Med Clin N Am 91 (2007) 701–712

Pathophysiology of Cardiogenic Shock

Complicating Acute Myocardial
Infarction
Eve D. Aymong, MD, MSc, FRCPCa,b,*,
Krishnan Ramanathan, MB, ChB,
FRACP, FRCPCa,b,c,
Christopher E. Buller, MD, FRCPC, FACCa,b,c
a
University of British Columbia, Vancouver, BC, Canada
b
Division of Cardiology, University of British Columbia, 1081 Burrard Street,
Room 474A, St. Paul’s Hospital, Vancouver, BC, Canada V6Z 1Y6
c
Gordon and Leslie Diamond Health Care Centre, Level 9, Cardiology,
2775 Laurel Street, Vancouver, BC, Canada V5Z 1M9

Cardiogenic shock complicating acute myocardial infarction (MI) re-

mains a significant clinical problem despite advances in reperfusion therapy.
Current estimates of the incidence of cardiogenic shock complicating MI
remain stable at approximately 7% [1,2]. This devastating complication
results in most early post-MI mortality [3].

Diagnostic criteria of cardiogenic shock

Cardiogenic shock is clinically defined as a state of end-organ dysfunc-
tion caused by hypoperfusion secondary to low cardiac output with
associated hypotension, classically defined as a systolic blood pressure less
than 90 mm Hg. Hypoperfusion can affect any organ system; those most
prone to ischemia are the kidney and brain, resulting in decreased level of
consciousness, cool extremities, and decreased urine output. Other hemody-
namic criteria of cardiogenic shock, as shown in Box 1, include decreased
cardiac index (!2.2 L/min/m2) and elevated left ventricular filling pressures
(pulmonary capillary wedge pressure or left ventricular end diastolic pres-
sure O15 mm Hg) [4]. Evidence of presumed cardiogenic pulmonary edema
is used as a surrogate for increased left ventricular filling pressure in the
* Corresponding author.
E-mail address: eaymong@providencehealth.bc.ca (E.D. Aymong).

0025-7125/07/$ - see front matter ! 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2007.03.006 medical.theclinics.com
702 AYMONG et al

Box 1. Diagnostic criteria of cardiogenic shock

Clinical criteria
Systolic blood pressure <90 mm Hg
Evidence of hypoperfusion
Cool, clammy periphery
Decreased urine output
Decreased level of consciousness
Hemodynamic criteria
Left ventricular end diastolic pressure or pulmonary capillary
wedge pressure >15 mm Hg
Cardiac index <2.2 L/min/m2

Data from Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in
acute myocardial infarction complicated by cardiogenic shock. SHOCK Investiga-
tors. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic
Shock. N Engl J Med 1999;341(9):625–34.

absence of direct measurement of pulmonary capillary wedge pressure or

left ventricular end diastolic pressure.
Any cut point of patient hemodynamics (ie, blood pressure or cardiac in-
dex) is obviously artificial and patient care must be guided on an individual
basis. In addition, interventions to treat patients who have complicated
myocardial infarction such as inotropes and intra-aortic balloon counter-
pulsation can cloud these arbitrary cut points.

Classical paradigm of cardiogenic shock

The progressive downward spiral that describes the clinical deterioration
of patients who have cardiogenic shock is portrayed in Fig. 1. The essential
feature is that decreased coronary blood flow results in decreased cardiac
output. This decrease in cardiac output leads to hypotension and progres-
sively more cardiac ischemia and dysfunction. The resulting stuttering ische-
mia and infarction eventually results in left ventricular failure and death.

