F1000Research 2018, 7(F1000 Faculty Rev):1378 Last updated: 03 SEP 2018

REVIEW
Understanding myocardial infarction [version 1; referees: 2
approved]
Moussa Saleh, John A Ambrose
Division of Cardiology, Department of Internal Medicine, University of California San Francisco-Fresno, 2335 E. Kashian Lane, Suite 460,
Fresno, CA 97301, USA

First published: 03 Sep 2018, 7(F1000 Faculty Rev):1378 (doi:  Open Peer Review

v1 10.12688/f1000research.15096.1)
Latest published: 03 Sep 2018, 7(F1000 Faculty Rev):1378 (doi: 
10.12688/f1000research.15096.1)
Referee Status:    

Abstract   Invited Referees
Over the last 40 years, our understanding of the pathogenesis of myocardial 1   2
infarction has evolved and allowed new treatment strategies that have greatly
improved survival. Over the years, there has been a radical shift in therapy from version 1
passive healing of the infarction through weeks of bed rest to early discharge  
published
usually within 2 to 3 days as a result of immediate reperfusion strategies and 03 Sep 2018
other guideline-directed medical therapies. Nevertheless, challenges remain.
Patients who develop cardiogenic shock still face a high 30-day mortality of at
least 40%. Perhaps even more important is how do we identify and prevent F1000 Faculty Reviews are commissioned
patients from developing myocardial infarction in the first place? This article from members of the prestigious F1000
discusses these milestones of therapy and considers important issues for Faculty. In order to make these reviews as
progress in the future.
comprehensive and accessible as possible,
Keywords peer review takes place before publication; the
Myocardial Infarction, CAD, cardiogenic shock, referees are listed below, but their reports are
not formally published.

1 Hans Mickley, Odense University
Hospital, Denmark

2 Akiko Maehara, Columbia University
Medical Center, USA

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 F1000Research 2018, 7(F1000 Faculty Rev):1378 Last updated: 03 SEP 2018

Corresponding author: John A Ambrose ([email protected])
Author roles: Saleh M: Writing – Original Draft Preparation; Ambrose JA: Writing – Review & Editing
Competing interests: No competing interests were disclosed.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright: © 2018 Saleh M and Ambrose JA. This is an open access article distributed under the terms of the  Creative Commons Attribution
Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite this article: Saleh M and Ambrose JA. Understanding myocardial infarction [version 1; referees: 2 approved] F1000Research
2018, 7(F1000 Faculty Rev):1378 (doi: 10.12688/f1000research.15096.1)
First published: 03 Sep 2018, 7(F1000 Faculty Rev):1378 (doi: 10.12688/f1000research.15096.1) 

 
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 F1000Research 2018, 7(F1000 Faculty Rev):1378 Last updated: 03 SEP 2018

