Stroke associated with myocardial infarction

Stroke associated with myocardial infarction

By: David Tanne and Solomon Behar

ICD Code Acute myocardial infarction:410

Other acute and subacute forms of ischemic heart disease:411
Old myocardial infarction:412
Intracerebral hemorrhage:431
Cerebral embolism:434.1

Historical note and nomenclature

Since the early 19th century, several authors have noted the
occurrence of mural thrombi complicating acute myocardial infarction.
Virchow postulated that 3 factors predispose patients to thrombosis: (1)
injury of the vascular endothelial or endocardial surface, (2) circulatory
stasis, and (3) a generalized hypercoagulant state (Virchow 1856). He
reported occlusion of arteries in the brain by thrombi, which seemed to
have originated in the heart, and named this phenomenon "embolism"
(from the Greek word for plug).
Gordinier suggested that the sudden arterial plugging of the vessels
of the brain, viscera, or extremities indicates involvement of a branch of
the left coronary, whereas signs of pulmonary infarct suggest involvement
of the right coronary or its branches (Gordinier 1924). Blumer was among
the first to extensively discuss the importance of embolism as a
complication of cardiac infarction. He stated that mural thrombi are
common following cardiac infarction, and that fragments may detach and
produce embolic phenomena (Blumer 1937).

Clinical manifestations
Stroke is a well-known, potentially disastrous complication of acute
myocardial infarction. A disorder as complex and heterogeneous as stroke
may manifest in a myriad of ways, according to the part of brain involved.
Clinical features are insufficiently predictive to reliably distinguish cerebral
infarction from hemorrhage, or thrombotic from embolic occlusion.
Features suggestive of embolic stroke, in addition to the presence of a
recent myocardial infarction or left ventricular thrombi, are abrupt onset,
headache, seizures, evidence for deficits in multiple vascular territories,
and embolization to other organs. Most ischemic strokes, after acute
myocardial infarction, involve the anterior circulation and are nonlacunar
(Mooe et al 1999). Approximately one-third occur within 24 hours following
admission, whereas about two-thirds occur in the first week after the
myocardial infarction (Behar et al 1991; Sloan et al 1997).
Symptomatic intracerebral hemorrhage, the most dreaded
complication of thrombolytic therapy, usually occurs during the first 2 days
after thrombolysis (Gore et al 1995; Gurwitz et al 1998). Patients usually
develop a change in the level of consciousness, headache, nausea, and
vomiting, in addition to specific focal neurologic deficits, depending on the
location of the bleeding (Sloan et al 1995). Onset can be catastrophic and
rapidly fatal.
Clinical vignette
A 55-year-old, right-handed, white male with past medical history of
hypertension and diabetes presented to the emergency room after 2 hours
of severe retrosternal pain radiating to the left arm and associated with
diaphoresis. The initial electrocardiogram was compatible with an acute
onset of an anteroseptal wall myocardial infarction. The patient was
treated with aspirin and intravenous streptokinase and, later,
subcutaneous heparin therapy was started. Forty-eight hours after
completion of streptokinase therapy, he developed nonfluent aphasia and
right hemiparesis (more severe in the face and upper extremity). Brain CT
revealed subtle early infarct changes in the left frontal lobe with no
evidence of blood. On transthoracic echocardiography, no left ventricular
thrombus was seen, but significant anterior wall motion abnormalities were
identified. Carotid duplex demonstrated 0% to 15% stenosis in both
internal carotid arteries. Over the next 48 hours, the neurologic deficit
improved substantially. A repeat brain CT did not reveal any secondary
hemorrhagic conversion, and the patient was discharged on oral
anticoagulants for secondary prevention of an embolic stroke.

