Review

Septic cardiomyopathy: characteristics, evaluation,

and mechanism
Wanlin Xuea,b,c, Jiaojiao Pangb,c,d, Jiao Liue, Hao Wanga,b,c, Haipeng Guoa,b,c,d,*, Yuguo Chenb,c,d,*

Abstract
Sepsis is a common clinical disease; if there is no early active treatment, it is likely to develop into multiple organ dysfunction syndrome and
even cause death. Septic cardiomyopathy is a complication of sepsis-related cardiovascular failure, characterized by reversible left ventric-
ular dilatation and decreased ventricular systolic and/or diastolic function. At present, echocardiography and biomarkers are often used to
screen septic cardiomyopathy in clinics. Although there is still a lack of clear diagnostic criteria for septic cardiomyopathy, according to
existing studies, the pathogenesis of several septic cardiomyopathy has been clarified, such as immune response caused by infection
and mitochondrial dysfunction. This review summarizes the characteristics, pathophysiology, and diagnosis of septic cardiomyopathy
and focuses on the mechanisms of infection immunity and mitochondrial dysfunction.
Keywords: Echocardiography, Infection immunity, Mitochondrial dysfunction, Sepsis-induced cardiomyopathy, Septic cardiomyopathy

Introduction In 1951, Waisbren[8] was the first to describe cardiac dysfunction

Sepsis is a life-threatening organ dysfunction caused by the body's
dysfunctional response to infection.[1] Although significant break-
throughs have been made in treatment, sepsis is still the most common
cause of death in critically ill patients worldwide.[2] According to a
study by the Institute for Health Metrics and Evaluation, there were
48.9 million cases of sepsis and 11 million sepsis-related deaths
worldwide in 2017,[3] and sepsis caused more than a quarter of
deaths in all intensive care units (ICUs).[4] The septic pathophysiol-
ogy includes inflammatory reaction, immune dysfunction, and coag-
ulation dysfunction.[5] The core of sepsis is the interaction between
organs: loss of one organ often leads to the dysfunction or failure of
other organs.[6]
Septic cardiomyopathy or sepsis-induced cardiomyopathy is a
manifestation of transient cardiac insufficiency in patients with sepsis.[7]
Sponsorships or competing interests that may be relevant to content are
disclosed at the end of this article.
a
Department of Critical Care Medicine, Qilu Hospital of Shandong University,
Jinan, Shandong, China, b The Key Laboratory of Emergency and Critical
Care Medicine of Shandong Province, Qilu Hospital of Shandong University,
Jinan, Shandong, China, c The Key Laboratory of Cardiovascular Remodeling
and Function Research, Chinese Ministry of Education and Chinese Ministry
of Health, Qilu Hospital of Shandong University, Jinan, Shandong, China,
d
Department of Emergency Medicine and Chest Pain Center, Qilu Hospital of
Shandong University, Jinan, Shandong, China, e Department of Critical Care
Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine,
Shanghai, China.
* Corresponding authors. Address: Qilu Hospital of Shandong University, 107
Wenhua Xi Road, Jinan, Shandong 250012, China. E-mail address:
chen919085@sdu.edu.cn (Y. Chen); Haipeng198334@163.com (H. Guo).
Copyright © 2022 Shandong University, published by Wolters Kluwer, Inc.
This is an open-access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-
NC-ND), where it is permissible to download and share the work provided it is
properly cited. The work cannot be changed in anyway or used commercially
without permission from the journal.
Emergency and Critical Care Medicine (2022) 2:3
Received: 6 June 2022; Accepted: 12 July 2022
Published online: 16 September 2022
http://dx.doi.org/10.1097/EC9.0000000000000060
caused by sepsis. Statistics show that more than 40% of patients
with sepsis develop myocardial dysfunction,[9] and the mortality
rate can rise to 70%[10] compared with patients without cardiac
dysfunction. Although there are no clear diagnostic criteria for
septic cardiomyopathy, several available features are still helpful
for further study.[11] Its characteristics can be summarized as left
ventricular dilatation with normal or low filling pressure, depressed
ejection fraction, and normalization within 7 to 10 days.[11] At pres-
ent, echocardiography is often used to evaluate the cardiac function
of patients, characterized by easy repeatability, noninvasion, and
wide availability. Therefore, it is the best index to evaluate septic
cardiomyopathy.[12]
In recent years, with the in-depth study of septic cardiomyopa-
thy, some progress has been made in its pathogenesis at home and
abroad. The pathogenesis of septic cardiomyopathy is very complex
and may involve abnormal inflammatory responses, such as activa-
tion of myocardial inhibitors such as tumor necrosis factor α (TNF-
α), interleukin 1 (IL-1), and interleukin 6 (IL-6); activation of the
complement system; and mitochondrial dysfunction, such as the
production of nitric oxide (NO) reactive oxygen species (ROS),
oxidative stress, calcium overload, and so on.[13–15] At present, the
signal pathways involved in different mechanisms are still contro-
versial and need to be further studied. To have a more systematic
understanding of septic cardiomyopathy, this article describes its
characteristics, evaluation methods, and mechanism.
Diagnosis and clinical characteristics of septic
cardiomyopathy
Septic cardiomyopathy is a nonischemic cardiac dysfunction that
occurs in patients with sepsis. Although there is a lack of clear diag-
nostic criteria for septic cardiomyopathy, most review articles and
experts agree on the following characteristics.[7]
Acute and reversible, gradually returned to standard 7 to
10 days after onset
In the early stage, Parker et al.[16,17] conducted continuous radionu-
clide cine angiography and thermodilution cardiac output studies
on the cardiac function of 20 patients with septic shock (including
13 surviving patients and 7 dead patients). In 10 of the 20 patients,