Introduction for the old transmural MI definition and was used for an MI that
Our understanding of the causes, diagnosis, and treatment of involved all three layers of the heart muscle and hence would
acute myocardial infarction (AMI) has evolved significantly over show a pathologic Q wave on ECG in two contiguous leads.
the last 40 years. In the early 20th century, AMI was gener- Non-transmural MI became known as non-Q wave MI, as it was
ally considered a fatal event diagnosed only at autopsy. Until the postulated that Q waves would not show up on ECG unless the
1970s, with appropriate understanding of its usual clinical entire thickness of the heart muscle was involved. However,
presentation and diagnosis, it was conservatively managed with over the next decade, autopsies failed to confirm that Q wave MI
prolonged bed rest and afterwards with a sedentary lifestyle. equated to a transmural MI; as a result, in the 1990s, ST segment
Since then, there has been an explosion of information which elevation MI (STEMI) and non-STEMI (NSTEMI) were adopted
has changed our understanding of its pathogenesis and mark- as the preferred terminology. This new nomenclature would
edly altered our treatment options, leading to vastly improved define MI by the ECG changes seen. STEMI was defined as an
outcomes. This article will review where we came from and what MI with ST segment elevations in two contiguous leads on
our current understanding and management of this important ECG (criteria differed somewhat depending on which leads
condition are. We will also explore future treatment options. were involved) that most often had complete occlusion of an
epicardial coronary artery. Conversely, an NSTEMI was defined
Definitions as ST depressions or other ECG ischemic changes not meeting
AMI, usually referred to in lay terms as a heart attack, is the criteria for STEMI. Angiographic studies, some from our
most often caused by a decrease or stoppage of blood flow to a own group, indicated that non-Q wave MI (similar to NSTEMI)
portion of the heart, leading to necrosis of heart muscle. This is could result from a total occlusion of a small branch, a total
generally the result of a blood clot in the epicardial artery that occlusion followed by spontaneous opening (reperfusion) of a
supplies that territory of heart muscle. It is now recognized that, large artery, or collateral blood flow from another territory
based on how AMI is defined, not all cases necessarily require lessening the effects of total occlusion3. In the latter two
a blood clot etiologically. In all living tissue such as heart instances, the amount of necrosis was such that ST elevation
muscle, the blood supply must equal the oxygen demands of did not occur or perhaps was transient.
the muscle. This is termed the supply–demand ratio. It is now
appreciated that an imbalance in this ratio (too little supply or In 2007, a consensus statement was released by the major
too much demand) as might occur with a very rapid heart rate American and European cardiac societies with a universal
(too much demand) or a drop in blood pressure (too little definition of MI. This definition expanded on the previous
supply) may lead to myocardial damage without the presence nomenclature to include lab tests and clinical history. MI
of a blood clot per se. Over the last 10 years, a universal became defined as an event with the rise or fall (or both) in a
definition of AMI has been available to help the clinician with blood test sensitive to heart muscle damage (troponin I or T)
its diagnosis1,2. This definition states that there must be a rise or along with clinical evidence for a diagnosis of AMI as outlined
fall (or both) in a blood test sensitive to heart muscle damage above. With this universal definition, many causes of NSTEMI
(troponin I or T) with at least one value above the 99th percen- did not necessarily require a thrombus in an epicedial artery.
tile of the upper reference limit along with clinical evidence for a
diagnosis of AMI. This clinical evidence includes symptoms of Pathogenesis of myocardial infarction and the role of
ischemia, which include either electrocardiographic evidence thrombosis
indicative of ischemia such as ST segment changes or new left The role of thrombosis as a cause of AMI was debated for dec-
bundle branch block, development of pathological Q waves on ades in the 20th century until the 1970s, when it was clearly
electrocardiogram (ECG), or new wall motion abnormalities on established as the cause of nearly all AMIs seen at autopsy and
cardiac testing or a combination of these. most large AMIs presenting clinically4,5 (Table 1). Atherosclero-
sis with subsequent inflammation is the most common and most
Nomenclature for myocardial infarction important driver of thrombosis. The cardinal feature of
Since the 1970s, the nomenclature defining myocardial infarc- atherosclerosis is endothelial dysfunction. Atherosclerosis is
tion (MI) has changed several times. During the 1960s and 1970s, a chronic inflammatory process of the inner wall (intima) of
MI was characterized as transmural MI versus non-transmural moderate and large-sized arteries and involves vascular endothe-
MI. In transmural MI, the ischemia and injury affected the lial cells, monocytes, macrophages, T lymphocytes, vascu-
entire thickness of the myocardial muscle (endocardium, lar smooth muscle cells, lipids, and platelets. Atherosclerotic
myocardium, and epicardium). This typically was the result of a lesions begin as intimal thickening in the coronary artery walls
complete occlusion of a large epicardial coronary artery by a or as fatty streaks. Some progress over time to either thick
thrombus resulting in decreased blood supply to all three layers fibrous-capped or thin fibrous-capped atheromas with a lipid-
of the heart muscle. On the other hand, non-transmural MI was laden core. Atherosclerotic lesions are prone to acute progres-
defined as ischemia and injury that did not affect all three sion through either asymptomatic thrombosis or intraplaque
layers of the heart muscle, typically sparing the epicardium. This hemorrhage.
was considered to result from a significant decrease in blood
supply to the territory with or without complete occlusion of a Atherosclerosis begins when low-density lipoprotein (LDL) is
coronary artery or branch. In the 1980s, the nomenclature taken up into the intima and oxidized, resulting in a cascade of
changed to include ECG evidence of MI. Q wave MI substituted inflammatory cytokine, enzyme, and cell adhesion molecule

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Table 1. Coronary thrombosis and acute myocardial infarction: a historical perspective.

