Artery disease. Lippincott: Williams and wilkins; 2005. p. 1–14.
[2] Wearn J. Thrombosis of the coronary arteries with infarction of the heart. Am J
Med Sci 1923;165(2):250–75.
[3] Braunwald E. Evolution of the management of acute myocardial infarction: a
20th century saga. Lancet 1998;352(9142):1771–4.
[4] Krehl L. Die Ekrankungen des Herzmuskels und die Nervosen Herzkrankheiten.
Vienna: Alfred Holder; 1901.
[5] Obrastzov W, Strazhesko N. Zur Kenntnis der Thrombose der Koronararterien
des Herzens. Z Klin Med 1910;71:116–32.
[6] Herrick J. Certain clinical features of sudden obstruction of the coronary arteries.
JAMA 1912;59:2015–20.
[7] Boisaubin E. Cardiology in ancient Egypt. Tex Heart Inst J 1988;15(2):80–5.
[8] Conti R. The Jeremiah Metzger Lecture: evolution of management of acute coronary
syndromes. Trans Am Clin Climatol Assoc 2005;116:46–53.
[9] Fye W. A history of the origin, evolution, and impact of electrocardiography. Am
J Cardiol 1994;73:937–49.
[10] Mehta N, Khan L. Cardiology's 10 greatest discoveries of the 20th century. Tex
Heart Inst J 2002;29:164–71.
[11] Bousfield G. Angina pectoris: changes in electrocardiogram during paroxysms.
Lancet 1918;2:475.
[12] Pardee H. An electrocardiographic sign of coronary artery obstruction. Arch Intern
Med 1920;26:244–57.
[13] Maroo A, Topol E. The early history and development of thrombolysis in acute
myocardial infarction. J Thromb Haemost 2004;2(11):1867–70.
[14] Lown B. The lost art of healing. 1st ed. Houghton Mifflin Company; 1996.
[15] Levine S, Lown B. “Armchair” treatment of acute coronary thrombosis. JAMA
1952;148(16):1365–9.
[16] Messerli FH, Messerli AW, Luscher TF. Eisenhower's billion-dollar heart attack —
50 years later. N Engl J Med 2005;353(12):1205–7.
[17] The health and medical history of President Dwight Eisenhower. Accessed
August 2012, at http://www.doctorzebra.com/prez/g34.htm.
[18] Beasley R, Aldington S, Weatherall M, Robinson G, McHaffie D. Oxygen therapy
in myocardial infarction: an historical perspective. J R Soc Med 2007;100:130–3.
[19] Russek H, Regan F, Naegele C. One hundred percent oxygen in the treatment of
acute myocardial infarction and severe angina pectoris. JAMA 1950;144:373–5.
[20] Thomas M, Malmcrona R, Shillingford J. Haemodynamic effects of oxygen in
patients with acute myocardial infarction. Br Heart J 1965;27:401–7.
[21] Kenmure A, Murdoch W, Beattie A, Marshall J, Cameron A. Circulatory and metabolic
effects of oxygen in myocardial infarction. Br Med J 1968;4:360–4.
[22] Neill W. Effects of arterial hypoxemia and hyperoxia on oxygen availability for
myocardial metabolism: patients with and without coronary heart disease. Am
J Cardiol 1969;24:166–71.
[23] Cabello J, Burls A, Emparanza J, Bayliss S, Quinn T. Oxygen therapy for acute
myocardial infarction. Cochrane Database Syst Rev 2010(6):CD007160.
[24] Julian D. Treatment of cardiac arrest in acute myocardial ischemia and infarction.
Lancet 1961;ii:840–4.
[25] Levine S. Coronary thrombosis: its various clinical features. Baltimore: Williams
& Wilkins; 1929.
[26] Killip T, Kimball J. Treatment of myocardial infarction in a coronary care unit: a
two-year experience with 250 patients. Am J Cardiol 1967;20:457–64.
[27] Fuster V. Myocardial infarction and coronary care units. J Am Coll Cardiol 1999;34(7):
1851–3.
 R. Teixeira et al. / International Journal of Cardiology 167 (2013) 1825–1834
[28] Swan H, Ganz W, Forrester J, Marcus H, Diamond G, Chonette D. Catheterization
of the heart in man with use of a flow-directed balloon-tipped catheter. N Engl J
Med 1970;283(9):447–51.