Etiology
The association between coronary artery disease and stroke can be
ascribed to a common pathophysiologic antecedent, atherosclerosis. In the
clinical setting of acute myocardial infarction and stroke, more specific
cause-and-effect relationships occur, such as the appearance of left
ventricular thrombi in large anterior infarctions, or homeostatic defects
associated with thrombolytic therapy. In addition, cardiac dysrhythmias or
a decrease in stroke volume during the acute phase of myocardial
infarction can reduce cardiac output to such a degree that hemodynamic
compromise results. Strokes occurring several weeks after myocardial
infarction may be due to chronic left ventricular thrombi, an akinetic left
ventricular segment, or left ventricular dysfunction. Indeed, cerebral
microembolism was detected by transcranial Doppler more often among
patients with acute myocardial infarction with reduced left ventricular
function, akinetic segments, or left ventricular thrombi (Nadareishvili et al
1999). For every decrease of 5% in the ejection fraction, an 18% increase
in the risk of long-term stroke has been found (Loh et al 1997). Other
potential cardiac causes of stroke, atherothrombotic large vessel disease
and small-vessel disease, must also be considered (Martin and
Bogousslavsky 1993). It may be difficult to determine the exact
mechanism of stroke in many patients, where different pathophysiologic
mechanisms may be equally likely.
Left ventricular thrombi occur frequently in the course of acute
myocardial infarction and are associated with an increased embolic risk
(Chiarella et al 1998). Although 2-dimensional echocardiography has some
limitations, it is a fairly accurate noninvasive method for detecting left
ventricular thrombi.
 Such thrombi develop in up to one-third of patients with anterior site
of myocardial infarction, but only in 0% to 5% of patients with inferior
infarctions. The highest rate of occurrence of left ventricular thrombi is
found in patients with anterior infarcts and a low ejection fraction or
congestive heart failure (Chiarella et al 1998). Overall, the published data
suggest that cerebral embolism occurs clinically within the first 3 months
after myocardial infarction in about 10% of those with
echocardiographically evident left ventricular thrombi, although it is often
difficult to classify acute ischemic events as embolic in patients with
advanced atherosclerotic disease. Mobile thrombi, or those that protrude
into the left ventricular cavity, appear to have the highest embolic risk.
The occurrence of intracranial hemorrhage complicating acute
myocardial infarction, still a rare event, was exceedingly rare before the
thrombolytic era. Intracranial hemorrhage alone, associated with
treatment of acute myocardial infarction, is mostly coagulopathy-induced
and is associated with thrombolytic therapy, or in combination with other
antithrombotic drugs (Simoons et al 1993; Giugliano et al 2001). The main
types of intracranial hemorrhage observed in this setting are
parenchymatous intracerebral hemorrhage, hemorrhagic transformation of
cerebral infarction, or subdural hemorrhage.

Pathogenesis and pathophysiology

Most strokes complicating acute myocardial infarction in patients not
receiving thrombolysis are likely cardioembolic, as indicated by their
association with large anterior myocardial infarcts and left ventricular
thrombi detected by echocardiography. Left ventricular thrombi usually
occur when the anterior wall or apex becomes akinetic or hypokinetic,
enlarging the apical zone of intraventricular stasis. Inflammatory changes
at the endocardial surface also enhance thrombogenicity. A systemic
hypercoagulable state may promote thromboembolism early after the
coronary event, whereas residual fresh thrombus may enhance
coagulation during the first 1 month to 3 months. The risk of systemic
embolization from left ventricular thrombi depends on the balance
between factors favoring thrombus formation within the ventricular cavity
(endocardial injury, regional circulatory stasis, and activation of the
intrinsic coagulation system) and dynamic forces of the circulation that
may project thrombotic material into the systemic circulation, to produce
clinical morbidity. Cardioembolic strokes have a propensity for secondary
hemorrhagic transformation. Hemorrhagic transformation may occur either
because of distal migration of embolic fragments with reperfusion of
infarcted tissue or because of collateral circulation.
Hypertensive intracerebral hemorrhages are classically located in the
distribution of perforating vessels and are associated with a number of
microvascular lesions, such as Charcot-Bouchard microaneurysms. With
thrombolytic therapy, intracerebral hemorrhages are often large, lobar,
and supratentorial, occasionally in multiple compartments and with fluid
levels inside the hematoma (Gebel et al 1998). Accordingly, other
underlying conditions may contribute to the cause of bleeding, such as
preexisting vascular malformations and, probably more important in an
elderly population, cerebral amyloid angiopathy (Sloan et al 1995). Diverse
hemostatic derangements, depending on the thrombolytic agent used,
dose, protocol of administration, and adjunctive therapy, contribute to the
bleeding tendency.