Fundamentals of myocardial physiology

To fully appreciate the pathophysiology that leads to cardiogenic shock,
the fundamental aspects of normal cardiac function must be understood.
The heart is an obligate aerobic organ and can tolerate only minimal
decreases in oxygen supply. The myocardial oxygen consumption of the nor-
mally contracting heart muscle is between 8 and 15 mL/min/100 g compared
with 1.5 mL/min/100 g in the noncontracting heart. Even in its basal,
 PATHOPHYSIOLOGY OF CARDIOGENIC SHOCK 703

Fig. 1. The classic paradigm of progressive left ventricular (LV) dysfunction in cardiogenic
shock. Consequences of progressive ischemia and infarction result in continually worsening
hemodynamics and eventually left ventricular failure and death. MVO2, myocardial oxygen
consumption. (From Ganz P, Braunwald E. Coronary blood flow and myocardial ischemia.
In: Braunwald E, editor. Heart disease. A textbook of cardiovascular medicine. 5th edition.
Philadelphia: WB Saunders; 1997. p. 1161–84; with permission.)

noncontracting state, it extracts two to three times more oxygen than other
organs.
Total myocardial oxygen consumption, or demand, is known as MVO2.
On a per-gram basis, this is determined by ventricular wall tension (wall
stress), heart rate, and contractility (Fig. 2). Laplace’s law approximates
wall tension as follows:

Wall stress ¼ ðP # rÞ=2h; where P is the transmural pressure;

r is the radius of the left ventricle; and
h is the thickness of the ventricular wall

Coronary blood flow, primarily a diastolic phenomenon, is an obvious

requirement for myocardial oxygen supply. Diastolic coronary blood flow
is directly proportional to perfusion pressure (which can be approximated
by mean aortic diastolic pressure minus mean left ventricular diastolic
704 AYMONG et al

Fig. 2. Myocardial oxygen balance. (A) On a per-gram basis, MVO2 is determined by heart
rate, contractility, and ventricular wall tension (wall stress). (B) Wall stress is approximated
by LaPlace’s law, where P is left ventricular pressure, r is left ventricular radius, and h is left
ventricular wall thickness. (C) Two of the primary determinants of coronary blood flow are
depicted.

pressure) and is inversely proportional to coronary vascular resistance. In

diastole, coronary vascular resistance is modulated primarily by compli-
cated intrinsic effectors of vascular tone. In the presence of epicardial coro-
nary stenoses and endothelial dysfunction that exists with ischemic heart
disease, the compensatory mechanisms for maintenance of coronary flow
are altered. Myocardial perfusion and coronary blood flow, especially of
the subendocardium, occur predominantly in diastole [5].

Continuum of myocardial ischemia leading to dysfunction

Within seconds of loss of coronary blood flow, heart muscle becomes is-
chemic and myocardial mechanics are abruptly altered, resulting in both
systolic and diastolic dysfunction. This process occurs before actual myocar-
dial cell death as a result of acute oxygen debt. As ischemia progresses, the
myocardium becomes stunned and will not immediately respond to reperfu-
sion. If injury progresses, myocytes die and infarction ensues.
Although patients who experience cardiogenic shock have significant
areas of dead myocardium, it is crucial to recognize that stunned or hiber-
nating myocardium may play a significant role in the ongoing left ventricu-
lar dysfunction [6–8]. This fact is particularly important in understanding
the fundamental role of complete revascularization in these patients [9].
Myocardial dysfunction can occur with viable tissue. Myocardial stun-
ning causes myocardial dysfunction resulting from ischemic injury without
myocardial necrosis or cell death [6–9]. It is defined as postischemic myocar-
dial dysfunction with eventual return of normal contractile activity. Of
 PATHOPHYSIOLOGY OF CARDIOGENIC SHOCK 705

course, whether myocardium will return to normal function is impossible to

determine and stunning can last for hours to weeks.
Stunned myocardium occurs when myocardium has been reperfused and
is still viable, yet displays ongoing dysfunction. Several mechanisms de-
scribed for stunning include oxidative stress, reactive oxygen species forma-
tion, and altered calcium homeostasis with increased intracellular calcium
[10]. Stunned myocardium may take days to fully recover. Experimental
evidence suggests that this stunned muscle will respond to inotropic therapy,
which remains a cornerstone of therapy for cardiogenic shock [11].
Distinct from myocardial stunning is hibernating myocardium [12].
Hibernating myocardium exists when myocardial perfusion is chronically
reduced but basal function is intact. As the term implies, the muscle is sleep-
ing to conserve energy. Hibernation results in both systolic and diastolic
dysfunction that can be reversed through restoration of coronary blood
flow with either percutaneous coronary intervention or coronary artery by-
pass grafting [13,14].
Hibernating myocardium may also contribute to the severity of left ven-
tricular dysfunction in patients who have cardiogenic shock. This muscle is
viable but in a state of persistent dysfunction because of chronically
decreased blood flow. This fact may be important in acute myocardial dys-
function during MI, because hibernating myocardium cannot be recruited to
become hypercontractile to preserve cardiac output. Although complete
revascularization is ideal, hibernating myocardium may also be at risk for
reperfusion injury through oxygen free radicals and increased cytosolic
calcium release [12–14].