[29] Bainton C, Peterson D. Deaths from coronary heart disease in persons fifty years
of age and younger. A community-wide study. N Engl J Med 1963;268:569–75.
[30] Beck C, Weckesser R, Barry F. Fatal heart attack and successful defibrillation: new
concepts in coronary artery disease. JAMA 1956;161:434–6.
[31] Zoll PM, Linenthal AJ, Gibson W, Paul MH, Norman LR. Termination of ventricular
fibrillation in man by externally applied electric countershock. N Engl J Med
1956;254(16):727–32.
[32] Kouwenhoven WB, Jude JR, Knickerbocker GG. Closed-chest cardiac massage.
JAMA 1960;173:1064–7.
[33] Pantridge J, Wilson C. A history of prehospital coronary care. Ulster Med J 1996;65:
68–73.
[34] Pantridge J, Geddes J. A mobile intensive-care unit in the management of myo-
cardial infarction. Lancet 1967;2:271–3.
[35] Mirowski M, Mower M, Staewen W, Tabatznik B, Mendeloff A. Standby automatic
defibrillator. An approach to prevention of sudden coronary death. Arch Intern
Med 1970;126:158–61.
[36] Diack A, Welborn W, Rullman R, Walter C, Wayne M. An automatic cardiac resusci-
tator for emergency treatment of cardiac arrest. Med Instrum 1979;13(2):78–83.
[37] Bocka J, Brown D. Automatic external defibrillation. Accessed July 2012 at http://
emedicine.medscape.com/article/780533-overview.
[38] Page RL, Joglar JA, Kowal RC, et al. Use of automated external defibrillators by a
U.S. airline. N Engl J Med 2000;343(17):1210–6.
[39] Valenzuela TD, Roe DJ, Nichol G, Clark LL, Spaite DW, Hardman RG. Outcomes of
rapid defibrillation by security officers after cardiac arrest in casinos. N Engl J
Med 2000;343(17):1206–9.
[40] Weisfeldt ML, Sitlani CM, Ornato JP, et al. Survival after application of automatic
external defibrillators before arrival of the emergency medical system: evalua-
tion in the resuscitation outcomes consortium population of 21 million. J Am
Coll Cardiol 2010;55(16):1713–20.
[41] Laver S, Farrow C, Turner D, Nolan J. Mode of death after admission to an inten-
sive care unit following cardiac arrest. Intensive Care Med 2004;30(11):2126–8.
[42] Mild therapeutic hypothermia to improve the neurologic outcome after cardiac
arrest. N Engl J Med 2002;346(8):549–56.
[43] Rea T, Eisenberg M, Becker L, Murray J, Hearne T. Temporal trends in sudden
cardiac arrest: a 25-year emergency medical services perspective. Circulation
2003;107(22):2780–5.
[44] Rea T, Crouthamel M, Eisenberg M, Becker L, Lima A. Temporal patterns in
long-term survival after resuscitation from out-of-hospital cardiac arrest. Circu-
lation 2003;108(10):1196–201.
[45] Bunch T, White R, Gersh B, et al. Long-term outcomes of out-of-hospital car-
diac arrest after successful early defibrillation. N Engl J Med 2003;348(26):
2626–33.
[46] Rosalki S, Roberts R, Katus H, Giannitsis E, Ladenson J. Cardiac miomarkers for
detection of myocardial infarction: perspectives from past to present. Clin Chem
2004;50:2205–13.
[47] LaDue J, Wroblewski F, Karmen A. Serum glutamic oxalacetic transaminase ac-
tivity in human acute transmura lmyocardial infarction. Science 1956;120:497.
[48] Stewart T, Warburton F. Serum lactic dehydrogenase estimations in myocardial
infarction. Br Heart J 1961;23:236.
[49] Warburton F, Bernstein A, Wright C. Serum creatine phosphokinase estimations
in myocardial infarction. Br Heart J 1965;27:740–5.
[50] Van der Veen K, Willebrands A. Isoenzymes of creatine phosphokinase in tissue
extracts and in normal and pathological sera. Clin Chim Acta 1966;13:312–7.
