Acute Myocardial Infarction

Willis E. Godin, D.O.

South Jersey Heart Group
Lourdes Cardiology Services

Acute Coronary Syndrome

(ACS)
Refers

to the array of clinical signs and

symptoms produced by acute
myocardial ischemia
Unstable angina
Non-ST-segment-elevation
ST-segment-elevation MI

Each

MI

condition shares common

pathophysiologic origins related to the
instability and rupture of artherosclerotic
vulnerable plaques

Unstable angina and NSTEMI

Differentiated

one from the other by

primarily by their severity
Whether the ischemia is prolonged
enough to lead to structural myocardial
damage and to the release of
detectable markers of myocardial injury
Troponin

I (TnI)
Troponin T (TnT)
Creatine kinase (CK)-MB

Coronary heart disease

Major

cause of morbidity and death in the

United States
Affecting approximately 16 million Americans
Someone in the US experiences a coronary
event every 25 seconds, and someone dies
from a coronary event every minute.
More than 1.4 million hospitalizations for ACS
in the US each year
Direct and indirect costs of CHD are
estimated to be more than $165 billion in
2009 alone

Pathophysiology
Unstable

angina and NSTEMI result

from a disparity between myocardial
oxygen delivery and demand, which
usually presents as angina occurring
with limited physical activity or at rest (a
crescendo pattern).

Demand-and-delivery mismatch
Associated with UA/NSTEMI
Can occur because of dynamic

from:

obstruction

Intense arterial spasm

Progressive, severe, flow-limiting atherosclerosis
due to intimal hyperplasia or to lipid, calcium, and
thrombus deposition, or to fibrointimal hyperplasia
after PCI
Coronary artery dissection
Conditions that alter myocardial oxygen demand
or supply, such as intense emotion, tachycardia, or
uncontrolled systemic hypertension (secondary
MI)

Pathophysiology
The

most frequent mechanism of

ischemia during limited physical activity
or at rest is a primary reduction of the
myocardial oxygen supply due to
rupture or ulceration of a vulnerable
atherosclerotic plaque
Results in endothelial injury and
associated thrombosis and dynamic
vasoconstriction

Pathophysiology
Plaque

fissure or rupture exposes the highly

thrombogenic subendothelium to circulating
platelets and white blood cells, which in turn
activates the coagulation cascade
The resultant platelet adhesion and
aggregation at the site of plaque disruption
leads to transient thrombosis or subtotal
coronary artery occlusion with dynamic
vasoconstriction
Activated platelets release powerful
promoters of vasoconstriction and platelet
aggregation, including thromboxane A2,
serotonin, adenosine diphosphate, and
platelet-activating factor

Plaque Rupture
Can

occur in mildly or severely

stenosed coronary arteries
Often occurs in arteries where the
atherosclerotic lesions previously had
caused only mild-to-moderate
obstruction

Duration of ischemia
The

duration of ischemia caused by the

platelet-fibrin thrombi and severe dynamic
vasoconstriction determines the overall
clinical picture.
If ischemia is neither severe nor prolonged
(usually <20min) and oftern occurs at rest,
patients are given a diagnosis of UA
If ischemia lasts longer than 30 minutes and
is associated with elevated cardiac markers,
the diagnosis of MI is made
Further classification as STEMI or NSTEMI is
made on the basis of electrocardiographic
findings.

Pathophysiology
Patients

with UA/NSTEMI remain at high risk

for a new infarction and its sequelae,
including sudden cardiac death, until the
endothelial injury is repaired
UA, NSTEMI, and STEMI represent a
pathophysiologic continuum
This concept has led to the development of
effective pharmacologic therapies that, used
in conjunction with careful and rapid riskassessment strategies and catheter-based
therapies, improve outcomes in UA/NSTEMI
patients.