135
Xue et al.  Emerg Crit Care Med (2022) Vol. 2 No. 3
the left ventricular ejection fraction (LVEF) was initially low, which
was 0.40 (SD, 0.04) (reference range, 0.45–0.55), and gradually in-
creased to 0.55 (SD, 0.05) within 7 to 10 days. The 13 survivors orig-
inally had an LVEF of 0.32 to 0.04 for approximately 4 days and then
significantly returned to normal within 7 to 10 days. These studies have
shown that survivors of septic shock have changes such as decreased
ejection fraction and increased end-diastolic volume, and these changes
will occur in the early stage and reverse within 7 to 10 days.[16,17]
Global and biventricular dysfunction (systolic and/or
diastolic) with decreased contractility
Early echocardiographic studies have shown that some patients with sep-
sis have impaired left ventricular systolic and diastolic function.[18,19]
From cellular level studies,[20] isolated heart studies[21,22] to living animal
models,[23–25] these experimental studies combined with human studies
have shown that decreased contractility and impaired myocardial com-
pliance are the main factors leading to myocardial dysfunction in sepsis.
Although there were some differences in the structure of the left and right
ventricles, similar changes were also observed in the right ventricle. These
show that the right ventricular dysfunction in patients with sepsis is
closely related to the left ventricle.[26–28] In recent years, more and
more studies on the right ventricle have shown that the right ventri-
cle may play an essential role in septic cardiomyopathy.[29]
Left ventricular dilatation
According to the study by Parker et al.[16] in 1984, left ventricular dila-
tation may be related to increased left ventricular compliance. A subse-
quent study compared the end-diastolic volume index (EDVI) between
patients with septic shock and the control group (the control group in-
cluded patients who had received fluid therapy for various reasons).
The increased EDVI in patients with septic shock may be due to active
fluid resuscitation as the initial treatment, or abnormal left ventricular
dilatation caused by sepsis. There was no significant increase in EDVI
in the control group, suggesting that the higher initial EDVI in pa-
tients with septic shock is likely to represent left ventricular dilatation
caused by inherent myocardial changes because of septic shock.[30]
Poor response to fluid resuscitation and catecholamines
In terms of fluid management, people gradually realize that exces-
sive fluid resuscitation will bring adverse consequences to patients
with sepsis. SOAP (Sepsis Occurrence in Acutely Ill Patients) tests
and other studies have shown that positive fluid balance is one of
the factors worsening the prognosis.[31] Concerning the use of cate-
cholamines, the current guidelines for surviving sepsis recommend
the use of catecholamines to enhance vascular pressure therapy in
appropriate clinical regimens.[32] However, there are still potential
risks, such as increased myocardial oxygen consumption.[7]
Except for other myocardial dysfunction
Stress-induced cardiomyopathy (SICMP), also known as takotsubo
cardiomyopathy, is a dysfunction of the apical part of the left ventri-
cle, characterized by decreased or dyskinesia in the middle segment,
with or without apical involvement in addition to the distribution of
a single coronary artery.[33] Stress-induced cardiomyopathy is com-
mon in patients with sepsis. A previous analysis reported that sepsis
is the most common cause of SICMP.[34] In addition, studies have
shown that SICMP increases the mortality of patients with sepsis
by more than 20%.[35,36] Although both septic cardiomyopathy
and SICMP are associated with sepsis, their pathogenesis is not
the same. In addition, other cardiomyopathy, such as dilated cardio-
myopathy and hypertrophic cardiomyopathy, which usually have a
136
www.eccmjournal.org
long history and slow progression, should be excluded.[15] There-
fore, it is necessary to exclude other myocardial dysfunction related
to sepsis for the diagnosis of septic cardiomyopathy.
However, there are still some shortcomings in the above charac-
teristics, and it is necessary to ensure the survival of patients with
sepsis to meet the conditions of reversibility. However, the high
mortality rate in patients with sepsis can lead to biases in the results
of septic cardiomyopathy.
Evaluation of septic cardiomyopathy
The prevalence of septic cardiomyopathy in patients with sepsis
ranges from 10% to 70%, and the epidemiological differences
may be due to lack of clear diagnostic criteria and lack of under-
standing.[37] Therefore, it is necessary to identify and deal with sep-
tic cardiomyopathy in the early stage.
Electrocardiograph
At present, there is no characteristic electrocardiographic (ECG)
manifestation that can directly diagnose septic cardiomyopathy.[7]
Some patients with septic cardiomyopathy may be accompanied
by ECG changes similar to those during acute coronary syn-
drome,[38] including depression or elevation of ST segment, appear-
ance of Q wave, new left bundle-branch block, T-wave peaking,
prolonged QTC interval, or positive J wave (Osborne wave).[39]
The electrocardiogram of patients with septic cardiomyopathy may
have temporary changes, which will disappear over time.[40] In addition,
the most common rhythms in patients with septic cardiomyopathy were
sinus tachycardia and atrial fibrillation.[7] According to a meta-analysis
in 2019, heart changes caused by sepsis can lead to atrial fibrillation.[41]
Studies by Klein Klouwenberg et al.[42] have shown that the cumulative
risks of new atrial fibrillation in patients with sepsis, severe sepsis, and
septic shock are 10% (95% confidence interval [CI], 8%–12%), 22%
(95% CI, 18%–25%), and 40% (95% CI, 36%–44%), respectively.
Although these studies associate septic cardiomyopathy with atrial
fibrillation through similar pathophysiological mechanisms, atrial
fibrillation itself does not serve as a basis for diagnosing septic car-
diomyopathy. There is no specific ECG manifestation for septic car-
diomyopathy; however, when ECG changes occur in patients with
sepsis, further monitoring measures should be taken immediately.
Echocardiography
Echocardiography is an essential method for the diagnosis of septic
cardiomyopathy. It has been agreed that every patient with hemody-
namic disorder needs intensive care echocardiography.[43,44] Bed-
side target-guided echocardiographic evaluation in patients with
sepsis usually provides the first evidence of septic cardiomyopa-
thy.[45] Although echocardiography is one of the primary methods
for diagnosing septic cardiomyopathy and evaluating the myocar-
dial function, there is no single diagnostic parameter currently.[15]
Left ventricular ejection fraction. Left ventricular ejection frac-
tion can be used to measure cardiac systolic dysfunction, and it is also
one of the indicators initially identified to describe septic cardiomyopa-
thy.[16] Although LVEF has easily obtained advantages, it is still not the
best indicator for the evaluation of left ventricular function because it is
affected mainly by load conditions,[46] and when using LVEF alone to
evaluate the cardiac function of patients with sepsis, it is likely to lead to
a missed diagnosis of septic cardiomyopathy. Therefore, when using
LVEF to assess cardiac function, it is necessary to consider the dosage
of vasopressin and the degree of shock.
A 2014 meta-analysis assessed left ventricular systolic function in
585 patients by transthoracic echocardiography. The results showed
Xue et al.  Emerg Crit Care Med (2022) Vol. 2 No. 3
that LVEF reduced the overall sensitivity to mortality by 52% (95%
CI, 29%–73%), and the combined specificity was 63% (95% CI,
53%–71%). The area under the subject operating characteristic
curve is 0.62 (95% CI, 0.58–0.67).[47] Therefore, LVEF can mea-
sure left ventricular systolic function to some extent and still has
some limitations.
Myocardial performance index. The cardiac function index,
also known as “the Tai index,” is a Doppler-derived index that eval-
uates systolic and diastolic function based on the proportion of the
heart's working cycle and gives indicators of cardiac function.[48] A
prospective study by Nizamuddin et al.[49] included 47 patients with
newly diagnosed severe sepsis or septic shock. The patients' myocar-
dial performance index (MPI) was evaluated by transthoracic echocar-
diography, and the relationship between MPI and 90-day mortality
was analyzed. The study showed that the deterioration of MPI was
associated with an increase in 90-day mortality during a 24-hour
study interval.[49] Therefore, a lower MPI is associated with better
prognosis. Using MPI to evaluate cardiac function is not affected
by preload and heart rate, which is different from ejection fraction.
Moreover, MPI can simultaneously monitor the changes in diastolic
and systolic phases in patients with septic cardiomyopathy.[49,50]
Mitral annular plane systolic excursion. Mitral annular plane
systolic excursion refers to the linear distance of the mitral annulus
moving toward the tip of left ventricular during contraction,[51]
which can be used as an index to evaluate the global and regional
systolic function of the left ventricle.[15] Mitral annular plane sys-
tolic excursion has the advantages of easy availability and repeat-
ability, but its disadvantage is that it will be affected by artificial
valve or valve calcification, thus affecting its accuracy.[52] A small
sample prospective study in 2018 included 58 patients with sepsis,
of whom 10 (17.24%) were excluded because of echo window dif-
ference, 29 (60.41%) survived, and 19 (39.58%) died. Multivariate
logistic regression analysis using echocardiographic parameters
showed that mitral annular plane systolic excursion was an indepen-
dent predictor of sepsis mortality.[53]
Global longitudinal strain. Strain imaging is a new technique
based on local myocardial deformation, which can detect subtle
changes in left ventricular systolic function before decreasing
LVEF.[54] At present, the most commonly used strain parameter is
global longitudinal strain (GLS).[55] Compared with LEVF, GLS is
more accurate in the evaluation of left ventricular systolic function[56]
and not affected by LVEF; hence, it can predict cardiovascular out-
come and prognosis.[57] A 2018 systematic review and meta-analysis
studied the relationship between GLS and the longest follow-up
mortality in patients with severe septicemia and/or septic shock.
Eight studies were included in the preliminary analysis. There were
a total of 794 patients (survival rate, 68%; n = 540). It was found
that the deterioration of left ventricular function was significantly
correlated with GLS and mortality: the standard mean deviation
was 0.26% (95% CI, 0.04–0.47; P = 0.02; low heterogeneity,
I2 = 43%).[57] Ehrman et al[58] proposed that GLS is the primary
choice to study the relationship between left ventricular systolic
function and prognosis in patients with septic cardiomyopathy.
However, there are no diagnostic criteria related to GLS. In addi-
tion, the limitation of GLS is that it requires good image quality
and is affected by artifacts, noise, and so on.[59]
e′ and E/e′. Many patients with sepsis have diastolic insuffi-
ciency.[18] The flow velocity of mitral annulus in early diastole (e′)
and the ratio of the mitral annulus velocity to mitral annulus veloc-
ity (E/e′) are the key indicators of left ventricular diastolic insuffi-
137
www.eccmjournal.org
ciency[48]; e′ is the first choice to evaluate diastolic function. The
lower the value, the worse the diastolic function.[60] A systematic re-
view and meta-analysis in 2017 discussed the relationship between e
′ and E/e′ and mortality in patients with severe sepsis or septic
shock. The study included 1507 patients with severe sepsis and/or
septic shock. The mortality was associated with lower e′ (standard
mean difference, 0.33%; 95% CI, 0.05–0.62; P = 0.02) and higher
E/e' (standard mean difference, 0.33; 95% CI, 0.10–0.57; P = 0.006)
significant correlation.[61] Although it can provide a more accurate
prediction of the prognosis of patients with sepsis,[62] it still has
some limitations, such as age, mitral valve disease, and mechanical
ventilation.[63]
Tricuspid annular plane of systolic excursion
Right ventricular dysfunction can lead to increased morbidity and
mortality under different conditions, such as heart failure and pul-
monary hypertension.[64,65] Tricuspid annular plane of systolic ex-
cursion (TAPSE) is a readily available and reusable index of right
ventricular function. It indirectly evaluates right ventricular function
by describing the shortening from apical to apical regions.[66] Some
studies have shown that the reduction of TAPSE is related to in-
creased mortality in critically ill patients.[67] However, a 2020 study
recruited 24 patients who were admitted to the emergency depart-
ment because of severe sepsis or septic shock and then compared
the admission rate, length of stay, and incidence of ICU with their
respective TAPSE values. Among them, 8 patients had TAPSE
values less than 16 mm, 2 patients had TAPSE values between 16
and 20 mm, and 14 patients had TAPSE values greater than
20 mm. Studies have shown that there is no statistically significant
correlation between TAPSE levels and ICU admission ( P = 0.16)
or death ( P = 0.14),[66] and the trial data of this study do not
show a correlation between severe sepsis or septic shock and
TAPSE. Therefore, a large number of trials are still needed to
prove the relationship between TAPSE and sepsis and septic
cardiomyopathy.
Biomarkers
Abnormal biomarkers occur in patients with sepsis when they de-
velop cardiac dysfunction, mainly troponin T (cTnT), troponin I
(cTnI), and B-type natriuretic peptide (BNP). These indicators can
provide information related to the heart.[68]
Troponin I/troponin T. The increase in plasma troponin in
patients with sepsis may be associated with left ventricular systolic
dysfunction and myocardial injury.[68] At present, the mechanism of
troponin release in sepsis is not clear, and there is a theory that it
may be caused by cytoplasmic leakage of cardiomyocytes induced
by inflammation.[69,70] However, some noncardiogenic factors can
also lead to the increase in troponin, such as renal insufficiency.
Therefore, there are some limitations in using troponin to evaluate
cardiac function in patients with sepsis.[46]
B-type natriuretic peptide and NT-pro–B-type natriuretic
peptide. The hormones BNP and N-terminal proBNP (NT-
proBNP) are secreted by pulling myocardial cells in the ventricular
wall, which can reflect the load state of the myocardium. Both
BNP and NT-proBNP increase in septic patients and are positively
correlated with the severity of the disease. These markers in mortal
patients are more likely to be higher than those in survivors.[71–74]
Like troponin, BNP and NT-proBNP are more closely related to dis-
ease severity, but specific diseases cannot be identified.[75]
Xue et al.  Emerg Crit Care Med (2022) Vol. 2 No. 3 www.eccmjournal.org

Other biomarkers. In recent years, studies have found that some
new biomarkers can be used to predict septic myocardial dysfunc-
tion and prognosis, such as heart-type fatty acid–binding protein
and pregnancy-associated plasma protein A.[76,77] However, the pre-
dictive value of pregnancy-associated plasma protein A and heart-type
fatty acid–binding protein alone is limited, and further research is needed.
In addition, myeloperoxidase is considered as a potential biomarker of
sepsis.[78]Table 1 summarizes the literature on biomarkers and echocar-
diography of septic cardiomyopathy.
Myocardial dysfunction caused by sepsis is generally considered
a dysfunction rather than a biochemical disorder.[46] Therefore,
the current biomarker information can indicate the change in the
disease, but the abnormal biomarker cannot be equated with the
diagnosis and prognosis of septic cardiomyopathy.

Table 1
Summary of Selected Articles on Septic Cardiomyopathy
Echo
Parameter/ Study
Biomarkers Study Design/Setting n Measured Outcome Results
Biomarkers Troponins Francis Bessiere et al. Meta-analysis 1227 To assess the relation between troponin Elevated troponin identifies a subset
(2013)[79] elevation in sepsis and mortality of patients with sepsis at a higher
risk of death
Sheyin et al. Meta-analysis 1857 To confirm the association between Troponin elevation in patients with
(2015)[80] troponin elevation in patients with sepsis confers poorer prognosis
sepsis and mortality and is a predictor of mortality
BNP/NT-proBNP Wang et al. Meta-analysis 1865 To evaluate the correlation between An elevated BNP or NT-proBNP level
(2012)[81] elevated levels of BNPs and death may prove to be a powerful
in septic patients predictor of mortality in
septic patients
Bai et al. (2018)[82] Meta-analysis 3417 To clarify the diagnostic role of plasma Both elevated plasma BNP and
BNP and NT-proBNP in predicting NT-proBNP have moderate
mortality for septic patients predictive value for the mortality of
septic patients, and the tested
method and observation endpoint
influence the results of BNP.
Left ventricle
Systolic EF Sevilla Berrios et al. Meta-analysis 585 Estimate of LVEF in the setting of severe LVEF is not a sensitive or specific
(2014)[47] sepsis and/or septic shock and predictor of sepsis-related left
its correlation with 30-d mortality ventricular systolic dysfunction
Sanfilippo et al. Meta-analysis 1081 To analyze the relationship between LVEF is not associated with mortality
(2021)[83] LVEF and mortality in patients in patients with sepsis (mean
with sepsis difference, 0.98; 95% CI,
1.79–3.75)
GLS Kalam et al. Meta-analysis 5721 To prove that GLS is a more accurate GLS is more valuable than LVEF in
(2014)[84] parameter than LVEF in predicting predicting adverse cardiac events
cardiovascular outcomes in patients in patients with sepsis
with sepsis
Sanfilippo et al. Meta-analysis 540 To evaluate the predictive value of In patients with severe septicemia or
(2018)[57] GLS in patients with sepsis and/or septic shock, the lower the GLS
septic shock value, the higher the mortality
MAPSE Zhang et al. Case-control 45 Whether left ventricular longitudinal Longitudinal systolic function (such as
(2017)[52] study systolic function is more sensitive than MAPSE) may be more sensitive than
LVEF in the evaluation of cardiac LVEF in detecting cardiac inhibition in
function in patients with sepsis patients with sepsis
Havaldar (2018)[53] Prospective 58 To evaluate cardiac insufficiency caused The combination of MAPSE and
observational by sepsis by 2-dimensional APACHE-II can be used as a good
study echocardiography and troponin I predictor of mortality in septic
patients
MPI Nizamuddin et al. Prospective 47 To evaluate the relationship between left The deterioration of MPI in patients with
(2017)[49] observational ventricular MPI changes and 90-d severe sepsis or septic shock within
study mortality in patients with severe sepsis 24 h after admission of ICU was
associated with higher 90-d mortality
Diastolic e′ and E/e′ Sanfilippo et al. Meta-analysis 1507 To evaluate the relationship between e′ There is a strong association between
(2017)[61] and E/e′ and mortality in patients with both lower e′ and higher E/e′ and
severe septicemia or septic shock mortality in septic patients
Right ventricle
Systolic TAPSE Lahham et al. Prospective 24 To evaluate right ventricular dysfunction There was no correlation between
(2020)[66] observational in patients with severe sepsis by TAPSE severe sepsis or septic shock
study and TAPSE
APACHE II, Acute Physiology and Chronic Health Evaluation II; BNP, B-type natriuretic peptide, GLS, global longitudinal strain; ICU, intensive care unit; LVEF, left ventricular ejection fraction; MAPSE, mitral annular plane
systolic excursion; MPI, myocardial performance index; NT-proBNP, N-terminal pro–B-type natriuretic peptide; TAPSE, tricuspid annular plane of systolic excursion.