Epidemiology
Development of carotid atherosclerosis closely parallels coronary
atherosclerosis. Many patients with clinically apparent or silent myocardial
ischemia have coexistent cerebrovascular disease. Conversely, many
patients with cerebrovascular disease have various degrees of coronary
artery disease. Indeed, myocardial infarction is the leading cause of death
in patients who recover from strokes or transient ischemic attacks. The
incidence of stroke during the acute phase, following myocardial infarction,
varies considerably between studies. Rates are mostly in the range of 0.8%
to 3.2%. Late stroke following myocardial infarction is relatively rare,
although patients are still at increased risk during the first 1 month to 2
months (Tanne et al 1993). Overall, about 1 in 40 elderly patients will
suffer an ischemic stroke within 6 months of hospital discharge from their
acute myocardial infarction (Lichtman et al 2002).
Compelling evidence advances the notion that thrombolytic therapy
reduces mortality from acute myocardial infarction; however, thrombolytic
therapy also carries a small, but significant risk of severe bleeding
complications, including intracranial hemorrhage. Results from placebo-
controlled thrombolysis trials demonstrate a shift in type and timing of
strokes including more intracranial hemorrhages and less ischemic strokes,
and more strokes in the first 2 days after thrombolytic treatment and
slightly less thereafter (Anonymous1988; Maggioni et al 1991). In a
collaborative overview of large randomized trials, an extra 4 strokes per
1000 were associated with thrombolysis versus placebo (Anonymous1994).
Compared to thrombolytic therapy, primary angioplasty for acute
myocardial infarction is associated with a significantly lower rate of stroke
(Cucherat et al 2001).
In the large-scale thrombolytic trials, the overall reported incidence of
stroke during hospitalization for acute myocardial infarction was 0.9% to
1.6%, of which intracranial hemorrhage represented 0.2% to 0.9%,
depending on the type and dose of agent used (Anonymous1992; Maggioni
et al 1992; Anonymous1993); however, caution must be exercised in the
interpretation of these reports, as recording and evaluation of strokes were
not standardized, and variable proportions of strokes were unclassifiable.
Furthermore, thrombolytic trials often excluded high-risk individuals
(above a certain age, with a history of stroke, or with uncontrolled
hypertension), so reported rates may underestimate the true magnitude of
this complication. Indeed, in clinical practice, a higher rate of elderly
patients with acute myocardial infarction experienced intracranial
hemorrhage (Gurwitz et al 1998; Brass et al 2000). The overall risk of
stroke due to thrombolytic therapy in properly selected acute myocardial
infarction patients is low, compared with the impressive reduction in
mortality and, thus, is associated with a favorable benefit-risk profile.
Indeed, the incidence of early cerebrovascular events among unselected
patients admitted to coronary care units in the prethrombolytic versus
thrombolytic eras remained similar, although mortality from acute
myocardial infarction decreased substantially (Tanne et al 1997). In
patients with acute coronary syndromes without persistent ST-segment
elevation, the incidence of stroke is low, but still associated with
substantial morbidity and morality (Mahaffey et al 1999b; Cronin et al
2001). Patients undergoing early coronary artery bypass grafting surgery,
but not early percutaneous coronary intervention, have a substantially
increased risk of stroke (Cronin et al 2001). Nevertheless, many valid
clinical reasons advocate performing earlier, rather than delayed, coronary
artery bypass grafting surgery.