Atherosclerosis
Progressive

in nature
Chronic inflammatory and multifocal disease
involving medium- and large-sized arteries
May begin in the subendothelium as early as
in the 1st decade of life
Usually develops in lesion-prone vascular
areas that exhibit underlying endothelial
dysfunction as a response to chronic,
multifactorial injury to the arterial wall

Endothelial injury
Flow shear stress
Hypertension
Immune-complex deposition

and complement

activation
Smoking
Diabetes mellitus
Aging
Substance abuse
Infection
Mechanical injury (coronary angioplasty, stent
placement, heart transplantation)

Endothelial Dysfunction
A process

regarded as a precursor to
the development of vascular disease
Characterized by disruption of vesselwall homeostasis, which is signified by
decreased vasodilation, increased
vasoconstriction, increased oxidative
stress and inflammation, deregulation of
thrombosis and fibrinolysis, abnormal
smooth-muscle-cell proliferation, and a
deficient repair mechanism.

Diagnosis & Risk Stratification

Early

risk stratification is vital in the

timely diagnosis and treatment of ACS
Assessment of patients with suspected
ACS should include:
Clinical

history
Physical examination
12 lead ECG
Biochemical marker measurement
Noninvasive risk stratification

Clinical History
A thorough

clinical history is of utmost

importance in the initial evaluation and
treatment of patients with suspected ACS
Typical symptoms of ACS include chest pain
or discomfort that may or may not radiate to
the arm, back, neck, jaw, or epigastrium
Women and elderly patients are more likely to
present with atypical features, such as
shortness of breath, weakness, diaphoresis,
nausea, and lightheadness

Physical Examination
Findings

of patients with suspected

ACS are often normal
Attention must be paid to the presence
of complications of ACS:
Acute

LV failure
Hypotension
S3 gallop
New or worsening mitral regurgitation
Pulmonary edema

Electrocardiography
Plays

an important role in initial

assessment, emergency treatment,
prognostication, and subsequent
decision-making regarding the definitive
treatment of patients with suspected
ACS
High specificity for diagnosing STEMI
Remains test of 1st choice

Electrocardiography
Complete

(>90%) occlusion of the

coronary arteries alters the electrical
potentials of the epicardial surface and
usually manifests itself as ST-segment
elevation in 2 or more adjacent leads
ST-segment depression associated with
UA/NSTEMI is transient and dynamic.
Its appearance is usually flat or downsloping

Biochemical markers
When

ischemia is prolonged enough to

produce myocardial necrosis, the
integrity of the myocytic membrane is
lost
Cardiac enzymes and other substances
then leak into the peripheral blood, and
their elevated levels in the bloodstream
are indicative of acute myocardial
infarction (AMI)

Biochemical markers
Cardiac

troponins: gold standard of

biomarkers for establishing a diagnosis
of AMI
Previously,

elevated levels of CK and its

cardiac-specific isoform CK-MB were used
to make a diagnosis of AMI

Any

elevation in the circulating levels of

these biomarkers may provide a clinical
distinction between UA and NSTEMI

Cardiac Troponins
Excellent

independent markers of shortterm and long-term prognoses

Risk of death within the first 42 days is
directly proportional to cardiac troponin
levels, and the prognostic information is
independent of other clinical and
electrocardiographic risk factors

Cardiac Troponins
Detectable

in the serum 4-12 hours

after onset of myocardial necrosis
Peak 12-48 hours from symptom onset
Serial sampling, including the
acquisition of a baseline sample and a
follow-up sample 8-12 hours after
symptom onset, is recommended

Risk Stratification
Clinical

features, ECG, and cardiac

troponin levels are fairly insensitive for
immediately ruling out ACS
It is important to reliably stratify patients
who are at high or low risk of an MI and
who are likely to have adverse events in
the near future
TIMI score
PURSUIT score
GRACE score

TIMI risk score

TIMI

IIB trial
Primary endpoint was the composite of
all-cause death, new or recurrent MI, or
severe recurrent ischemia that prompts
urgent revascularization by day 14
Simple 7-point score that can be
calculated easily at the bedside

Treatment strategies
Initial

treatment: Invasive vs.