•  1910: Obrastzowo and Straschesko described clinical features of AMI 

•  1912: J. Herrick showed that coronary thrombosis was not invariably fatal 
•  During the next 50 to 60 years, there was controversy as to the cause of AMI
•  1966: Constantinitis et al. – autopsy of AMI in 16 patients showed that thrombus occurs at the site of plaque fissuring and was the
primary event leading to myocardial infarction
•  1972: Roberts et al. – thrombosis was secondary to AMI and not the primary event leading to AMI 
•  1974: Chandler et al. – National Institutes of Health workshop concluded that thrombosis is the primary event leading to AMI 
•  1976: Chazov et al. – intracoronary steptokinase used in two patients with AMI 
•  1979: Rentrop et al. – intracoronary steptokinase used in five patients with AMI
•  1980: DeWood et al. conclusively showed that thrombosis is the primary event, with 84% demonstrating total occlusion at angiography
in less than 4 hours after evolving transmural AMI
•  1980s: Davies, Falk, and others – plaque disruption/erosion at thrombotic site was demonstrated routinely at autopsy in fatal AMI/
sudden cardiac death
AMI, acute myocardial infarction.

production. This process results in the attraction of T lym- which confirmed the primary importance of thrombosis as the
phocytes and monocytes into the subintimal space. The cause of AMI5 and later by intravascular devices such as
accumulation of oxidized LDL further damages the endothe- optical coherence tomography performed just prior to coronary
lial cells and results in more cytokine- and oxygen-derived free stent implantation during the acute event9. These intravascular
radical production into the subintimal space. Oxidized LDL is devices can define plaque types associated with AMI.
subsequently ingested by monocyte-derived macrophages and
transformed into foam cells. Over time, smooth muscle cells Non-ST segment elevation myocardial infarction
migrate from the media to the intima and lipid accumulates under Multiple mechanisms as referred to above can cause NSTEMI.
a fibrous cap composed of vascular smooth muscle cells, elastin, Thrombosis is a frequent, but not universal, etiology in NSTEMI,
and collagen. Furthermore, low-grade inflammation as epito- although in this situation, for a multitude of potential reasons,
mized by an elevated C-reactive protein, independent of LDL the amount of necrosis is usually less than that in STEMI. All
levels, has been shown to contribute to myocardial events and of the above (STEMI or NSTEMI), where a culprit lesion with
hence thought to contribute to the formation and progression of a presumed thrombus is present in an epicardial artery lead-
atherosclerotic disease6. As previously mentioned, inflammatory ing to AMI, are referred to as a type 1 MI. Other types of AMI
cells such as macrophages and T lymphocytes play a direct role include a type 2 MI (supply demand mismatch from any process
in the formation and destabilization of atherosclerotic plaques. that alters this balance including tachyarrhythmias, extreme
Inflammation also indirectly activates the intrinsic and extrinsic swings in blood pressure, and so on), post-percutaneous coronary
clotting cascades, further contributing to atherosclerotic plaque intervention (post-PCI) (stent implantation), which is a type 4a
formation and destabilization7. MI by the universal definition, and post-coronary artery bypass
surgery, which is type 5 by the universal definition. Another
The thin-cap fibroatheroma (TCFA), which has a lipid-rich, rare type of AMI is type 3 MI, which occurs when a patient dies
necrotic core regarded by some as a “vulnerable plaque”, can from an acute coronary occlusion but no cardiac enzyme marker
rupture suddenly because of macrophage infiltration and matrix was obtained prior to the patient’s death or was obtained too early
degradation of the fibrous cap. This results in a cascade of to show a positive value. Some of these causes are discussed
platelet aggregation and thrombus formation that can lead to below.
myocardial ischemia distally or subsequent infarction or both.
It is important to keep in mind that a troponin elevation
Conversely, plaque erosion, another cause of coronary thrombo- alone does not necessarily indicate MI unless the appropri-
sis that occurs less frequently than plaque rupture, can occur in ate clinical evidence is present. Furthermore, although troponin
a lesion rich in proteoglycans and smooth muscle cells but not is sensitive for myocardial injury, it is not specific for AMI. As
necessarily in one that is lipid rich. The thrombus here origi- demonstrated by Javed et al., about two-thirds of the time
nates from a defect in the endothelial layer that covers the inside with a sensitive assay (upper reference level of 0.04 ng/dL), a
wall of all blood vessels. Plaque erosions tend to have fewer troponin elevation did not meet criteria for MI by the universal
inflammatory cells as compared with plaque ruptures. The third definition10.
mechanism of thrombus formation, which is infrequent (prob-
ably seen in <10% of cases), occurs when a calcified nodule Myocardial infarction due to causes other than
protrudes through the thin fibrous cap and results in the platelet atherosclerosis
aggregation and thrombus formation8. These post-mortem The etiology of MI is not limited to atherosclerosis. Among
observations were confirmed in vivo initially by coronary its causes, there are several diverse etiologies (Table 2). Coro-
angiography performed during an acute transmural infarction nary artery embolization is a rare cause. The emboli can arise