138
Xue et al.  Emerg Crit Care Med (2022) Vol. 2 No. 3
Pathology and pathophysiology of sepsis-induced
cardiomyopathy
In histopathology, a study by Rossi et al[85] included 8 patients
(male and female patients aged from 42 to 78 years) who died of
long-term severe sepsis or septic shock. Through the histological
analysis of their myocardial sections, 4 main conclusions were drawn
as follows: (1) the myocardium of patients with sepsis showed in-
creased macrophage infiltration, larger and longer cells, and increased
expression of TNF-1; (2) lipid accumulation in myocardial cells of pa-
tients with sepsis; (3) diffuse distribution of myosin and myosin, my-
osin fragmentation, and myolysis; and (4) significantly increased ex-
pression of inducible NO synthase (iNOS) and nitrotyrosine in car-
diomyocytes and interstitial macrophages in patients with sepsis.[85]
In terms of pathophysiology, septic cardiomyopathy has a com-
plex pathophysiological process, and one of its basic characteristics
is obvious reversibility. Many studies have pointed out that the car-
diac function of patients can recover to the level before the dis-
ease.[11,16,86,87] Based on the hypothesis of the early animal experi-
mental model, septic cardiomyopathy is similar to coronary artery
disease, which is caused by decreased coronary blood flow and car-
diomyocyte ischemia.[88] However, some subsequent studies have
shown that coronary blood flow increases in some patients with
sepsis.[89] The physiological disorder of cardiomyocytes still plays
a role in septic cardiomyopathy, at the level of microcirculation in-
stead of macrocirculation.[11]
Among the many pathogenic factors of septic cardiomyopathy,
the imbalance of inflammatory response induced by sepsis is considered
to be directly related to the occurrence of myocardial dysfunction.[37]
The imbalance of inflammatory response causes the body to produce
and release proinflammatory mediators and signal molecules, which
then produce and release anti-inflammatory mediators. These mol-
ecules function through different signal transduction pathways and
activate positive and negative feedback circuits in the immune sys-
tem.[90] There have been extensive studies on “myocardial inhibitory
factor” to identify cytokines (including IL-1β, TNF-α, IL-6, etc),[91,92]
complement system, NO disorder,[93] high-mobility group box protein
1 (HMGB1; involved in the pathogenesis of sepsis and signal mole-
cules),[94] and lipopolysaccharide as potential pathogenic factors
of septic cardiomyopathy. The injury of inflammatory factors will
change the endothelial permeability,[95] leading to uneven microvas-
cular flow and myocardial edema.[96] This is a mechanism that has
not been studied yet in septic cardiomyopathy.
Mechanism of sepsis-induced cardiomyopathy
At present, the mechanism of septic cardiomyopathy is still in the
exploratory stage.[15] The widely recognized mechanisms include
cytokines, complement system, oxidative stress, changes in NO me-
tabolism, imbalance of calcium homeostasis in cardiomyocytes, and
so on (Fig. 1).[12,97]
Infection immune mechanism of sepsis-induced
cardiomyopathy
Sepsis results from an imbalance in the body's response to infection and is
a life-threatening physiological state, often accompanied by organ dys-
function.[98] The progress from infection to sepsis has always been the fo-
cus of research, which is caused by pathogen-associated molecular pat-
terns (PAMPs) and damage-associated molecular patterns (DAMPs).[99]
Pathogen-associated molecular patterns. The body's innate
immune defense system is the first line of defense against bacterial
infection.[100] The body's defense system can recognize the molecu-
139
www.eccmjournal.org
lar components of invasive pathogens, called PAMPs, which have
special receptors called pattern recognition receptors (PRRs).[101,102]
Lipopolysaccharide, also known as bacterial endotoxin, is a
component of the outer membrane of gram-negative bacteria
and is a well-known PAMP. Lipopolysaccharide is considered as
one of the main drivers of cytokine storm and one of the critical trig-
gers of fatal shock.[103] Lipopolysaccharide forms a complex with
lipopolysaccharide-binding protein and CD14. When it binds to
Toll-like receptor 4 (TLR4), it triggers an excessive immune response
and stimulates the release of a variety of cytokines, such as type I in-
terferon gene, TNF-α, and several ILs. If there is no early active treat-
ment, it will further lead to multiple organ dysfunction.[104–106] Car-
diomyocytes express TLR4, so PAMP binds not only the immune re-
ceptors on the surface of inflammatory cells but also the receptors on
the surface of cardiomyocytes, which leads to the decrease in myocar-
dial contractility and the occurrence of inflammation.[107] A study of
healthy volunteers by Suffredini et al[108] showed that injection of en-
dotoxin resulted in a decrease in LVEF and an increase in left ventric-
ular end-diastolic volume.
A recent study showed that endotoxin could improve the bio-
chemical indexes of inflammatory cell infiltration, cardiac dysfunc-
tion, and cardiomyocyte injury in mice by activating acetaldehyde
dehydrogenase 2.[109] Acetaldehyde dehydrogenase 2 may have a
protective effect on cardiac abnormalities induced by endotoxin by
inhibiting endoplasmic reticulum stress and autophagy.[110] Other
widely studied PAMPs include lipoprotein, peptide polysaccharides,
lipoteichoic acid, and nucleic acid,[106] which play an essential role
in the occurrence and development of sepsis.
In addition to PAMPs such as lipopolysaccharide, viruses can
stimulate the production and release of cytokines, such as coronavi-
rus disease 2019 (COVID-19).[111] Despite the pathogenesis of
COVID-19 has not been fully elucidated, previous studies have
shown that serum cytokines are high in patients with severe
COVID-19, similar to those in patients with sepsis.[112–115]
Danger-associated molecular patterns. Cell damage caused
by PAMP may cause injured cells to release various cytokines and
endogenous molecules, called DAMPs, leading to a vicious cycle
by further stimulating PRRs.[116,117]
High-mobility group box protein 1 is a highly conserved nuclear
protein. It is expressed in almost all human cells except those with-
out nuclei. Yang et al[118] have demonstrated the role of HMGB1
as a proinflammatory cytokine in the immune response to tissue in-
jury. In patients with sepsis, monocytes, neutrophils, and macro-
phages release HMGB1, which can amplify the systemic and local
inflammatory response and even lead to multiple organ dysfunction
syndrome.[119] Heat shock proteins (HSPs) are a family of molecular
chaperones involved in all steps of protein synthesis and play a cru-
cial role in protecting cells from stress-related damage.[120] Early
studies have shown that HSP72 can reverse cardiac dysfunction in
a septic model induced by cecal ligation and puncture (CLP).[121]
A recent study indicates that HSP22 has a particular protective ef-
fect on septic cardiomyopathy caused by LPS.[122] The specific mech-
anism of HSPs in sepsis needs to be further studied. In addition,
DAMPs are involved in mitochondrial DNA (mtDNA), where mtDNA
fragments are released into the extracellular matrix from damaged or
dead cells, leading to the activation of immune cascades and inflamma-
tion. Both aseptic and infectious tissue damage is related to the in-
creased release of mtDNA.[123,124]
Myocardial inhibitory factor. In 1985, a study proved the exis-
tence of a myocardial inhibitory factor. Parrillo et al[125] incubated
isolated rat cardiomyocytes with the serum of patients with septic
Xue et al.  Emerg Crit Care Med (2022) Vol. 2 No. 3 www.eccmjournal.org

Figure 1. The mechanism of septic cardiomyopathy. After binding to PRRs, PAMPs and DAMPs activate the corresponding signal pathways and produce a
large number of cytokines such as TNF-α and IL-1β. These cytokines cause immune response disorders and lead to myocardial dysfunction. H+ enters the
mitochondrial matrix by UCP rather than ATPase, uncoupling the production of ATP in mitochondria with the consumption of O2 and reducing the
production of ATP, which leads to myocardial dysfunction. In septic patients, the calcium channels on the myocardial cell membrane are opened, which
makes a large amount of calcium influx into the cytoplasm, and a large amount of calcium ions open the mPTP on the mitochondria, which makes mtDNA
and cytochrome C enter the cytoplasm and enter the cell apoptosis. L-Arginine produces NO and NO under the action of NOS and combines with
superoxide O−2 to form a strongly oxidizing ONOO−, which promotes the occurrence of oxidative stress and aggravates myocardial dysfunction. These
factors are involved in the occurrence and development of septic cardiomyopathy. DAMPs, damage-associated molecular patterns; IL-1β, interleukin 1β;
LPS, lipopolysaccharide; mPTP, mitochondrial permeability transition pore; mtDNA, mitochondrial DNA; NF-κB, nuclear factor κB; NO, nitric oxide; NOS,
nitric oxide synthase; O−2, superoxide; PAMPs, pathogen-associated molecular patterns; PGN, peptide polysaccharides; TNF-α, tumor necrosis factor α;
UCP, uncoupling protein.

shock, resulting in a decrease in the amplitude and speed of myocardial
cell contraction, which further proved the existence of myocardial in-
hibitory factor. It confirms that several myocardial inhibitory factors,
such as TNF-α and IL-1β, increase in circulation during sepsis and
are found to directly inhibit myocardial contractility in vitro.[91,126,127]
Tumor necrosis factor is generally released by activated macro-
phages and is one of the crucial mediators of septic shock caused
by endotoxin.[48] Recent studies have shown that cardiomyocytes
can also release TNF.[128] Interleukin 1 is also one of the cytokines
of myocardial dysfunction in patients with sepsis. They are synthe-
sized by macrophages, monocytes, and neutrophils under the action
of circulating TNF.[48] Tumor necrosis factor α and IL-1β may play
a key role in early systolic dysfunction, but it does not explain per-
sistent myocardial dysfunction caused by sepsis, because TNF-α of-
ten reaches a peak within 48 hours after administration.[129] Be-
sides, both TNF-α and IL-1β can induce the release of additional
factors (such as NO), which in turn change myocardial func-
tion.[126,130] Interleukin 6 is also a proinflammatory cytokine and
is involved in the pathogenesis of sepsis. It should be noted that
the half-lives of TNF-α, IL-1, and IL-6 are all less than 6 hours, so
they are not independent risk factors for septic cardiomyopathy.[5]
In addition, there are many other cytokines involved in the occur-
rence and development of septic cardiomyopathy. Type I interferon
may aggravate sepsis by up-regulating caspase-11 and gasdermin
D.[131] Exotoxin can activate T lymphocytes to produce proinflam-
matory mediators interferon c and IL-2, thereby stimulating iNOS
to produce NO.[132] Lipopolysaccharide-induced sepsis damages the
integrity of the endothelial cell barrier and increases the level of
endothelin 1 in the plasma of patients with sepsis, which stimulates
the production of ROS and further leads to the development of oxida-
tive stress.[132] The specific mechanisms of different cytokines in the
pathogenesis of septic cardiomyopathy need to be further studied.
Toll-like receptors. Toll-like receptors are a transmembrane gly-
coprotein located on the surface of the cell membrane and an inte-
gral part of the immune system,[15] which can distinguish different
pathogens and cause an immune response quickly.[133] Toll-like re-
ceptors increase the production of inflammatory cytokines and
interferon-induced genes through intracellular signaling pathways
such as nuclear factor κB (NF-κB) and mitogen-activated protein ki-
nase (MAPKs).[134] Various studies have identified the presentation
of human TLRs, including the expression of TLR2, TLR4, and