[51] Puleo P, Meyer D, Wathen C, et al. Use of a rapid assay of subforms of creatine
kinase-MB to diagnose or rule out acute myocardial infarction. N Engl J Med
1988;9:561–6.
[52] Brown C, Bertolet B. Cardiac troponin. See ya later, CK! Chest Jan 1997;111(1):2–4.
[53] Cummins B, Auckland M, Cummins P. Cardiac-specific troponin-I radioimmuno-
assay in the diagnosis of acute myocardial infarction. Am Heart J 1987;113:
1333–44.
[54] Katus H, Remppis A, Looser S, Hallermeier K, Scheffold T, Kubler W. Enzyme
linked immunoassay of cardiac troponin T for the detection of acute myocardial
infarction in patients. J Mol Cell Cardiol 1989;21:1349–53.
[55] Silva D, Landt Y, Porter S, Ladenson J. Development and application of monoclonal
antibodies to human cardiac myoglobin in a rapid fluorescence immunoassay.
Clin Chem 1991;37:1356–64.
[56] Adams III J, Bodor G, Dávila-Román V, et al. Cardiac troponin I: a marker with
high specificity for cardiac injury. Circulation 1993;88:101–6.
[57] Ladenson J. A personal history of markers of myocyte injury [myocardial infarction].
Clin Chim Acta 2007;381:3–8.
[58] Robert L. On the relative value of an assay versus that of a test: a history of troponin
for the diagnosis of myocardial infarction. J Am Coll Cardiol 2010;55:2125–8.
[59] Gofman J, Jones H, Lindgren F, Lyon T, Elliot H, Strisower B. Blood lipids and
human atherosclerosis. Circulation 1950;2:161–78.
[60] Constantinides P. Plaque fissuring in human coronary thrombosis. J Atheroscler
Res 1966;6:1.
[61] Maseri A, Mimmo R, Chierchia S, Marchersi C, Pesola A, L'Abbate A. Coronary
spasm as a cause of acute myocardial ischemia in man. Chest 1975;68:625.
[62] Friedberg C, Horn H. Acute myocardial infarction not due to coronary artery
occlusion. JAMA 1939;59:2015–20.
[63] Roberts W, Ferrans V. The role of thrombosis in the etiology of atherosclerosis
(a positive one) and in precipitating fatal ischemic heart disease (a negative one).
Semin Thromb Hemost 1976;2:123–35.
1833
[64] Oliva PB, Hilgenberg A, McElroy D. Obstruction of the proximal right coronary
artery with acute inferior infarction due to blunt chest trauma. Ann Intern
Med 1979;91(2):205–7.
[65] DeWood M, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the
early hours of transmural myocardial infarction. N Engl J Med 1980;303:897–902.
[66] Tillet W, Garner R. The fibrinolytic activity of hemolytic streptococci. J Exp Med
1933;58:485–502.
[67] Christensen L, MacLeod C. A proteolytic enzyme of the serum: characterization,
activation, and reaction with inhibitors. J Gen Physiol 1945;28:559–83.
[68] Sherry S, Tillet W, Read C. The use of stretokinase–streptodornase in the treat-
ment of hemothorax. J Thorac Surg 1950;20:393–418.
[69] Tillet W, Sherry S, Read C. The use of streptokinase–streptodornase in the treat-
ment of chronic empyema. J Thorac Surg 1951;21:325–42.
[70] Johnson A, Tillet W. The lysis in rabbits of intravascular blood clots by the strep-
tococcal fibrinolytic system (streptokinase). J Exp Med 1952;95:449–56.
[71] Sherry S, Fletcher A, Alkjaersig N, Smyrniotis F. An approach to intravascular
fibrinolysis in man. Trans Assoc Am Physicians 1957;70:288–96.
[72] Fletcher A, Alkjaersig N, Smyrniotis F, Sherry S. The treatment of patients suffer-
ing from early myocardial infarction with massive and prolonged streptokinase
therapy. Trans Assoc Am Physicians 1958;71:287–96.
[73] Effectiveness of intravenous thrombolytic treatment in acute myocardial infarc-
tion. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico
(GISSI). Lancet 1986;1(8478):397–402.