Compensatory responses to myocardial infarction

In the SHOCK (SHould we emergently revascularize Occluded Coronaries
in cardiogenic shocK?) registry, the median time from MI symptoms to shock
onset was 6.2 hours although the interquartile range was broad, from 1.7 to
20.1 hours [15]. These data indicate variability in the rate of full-blown shock
onset after the initial ischemic insult. Vasoconstriction from falling cardiac
output is believed to be the major compensatory mechanism. Patients in
this ‘‘preshock’’ phase have low cardiac output and evidence of low organ per-
fusion but a falsely reassuring preserved systolic blood pressure.
Other compensatory responses to MI and falling cardiac output result in
increased MVO2. In response to stress and decrease in cardiac output, heart
rate increases. In addition, noninfarcted myocardium is recruited to preserve
forward output and contractility increases. As myocytes die, the left ventri-
cle dilates acutely to preserve stroke volume and wall thickness decreases.
Finally, diastolic relaxation is impaired in addition to systolic dysfunction,
and left ventricular pressure increases. All of these features lead to increased
MVO2 (see Fig. 2). In the setting of cardiogenic shock, these mechanisms
706 AYMONG et al

perpetuate the cycle of inadequate oxygen delivery and further ischemia

ensues, as illustrated in Fig. 1.

Extent of atherosclerosis and myocardial infarction

Cardiogenic shock complicating acute MI is caused by predominant left
ventricular failure in 80% of cases [16,17]. In the remaining 20%, shock re-
sults from right ventricular infarction or mechanical complications of MI,
including ventricular septal rupture, acute mitral regurgitation, and free
wall rupture. In patients who have predominantly left ventricular failure, ex-
tensive necrosis is evident and involves more than 40% of the left ventricle
on autopsy [18]. Early pathologic studies of fatal cases of cardiogenic shock
predating modern reperfusion showed the frequent occurrence of multiple
acute and subacute infarctions of varying ages remote from the primary in-
farct. This evidence supports the concept that patients who have multivessel
coronary artery disease who develop shock are prone to demand driven
infarcts in remote coronary territories [19].
In many patients, acute occlusion of the left anterior descending artery is
the culprit lesion and, in two thirds of all patients, multivessel disease is
present [20]. The inciting clinical event leading to shock may not be a massive
MI secondary to a single arterial occlusion, but the result of multiple small
MIs with the final myocardial insult leading to a sudden loss of critical func-
tioning myocardial mass [19,20].
Cardiogenic shock is a recognized complication in patients presenting
with the full spectrum of acute coronary syndromes. The incidence of car-
diogenic shock is more common in patients presenting with ECG evidence
of ST elevation, occurring in between 4.2% and 7.2% of those who have
ST-elevation MI undergoing thrombolytic therapy. It has also been de-
scribed in up to 2.9% of patients who have other forms of acute coronary
syndromes [21].
Infarct expansion and reinfarction have been identified as important risk
factors for development of shock in STEMI and nonSTEMI. In settings of
low coronary blood flow, thrombus may propagate to involve side branches
and increase infarct size. MI is a hypercoagulable clinical state, and reocclu-
sion of recanalized arteries leading to reinfarction can occur in up to 20% of
patients undergoing thrombolytic therapy and 2% of patients post-percuta-
neous coronary intervention. Patients who experience reinfarction have
significantly increased chance of developing cardiogenic shock [22,23].
When multivessel coronary artery disease is present, the ability of the un-
affected myocardium to be recruited to preserve left ventricular function is
impaired. This loss of compensatory hypercontractility in remote myocar-
dium results in the inability to maintain cardiac output, possibly leading
to progressive ischemia in territories remote from the initial infarct and
contributing to the progressive deterioration in function.
 PATHOPHYSIOLOGY OF CARDIOGENIC SHOCK 707