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Table 2. Causes of acute myocardial infarction without and other meds to improve healing of the vessel wall and
coronary atherosclerosis. the myocardium, thus reducing the incidence of other
post-infarction complications, including arrhythmias and heart
•  Coronary artery disease other than atherosclerosis (for failure (Table 3). It should be noted that there has also been a
example, Kawasaki’s syndrome) trend toward a reduction in the incidence of STEMI over the
•  Trauma to coronary arteries  last several years and this is likely attributable to better preventive
•  Spontaneous coronary dissection strategies, including the use of statins and reduced prevalence of
•  Coronary mural thickening with metabolic disease or intimal cigarette smoking11.
proliferation (for example, amyloid and Fabry’s disease)
•  Other causes of luminal narrowing (for example, spasm)  Today, the preferred acute management strategy of STEMI is
•  Coronary emboli  PCI of the infarct lesion if the patient is in a hospital with these
•  Congenital coronary anomalies  capabilities. Otherwise, thrombolytic agents are still used when
•  Supply–demand mismatch  PCI cannot be performed rapidly after a patient’s presentation,
usually because the patient is admitted to a non-PCI-performing
•  In situ thrombosis
hospital12. Typically, thrombolytics are used only within 6 to
•  Other (for example, contusion, complications of angiography,
Takotsubo, Takayasu’s arteritis, and giant cell arteritis) 12 hours after the onset of symptoms, and the most myocardial
salvaging occurs when the agent is given within a few hours of
symptom onset. Following thrombolytic intervention, patients are
often transferred to a PCI-capable hospital for angiography and
from the left atrium as a consequence of atrial fibrillation or possible PCI of the infarct artery. This is needed since there is
from clots in the left ventricle as a consequence of ventricu- usually a severe residual narrowing of the infarct-related lesion
lar aneurysms or severely poor left ventricle systolic function or after the thrombus is partially dissolved and a stent is needed to
from prosthetic valves or infected native heart valves. Systemic maximize opening of the artery.
hypotension, as a result of any etiology of shock, can result in
global myocardial ischemia and subsequent infarction. Increased Reperfusion therapy has reduced long-term complications of
oxygen demand (such as in situations of severe anemia, infarction, including mortality, by as much as 50 to 70%. No
tachyarrhythmias, or hyperthyroidism), especially in patients longer are most patients condemned to weeks of bed rest and
with moderate epicardial coronary artery stenosis, can result in limited activity afterwards. With early reperfusion (usually
significant ischemia and subsequent infarction if not corrected. defined as less than 3 to 6 hours after symptom onset) and the
appropriate guideline-directed medical and lifestyle therapies,
Spontaneous coronary artery dissection is becoming a more most patients are discharged within 2 to 3 days of their infarction
recognized etiology of AMI. This occurs when an abrupt and and can resume normal or near normal lives. However, there are
sudden tear occurs in the wall of the coronary artery, resulting exceptions. Mechanical complications such as rupture of either
in decreased blood flow distally by either thrombus formation a papillary muscle head with severe mitral regurgitation or the
or obstructive hematoma formation. It is more common in interventricular septum are usually surgical emergencies. Severe
younger patients and women, and the incidence is higher triple-vessel or left main disease is another area where a coro-
during pregnancy. Coronary spasm, either idiopathic or nary artery bypass graft (CABG) should be considered, although
drug-induced such as in cocaine use, results in MI as well by
decreasing blood supply to the heart muscle. Furthermore,
Takayasu’s arteritis and giant cell arteritis have been reported to
cause MI as well. Table 3. Common
complications of ST
segment elevation
From the late 1970s to the present myocardial infarction.
Thrombolytic therapy to dissolve intracoronary thrombus
revolutionized the treatment of acute STEMI in the late 1970s. •  Congestive heart failure 
The therapy was first applied directly into the affected
•  Cardiogenic shock 
coronary artery and then later infused intravenously, providing a
•  Tachyarrhythmias 
mechanism to limit infarct size by opening the infarct artery,
•  Bradyarrhythmias 
restore flow to the muscle, and reduce mortality. In the 1980s,
balloon angioplasty was introduced as another method for open- •  Heart block 
ing occluded vessels and later the use of a stent became the •  Pericarditis 
preferred non-surgical methodology. These types of catheter •  Bleeding 
interventions are generally referred to as PCIs. Randomized •  Mechanical complications 
trials and registries taught us the importance of rapid reper- •  Death
fusion since “time was muscle”. Our goals of therapy (short- and
Appropriate reperfusion therapy,
long-term) included not only rapid reperfusion of the infarct particularly percutaneous coronary
artery but keeping the vessel open with appropriate adjunctive intervention, has decreased all
anti-platelet agents, prescribing statins to lower LDL cholesterol complications except bleeding.