[74] Randomised trial of intravenous streptokinase, oral aspirin, both, or neither
among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second
International Study of Infarct Survival) Collaborative Group. Lancet 1988;2(8607):
349–60.
[75] Rijken D, Collen D. Purification and characterization of the plasminogen activator
secreted by human melanoma cells in culture. J Biol Chem 1981;256:7035–41.
[76] The GUSTO investigators. A comparison of immediate angioplasty with throm-
bolytic therapy for acute myocardial infarction. The primary angioplasty in myo-
cardial infarction study group. N Engl J Med 1993;328(10):673–9.
[77] Armstrong P, Collen D, Antman E. Fibrinolysis for acute myocardial infarction.
Circulation 2003;107(20):2533–7.
[78] Yusuf S, Collins R, Peto R, et al. Intravenous and intracoronary fibrinolytic therapy
in acute myocardial infarction: overview of results on mortality, reinfarction and
side-effects from 33 randomized controlled trials. Eur Heart J 1985;6:556–85.
[79] Forssmann W. Experiments on myself. Memoirs of a surgeon in Germany. New
York: St Martin's Press; 1974.
[80] Seldinger SI. Catheter replacement of the needle in percutaneous arteriography;
a new technique. Acta Radiol 1953;39(5):368–76.
[81] Coelho E, Fonseca J, Nunes A, Pinto R. L'artériographie des coronaires chez
I'homme vivant. Cardiologia 1953;22:45–61.
[82] Dotter CT, Frische LH. Visualization of the coronary circulation by occlusion
aortography: a practical method. Radiology Oct 1958;71(4):502–24.
[83] Sones F, Shirey E, Proudfit W. Cine coronary arteriography. Circulation 1959;20:
773 [Abstract].
[84] Judkins M. Selective coronary arteriography. Part 1. A percutaneous transfemoral
technic. Radiology 1967;89:815–24.
[85] Payne MM. Charles Theodore Dotter. The father of intervention. Tex Heart Inst J
2001;28(1):28–38.
[86] Gruntzig A, Kumpe DA. Technique of percutaneous transluminal angioplasty
with the Gruntzig ballon catheter. Am J Roentgenol 1979;132(4):547–52.
[87] Hurst JW. The first coronary angioplasty as described by Andreas Gruentzig. Am J
Cardiol 1986;57(1):185–6.
[88] Gruntzig A, Senning A, Siegenthaler W. Nonoperative dilatation of coronary-
artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med
1979;301:61–8.
[89] Puel J, Joffre F, Rousseau H, et al. Self-expanding coronary endoprosthesis in the
prevention of restenosis following transluminal angioplasty. Preliminary clinical
study. Arch Mal Coeur Vaiss 1987;80(8):1311–2.
[90] Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L. Intravascular stents to
prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med
1987;316(12):701–6.
[91] Meyer J, Merx W, Schmitz H, et al. Percutaneous transluminal coronary angioplasty
immediately after intracoronary streptolysis of transmural myocardial infarction.
Circulation 1982;66(5):905–13.
[92] Hartzler G, Rutherford B, McConahay D, et al. Percutaneous transluminal coro-
nary angioplasty with and without thrombolytic therapy for treatment of acute
myocardial infarction. Am Heart J 1983;106(5):965–73.
[93] O'Neill W, Timmis G, Bourdillon P, et al. A prospective randomized clinical trial
of intracoronary streptokinase versus coronary angioplasty for acute myocardial
infarction. N Engl J Med 1986;314(13):812–8.
[94] Grines C, Browne K, Marco J, et al. A comparison of immediate angioplasty with
thrombolytic therapy for acute myocardial infarction. The primary angioplasty
in myocardial infarction study group. N Engl J Med 1993;328(10):673–9.
[95] A clinical trial comparing primary coronary angioplasty with tissue plasminogen
activator for acute myocardial infarction. The Global Use of Strategies to Open
Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angio-
plasty Substudy Investigators. N Engl J Med 1997;336(23):1621–8.
[96] Weaver W, Simes R, Betriu A, et al. Comparison of primary coronary angioplasty
and intravenous thrombolytic therapy for acute myocardial infarction: a quanti-
tative review. JAMA 1997;278(23):2093–8.