The vicious cycle of diminished myocardial blood flow during shock

As a result of MI, left ventricular diastolic pressure increases. Subendo-
cardial myocardial perfusion occurs almost solely during diastole, and is de-
pendent on the pressure difference between aortic diastolic pressure and left
ventricular cavity pressure. In cardiogenic shock, aortic pressure decreases
and left ventricular pressure increases, leading to decreased coronary perfu-
sion and progressive ischemia. Intra-aortic balloon counterpulsation may
help coronary perfusion through increasing aortic diastolic pressure and
should be used in patients who have cardiogenic shock [24].
To increase cardiac output, the heart rate increases, thereby increasing
myocardial oxygen consumption directly and affecting coronary perfusion.
As heart rate increases, the time spent in diastole decreases. The time for tis-
sue perfusion decreases resulting in further ischemia of the subendocardium.
The wavefront of ischemia results in eventual global dysfunction, and the
spiral deterioration continues.

Cellular contribution to the continuum of deterioration

During acute MI, heart muscle dies. Cell death is predominantly caused
by myonecrosis and lysosomal activation caused by ischemia. However, ap-
optosis, or programmed cell death, may play an important role in infarct ex-
tension, especially in the border zone adjacent to infarcted muscle [25–28].
Mitochondria are the powerhouses of the cardiac cells, generating energy
in the form of adenosine triphosphate (ATP) to enable myocardial contrac-
tion, relaxation, and ion fluxes. In ischemia, the cardiomyocytes’ ATP pro-
duction is reduced by almost 99% [29]. Mitochondria are particularly
sensitive to ischemia, reperfusion, and the generation of reactive oxygen spe-
cies [30]. Several studies have shown that mitochondrial respiratory activity
is impaired in the mitochondria of noninfarcted myocardium, and that this
is associated with declining pump function. Free radical production may
also be associated with alterations in mitochondrial function. Alterations
in mitochondrial DNA production may be important in the development
of cardiogenic shock post-MI [28–30].
In ischemia and infarction, hypoxia-inducible factor 1 (HIF-1) alpha is
generated by the mitochondria to sense myocardial oxygenation. In
response to low levels of myocardial oxygen, HIF-1 alpha is up-regulated,
which may be an important mechanism for inducing a state of hibernation
in the peri-infarct border zone [31].

Circulating mediators: the inflammatory paradigm

It is perplexing that some patients develop cardiogenic shock despite
modestly sized risk territories, relative preservation of ejection fraction,
and timely reperfusion therapy. In clinical studies of reperfusion therapy,
708 AYMONG et al

