Sepsis and Myocardial Dysfunction: A Mini Review-Juniper Publishers
JUNIPER PUBLISHERS-OPEN ACCESS JOURNAL OF CARDIOLOGY & CARDIOVASCULAR THERAPY
Sepsis is one of the leading causes of mortality and
morbidity around the world. Myocardial dysfunction is one of the
important factors in the hemodynamic compromise seen in sepsis. Numerous
mechanisms have been studied in identifying the pathophysiology,
however, no definitive hypothesis has been proven. This review attempts
to evaluate, and understand some of the known biochemical and
pathophysiological mechanisms leading to cardiac dysfunction and sepsis.
Sepsis is the leading cause of mortality and a major
healthcare concern worldwide [1]. It is characterized as a
life-threatening disease, enhanced by a dysregulated immune host
response to a precipitating infection. It’s a multifaceted disease,
encompassing various organs and may lead to end-organ failure, shock and
death. In a healthy human being the pro-inflammatory response triggered
by microbes is countered by the body’s anti-inflammatory mechanism;
however, during sepsis this mechanism gets dysregulated, leading to
organ failure.
The association of sepsis and the cardiovascular
system has been studied over a period of several decades; however, the
exact pathophysiology remains unclear. Myocardial depression is defined
as cardiac output that fails to meet the body’s metabolic demands [2,3].
Approximately 15% of the deaths related to septic shock are due to
myocardial depression [3].
In septic shock, there is a significant change in the
microcirculatory system including peripheral vascular dysfunction,
endothelial damage and induction of the coagulation cascade which can
result in heterogeneous microcirculatory flow. Septic shock is a form of
distributive shock, characterized by circulatory abnormalities that are
usually related to intravascular volume depletion and vasodilation,
resulting in oxygen supply-demand mismatch and end-organ damage [4].
Studies in animal models showed that cardiac dysfunction occurs if the
initial resuscitation is inadequate [5]. Therefore, earlier theories
suggested that global myocardial ischemia could be responsible for
myocardial dysfunction in sepsis. However, in 1986, Cunnion et al. [6]
performed studies on coronary sinus catheterization, which demonstrated
that coronary flow was the same or greater in early septic shock
patients when compared to normal individuals. Therefore, the observed
myocardial dysfunction associated with sepsis is not related to abnormal
coronary blood flow and development of coronary ischemia, proving that
global ischemia is not the reason for myocardial dysfunction in sepsis.
However, it may still be true that abnormal coronary blood flow may play
a role in myocardial dysfunction in patients with the pre-existing
atherosclerotic disease.
Endotoxins are also believed to play a crucial role
in causing cardiac dysfunction. They interact with the cell membrane
receptor, known as Toll-like receptor4 (TLR-4) found in the cardiac
immune cells. Endotoxins such as lipopolysaccharides (LPS), lipoteichoic
acid, mannan in fungi, RNA in viruses interact with TLR-4 and initiate
inflammation through mediators such as interleukins, cytokines, nitric
oxide (NO), and C5 [7]. Although these inflammatory changes havebeen
clearly demonstrated in gram negative sepsis, there is
minimal data in gram-positive sepsis. Thus, while endotoxins
and inflammation may play a role, it is not the only cause of
myocardial dysfunction in sepsis.
Myocardial depressant factors (MDF) are also believed
to play a part in causing cardiac dysfunction in sepsis. In the
mid-1970s, Lefer & Martin [8] highlighted the presence of an
MDF in the blood of dogs during induced endotoxic shock and
suggested that it was a peptide of 800 to 1,000 daltons that
originated in the pancreas. Since then numerous MDF such
as interleukins 1, and 6, tumor necrosis factor-α (TNF-α),
complement anaphylatoxin (C5a), High mobility group box
1(HMGB1), extracellular histones, matrix metalloproteinase-9
(MMP 9) have been identified and reported in the literature
[9]. TNF-α and interleukins are considered to be the most
important myocardial depressive factors. In an inflammatory
state, TNF-α is usually released from the activated
macrophages but, Horton et al showed that TNF-α is also
released by the cardiac myocytes in response to sepsis [10].
Monoclonal antibodies directed against TNF-α are believed to
improve the left ventricular function; however, they failed to
improve survival in patients with sepsis [11,12]. IL-1 alters the
cardiac contractility by stimulating the release of nitric oxide
synthase (NOS) [13]. The roles of recombinant IL-1 receptor
antagonist have been studied, but to date, it has failed to show
statistically significant benefit in patients with sepsis [14].
Thus, a multitude of factors, rather than any individual
factor are responsible for the onset of sepsis-induced
myocardial dysfunction. More prospective studies are needed
to elucidate their roles and provide a substrate for future
therapeutic interventions.
Cardiac dysfunction in sepsis is believed to be
multifactorial; therefore it is vital to identify individual
receptors and molecules, so as to develop targeted therapeutic
agents. Currently, supportive measures including intravenous
crystalloid infusion, broad-spectrum antibiotics, surgical
intervention if required to remove the septic foci, and close
monitoring in an intensive care unit are the mainstay of
treatment. As per the recent surviving sepsis guidelines,
aggressive intravenous hydration with crystalloid solution of
at least 30mL/kg should be given within the first 3 hours in
patients with septic shock to maintain mean arterial pressure
≥65mmhg and inotropic support be given to patients not
responding to the initial aggressive hydration [15]. One should
also be vigilant while administering intravenous fluids as the
excessive fluid administration may lead to pulmonary edema
due to increased permeability of the microcirculation and
cardiac dysfunction, associated with sepsis.
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