[97] Grines C, Cox D, Stone G, et al. Coronary angioplasty with or without stent implan-
tation for acute myocardial infarction. Stent Primary Angioplasty in Myocardial
Infarction Study Group. N Engl J Med 1999;341(26):1949–56.
1834 R. Teixeira et al. / International Journal of Cardiology 167 (2013) 1825–1834
[98] Nordmann A, Bucher H, Hengstler P, Harr T, Young J. Primary stenting versus
primary balloon angioplasty for treating acute myocardial infarction. Cochrane
Database Syst Rev 2005(2):CD005313.
[99] Widimsky P, Budesinsky T, Vorac D, et al. Long distance transport for primary
angioplasty vs immediate thrombolysis in acute myocardial infarction. Final
results of the randomized national multicentre trial-PRAGUE-2. Eur Heart J
2003;24(1):94–104.
[100] Sampson JJ, Eliaser MJ. The diagnosis of impending acute coronary artery occlusion.
Am Heart J 1937;13:675–86.
[101] Beamish RE, Storrie VM. Impending myocardial infarction. Recognition and
management. Circulation 1960;21:1107–15.
[102] Fowler NO. “Preinfarctional” angina. A need for an objective definition and for a
controlled clinical trial of its management. Circulation 1971;44(5):755–8.
[103] Krauss KR, Hutter Jr AM, DeSanctis RW. Acute coronary insufficiency. Course and
follow-up. Arch Intern Med 1972;129(5):808–13.
[104] Gazes PC, Mobley Jr EM, Faris Jr HM, Duncan RC, Humphries GB. Preinfarctional
(unstable) angina—a prospective study–ten year follow-up. Prognostic signifi-
cance of electrocardiographic changes. Circulation 1973;48(2):331–7.
[105] Favaloro RG, Effler DB, Cheanvechai C, Quint RA, Sones Jr FM. Acute coronary
insufficiency (impending myocardial infarction and myocardial infarction): sur-
gical treatment by the saphenous vein graft technique. Am J Cardiol 1971;28(5):
598–607.
[106] Unstable angina pectoris—National Cooperative Study Group to Compare Surgical
and Medical Therapy II; in hospital experience and initial follow-up results in
patients with one, two and three vessel disease. Am J Cardiol 1978;42:839–48.
[107] Anderson HV, Cannon CP, Stone PH, et al. One-year results of the Thrombolysis
in Myocardial Infarction (TIMI) IIIB clinical trial. A randomized comparison
of tissue-type plasminogen activator versus placebo and early invasive versus
early conservative strategies in unstable angina and non-Q wave myocardial
infarction. J Am Coll Cardiol 1995;26(7):1643–50.
[108] Bavry AA, Kumbhani DJ, Rassi AN, Bhatt DL, Askari AT. Benefit of early invasive
therapy in acute coronary syndromes: a meta-analysis of contemporary ran-
domized clinical trials. J Am Coll Cardiol 2006;48(7):1319–25.
[109] Montalescot G, Cayla G, Collet JP, et al. Immediate vs delayed intervention for acute
coronary syndromes: a randomized clinical trial. JAMA 2009;302(9):947–54.
[110] Riezebos RK, Ronner E, Ter Bals E, et al. Immediate versus deferred coronary angio-
plasty in non-ST-segment elevation acute coronary syndromes. Heart 2009;95(10):
807–12.
[111] Lewis Jr HD, Davis JW, Archibald DG, et al. Protective effects of aspirin against
acute myocardial infarction and death in men with unstable angina. Results
of a Veterans Administration Cooperative Study. N Engl J Med 1983;309(7):
396–403.
[112] Yusuf S, Zhao F, Mehta S, Chrolavicius S, Tognoni G, Fox K. Effects of clopidogrel
in addition to aspirin in patients with acute coronary syndromes without ST-
segment elevation. N Engl J Med 2001;345(7):494–502.
[113] Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight
heparin with unfractionated heparin for unstable coronary artery disease. Efficacy
and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study
Group. N Engl J Med 1997;337(7):447–52.
[114] Elizabeth N, Braunwald E. A tale of coronary artery disease and myocardial in-
farction. N Engl J Med 2012;366:54–63.