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each case must be individualized. Opening the infarct vessel NSTEMIs. There has been great interest in attempting to identify
with PCI followed by staged intervention of the other blockages these vulnerable plaques (mainly the TCFA) prior to a future
(either CABG or stenting) represents another option. coronary event with the idea of modifying the presumed MI cul-
prit with a stent and thus preventing the adverse event from
A continued problem is the patient with an acute infarction who occurring16. There are theoretical reasons supporting and refut-
develops cardiogenic shock unrelated to mechanical compli- ing this approach, and trials examining this issue are ongoing.
cations. This complicates up to 5 to 7% of cases. In-hospital However, this approach is not validated at present.
mortality even with rapid reperfusion strategies (usually PCI and
occasionally CABG) is at least 40%. Although successful reper- If one cannot identify the plaque, can the patient most likely to
fusion reduces mortality versus failed or no reperfusion, there develop an acute event be found? Of course, we as physicians
is still the need to significantly improve outcomes13. Other use risk scores based on well-established factors associated with
than trying to shorten the time to reperfusion, which in itself is the presence of coronary artery disease (CAD). These are the
complex as the delays are multifactorial including the patient so-called risk factors such as high blood pressure, high choles-
arriving late to the hospital after symptom onset (several hours terol, diabetes, and smoking which can be used to categorize
to days), new approaches, including the early use of ventricular patients into low, intermediate, and high risk. Although it makes
support to unload the left ventricle and give it time to recover, are intuitive sense that the highest-risk individuals are most likely
being evaluated. to develop an adverse event, most initial events on follow-up
arise from the lower-risk individuals, as high-risk individuals
In NSTEMI, our guidelines recommend early risk stratification represent a small portion of the population (<10%)17. At present,
to help decide downstream management14. Those in a higher risk there is no consensus about how to find these lower-risk patients
category usually pursue an invasive strategy (angiography fol- in primary prevention, while patients in secondary prevention are
lowed by PCI or CABG, if indicated) along with optimal all treated with appropriate guideline-directed therapy, as they
medical therapy. Those at lower risk are generally managed are considered high-risk. Should we be more aggressive than the
conservatively. In truth, the vast majority will undergo coronary guidelines indicate in primary prevention and treat more patients
angiography during hospitalization either invasively or non- with medications such as statins in addition to lifestyle changes
invasively with computed tomographic angiography. A conun- of a healthy diet and exercise, and at what age should one start?
drum often revolves around interpretation of the elevated These remain unanswered questions.
troponin as referred to previously. Does it represent MI or is
it a non-specific indicator of myocardial injury/necrosis? This Future directions
elevation is frequently seen in patients with worsening heart We have come a long way over the last several decades in our
failure, renal failure, and so on but does not meet the criteria as understanding and treatment of coronary atherosclerosis and its
outlined in the universal definition of MI. Those individuals complications. Although we have not considered stroke, many
do not mandate coronary angiography. of the same drugs and techniques described above for MI are
applicable in its prevention and acute treatment. What are the
It also remains unclear how to definitely diagnose and treat a next steps? Billions of dollars are spent yearly on new drug and
type 2 MI. Other than treating the underlying cause of the other treatment strategies in CAD which are generally applied
supply–demand mismatch (that is, hypotension and tachycardia), either in secondary prevention or in high-risk primary pre-
do all patients require identification of their coronary anatomy and vention. But isn’t that a little late? To significantly reduce the
the same acute management strategy of a type 1 MI? Until more incidence and improve outcomes above those seen with our later
studies become available, one needs to individualize therapy on the therapies as described above, we think the best option is earlier
basis of the risk profile and presentation. intervention18.