140
Xue et al.  Emerg Crit Care Med (2022) Vol. 2 No. 3
TLR6 in the heart.[135–137] In the study of septic cardiomyopathy,
TLR4 is the most studied item in the TLR family. Studies have shown
that TLR4 plays an important role in regulating neutrophil migration
and phagocytosis, reducing inflammation, reducing ROS production,
and enhancing bacterial clearance.[138] Toll-like receptor 4 can bind to
endotoxin and cause the release of a variety of inflammatory factors, re-
sulting in cardiac insufficiency.[139] In addition, TLR4 regulates the oxi-
dative stress of ryanodine receptor 2, resulting in increased sarcoplasmic
reticulum calcium leakage in cardiomyocytes.[140] In an animal experi-
mental model, inhibition of TLR4 has a specific protective effect on sep-
tic cardiomyopathy.[140,141] Other TLR-related genes (TLR3, TLR9) are
also associated with cardiac dysfunction caused by sepsis. A study by
Fattahi et al[142] found that LVEF was significantly increased, and proin-
flammatory factors such as TNF-α, IL-1, and IL-6 were significantly de-
creased in septic mice with TLR9 and TLR3 deletion, suggesting that the
activation of TLR9 and TLR3 is related to cardiac dysfunction in sepsis.
Current studies confirm that TLRs and their downstream signal path-
ways are associated with the occurrence and development of septic
cardiomyopathy. Based on these studies, it is hopeful of finding
new targeted treatments.
The complement system. Sepsis can lead to the activation of
the complement system in the body and trigger a cascade of comple-
ment proteins. After the complement system is activated, the num-
ber of complement component 5 (C5) increases, and the final cleav-
age of C5 produces C5a and C5b. C5a is an allergic toxin. C5b is a
component of the terminal membrane attack complex, which can
cleave the membrane of bacteria.[143] C5a reacts with its receptor,
resulting in cytokine storms, lymphocyte apoptosis, loss of innate
immune function of neutrophils, and so on. At the same time, C5a
affects intracellular calcium homeostasis.[144,145] There are 3 essen-
tial complement receptor dependent enzymes in cardiomyocytes asso-
ciated with septic cardiomyopathy: SERCA2, NCX, and Na+/K+-
ATPase.[144] Some studies have shown that histone may be one of
the targets to reduce myocardial damage in sepsis, and extracellular
histones in septic plasma need a C5a receptor.[146] Niederbichler
et al.[127] confirmed the relationship between C5a and septic cardio-
myopathy by studying the effects of C5a on rat hearts in vivo and cul-
tured cardiomyocytes in vitro during CLP-induced sepsis. CLP signif-
icantly reduced global left ventricular pressure, which could be re-
versed by anti-C5a antibody immediately after CLP. On the other
hand, C5 inhibitors can reduce the increase in plasma soluble uPAR,
thrombomodulin, and angiopoietin 2 induced by sepsis, suggesting
that inhibition of C5 production may also protect endothelial cell dys-
function.[147] These studies indicate that C5 is closely related to the
occurrence of septic cardiomyopathy.
Mitochondrial dysfunction
Rich adenosine triphosphate (ATP) is produced by high-energy ox-
idative phosphorylation of fatty acid β, which mainly exists in the
rich mitochondria of the heart. Adenosine triphosphate provides
energy for the energy-consuming reaction and the energy-releasing reac-
tion. Because the systolic and diastolic functions of the heart are main-
tained by ATP, severe mitochondrial dysfunction plays a vital role in
the occurrence and development of septic cardiomyopathy.[148] The
mechanisms of mitochondrial dysfunction mainly include producing
ROS and NO, oxidative stress, mitochondrial uncoupling, calcium
overload, and changes in mitochondrial permeability.
Production of reactive oxygen species and nitric oxide and
oxidative stress. Sepsis is usually accompanied by the production
of NO, cytokines, and ROS.[149] Nitric oxide synthase (NOS) oxidizes
L-arginine to NO in cardiomyocytes. Nitric oxide synthase can be
141
www.eccmjournal.org
divided into 3 subtypes: neuronal NOS, iNOS, and endothelial NOS
(eNOS).[150] In general, eNOS and neuronal NOS produce a small
amount of NO, and NO produced by eNOS has a certain protective
effect on vascular endothelium and vascular function.[15] Under
normal physiological conditions, iNOS is not responsible for mak-
ing NO. However, when inflammation occurs, the invasion of bac-
teria will activate TLRs and lead to the release of cytokines and
other substances and overstimulate neutrophils. Because neutro-
phils also express iNOS, iNOS will produce a large amount of
NO.[150] Experiments have shown that NO produced by iNOS
can damage cardiac function, such as reducing the sensitivity of car-
diomyocytes to Ca2+ and causing damage to mitochondria.[151]
Nitric oxide reacts rapidly with superoxide (O−2) to form a toxic
product peroxynitrite anion (ONOO−).[152] ONOO− is a strong oxi-
dant and a key cytotoxic factor in tissue damage induced by oxidative
stress. It can lead to direct oxidative or nitrosation damage, inhibit
OXPHOS complex, and then inhibit mitochondrial the respiratory
chain.[153–156]
On the other hand, the increase in ROS production, significantly
the increase in O2·−, will lead to high endogenous antioxidant capac-
ity,[157] and the rise in O2·− will increase ROS in turn, thus forming a
vicious cycle of oxidative stress.[158,159] Significantly increased ROS
and NO can inhibit OXPHOS complex I and complex IV. Complex
I will be permanently inhibited and maintained for a long time under
high NO conditions.[160,161]
Mitochondrial uncoupling. In mitochondria, most protons
return to the matrix through the F0 subunit of F0F1-ATPase and re-
generate ATP from ADP. In general, some H+ is returned to the ma-
trix through uncoupling proteins (UCPs) rather than F0F1-ATPase,
resulting in the uncoupling between mitochondrial ATP synthesis
and O2 consumption. The level of uncoupling is one of the deci-
sive factors in the story of ROS in mitochondria. However, in
some cases, an increase in the level of uncoupling can reduce ox-
ygen consumption, leading to myocardial dysfunction.[162,163]
Uncoupling protein–mediated uncoupling may aggravate cardiac
dysfunction in patients with septic cardiomyopathy.[164] A 2015
study found that increased expression of UCP2mRNA was asso-
ciated with increased ROS and mitochondrial dysfunction,
whereas inhibition of UCP2 offset these changes and alleviated
mitochondrial dysfunction.[165]
Mitochondrial permeability and calcium overload.
Mitochondrial permeability transition pore (mPTP) is a histone
complex between the inner and outer membranes of mitochondria,
which is a nonspecific channel. Its permeability depends on the
voltage-dependent anion channel, calcium-dependent anion channel,
and cyclosporine A–sensitive high conductance channel located in the
mitochondrial inner membrane. The opening of mPTP results in mito-
chondrial swelling and rupture of the mitochondrial outer membrane,
which finally leads to activation of the proapoptotic pathway and cell
necrosis. Calcium overload is the main trigger factor of mPTP opening.
In the early stage of sepsis, the concentration of intracellular calcium in-
creased significantly, and the excessive influx of extracellular calcium
led to intracellular calcium overload[166,167] and then led to the opening
of mPTP, induced the release of mtDNA and cytochrome C into the cy-
toplasm, and finally activated the apoptosis signal. Although apoptosis
occurs in only a small number of cardiomyocytes, the activation of ap-
optotic pathway may lead to myocardial dysfunction.[168,169] Studies
have shown that the cardiomyocytes of septic rats will have mito-
chondrial ridge damage and mitochondrial vacuolation, and the level
of cytochrome C in the cytoplasm will increase.[170] This further
proves that sepsis can lead to changes in mitochondrial permeability.
Xue et al.  Emerg Crit Care Med (2022) Vol. 2 No. 3 www.eccmjournal.org

Signal pathway
It is generally believed that the recognition of PAMPs and DAMPs is
the first step in the occurrence of sepsis. The recognition process is
guaranteed by a series of PRRs, which exist in the cell membrane
or intracellular space. The recognition process will lead to the acti-
vation of intracellular signal pathways and lead to myocardial dys-
function (Fig. 2).
The pathogenesis of septic cardiomyopathy is very complex.
Studies have shown that TLR4 is an essential mediator of innate immu-
nity and inflammation and plays a crucial role in myocardial damage
caused by sepsis.[11,171] Furthermore, it participates in signal transduc-
tion of specific antigens produced by pathogens and endotoxins, in-
cluding NF-κB and MAPKs.[172] When endotoxin invades the body,
it binds to TLR4 on the surface of neutrophils, macrophages, and other
immunological cells. The binding of TLR4 and its homologous re-
ceptor mediates signal transduction to the homologous region of
the Toll/IL-1 receptor, which is a highly conserved domain homolo-
gous to the intracellular domain of IL-1. After that, NF-κB is acti-
vated to induce the expression of inflammation-related genes and
produce cytokines such as TNF-a, IL-1b, and IL-6, which are the
main causes of myocardial dysfunction in patients with sepsis.[92,173]
During sepsis, the activation of the complement system leads to
the massive production of complement C5a,[174] and its elevated
level is related to the severity of sepsis. Studies have shown that
C5a plays a vital role in myocardial dysfunction caused by sepsis
by binding to its receptors (C5aR1 and C5aR2).[175] The interaction
of C5a-C5aR will activate MAPKs and other signal pathways in car-
diomyocytes, and the activated signal pathways will act on transcrip-
tion factors, thus enhancing gene expression.[176] Mitogen-activated
protein kinase often appears as an essential signaling pathway in dif-
ferent biological processes of many cell types, such as cell growth, cell
differentiation, inflammation, sepsis, and so on.[177] At present, there
are 3 relatively straightforward MAPK pathways, namely, ERK-1/2,
JNK-1/2, and p38.[178] The activation of MAPK was initially thought
to be mediated by cascading Shc/Grb2/RAS signals to activate mem-
bers of the Src family of tyrosine kinases.[179] Mitogen-activated
protein kinase phosphorylates other downstream protein kinases
and transcription factors.[177] In addition to MAPK, RAS-GTP
can bind and activate PI3K, and PI3K to activate the downstream
of serine/threonine-specific protein kinase, namely, AKT (also known
as PKB). Studies have shown that the incubation of cardiomyocytes
in vitro leads to the activation of MAPK and Akt, and the phosphor-
ylation of MAPKs (p38, ERK-1/2, and JNK-1/2) and Akt in

Figure 2. The signal pathway of septic cardiomyopathy. IL-1, TNF-α, or bacteria, viruses, and fungi can activate NF-κB–related pathways when they bind to the
corresponding receptors. After being stimulated by ligands, the receptor activates IKK and phosphorylates the inactivated NF-κB. NF-κB activates the
corresponding target genes. IFN-γ binds IFNGR to activate JAK-STAT pathway, and microorganisms stimulate TLR to activate MAPK pathway and
corresponding target genes. The activation of these target genes will lead to the production of a large number of cytokines such as TNF-α, IL-1, and IL-6,
which leads to cellular responses such as immunity, inflammation, and stress. In addition, mitochondrial dysfunction is one of the important causes of septic
cardiomyopathy. The large production of NO and ROS will directly lead to cell damage and interact with mtDNA. When mPTP is opened due to calcium
overload, mtDNA and cytochrome C enter the cytoplasm and will accelerate cell apoptosis. ALDH2, acetaldehyde dehydrogenase 2; AP-1, activator protein
1; CaM, calmodulin; IFN-γ, interferon-γ; IFNGR, interferon-γ receptor; IKK, I κB kinase; IL-1, interleukin 1; IL-1R, interleukin 1 receptor; IRAK, interleukin 1
receptor–associated kinases; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; mtDNA, mitochondrial DNA; mPTP, mitochondrial permeability
transition pore; MyD88, myeloid differentiation factor 88; NAFT, nuclear factor of activated T cells; NF-κB, nuclear factor κB; ROS, reactive oxygen species;
SFKs, Src family of protein tyrosine kinases; STAT1, signal transducer and activator of transcription 1; TLR, Toll-like receptor; TNF-α, tumor necrosis factor
α; TNFR1, tumor necrosis factor receptor1; TRAF, TNF receptor–associated factor.