Conservative
Despite the debate, it is now widely
accepted that the initial medical therapy
for patients with suspected ACS should
include relieving the ischemia and
preventing further myocardial damage

Treatment strategies
How

clinicians go about this is largely dictated

by the initial risk assessment and continued
patient monitoring in a controlled environment
Hemodynamically unstable patients with
refractory ischemic pain are monitored in a
critical care environment and are taken to the
cardiac catheterization laboratory as soon as
possible
Most patients conditions stabilize after a brief
period of medical therapy at which time they
can be further triaged according to ACS
guidelines

Nitrates
Endothelium-independent

vasodilatory effects
on the coronary and peripheral vascular beds
Dilate venous capacitance vessels and
peripheral arterioles
Decrease preload and afterload
Lead to decrease in both myocardial wall
stress and oxygen demand
Relieve coronary spasm in atherosclerotic
vessels and increase oxygen delivery to the
subendocardial region that is supplied by the
severely narrowed coronary artery

Nitrates
ISIS-4 and GISSI-3 studies
No survival benefit or decrease

in recurrent

myocardial infarction
Should be used in patients who have
refractory ischemic discomfort
Contraindicated:

Patients who have taken sildenafil, tadalafil, or

vardenafil in the previous 24 hours
Systemic hypotension
Marked tachycardia
Severe aortic stenosis
Right ventricular infarct

B-Adrenergic Blockers
Decrease

sinus node rate and

atrioventricular node conduction
velocity, systolic blood pressure, and
contractile responses at rest and during
exercise
Decrease myocardial oxygen demand
and increase the length of diastole
Good anti-ischemic agents

B-Blockers
Recommended

that ACS patients without

contraindications should receive their initial
dose of an oral B-blocker within the first 24
hours of medical therapy
Overview of literature (1988) showed a 13%
relative reduction in the risk of progression
from UA to an MI
Pooled analysis of 5 trials (2003) showed a
50% reduction in mortality at 30 days and 6
months

Calcium channel blockers

Reduces

myocardial contraction and

relaxation of vascular smooth muscle, which
increases coronary blood flow
Decrease afterload and heart rate, while
relaxing the left ventricle and increasing
arterial compliance
2 major classes:

Dihydropyridine
Nifedipine,

amlodipine

Nondihydropyridine
Verapamil,

diltiazem

Calcium channel blockers

Not

routinely given to AMI patients due

to lack of convincing evidence that they
actually reduce death
CCBs can be used as 3rd-line antiischemic agents (after nitrates and Bblockers) in patients who have elevated
blood pressure or angina at rest
Short acting nifedipine should be
avoided due to increased adverse
events

Antiplatelet therapy
Acetylsalicylic

acid (Aspirin)
Thienopyridines
Ticlopidine
Clopidogrel
Prasugrel

Aspirin
Causes

irreversible acetylation of serine

529 of cyclooxygenase (COX-1) in
platelets and the endothelium, thereby
preventing thromboxane A2 (TXA2)
production and resultant platelet
aggregation

Aspirin
Reduces

the risk of angina, death, or MI

by approximately 30% in patients with
CAD
1994 - the Antiplatelet Trialists
Collaboration meta-analysis of 174
trials (70,000 pts)
2002 - meta-analysis of 287 studies
(135,000 pts)

Thienopyridines
Block

P2Y12 receptor signaling to

prevent production of adenyl cyclase,
thereby inhibiting platelet activation
through adenosine diphosphate (ADP)
Limit ADP-mediated conversion of
GPIIb/IIIa to its active form
Mechanism of action is independent of
and complementary to that of aspirin

Ticlopidine
1st-generation

thienopyridine
In combination with ASA, reduces rate
of vascular death and MI by 46% in
NSTEMI patients
Used less frequently than the newer
thienopyridines because of its potential
for side effects:
Rash,

nausea, neutropenia,
thrombocytopenia

Clopidogrel
2nd-generation

thienopyridine
Most widely used and studied ADPreceptor-blocking agent
CAPRIE study (1996) : 19,185 pts
CURE trial (2001) : 12,562 pts
CHARISMA trial (2006)
PCI-CURE trial (2001)

Clopidogrel
9%

relative risk reduction in adverse

cardiovascular events (vascular death,
MI, or ischemic stroke) when compared
to aspirin - (CAPRIE)
20% reduction in the primary composite
endpoint (cardiovascular death, MI, or
stroke) up to 12 months of f/u - (CURE)
31% reduction in cardiovascular death
or MI in patients undergoing PCI - (PCICURE)

Glycoprotein IIb/IIIa Inhibitors

Platelets

are activated through multiple

pathways, however, the final common
pathway of platelet activation and
aggregation invloves a conformational
change of the GPIIb/IIIa receptors from
a resting state to an active state