Vulnerable plaques/vulnerable patients Symptomatic CAD occurs decades after the onset of atheroscle-
Vulnerable plaque is usually defined as a plaque prone to rosis. Like an iceberg, it does not rear its head above the water
thrombosis and a future acute coronary event (AMI or sudden line (or, in CAD management, become symptomatic) until there
coronary death and occasionally unstable angina)15. In most is a critical mass of ice (a large burden of atherosclerosis). This
instances (>90%), the underlying pathophysiology is either asymptomatic stage is where our efforts should be concentrated
plaque rupture or plaque erosion with a superimposed thrombus if we want to eliminate a majority of future coronary events.
partially or totally occluding the lumen of the artery. When These should include earlier identification and treatment of high
plaque rupture is the cause which accounts for the majority of blood pressure, eliminating tobacco, and lowering average LDL
STEMIs and a large percentage of sudden coronary deaths, the levels. Earlier identification of atherosclerosis will lead to lower
plaque responsible is, as previously discussed, a TCFA with a event rates if the proper lifestyle and possibly drug therapies are
large lipid-rich, necrotic core, inflamed, and possessing a thin initiated. In the future, new strategies and risk profiles (possibly
fibrous cap (<65 μm). The tear in the fibrous cap leads to the with genetic profiling) may help to better identify those at risk.
formation of a platelet-rich white thrombus at the site of rupture New treatments specifically targeting inflammation might also
followed by a red cell and fibrin red thrombus if the artery result in a reduction in events as long as the treatments do not
becomes totally occluded. Plaque erosion accounts for about interfere with a patient’s natural immunity and erase any
one-third of STEMIs and possibly a higher percentage of potential benefits. Another possibility for the future is a vaccine

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against atherosclerosis. Finally, wouldn’t it be a crowning infarction, NSTEMI, non-ST segment elevation myocardial
achievement of this century if articles such as this should infarction; PCI, percutaneous coronary intervention; STEMI,
become more of historic interest rather than a review of current ST segment elevation myocardial infarction; TCFA, thin-cap
practice? fibroatheroma

Abbreviations
AMI, acute myocardial infarction; CABG, coronary artery Grant information
bypass graft; CAD, coronary artery disease; ECG, electro- The author(s) declared that no grants were involved in supporting
cardiogram; LDL, low-density lipoprotein; MI, myocardial this work.

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 F1000Research 2018, 7(F1000 Faculty Rev):1378 Last updated: 03 SEP 2018

Open Peer Review

Current Referee Status:

Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a
service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees
provide input before publication and only the final, revised version is published. The referees who approved the
final version are listed with their names and affiliations but without their reports on earlier versions (any comments
will already have been addressed in the published version).

The referees who approved this article are:

Version 1
1 Akiko Maehara Cardiovascular Research Foundation, Columbia University Medical Center, New York, USA 
Competing Interests: No competing interests were disclosed.
2 Hans Mickley Department of Cardiology, Odense University Hospital, Odense, Denmark 
Competing Interests: No competing interests were disclosed.

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