cardiogenic shock occurs in up to 5% to 8% of patients after successful

thrombolysis and 2% to 5% of patients who undergo successful primary an-
gioplasty [22,23]. In the randomized SHOCK trial of patients who experi-
enced confirmed cardiogenic shock, the average ejection fraction was 31%
using left ventriculogram or echocardiogram [32]. Similar systolic impair-
ment is seen in uncomplicated MI and routinely observed in the stable heart
failure population. In addition, survivors of cardiogenic shock have good
functional status at follow-up [33]. Together, these observations suggest
a reversible and temporary component to cardiogenic shock, which has
led researchers to seek other mechanisms beyond the classic paradigm of
progressive myocardial ischemia and dysfunction.
Observational evidence supports the hypothesis that inflammatory cyto-
kines are responsible for the vasodilation and inappropriately low systemic
vascular resistance seen in patients who had cardiogenic shock despite suc-
cessful revascularization [34]. Many patients then develop a systemic inflam-
matory response syndrome (SIRS) that is similar to that in patients who
have sepsis and other shock syndromes. For instance, patients who have car-
diogenic shock have similar levels of interleukin (IL)-6 as those who have
septic shock. IL-6 is prognostically linked to the development of multisys-
tem organ failure and mortality in these patients [35]. Alterations in many
other cytokines have been observed, including IL-1 and tumor necrosis
factor a [36]. Although IL-6 is recognized as a myocardial depressant, the
exact mechanism through which IL-6 exerts its negative effects is undergoing
further investigation.
The clinical effects of IL-6 and other cytokines are mediated partially by
inappropriate up-regulation of nitric oxide [37]. In health, nitric oxide is
a coronary vasodilator and myocardial protectant. However, nitric oxide
at inappropriately high levels is a systemic vasodilator and direct myocardial
depressant [38]. In addition, some experts believe that nitric oxide may me-
diate myocardial stunning and cell death through apoptosis, among other
mechanisms [39].
Several small studies have tested the hypothesis that inhibiting nitric ox-
ide production using the nitric oxide synthase inhibitor L-N(G)-mono-
methyl arginine (L-NMMA) has resulted in improved hemodynamic
parameters and survival to hospital discharge [40,41]. However, the multi-
center randomized trial testing this hypothesis has recently been stopped be-
cause of futility [42], leaving the nitric oxide–mediated inflammatory
paradigm unproven, although a role for acute inflammation in the genesis
of cardiogenic shock complicating MI remains compelling.

Other cardiac causes of shock

In all of the following causes of cardiogenic shock complicating acute MI,
the primary problem is decreased forward cardiac output. However, the
specific mechanism of decreased output is different in each case.
 PATHOPHYSIOLOGY OF CARDIOGENIC SHOCK 709

Right ventricular infarction

Patients who have right ventricular infarction have a distinct clinical pic-
ture with elevated right atrial pressures and low pulmonary capillary wedge
pressures. After revascularization, optimal fluid resuscitation is the corner-
stone of therapy for these patients to maintain right ventricular preload
while not at the expense of left ventricular filling. Patients who have right
ventricular MI are particularly sensitive to rhythm disturbances and depend
on the atrial kick of sinus rhythm for ventricular filling. Inotropic therapy
may be required to increase right ventricular performance.

Acute mitral regurgitation

Mitral regurgitation can occur with acute MI, resulting in dramatic pul-
monary edema and hypotension. Although up to 15% of patients who have
MI have an element of mitral regurgitation, acute mitral regurgitation
caused by posterior papillary muscle rupture is a rare complication. It is
usually associated with inferior and posterior MIs, but can also occur in
the setting of anterior MI. Surgical repair is indicated to fix the mechanical
problem, but strategies to decrease afterload and thereby the regurgitant
fraction should be instituted.

Ventricular septal rupture and free wall rupture

Ventricular septal rupture and free wall rupture are both catastrophic
events leading to cardiogenic shock. Medical stabilization is a temporizing
measure until definitive therapy with primarily surgery can be instituted.
The capacity to have compound ischemic and mechanical factors contrib-
uting to cardiogenic shock constitutes the basis of practice guidelines that
urge the use of expedited echocardiography coincident with emergency
cardiac catheterization early in the course of shock. Diminished contractil-
ity, low cardiac output, mechanical ventilation, and intra-aortic balloon
counterpulsation may all mask mechanical cardiac lesions.
Finally, recognition and rapid treatment of other causes of shock are
essential to the management of these patients. Particularly important is vol-
ume status and treatment of hypovolemia. Also, sepsis can occur in patients
who undergo prolonged ventilation and invasive procedures. Recognition
and treatment of other reversible causes of shock is paramount in patients
who have limited myocardial reserve.

Summary
Cardiogenic shock is a rapidly progressive, often fatal complication of
MI. Rapid restoration of myocardial perfusion is the critical first step in
preventing shock in acute MI and treating patients who have cardiogenic
710 AYMONG et al

shock. The increasing mismatch between myocardial oxygen supply and de-
mand in this syndrome and its consequences begins to explain the unrelent-
ing nature of this condition as outlined above. Whether the inflammatory
paradigm can be proven and mediated remains to be seen.

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