[115] Bassand JP, Danchin N, Filippatos G, et al. Implementation of reperfusion therapy
in acute myocardial infarction. A policy statement from the European Society of
Cardiology. Eur Heart J 2005;26(24):2733–41.
[116] Jollis JG, Al-Khalidi HR, Monk L, et al. Expansion of a regional ST-segment-elevation
myocardial infarction system to an entire state. Circulation 2012;126(2):189–95.
[117] Goldberg RJ, Steg PG, Sadiq I, et al. Extent of, and factors associated with, delay to
hospital presentation in patients with acute coronary disease (the GRACE registry).
Am J Cardiol 2002;89(7):791–6.
[118] Andersen HR, Nielsen TT, Rasmussen K, et al. A comparison of coronary angio-
plasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med
2003;349(8):733–42.
[119] Widimsky P, Groch L, Zelizko M, Aschermann M, Bednar F, Suryapranata H.
Multicentre randomized trial comparing transport to primary angioplasty vs im-
mediate thrombolysis vs combined strategy for patients with acute myocardial
infarction presenting to a community hospital without a catheterization labora-
tory. The PRAGUE study. Eur Heart J 2000;21(10):823–31.
[120] Henry TD, Sharkey SW, Burke MN, et al. A regional system to provide timely
access to percutaneous coronary intervention for ST-elevation myocardial in-
farction. Circulation 2007;116(7):721–8.
[121] Henry TD. From concept to reality: a decade of progress in regional ST-elevation
myocardial infarction systems. Circulation 2012;126(2):166–8.
[122] Clemmensen P, Loumann-Nielsen S, Sejersten M. Telemedicine fighting acute
coronary syndromes. J Electrocardiol 2010;43(6):615–8.
[123] Boersma E, Maas AC, Deckers JW, Simoons ML. Early thrombolytic treatment in acute
myocardial infarction: reappraisal of the golden hour. Lancet 1996;348(9030):771–5.
[124] Terkelsen CJ, Lassen JF, Norgaard BL, et al. Reduction of treatment delay in patients
with ST-elevation myocardial infarction: impact of pre-hospital diagnosis and direct
referral to primary percutaneous coronary intervention. Eur Heart J 2005;26(8):
770–7.
[125] Sejersten M, Sillesen M, Hansen PR, et al. Effect on treatment delay of prehospital
teletransmission of 12-lead electrocardiogram to a cardiologist for immediate
triage and direct referral of patients with ST-segment elevation acute myocardial
infarction to primary percutaneous coronary intervention. Am J Cardiol 2008;101(7):
941–6.
[126] Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta Blockade after myo-
cardial infarction: systematic review and meta regression analysis. Br Med J
1999;318(7200):1730–7.
[127] Flather M, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients
with heart failure or left-ventricular dysfunction: a systematic overview of
data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative
Group. Lancet 2000;355(9215):1575–81.
[128] Domanski M, Exner D, Borkowf C, Geller N, Rosenberg Y, Pfeffer M. Effect of
angiotensin converting enzyme inhibition on sudden cardiac death in patients
following acute myocardial infarction. A meta-analysis of randomized clinical
trials. J Am Coll Cardiol 1999;33(3):598–604.
[129] Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myo-
cardial infarction complicated by heart failure, left ventricular dysfunction, or
both. N Engl J Med 2003;349(20):1893–906.
[130] Collaborative meta-analysis of randomised trials of antiplatelet therapy for pre-
vention of death, myocardial infarction, and stroke in high risk patients. Br Med J
2002;324(7329):71–86.
[131] Mehta S, Tanguay J, Eikelboom J, et al. Double-dose versus standard-dose clopidogrel
and high-dose versus low-dose aspirin in individuals undergoing percutaneous
coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a
randomised factorial trial. Lancet 2010;376(9748):1233–43.
[132] Rosenson R. Pluripotential mechanism of cardioprotection with HMG-CoA
reductase inhibitor therapy. Am J Cardiovasc Drugs 2001;1:411.
[133] Laing BY, Katz MH. Coronary arteries, myocardial infarction, and history. N Engl J
Med 2012;366(13):1258–9.