142
Xue et al.  Emerg Crit Care Med (2022) Vol. 2 No. 3
cardiomyocytes after sepsis depends on C5aR.[178] These studies
suggest that C5a plays a role in MAPK and Akt signaling pathways
and has a certain impact on the occurrence and development of sep-
tic cardiomyopathy.
Other signal pathways are involved in the occurrence and devel-
opment of septic cardiomyopathy. For example, miR-135a may me-
diate myocardial damage in sepsis by regulating the p38 MAPK–
NF-κB signal pathway.[180] The combined action of TNF-α and
IFN-γ can activate JAK/STAT1/IRF1 signal pathway and induce
the production of NO[181] and then cause myocardial damage.
Conclusion
Although septic cardiomyopathy is reversible, it still has a high mor-
tality rate, because its pathogenesis is not completely clear. In this re-
view, we discuss the characteristics, diagnostic methods, pathophys-
iology, and pathogenesis of septic cardiomyopathy. At present, it is
known that inflammatory response and mitochondrial dysfunction
play an important role in the occurrence and development of septic
cardiomyopathy. However, a large number of studies are still
needed to improve the understanding of its pathophysiology and
pathogenesis. At the same time, we need to rely on its pathogenesis
to develop new treatments to reduce the incidence and mortality of
septic cardiomyopathy.
Conflict of interest statement
Yuguo Chen is the editor-in-chief of Emergency and Critical Care
Medicine. The article was subject to the journal's standard proce-
dures, with peer review handled independently of the editor-in-
chief and their research groups. The authors declare that they have
no financial conflict of interest.
Author contributions
Xue W, Guo H, and Chen Y participated in research design. Xue W,
Pang J, and Guo H participated in writing the paper. Liu J and
Wang H participated in the performance of the research. Xue W,
Guo H, and Chen Y participated in data analysis. All authors ap-
proved the final manuscript and are responsible for the content.
Funding
This work was supported by grants from the National Natural Science
Foundation of China (82172165) and Taishan Young Scholar Pro-
gram of Shandong Province (tsqn202103171). Project was funded by
China Postdoctoral Science Foundation (2020T130072ZX) and Clin-
ical Research Center of Shandong University (2020SDUCRCC007).
Ethical approval of studies and informed consent
None.
Acknowledgements
The authors thank our colleagues from the Department of Critical
Care Medicine, Qilu Hospital of Shandong University for their valu-
able comments on the manuscript.
References
[1] Singer M, Deutschman CS, Seymour CW, et al. The third international
consensus definitions for sepsis and septic shock (sepsis-3). JAMA.
2016;315(8):801–810. doi:10.1001/jama.2016.0287
[2] Vincent JL, Marshall JC, Namendys-Silva SA, et al. Assessment of the
worldwide burden of critical illness: the Intensive Care Over Nations
(ICON) audit. Lancet Respir Med. 2014;2(5):380–386. doi:10.1016/
S2213-2600(14)70061-X
143
www.eccmjournal.org
[3] Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and
national sepsis incidence and mortality, 1990–2017: analysis for the
Global Burden of Disease Study. Lancet. 2020;395(10219):200–211.
doi:10.1016/S0140-6736(19)32989-7
[4] Perner A, Cecconi M, Cronhjort M, et al. Expert statement for the
management of hypovolemia in sepsis. Intensive Care Med. 2018;44
(6):791–798. doi:10.1007/s00134-018-5177-x
[5] Liu YC, Yu MM, Shou ST, Chai YF. Sepsis-induced cardiomyopathy:
mechanisms and treatments. Front Immunol. 2017;8:1021. doi:10.
3389/fimmu.2017.01021
[6] Abraham E, Singer M. Mechanisms of sepsis-induced organ
dysfunction. Crit Care Med. 2007;35(10):2408–2416. doi:10.1097/
01.ccm.0000282072.56245.91
[7] L'Heureux M, Sternberg M, Brath L, Turlington J, Kashiouris MG.
Sepsis-induced cardiomyopathy: a comprehensive review. Curr
Cardiol Rep. 2020;22(5):35. doi:10.1007/s11886-020-01277-2
[8] Waisbren BA. Bacteremia due to gram-negative bacilli other than the
Salmonella; a clinical and therapeutic study. AMA Arch Intern Med.
1951;88(4):467–488. doi:10.1001/archinte.1951.03810100051005
[9] Fernandes CJ, Jr., Akamine N, Knobel E. Cardiac troponin: a new
serum marker of myocardial injury in sepsis. Intensive Care Med.
1999;25(10):1165–1168. doi:10.1007/s001340051030
[10] Blanco J, Muriel-Bombin A, Sagredo V, et al. Incidence, organ
dysfunction and mortality in severe sepsis: a Spanish multicentre
study. Crit Care. 2008;12(6):R158. doi:10.1186/cc7157
[11] Sato R, Nasu M. A review of sepsis-induced cardiomyopathy. J
Intensive Care. 2015;3:48. doi:10.1186/s40560-015-0112-5
[12] Ehrman RR, Sullivan AN, Favot MJ, et al. Pathophysiology,
echocardiographic evaluation, biomarker findings, and prognostic
implications of septic cardiomyopathy: a review of the literature.
Crit Care. 2018;22(1):112. doi:10.1186/s13054-018-2043-8
[13] Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac
dysfunction. Crit Care Med. 2007;35(6):1599–1608. doi:10.1097/
01.CCM.0000266683.64081.02
[14] Romero-Bermejo FJ, Ruiz-Bailen M, Gil-Cebrian J, Huertos-Ranchal
MJ. Sepsis-induced cardiomyopathy. Curr Cardiol Rev. 2011;7(3):
163–183. doi:10.2174/157340311798220494
[15] Lin H, Wang W, Lee M, Meng Q, Ren H. Current status of septic
cardiomyopathy: basic science and clinical progress. Front Pharmacol.
2020;11:210. doi:10.3389/fphar.2020.00210
[16] Parker MM, Shelhamer JH, Bacharach SL, et al. Profound but
reversible myocardial depression in patients with septic shock. Ann
Intern Med. 1984;100(4):483–490. doi:10.7326/0003-4819-100-4-483
[17] Parker MM, Shelhamer JH, Natanson C, Alling DW, Parrillo JE.
Serial cardiovascular variables in survivors and nonsurvivors of human
septic shock: heart rate as an early predictor of prognosis. Crit Care
Med. 1987;15(10):923–929. doi:10.1097/00003246-198710000-00006
[18] Jafri SM, Lavine S, Field BE, Bahorozian MT, Carlson RW. Left
ventricular diastolic function in sepsis. Crit Care Med. 1990;18(7):
709–714. doi:10.1097/00003246-199007000-00005
[19] Munt B, Jue J, Gin K, Fenwick J, Tweeddale M. Diastolic filling in
human severe sepsis: an echocardiographic study. Crit Care Med.
1998;26(11):1829–1833. doi:10.1097/00003246-199811000-00023
[20] Ren J, Ren BH, Sharma AC. Sepsis-induced depressed contractile
function of isolated ventricular myocytes is due to altered calcium
transient properties. Shock. 2002;18(3):285–288. doi:10.1097/00024382-
200209000-00014
[21] McDonough KH, Smith T, Patel K, Quinn M. Myocardial
dysfunction in the septic rat heart: role of nitric oxide. Shock. 1998;
10(5):371–376. doi:10.1097/00024382-199811000-00011
[22] Merx MW, Liehn EA, Janssens U, et al. HMG-CoA reductase
inhibitor simvastatin profoundly improves survival in a murine
model of sepsis. Circulation. 2004;109(21):2560–2565. doi:10.1161/
01.CIR.0000129774.09737.5B
[23] Natanson C, Fink MP, Ballantyne HK, MacVittie TJ, Conklin JJ,
Parrillo JE. Gram-negative bacteremia produces both severe systolic
and diastolic cardiac dysfunction in a canine model that simulates
human septic shock. J Clin Invest. 1986;78(1):259–270. doi:10.1172/
JCI112559
[24] Stahl TJ, Alden PB, Ring WS, Madoff RC, Cerra FB. Sepsis-induced
diastolic dysfunction in chronic canine peritonitis. Am J Physiol. 1990;
258(3 pt 2):H625–H633. doi:10.1152/ajpheart.1990.258.3.H625
[25] Merx MW, Liehn EA, Graf J, et al. Statin treatment after onset of
sepsis in a murine model improves survival. Circulation. 2005;112
(1):117–124. doi:10.1161/CIRCULATIONAHA.104.502195
Xue et al.  Emerg Crit Care Med (2022) Vol. 2 No. 3
[26] Vincent JL, Thirion M, Brimioulle S, Lejeune P, Kahn RJ. Thermodilution
measurement of right ventricular ejection fraction with a modified
pulmonary artery catheter. Intensive Care Med. 1986;12(1):33–38.
doi:10.1007/BF00315367
[27] Dhainaut JF, Brunet F, Monsallier JF, et al. Bedside evaluation of right
ventricular performance using a rapid computerized thermodilution
method. Crit Care Med. 1987;15(2):148–152. doi:10.1097/00003246-
198702000-00014
[28] Parker MM, McCarthy KE, Ognibene FP, Parrillo JE. Right ventricular
dysfunction and dilatation, similar to left ventricular changes, characterize
the cardiac depression of septic shock in humans. Chest. 1990;97(1):
126–131. doi:10.1378/chest.97.1.126
[29] Chan CM, Klinger JR. The right ventricle in sepsis. Clin Chest Med.
2008;29(4):661–676, ix. doi:10.1016/j.ccm.2008.07.002
[30] Ognibene FP, Parker MM, Natanson C, Shelhamer JH, Parrillo JE.
Depressed left ventricular performance. Response to volume infusion
in patients with sepsis and septic shock. Chest. 1988;93(5):903–910.
doi:10.1378/chest.93.5.903
[31] Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care
units: results of the SOAP study. Crit Care Med. 2006;34(2):344–353.
doi:10.1097/01.ccm.0000194725.48928.3a
[32] Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign:
international guidelines for management of sepsis and septic shock
2021. Intensive Care Med. 2021;47(11):1181–1247. doi:10.1007/
s00134-021-06506-y
[33] Kurowski V, Kaiser A, von Hof K, et al. Apical and midventricular
transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy):
frequency, mechanisms, and prognosis. Chest. 2007;132(3):809–816.
doi:10.1378/chest.07-0608
[34] Cappelletti S, Ciallella C, Aromatario M, Ashrafian H, Harding S,
Athanasiou T. Takotsubo cardiomyopathy and sepsis. Angiology.
2017;68(4):288–303. doi:10.1177/0003319716653886
[35] Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E. Apical