Glycoprotein IIb/IIIa Inhibitors

Abciximab
Tirofiban
eptifibatide

Glycoprotein IIb/IIIa Inhibitors

EPIC

trial (1994) - 35% reduction in primary

composite endpoint (death, MI, recurrent
ischemia) in pts given abciximab vs placebo
CAPTURE trial (1997) - 30% relative
reduction of death, MI, or recurrent ischemia
in pts given abciximab
PRISM study (1998) - 32% reduction in
death, MI, or recurrent ischemia in pts given
tirofiban
PURSUIT trial (1998) - 10% reduction in the
relative risk of death and MI in pts given
eptifibatide

Anticoagulants
Unfractionated

heparin
Low-molecular-weight heparin
Enoxaparin
dalteparin

Factor

X inhibitors

fondaparinux

Heparin
Anticoagulative

effect by activating and

accelerating the proteolytic activity of
plasma cofactor antithrombin (AT)
Close and frequent monitoring of the
activated partial thromboplastin time
(PTT) is necessary to ensure that a
safe therapeutic range is maintained

Heparin (UFH and LMWH)

FRISC

trial (1997) - 63% relative risk

reduction in death or MI in pts given
dalteparin vs placebo
ESSENCE trial (1997) - the risk of death, MI,
or recurrent angina was significantly lower in
pts given enoxaparin vs UFH (16.6% vs
19.8%)
TIMI 11B trial (1999) - 14.3% risk reduction of
death, MI, or need of urgent revascularization
in pts given enoxaparin vs UFH

Early-Conservative and EarlyInvasive Strategies

Coronary

angiography aids in defining

the extent and location of CAD and in
directing the definitive care strategy
PCI/stenting
CABG
Medical

management

Angiography

is an invasive procedure
and there is a small risk of serious
complications (~1 in 1,000 cases)

Early-Conservative and EarlyInvasive Strategies

In

the early-invasive strategy, all

patients without contraindications
undergo coronary angiography with the
intent to perform revascularization
within 4 to 24 hours of hospital
admission.
The early-conservative strategy
consists of aggressive medical therapy
for patients

TIMI-IIIB trial
Compared

an early-invasive strategy to an
early-conservative strategy in UA/NSTEMI pts
(1994)
Primary endpoint: composite of death, MI, or
abnormalities on a exercise stress test at 6
weeks
No significant difference in the occurrence of
the composite endpoint between the groups.
However, the average length of initial
hospitalization, the incidence of
rehospitalization within 6 weeks, and the
number of days of rehospitalization all were
significantly lower in the early-invasive group

VANQUISH trial
Compared

an early-conservative
strategy to an early-invasive strategy
(1998)
Combined endpoint of death and nonfatal MI occurred in 3.3% of pts in the
early-conservative group and 7.7% of
pts in the early-invasive group
(No

benefit of early-invasive strategy)

FRISC-II trial
Compared

an early-conservative strategy to
an early-invasive strategy (1999)
Incidence of the composite endpoint of death
or MI was 9.4% in the early-invasive group
and 12.1% in the early-conservative group
Furthermore, angina symptoms and hospital
readmissions were reduced by 50% with the
use of the early-invasive strategy

Conclusions
ACS

is associated with high rates of

adverse cardiovascular events, despite
recent therapeutic advances
Plaque composition and inflammation
are more important in the pathogenesis
of ACS than is the actual degree of
stenosis

Conclusions
The

cornerstone of contemporary
treatment remains early risk
stratification and aggressive medical
therapy, supplemented by coronary
angiography in appropriately selected
patients

Conclusions
An

early-invasive treatment strategy is

of most benefit to high-risk patients
An early-conservative strategy is
recommended for low-risk patients

Conclusions
Adjunctive

medical therapy with ASA,

clopidogrel, GPIIb/IIIa inhibitors, and either
LMWH or UFH, in the appropriate setting,
further reduces the risk of ischemic events
secondary to thrombosis
Anticoagulation and short- and long-term
inhibition of platelet aggregation should be
achieved by appropriately evaluating the risk
of bleeding complications in each patient
Our goal: enhance both short- and long-term
event-free survival