Prevention
An optimal strategy for managing this potentially catastrophic
complication of myocardial infarction includes identification of stroke-prone
patients and institution of preventive measures. The main predictors of
stroke after acute myocardial infarction are older age, higher heart rate,
diabetes, hypertension, anterior site of myocardial infarction, high cardiac
enzyme levels, impaired left ventricular function, atrial arrhythmias,
coronary angiography or bypass surgery, lack of aspirin use, and prior
cerebrovascular disease, peripheral vascular disease, or angina (Behar et
al 1991; Mooe et al 1997; Mahaffey et al 1998; Lichtman et al 2002). These
data are in accord, in part, with findings that left ventricular thrombi more
commonly complicate anterior infarctions, and that these thrombi,
especially if protruding and mobile, are a source of embolization. A useful
and simple scoring monogram for risk assessment in the acute phase was
developed based on the results of the Global Use of Strategies to Open
Occluded Coronary Arteries (GUSTO-1) trial (Mahaffey et al 1998). The
strongest predictor identified for late stroke following myocardial infarction
is chronic atrial fibrillation (Tanne et al 1993). A risk stratification score
was constructed from the Cooperative Cardiovascular Project for elderly
patients discharged from hospital after an acute myocardial infarction. The
6-month stroke admission rate for patients with a score of 4 or higher
(equaling 20% of the total sample) was equal to 4% (Lichtman et al 2002).
Anticoagulation with full-dose heparin decreases the risk of left
ventricular thrombi in patients with acute anterior myocardial infarction,
and may be effective in reducing the risk of embolization in those with left
ventricular thrombi. Aspirin reduced the risk of early ischemic stroke by
half in the ISIS-2 mega-trial (Anonymous 1988). Long-term oral
anticoagulant treatment in survivors of myocardial infarction has been
shown to reduce the frequency of stroke by 40% to 50% over a 3-year
period (Azar et al 1996; Loh et al 1997). Hemorrhagic complications are an
uncommon, but serious occurrence in patients treated with long-term oral
anticoagulants, with rates related to the intensity of anticoagulation. In
patients after acute myocardial infarction, anticoagulation therapy is
indicated for embolic stroke prevention, and antiplatelet therapy is a
matter of ongoing investigation (Fiore et al 2002; Hurlenet al 2002).
Statins reduce the risk of stroke among patients at-risk for
atherothrombotic disease (Heart Protection Study Collaborative Group
2002), and preliminary data suggest they may reduce of stroke the risk
during the early period after an acute coronary syndrome (Waters et al
2002).
Risk factors for embolic stroke and intracranial hemorrhage following
myocardial infarction differ. Patients at increased risk of embolic stroke,
such as those with large anterior infarctions, may have the greatest
survival benefit from thrombolytic therapy. The risk of intracerebral
hemorrhage was reported to increase with the following: age; a history of
hypertension, cerebrovascular disease or head trauma; a high dose of
thrombolytic therapy; being of the female gender; being of African
ancestry, having a low body weight; high blood pressure on presentation;
and excessive prolongation of the aPTT with heparin (Gore et al 1995;
Gurwitz et al 1998; Brass et al 2000). Life threatening ventricular
arrhythmia and hypofibrinogenemia may play a role in some cases (Sloan
et al 1995). Treatment with tissue plasminogen activator or anisoylated
plasminogen-streptokinase activator complex was associated with a higher
risk of hemorrhage than streptokinase (Anonymous1992; Maggioni et al
1992; Anonymous1993). The higher than anticipated rate of intracranial
hemorrhage among patients treated with heparin or hirudin in conjunction
with thrombolysis, in several recent trials, emphasizes the risks of more
potent anticoagulation in combination with thrombolysis. The currently
recommended heparin regimen is of lower-dose and is weight-adjusted
(Giugliano et al 2001). An analysis, combining data from different
thrombolytic trials, identified 4 independent predictors for intracranial
hemorrhage: (1) age over 65 years, (2) body weight below 70 kg, (3)
hypertension on hospital admission, and (4) administration of alteplase
(Simoons et al 1993). Models for individual risk assessment were
developed that can be used early in clinical practice (Simoons et al 1993;
Brass et al 2000). Although a history of stroke increases the overall risk of
intracranial hemorrhage, preliminary observational data suggest that
thrombolytic therapy may be beneficial in selected patients with acute
myocardial infarction and a history of a nonrecent stroke (Tanne et al
1998). Such patients may be treated by primary coronary angioplasty, but
the option of thrombolytic therapy should not be categorically excluded.

Differential diagnosis
Most strokes can be readily recognized. A patient with an acute
myocardial infarction who develops a rapid change in neurologic status
should be suspected of suffering a stroke. Rarely, other brain disorders (ie,
seizure, tumor, subdural hematoma, or demyelination) and some
metabolic abnormalities (ie, hypoglycemia or hypoxemia) may present in a
similar fashion.