ballooning syndrome or takotsubo cardiomyopathy: a systematic review.
Eur Heart J. 2006;27(13):1523–1529. doi:10.1093/eurheartj/ehl032
[36] Brinjikji W, El-Sayed AM, Salka S. In-hospital mortality among
patients with takotsubo cardiomyopathy: a study of the National
Inpatient Sample 2008 to 2009. Am Heart J. 2012;164(2):215–221.
doi:10.1016/j.ahj.2012.04.010
[37] Beesley SJ, Weber G, Sarge T, et al. Septic cardiomyopathy. Crit Care
Med. 2018;46(4):625–634. doi:10.1097/CCM.0000000000002851
[38] Sharkey SW, Shear W, Hodges M, Herzog CA. Reversible myocardial
contraction abnormalities in patients with an acute noncardiac illness.
Chest. 1998;114(1):98–105. doi:10.1378/chest.114.1.98
[39] Martinez JD, Babu RV, Sharma G. Escherichia coli septic shock
masquerading as ST-segment elevation myocardial infarction. Postgrad
Med. 2009;121(2):102–105. doi:10.3810/pgm.2009.03.1981
[40] Ruiz Bailen M, Aguayo de Hoyos E, Lopez Martnez A, et al.
Reversible myocardial dysfunction, a possible complication in
critically ill patients without heart disease. J Crit Care. 2003;18(4):
245–252. doi:10.1016/j.jcrc.2003.10.008
[41] Bosch NA, Cohen DM, Walkey AJ. Risk factors for new-onset atrial
fibrillation in patients with sepsis: a systematic review and meta-analysis.
Crit Care Med. 2019;47(2):280–287. doi:10.1097/CCM.0000000000003560
[42] Klein Klouwenberg PM, Frencken JF, Kuipers S, et al. Incidence,
predictors, and outcomes of new-onset atrial fibrillation in critically
ill patients with sepsis. A cohort study. Am J Respir Crit Care Med.
2017;195(2):205–211. doi:10.1164/rccm.201603-0618OC
[43] Vieillard-Baron A, Millington SJ, Sanfilippo F, et al. A decade of
progress in critical care echocardiography: a narrative review. Intensive
Care Med. 2019;45(6):770–788. doi:10.1007/s00134-019-05604-2
[44] Expert Round Table on Echocardiography in ICU. International
consensus statement on training standards for advanced critical care
echocardiography. Intensive Care Med 2014;40(5):654–666. doi:10.
1007/s00134-014-3228-5
[45] Walley PE, Walley KR, Goodgame B, Punjabi V, Sirounis D. A
practical approach to goal-directed echocardiography in the critical care
setting. Crit Care. 2014;18(6):681. doi:10.1186/s13054-014-0681-z
[46] Hollenberg SM, Singer M. Pathophysiology of sepsis-induced
cardiomyopathy. Nat Rev Cardiol. 2021;18(6):424–434. doi:10.
1038/s41569-020-00492-2
[47] Sevilla Berrios RA, O'Horo JC, Velagapudi V, Pulido JN. Correlation
of left ventricular systolic dysfunction determined by low ejection
fraction and 30-day mortality in patients with severe sepsis and
septic shock: a systematic review and meta-analysis. J Crit Care.
2014;29(4):495–499. doi:10.1016/j.jcrc.2014.03.007
144
www.eccmjournal.org
[48] Ravikumar N, Sayed MA, Poonsuph CJ, Sehgal R, Shirke MM, Harky
A. Septic cardiomyopathy: from basics to management choices. Curr Probl
Cardiol. 2021;46(4):100767. doi:10.1016/j.cpcardiol.2020.100767
[49] Nizamuddin J, Mahmood F, Tung A, et al. Interval changes in myocardial
performance index predict outcome in severe sepsis. J Cardiothorac Vasc
Anesth. 2017;31(3):957–964. doi:10.1053/j.jvca.2016.11.007
[50] Gerede DM, Turhan S, Kaya CT, et al. Effects of hemodialysis on Tei
index: comparison between flow Doppler and tissue Doppler imaging.
Echocardiography. 2015;32(10):1520–1526. doi:10.1111/echo.12895
[51] Paraskevaidis IA, Kyrzopoulos S, Farmakis D, et al. Ventricular
long-axis contraction as an earlier predictor of outcome in asymptomatic
aortic regurgitation. Am J Cardiol. 2007;100(11):1677–1682. doi:
10.1016/j.amjcard.2007.06.074
[52] Zhang HM, Wang XT, Zhang LN, et al. Left ventricular longitudinal
systolic function in septic shock patients with normal ejection fraction:
a case-control study. Chin Med J (Engl). 2017;130(10):1169–1174.
doi:10.4103/0366-6999.205856
[53] Havaldar AA. Evaluation of sepsis induced cardiac dysfunction as a
predictor of mortality. Cardiovasc Ultrasound. 2018;16(1):31. doi:
10.1186/s12947-018-0149-4
[54] Basu S, Frank LH, Fenton KE, Sable CA, Levy RJ, Berger JT. Two-
dimensional speckle tracking imaging detects impaired myocardial
performance in children with septic shock, not recognized by
conventional echocardiography. Pediatr Crit Care Med. 2012;13(3):
259–264. doi:10.1097/PCC.0b013e3182288445
[55] Smiseth OA, Torp H, Opdahl A, Haugaa KH, Urheim S. Myocardial
strain imaging: how useful is it in clinical decision making?. Eur Heart
J. 2016;37(15):1196–1207. doi:10.1093/eurheartj/ehv529
[56] Chang WT, Lee WH, Lee WT, et al. Left ventricular global longitudinal
strain is independently associated with mortality in septic shock
patients. Intensive Care Med. 2015;41(10):1791–1799. doi:10.1007/
s00134-015-3970-3
[57] Sanfilippo F, Corredor C, Fletcher N, et al. Left ventricular systolic function
evaluated by strain echocardiography and relationship with mortality in
patients with severe sepsis or septic shock: a systematic review and meta-
analysis. Crit Care. 2018;22(1):183. doi:10.1186/s13054-018-2113-y
[58] Ehrman RR, Moore SC, Favot MJ, et al. Scientific letter to the editor:
need for a definitive study of global longitudinal strain for
prognostication in septic cardiomyopathy. J Am Soc Echocardiogr
2019;32(4):549–552.e3. doi:10.1016/j.echo.2018.12.005
[59] Nelson MR, Hurst RT, Raslan SF, Cha S, Wilansky S, Lester SJ.
Echocardiographic measures of myocardial deformation by speckle-tracking
technologies: the need for standardization?. J Am Soc Echocardiogr.
2012;25(11):1189–1194. doi:10.1016/j.echo.2012.08.006
[60] Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for
the evaluation of left ventricular diastolic function by echocardiography:
an update from the American Society of Echocardiography and the
European Association of Cardiovascular Imaging. Eur Heart J
Cardiovasc Imaging. 2016;17(12):1321–1360. doi:10.1093/ehjci/jew082
[61] Sanfilippo F, Corredor C, Arcadipane A, et al. Tissue Doppler
assessment of diastolic function and relationship with mortality in
critically ill septic patients: a systematic review and meta-analysis. Br
J Anaesth. 2017;119(4):583–594. doi:10.1093/bja/aex254
[62] Vieillard-Baron A. Septic cardiomyopathy. Ann Intensive Care. 2011;
1(1):6. doi:10.1186/2110-5820-1-6
[63] Lanspa MJ, Shahul S, Hersh A, et al. Associations among left ventricular
systolic function, tachycardia, and cardiac preload in septic patients.
Ann Intensive Care. 2017;7(1):17. doi:10.1186/s13613-017-0240-2
[64] Damy T, Ghio S, Rigby AS, et al. Interplay between right ventricular
function and cardiac resynchronization therapy: an analysis of the
CARE-HF trial (Cardiac Resynchronization–Heart Failure). J Am
Coll Cardiol. 2013;61(21):2153–2160. doi:10.1016/j.jacc.2013.02.049
[65] Forfia PR, Fisher MR, Mathai SC, et al. Tricuspid annular displacement
predicts survival in pulmonary hypertension. Am J Respir Crit Care Med.
2006;174(9):1034–1041. doi:10.1164/rccm.200604-547OC
[66] Lahham S, Lee C, Ali Q, et al. Tricuspid annular plane of systolic
excursion (TAPSE) for the evaluation of patients with severe sepsis
and septic shock. West J Emerg Med. 2020;21(2):348–352. doi:10.
5811/westjem.2019.11.44968
[67] Gajanana D, Seetha Rammohan H, Alli O, et al. Tricuspid annular
plane systolic excursion and its association with mortality in critically ill
patients. Echocardiography. 2015;32(8):1222–1227. doi:10.1111/echo.12926
[68] Maeder M, Fehr T, Rickli H, Ammann P. Sepsis-associated
myocardial dysfunction: diagnostic and prognostic impact of cardiac
troponins and natriuretic peptides. Chest. 2006;129(5):1349–1366.
doi:10.1378/chest.129.5.1349
Xue et al.  Emerg Crit Care Med (2022) Vol. 2 No. 3
[69] Wu AH. Increased troponin in patients with sepsis and septic shock:
myocardial necrosis or reversible myocardial depression? Intensive
Care Med. 2001;27(6):959–961. doi:10.1007/s001340100970
[70] Ostermann M, Ayis S, Tuddenham E, et al. Cardiac troponin release is
associated with biomarkers of inflammation and ventricular dilatation
during critical illness. Shock. 2017;47(6):702–708. doi:10.1097/SHK.
0000000000000811
[71] Cheng H, Fan WZ, Wang SC, et al. N-terminal pro–brain natriuretic
peptide and cardiac troponin I for the prognostic utility in elderly
patients with severe sepsis or septic shock in intensive care unit: a
retrospective study. J Crit Care. 2015;30(3):654.e9–654.e14. doi:10.
1016/j.jcrc.2014.12.008
[72] Masson S, Caironi P, Fanizza C, et al. Sequential N-terminal pro–B-type
natriuretic peptide and high-sensitivity cardiac troponin measurements
during albumin replacement in patients with severe sepsis or septic
shock. Crit Care Med. 2016;44(4):707–716. doi:10.1097/CCM.
0000000000001473
[73] Richards AM, Crozier IG, Yandle TG, Espiner EA, Ikram H, Nicholls
MG. Brain natriuretic factor: regional plasma concentrations and
correlations with haemodynamic state in cardiac disease. Br Heart J.
1993;69(5):414–417. doi:10.1136/hrt.69.5.414
[74] Varpula M, Pulkki K, Karlsson S, Ruokonen E, Pettila V,
FINNSEPSIS Study Group. Predictive value of N-terminal pro–brain
natriuretic peptide in severe sepsis and septic shock. Crit Care Med.
2007;35(5):1277–1283. doi:10.1097/01.CCM.0000261893.72811.0F
[75] Papanikolaou J, Makris D, Mpaka M, Palli E, Zygoulis P,
Zakynthinos E. New insights into the mechanisms involved in B-type
natriuretic peptide elevation and its prognostic value in septic
patients. Crit Care. 2014;18(3):R94. doi:10.1186/cc13864
[76] Zhang ZC, Dai HW, Yu YH, Yang JD, Hu CB. Usefulness of
