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New insights into the molecular pathogenesis
of sepsis-induced myocardial dysfunction
By Jesus G. Vallejo, MD
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Human sepsis is responsible for
20,000 to 50,000 deaths per year in the United States.
Septicemia, the term used for recording vital statistics, is the
13th leading cause of death and accounts for an estimated $5
billion to $10 billion in annual U.S. health care expenditures.
The word sepsis has become synonymous with gram-negative
bacteremia or endotoxemia. This perception arose from the
intensive effort in the 1970s to study gram-negative sepsis in
view of its extremely high mortality rate. However, data from
recent studies indicate that an upsurge in gram-positive
infections occurred in the past decade and a half in this
country. Gram-positive bacteria now account for 30 percent to 50
percent of severe sepsis or septic shock cases. Staphylococcus aureus and
Streptococcus pneumoniae account for a significant
number of sepsis cases in both adults and children. Mortality
due to gram-positive-sepsis ranges from 15 percent to 60 percent
depending on the patient’s underlying medical conditions,
etiologic agent, host response, antimicrobial therapy instituted
and the timing of shock. More importantly, in patients with
sepsis who develop cardiovascular impairment, mortality can rise
to 90 percent, demonstrating a correlation between cardiac
function and survival.
Despite the increased cardiac index
commonly associated with septic shock, myocardial depression
often is present. From the limited data available, the severity
of cardiac dysfunction associated with human sepsis seems to be
independent of the causative organism. The basic paradigm of
septic shock contends that microbially derived components
initiate an uncontrolled network of host-derived proinflammatory
mediators, which lead to cardiovascular failure (i.e., abnormal
vascular tone and left ventricular dysfunction) and death. A
circulating myocardial depressant factor in patients with septic
shock was proposed more than 50 years ago, but it was not until
the late 1980s that myocardial dysfunction was quantitatively
linked to a serum factor. Subsequently, it was demonstrated that
tumor necrosis factor (TNF) was capable of eliciting the pattern
of hemodynamic abnormalities and myocardial dysfunction observed
in human septic shock. Recent observations suggest that
biosynthesis of TNF protein is not strictly confined to
peripheral mononuclear cells, but may also occur within a number
of different tissue compartments. Indeed, studies have shown
that the cardiac compartment can be a significant source of TNF during gram-negative or gram-positive sepsis. Thus, the
production of TNF within the heart may be one of the reasons why
circulating TNF levels do not necessarily predict clinical
outcome in systemic sepsis. However, how gram-positive or
gram-negative bacteria induced the production of inflammatory
mediators within the heart had remained unknown.
Toll-like
receptors may hold the key
A major advance in the understanding
of the early events in gram-positive and gram negative bacterial
signaling has been the identification of Toll-like receptors (TLRs).
TLR2 and TLR4 are human homologues of Toll, a protein first
identified in the study of embryonic development in Drosophila melanogaster. Several lines of evidence suggest that TLR2
recognizes gram-positive organisms and their cell wall
components while TLR4 recognizes the lipopolysacharide (LPS) of
gram-negative bacteria. Studies from this and other laboratories
have shown that the heart expresses TLR2 and TLR4, raising the
interesting possibility that TLRs may be responsible for
mediating the deleterious effects of bacterial pathogens on
cardiac function. Using mice deficient in TLR2, we have defined
the role of this receptor in myocardial dysfunction induced by
Staphylococcus aureus. S. aureus challenge significantly
increased the myocardial depressant cytokines TNF and IL-1 in
hearts of wild-type mice. This response was significantly
blunted in the hearts of TLR2 deficient mice. Moreover, hearts
from TLR2-deficient mice were protected against S aureus-induced
contractile dysfunction (Figure). These studies demonstrated for
the first time that TLR2 signaling contributes to the
development of S aureus–induced left ventricular dysfunction. More importantly, these studies suggest that
pharmacological agents that would allow manipulation of common
targets within the TLR receptor signaling cascades may represent
a novel strategy to protect the heart against the dysfunctional
inflammatory response associated with S. aureus sepsis.
Jesus G. Vallejo, M.D. is assistant professor of Pediatrics
and Medicine, Section of Infectious Diseases, at Baylor College
of Medicine.
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