Diagnostic workup

The assessment of stroke complicating myocardial infarction should

include substantial efforts to delineate the stroke subtype. Brain imaging
(CT scan or MRI) is essential for distinguishing between infarct and
hemorrhage. In trying to determine whether the etiology of a cerebral
infarction following myocardial infarction is indeed of embolic origin or of
another etiology (ie, large vessel or small vessel atherosclerotic disease),
neurologic features are insufficiently predictive to establish the etiology.
Echocardiography and other ancillary tests, such as duplex examination of
the cervical arteries and transcranial Doppler, may help define specific
vascular lesions and disease processes responsible for the stroke.
A high degree of suspicion is needed when caring for patients treated
with a thrombolytic agent, so that diagnosis can be established as rapidly
as possible. The occurrence of a decreased level of alertness or
appearance of a neurologic deficit, particularly during the first 24 hours
after thrombolytic infusion, should raise suspicion of an intracranial
hemorrhage until proven otherwise (Sloan et al 1995). Thrombolytic,
anticoagulant, or combined therapies should be discontinued as soon as
symptoms and signs are recognized. Coagulation studies should be
obtained immediately to document the severity of the coagulopathy, and
preparations for reversing homeostatic abnormalities should be made,
although the appropriate management is not clear (Conrad et al 1997).
Emergent CT scan of the brain is necessary to distinguish intracranial
hemorrhage from cerebral infarction and other neurologic disorders. It
occasionally may be difficult to differentiate an intracerebral hemorrhage
from a cerebral infarction with hemorrhagic transformation.

Prognosis and complications

Stroke, complicating acute myocardial infarction, adversely affects
outcome. An estimated 3-fold in-hospital and long-term mortality was
observed among patients with a cerebral event, in comparison with those
without (Behar et al 1991; Tanne et al 1997). Later strokes (in the year
following hospitalization for the myocardial infarction) were associated
with 2-fold to 3-fold increased mortality as well (Tanne et al 1993).
Although thrombolytic therapy has little effect on overall stroke
occurrence, it increases the risk of stroke death substantially (Maggioni et
al 1991). In the GUSTO mega-trial, 60% of patients with primary
intracerebral hemorrhage died and 25% were disabled, versus 17% dead
and 40% disabled with nonhemorrhagic infarcts. In a quality-of-life study,
patients with moderate or severe residual deficits showed significantly
decreased quality of life (Gore et al 1995). Strokes were associated with a
60% increase in cumulative 1-year medical costs, and follow-up costs were
more than quadrupled for stroke survivors, dominated by the cost of
institutional care (Tung et al 1999).

Management
The patient with acute ischemic stroke requires appropriate
supportive care and treatment of acute complications. Following an acute
cardioembolic stroke due to a left ventricular thrombi, risk for a recurrent
early embolic event is high. To decide when to start anticoagulant
treatment, one has to balance the benefit of reduction in early recurrent
embolism against the risk of potentiating secondary brain hemorrhage.
Cardioembolic strokes have a propensity for secondary hemorrhagic
transformation. Large embolic infarcts, as well as infarcts visible on early
CT scans and with mass effect, are especially prone to secondary
hemorrhage. Most spontaneous hemorrhagic transformations occur within
2 days to 4 days of cardioembolic stroke, but are rarely associated with
clinical deterioration. Conflicting evidence exist concerning whether
anticoagulation during this period can result in neurologic impairment and,
therefore, no consensus has been reached on the optimum strategy.
In any central nervous system bleeding, early cooperation of
cardiologists with neurologists, neurosurgeons, and hematologists will
optimize management decisions. Immediate treatment with protamine (if
the patient received heparin), cryoprecipitate, fresh frozen plasma,
platelets, and an antifibrinolytic agent should be considered for an
algorithm to the management of bleeding complications (Conrad et al
1997). Although onset may be catastrophic and rapidly fatal, rapid
neurosurgical intervention may be beneficial in selected cases as
suggested from the GUSTO I experience (Mahaffey et al 1999a), but
evidence from randomized clinical trials is lacking.

Pregnancy
No information was provided by the author.

Anesthesia
Patients suffering from both acute myocardial infarction and stroke
are at an especially high anesthetic risk and, thus, are prone to high
perioperative morbidity and mortality. Indeed, those who have suffered a
recent myocardial infarction demonstrate high perioperative infarction and
death. During neurosurgical procedures, the degree and potential for
increase in intracranial pressure are important considerations. The more
information available to predict potential intraoperative and postoperative
problems, the better is the anesthesiologist to avoid or lessen the risk for
those events.

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