heart-type fatty acid–binding protein in patients with severe sepsis. J
Crit Care 2012;27(4):415.e13–415.e18. doi:10.1016/j.jcrc.2012.01.004
[77] Zhang Z, Dai H, Yu Y, Yang J, Chen J, Wu L. Elevated
pregnancy-associated plasma protein A predicts myocardial dysfunction
and death in severe sepsis. Ann Clin Biochem. 2014;51(pt 1):22–29.
doi:10.1177/0004563213489275
[78] Schrijver IT, Kemperman H, Roest M, Kesecioglu J, de Lange DW.
Myeloperoxidase can differentiate between sepsis and non-infectious
SIRS and predicts mortality in intensive care patients with SIRS. Intensive
Care Med Exp. 2017;5(1):43. doi:10.1186/s40635-017-0157-y
[79] Bessiere F, Khenifer S, Dubourg J, Durieu I, Lega JC. Prognostic value
of troponins in sepsis: a meta-analysis. Intensive Care Med. 2013;39
(7):1181–1189. doi:10.1007/s00134-013-2902-3
[80] Sheyin O, Davies O, Duan W, Perez X. The prognostic significance of
troponin elevation in patients with sepsis: a meta-analysis. Heart
Lung. 2015;44(1):75–81. doi:10.1016/j.hrtlng.2014.10.002
[81] Wang F, Wu Y, Tang L, et al. Brain natriuretic peptide for prediction
of mortality in patients with sepsis: a systematic review and meta-
analysis. Crit Care 2012;16(3):R74. doi:10.1186/cc11331
[82] Bai YL, Hu BL, Wen HC, Zhang YL, Zhu JJ. Prognostic value of
plasma brain natriuretic peptide value for patientswith sepsis: a
meta-analysis. J Crit Care. 2018;48:145–152. doi:10.1016/j.jcrc.2018.
08.040
[83] Sanfilippo F, Huang S, Messina A, et al. Systolic dysfunction as
evaluated by tissue Doppler imaging echocardiography and mortality
in septic patients: a systematic review and meta-analysis. J Crit Care.
2021;62:256–264. doi:10.1016/j.jcrc.2020.12.026
[84] Kalam K, Otahal P, Marwick TH. Prognostic implications of global
LV dysfunction: a systematic review and meta-analysis of global
longitudinal strain and ejection fraction. Heart. 2014;100(21):1673–1680.
doi:10.1136/heartjnl-2014-305538
[85] Rossi MA, Celes MR, Prado CM, Saggioro FP. Myocardial structural
changes in long-term human severe sepsis/septic shock may be responsible
for cardiac dysfunction. Shock. 2007;27(1):10–18. doi:10.1097/01.shk.
0000235141.05528.47
[86] Kakihana Y, Ito T, Nakahara M, Yamaguchi K, Yasuda T. Sepsis-
induced myocardial dysfunction: pathophysiology and management.
J Intensive Care. 2016;4:22. doi:10.1186/s40560-016-0148-1
[87] Jardin F, Fourme T, Page B, et al. Persistent preload defect in severe
sepsis despite fluid loading: a longitudinal echocardiographic study
in patients with septic shock. Chest. 1999;116(5):1354–1359. doi:
10.1378/chest.116.5.1354
[88] Bruni FD, Komwatana P, Soulsby ME, Hess ML. Endotoxin and
myocardial failure: role of the myofibril and venous return. Am J
Physiol. 1978;235(2):H150–H156. doi:10.1152/ajpheart.1978.235.2.H150
145
www.eccmjournal.org
[89] Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE. The
coronary circulation in human septic shock. Circulation. 1986;73(4):
637–644. doi:10.1161/01.cir.73.4.637
[90] Conway-Morris A, Wilson J, Shankar-Hari M. Immune activation in
sepsis. Crit Care Clin. 2018;34(1):29–42. doi:10.1016/j.ccc.2017.08.002
[91] Kumar A, Thota V, Dee L, Olson J, Uretz E, Parrillo JE. Tumor
necrosis factor alpha and interleukin 1beta are responsible for in
vitro myocardial cell depression induced by human septic shock
serum. J Exp Med. 1996;183(3):949–958. doi:10.1084/jem.183.3.949
[92] Pathan N, Franklin JL, Eleftherohorinou H, et al. Myocardial
depressant effects of interleukin 6 in meningococcal sepsis are regulated
by p38 mitogen-activated protein kinase. Crit Care Med. 2011;39(7):
1692–1711. doi:10.1097/CCM.0b013e3182186d27
[93] Kumar A, Brar R, Wang P, et al. Role of nitric oxide and cGMP in
human septic serum-induced depression of cardiac myocyte contractility.
Am J Physiol. 1999;276(1):R265–R276. doi:10.1152/ajpregu.1999.
276.1.R265
[94] Tzeng HP, Fan J, Vallejo JG, et al. Negative inotropic effects of
high-mobility group box 1 protein in isolated contracting cardiac
myocytes. Am J Physiol Heart Circ Physiol. 2008;294(3):H1490–H1496.
doi:10.1152/ajpheart.00910.2007
[95] Madorin WS, Rui T, Sugimoto N, Handa O, Cepinskas G, Kvietys
PR. Cardiac myocytes activated by septic plasma promote neutrophil
transendothelial migration: role of platelet-activating factor and the
chemokines LIX and KC. Circ Res. 2004;94(7):944–951. doi:10.1161/
01.RES.0000124395.20249.AE
[96] Vasques-Novoa F, Laundos TL, Madureira A, et al. Myocardial
edema: an overlooked mechanism of septic cardiomyopathy? Shock.
2020;53(5):616–619. doi:10.1097/SHK.0000000000001395
[97] Lv X, Wang H. Pathophysiology of sepsis-induced myocardial
dysfunction. Mil Med Res. 2016;3:30. doi:10.1186/s40779-016-
0099-9
[98] Martin L, Koczera P, Zechendorf E, Schuerholz T. The endothelial
glycocalyx: new diagnostic and therapeutic approaches in sepsis.
Biomed Res Int. 2016;2016:3758278. doi:10.1155/2016/3758278
[99] Sergi C, Shen F, Lim DW, et al. Cardiovascular dysfunction in sepsis at
the dawn of emerging mediators. Biomed Pharmacother. 2017;95:
153–160. doi:10.1016/j.biopha.2017.08.066
[100] Rivera A, Siracusa MC, Yap GS, Gause WC. Innate cell communication
kick-starts pathogen-specific immunity. Nat Immunol. 2016;17(4):
356–363. doi:10.1038/ni.3375
[101] van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The
immunopathology of sepsis and potential therapeutic targets. Nat
Rev Immunol. 2017;17(7):407–420. doi:10.1038/nri.2017.36
[102] Kieser KJ, Kagan JC. Multi-receptor detection of individual bacterial
products by the innate immune system. Nat Rev Immunol. 2017;17
(6):376–390. doi:10.1038/nri.2017.25
[103] Cohen J. The immunopathogenesis of sepsis. Nature. 2002;420
(6917):885–891. doi:10.1038/nature01326
[104] Vazquez-Carballo C, Guerrero-Hue M, Garcia-Caballero C, et al.
Toll-like receptors in acute kidney injury. Int J Mol Sci. 2021;22(2):
816. doi:10.3390/ijms22020816
[105] Mazgaeen L, Gurung P. Recent advances in lipopolysaccharide
recognition systems. Int J Mol Sci. 2020;21(2):379. doi:10.3390/
ijms21020379
[106] Rajaee A, Barnett R, Cheadle WG. Pathogen- and danger-associated
molecular patterns and the cytokine response in sepsis. Surg Infect
(Larchmt). 2018;19(2):107–116. doi:10.1089/sur.2017.264
[107] Boyd JH, Mathur S, Wang Y, Bateman RM, Walley KR. Toll-like
receptor stimulation in cardiomyoctes decreases contractility and
initiates an NF-kappaB dependent inflammatory response. Cardiovasc
Res. 2006;72(3):384–393. doi:10.1016/j.cardiores.2006.09.011
[108] Suffredini AF, Fromm RE, Parker MM, et al. The cardiovascular
response of normal humans to the administration of endotoxin. N Engl
J Med. 1989;321(5):280–287. doi:10.1056/NEJM198908033210503
[109] Ji W, Wan T, Zhang F, Zhu X, Guo S, Mei X. Aldehyde dehydrogenase
2 protects against lipopolysaccharide-induced myocardial injury by
suppressing mitophagy. Front Pharmacol. 2021;12:641058. doi:10.
3389/fphar.2021.641058
[110] Pang J, Peng H, Wang S, et al. Mitochondrial ALDH2 protects against
lipopolysaccharide-induced myocardial contractile dysfunction by
suppression of ER stress and autophagy. Biochim Biophys Acta Mol
Basis Dis. 2019;1865(6):1627–1641. doi:10.1016/j.bbadis.2019.03.015
[111] Kocak Tufan Z, Kayaaslan B, Mer M. COVID-19 and sepsis. Turk J
Med Sci. 2021;51(SI-1):3301–3311. doi:10.3906/sag-2108-239
Xue et al.  Emerg Crit Care Med (2022) Vol. 2 No. 3
[112] Huang C, Wang Y, Li X, et al. Clinical features of patients infected
with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395
(10223):497–506. doi:10.1016/S0140-6736(20)30183-5
[113] Liu J, Li S, Liu J, et al. Longitudinal characteristics of lymphocyte
responses and cytokine profiles in the peripheral blood of SARS-
CoV-2 infected patients. EBioMedicine. 2020;55:102763. doi:10.
1016/j.ebiom.2020.102763
[114] Satış H, Ozger HS, Aysert Yıldız P, et al. Prognostic value of
interleukin-18 and its association with other inflammatory markers
and disease severity in COVID-19. Cytokine. 2021;137:155302.
doi:10.1016/j.cyto.2020.155302
[115] Bellinvia S, Edwards CJ, Schisano M, Banfi P, Fallico M, Murabito P.
The unleashing of the immune system in COVID-19 and sepsis: the
calm before the storm?. Inflamm Res. 2020;69(8):757–763. doi:10.
1007/s00011-020-01366-6
[116] Darden DB, Kelly LS, Fenner BP, Moldawer LL, Mohr AM, Efron PA.
Dysregulated immunity and immunotherapy after sepsis. J Clin Med.
2021;10(8):1742. doi:10.3390/jcm10081742
[117] Huber-Lang M, Lambris JD, Ward PA. Innate immune responses to trauma.
Nat Immunol. 2018;19(4):327–341. doi:10.1038/s41590-018-0064-8
[118] Yang H, Wang H, Chavan SS, Andersson U. High mobility group box
protein 1 (HMGB1): the prototypical endogenous danger molecule.
Mol Med. 2015;21(Suppl 1):S6–S12. doi:10.2119/molmed.
2015.00087
[119] Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in
sepsis. Nat Rev Immunol. 2008;8(10):776–787. doi:10.1038/nri2402
[120] Kregel KC. Heat shock proteins: modifying factors in physiological
stress responses and acquired thermotolerance. J Appl Physiol
(1985). 2002;92(5):2177–2186. doi:10.1152/japplphysiol.01267.2001
[121] Chen HW, Hsu C, Lu TS, Wang SJ, Yang RC. Heat shock
pretreatment prevents cardiac mitochondrial dysfunction during sepsis.
Shock. 2003;20(3):274–279. doi:10.1097/00024382-200309000-00013
[122] Yu Y, Hu LL, Liu L, et al. HSP22 ameliorates lipopolysaccharide-induced
myocardial injury by inhibiting inflammation, oxidative stress, and apoptosis.