[134] Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes III J. Factors of risk in
the development of coronary heart disease—six year follow-up experience. The
Framingham Study. Ann Intern Med 1961;55:33–50.
[135] Kannel WB. Clinical misconceptions dispelled by epidemiological research. Circulation
1995;92(11):3350–60.
[136] Report of the national cholesterol education program expert panel on detection,
evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med
1988;148:36–9.
[137] Certo CM. History of cardiac rehabilitation. Phys Ther 1985;65(12):1793–5.
[138] Detrich H. Effects of immobilization upon various metabolic and physiologic
functions of normal men. Am J Med 1948;4(3).
[139] Saltin B, Blomqvist G, Mitchell JH, Johnson RL, Wildenthal K, Chapman CB. Response
to exercise after bed rest and after training. Circulation 1968;38(5):VII1-78.
[140] Hellerstein H. Exercise therapy in coronary disease. Bull N Y Acad Med 1968;44(8):
1028–47.
[141] Clark AM, Hartling L, Vandermeer B, McAlister FA. Meta-analysis: secondary pre-
vention programs for patients with coronary artery disease. Ann Intern Med
2005;143(9):659–72.
[142] Heidenreich PA, McClellan M. Trends in treatment and outcomes for acute myo-
cardial infarction: 1975–1995. Am J Med 2001;110(3):165–74.
[143] Nikus KC, Eskola MJ, Virtanen VK, et al. Mortality of patients with acute coronary
syndromes still remains high: a follow-up study of 1188 consecutive patients
admitted to a university hospital. Ann Med 2007;39(1):63–71.
[144] Setoguchi S, Glynn R, Avorn J, Mittleman M, Levin R, Winkelmayer W. Improve-
ments in long-term mortality after myocardial infarction and increased use of
cardiovascular drugs after discharge: a 10-year trend analysis. J Am Coll Cardiol
2008;51(13):1247–54.
[145] Hirsch A, Windhausen F, Tijssen JG, Verheugt FW, Cornel JH, de Winter RJ.
Long-term outcome after an early invasive versus selective invasive treatment
strategy in patients with non-ST-elevation acute coronary syndrome and elevated
cardiac troponin T (the ICTUS trial): a follow-up study. Lancet 2007;369(9564):
827–35.
[146] Hochman JS, Lamas GA, Buller CE, et al. Coronary intervention for persistent
occlusion after myocardial infarction. N Engl J Med 2006;355(23):2395–407.
[147] Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without
PCI for stable coronary disease. N Engl J Med 2007;356(15):1503–16.
[148] Hill A, Rand D, Nowak M, Christakis N. Infectious disease modeling of social con-
tagious. PLoS Comput Biol 2010;6(11):1–15.
[149] Gaziano TA, Bitton A, Anand S, Abrahams-Gessel S, Murphy A. Growing epidemic of
coronary heart disease in low- and middle-income countries. Curr Probl Cardiol
2010;35(2):72–115.
[150] Bueno H, Betriu A, Heras M, et al. Primary angioplasty vs. fibrinolysis in very old
patients with acute myocardial infarction: TRIANA (TRatamiento del Infarto
Agudo de miocardio eN Ancianos) randomized trial and pooled analysis with
previous studies. Eur Heart J 2011;32(1):51–60.
[151] Gilbert S. A small dose of toxicology. The Health effects of common chemicals.
2nd edition. Healthy World Press; 2012.
[152] de Vreede JJ, Gorgels AP, Verstraaten GM, Vermeer F, Dassen WR, Wellens HJ. Did
prognosis after acute myocardial infarction change during the past 30 years? A
meta-analysis. J Am Coll Cardiol 1991;18(3):698–706.
[153] Goldman L, Cook F, Hashimotso B, Stone P, Muller J, Loscalzo A. Evidence that
hospital care for acute myocardial infarction has not contributed to the decline in
coronary mortality between 1973–1974 and 1978–1979. Circulation 1982;65(5):
936–42.
[154] Kostis WJ, Deng Y, Pantazopoulos JS, Moreyra AE, Kostis JB. Trends in mortality of
acute myocardial infarction after discharge from the hospital. Circ Cardiovasc
Qual Outcomes 2010;3(6):581–9.