Bioengineered. 2021;12(2):12544–12554. doi:10.1080/21655979.
2021.2010315
[123] Krysko DV, Agostinis P, Krysko O, et al. Emerging role of
damage-associated molecular patterns derived from mitochondria in
inflammation. Trends Immunol. 2011;32(4):157–164. doi:10.1016/
j.it.2011.01.005
[124] Sursal T, Stearns-Kurosawa DJ, Itagaki K, et al. Plasma bacterial and
mitochondrial DNA distinguish bacterial sepsis from sterile systemic
inflammatory response syndrome and quantify inflammatory tissue
injury in nonhuman primates. Shock. 2013;39(1):55–62. doi:10.
1097/SHK.0b013e318276f4ca
[125] Parrillo JE, Burch C, Shelhamer JH, Parker MM, Natanson C, Schuette
W. A circulating myocardial depressant substance in humans with septic
shock. Septic shock patients with a reduced ejection fraction have a
circulating factor that depresses in vitro myocardial cell performance.
J Clin Invest. 1985;76(4):1539–1553. doi:10.1172/JCI112135
[126] Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL.
Negative inotropic effects of cytokines on the heart mediated by nitric
oxide. Science. 1992;257(5068):387–389. doi:10.1126/science.1631560
[127] Niederbichler AD, Hoesel LM, Westfall MV, et al. An essential role
for complement C5a in the pathogenesis of septic cardiac dysfunction.
J Exp Med. 2006;203(1):53–61. doi:10.1084/jem.20051207
[128] Horton JW, Maass D, White J, Sanders B. Nitric oxide modulation of
TNF-alpha–induced cardiac contractile dysfunction is concentration
dependent. Am J Physiol Heart Circ Physiol. 2000;278(6):H1955–H1965.
doi:10.1152/ajpheart.2000.278.6.H1955
[129] Natanson C, Eichenholz PW, Danner RL, et al. Endotoxin and tumor
necrosis factor challenges in dogs simulate the cardiovascular profile
of human septic shock. J Exp Med. 1989;169(3):823–832. doi:10.
1084/jem.169.3.823
[130] Schulz R, Nava E, Moncada S. Induction and potential biological
relevance of a Ca(2+)-independent nitric oxide synthase in the
myocardium. Br J Pharmacol. 1992;105(3):575–580. doi:10.1111/j.
1476-5381.1992.tb09021.x
[131] Wang Y, Zhang X, Guo Y, et al. Type 1 interferon aggravates
lipopolysaccharide-induced sepsis through upregulating caspase-11
and gasdermin D. J Physiol Biochem. 2021;77(1):85–92. doi:10.
1007/s13105-021-00785-1
[132] Kowalczyk A, Kleniewska P, Kolodziejczyk M, Skibska B, Goraca A.
The role of endothelin-1 and endothelin receptor antagonists in
inflammatory response and sepsis. Arch Immunol Ther Exp (Warsz).
2015;63(1):41–52. doi:10.1007/s00005-014-0310-1
146
www.eccmjournal.org
[133] Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol.
2003;21:335–376. doi:10.1146/annurev.immunol.21.120601.141126
[134] Walley KR. Sepsis-induced myocardial dysfunction. Curr Opin Crit
Care. 2018;24(4):292–299. doi:10.1097/MCC.0000000000000507
[135] Frantz S, Kobzik L, Kim YD, et al. Toll4 (TLR4) expression in cardiac
myocytes in normal and failing myocardium. J Clin Invest. 1999;104
(3):271–280. doi:10.1172/JCI6709
[136] Frantz S, Ertl G, Bauersachs J. Mechanisms of disease: Toll-like
receptors in cardiovascular disease. Nat Clin Pract Cardiovasc Med.
2007;4(8):444–454. doi:10.1038/ncpcardio0938
[137] Frantz S, Kelly RA, Bourcier T. Role of TLR-2 in the activation of
nuclear factor kappaB by oxidative stress in cardiac myocytes. J Biol
Chem. 2001;276(7):5197–5203. doi:10.1074/jbc.M009160200
[138] Zhang M, Zou L, Feng Y, et al. Toll-like receptor 4 is essential to preserving
cardiac function and survival in low-grade polymicrobial sepsis. Anesthesiology.
2014;121(6):1270–1280. doi:10.1097/ALN.0000000000000337
[139] Vallejo JG. Role of Toll-like receptors in cardiovascular diseases. Clin
Sci (Lond). 2011;121(1):1–10. doi:10.1042/CS20100539
[140] Yang J, Zhang R, Jiang X, et al. Toll-like receptor 4–induced
ryanodine receptor 2 oxidation and sarcoplasmic reticulum Ca(2+)
leakage promote cardiac contractile dysfunction in sepsis. J Biol
Chem. 2018;293(3):794–807. doi:10.1074/jbc.M117.812289
[141] Fenhammar J, Rundgren M, Hultenby K, et al. Renal effects of
treatment with a TLR4 inhibitor in conscious septic sheep. Crit
Care. 2014;18(5):488. doi:10.1186/s13054-014-0488-y
[142] Fattahi F, Russell MW, Malan EA, et al. Harmful roles of TLR3 and
TLR9 in cardiac dysfunction developing during polymicrobial Sepsis.
Biomed Res Int. 2018;2018:4302726. doi:10.1155/2018/4302726
[143] Hoesel LM, Niederbichler AD, Ward PA. Complement-related
molecular events in sepsis leading to heart failure. Mol Immunol.
2007;44(1–3):95–102. doi:10.1016/j.molimm.2006.06.009
[144] Fattahi F, Frydrych LM, Bian G, et al. Role of complement C5a and
histones in septic cardiomyopathy. Mol Immunol. 2018;102:32–41.
doi:10.1016/j.molimm.2018.06.006
[145] Ward PA, Fattahi F. New strategies for treatment of infectious sepsis. J
Leukoc Biol. 2019;106(1):187–192. doi:10.1002/JLB.4MIR1118-425R
[146] Kalbitz M, Grailer JJ, Fattahi F, et al. Role of extracellular histones in
the cardiomyopathy of sepsis. FASEB J. 2015;29(5):2185–2193. doi:
10.1096/fj.14-268730
[147] Keshari RS, Silasi R, Popescu NI, et al. Inhibition of complement C5
protects against organ failure and reduces mortality in a baboon
model of Escherichia coli sepsis. Proc Natl Acad Sci U S A. 2017;
114(31):E6390–E6399. doi:10.1073/pnas.1706818114
[148] Wang R, Xu Y, Fang Y, et al. Pathogenetic mechanisms of septic
cardiomyopathy. J Cell Physiol. 2022;237(1):49–58. doi:10.1002/jcp.30527
[149] Balija TM, Lowry SF. Lipopolysaccharide and sepsis-associated
myocardial dysfunction. Curr Opin Infect Dis. 2011;24(3):248–253.
doi:10.1097/QCO.0b013e32834536ce
[150] Martin L, Derwall M, Al Zoubi S, et al. The septic heart: current
understanding of molecular mechanisms and clinical implications.
Chest. 2019;155(2):427–437. doi:10.1016/j.chest.2018.08.1037
[151] Preiser JC, Zhang H, Vray B, Hrabak A, Vincent JL. Time course of
inducible nitric oxide synthase activity following endotoxin administration
in dogs. Nitric Oxide. 2001;5(2):208–211. doi:10.1006/niox.2001.0342
[152] Squadrito GL, Pryor WA. Oxidative chemistry of nitric oxide: the
roles of superoxide, peroxynitrite, and carbon dioxide. Free Radic
Biol Med. 1998;25(4–5):392–403.
[153] Hauser B, Bracht H, Matejovic M, Radermacher P, Venkatesh B.
Nitric oxide synthase inhibition in sepsis? Lessons learned from
large-animal studies. Anesth Analg. 2005;101(2):488–498. doi:10.
1213/01.ANE.0000177117.80058.4D
[154] Chen X, Chen H, Deng R, Shen J. Pros and cons of current approaches
for detecting peroxynitrite and their applications. Biomed J. 2014;37
(3):120–126. doi:10.4103/2319-4170.134084
[155] Brealey D, Karyampudi S, Jacques TS, et al. Mitochondrial
dysfunction in a long-term rodent model of sepsis and organ failure.
Am J Physiol Regul Integr Comp Physiol. 2004;286(3):R491–R497.
doi:10.1152/ajpregu.00432.2003
[156] Calcerrada P, Peluffo G, Radi R. Nitric oxide–derived oxidants with a
focus on peroxynitrite: molecular targets, cellular responses and
therapeutic implications. Curr Pharm Des. 2011;17(35):3905–3932.
doi:10.2174/138161211798357719
[157] Neri M, Riezzo I, Pomara C, Schiavone S, Turillazzi E. Oxidative-
nitrosative stress and myocardial dysfunctions in sepsis: evidence
from the literature and postmortem observations. Mediators Inflamm.
2016;2016:3423450. doi:10.1155/2016/3423450
Xue et al.  Emerg Crit Care Med (2022) Vol. 2 No. 3
[158] Chen YR, Zweier JL. Cardiac mitochondria and reactive oxygen
species generation. Circ Res. 2014;114(3):524–537. doi:10.1161/
CIRCRESAHA.114.300559
[159] Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen
species (ROS) and ROS-induced ROS release. Physiol Rev. 2014;94
(3):909–950. doi:10.1152/physrev.00026.2013
[160] Clementi E, Brown GC, Feelisch M, Moncada S. Persistent inhibition
of cell respiration by nitric oxide: crucial role of S-nitrosylation of
mitochondrial complex I and protective action of glutathione. Proc Natl
Acad Sci U S A. 1998;95(13):7631–7636. doi:10.1073/pnas.95.13.7631
[161] Joshi MS, Julian MW, Huff JE, Bauer JA, Xia Y, Crouser ED.
Calcineurin regulates myocardial function during acute endotoxemia.
Am J Respir Crit Care Med. 2006;173(9):999–1007. doi:10.1164/
rccm.200411-1507OC
[162] Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy.
Diabetologia. 2014;57(4):660–671. doi:10.1007/s00125-014-3171-6
[163] Ricquier D, Bouillaud F. Mitochondrial uncoupling proteins: from
mitochondria to the regulation of energy balance. J Physiol. 2000;
529(pt 1):3–10. doi:10.1111/j.1469-7793.2000.00003.x
[164] Dando I, Fiorini C, Pozza ED, et al. UCP2 inhibition triggers
ROS-dependent nuclear translocation of GAPDH and autophagic
cell death in pancreatic adenocarcinoma cells. Biochim Biophys
Acta. 2013;1833(3):672–679. doi:10.1016/j.bbamcr.2012.10.028
[165] Zheng G, Lyu J, Liu S, et al. Silencing of uncoupling protein 2 by small
interfering RNA aggravates mitochondrial dysfunction in cardiomyocytes
under septic conditions. Int J Mol Med. 2015;35(6):1525–1536. doi:10.
3892/ijmm.2015.2177
[166] Celes MR, Malvestio LM, Suadicani SO, et al. Disruption of calcium
homeostasis in cardiomyocytes underlies cardiac structural and
functional changes in severe sepsis. PLoS One. 2013;8(7):e68809.
doi:10.1371/journal.pone.0068809
[167] Hobai IA, Edgecomb J, LaBarge K, Colucci WS. Dysregulation of intracellular
calcium transporters in animal models of sepsis-induced cardiomyopathy.
Shock. 2015;43(1):3–15. doi:10.1097/SHK.0000000000000261
[168] Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore
way to die. Biochem Soc Trans. 2006;34(pt 2):232–237. doi:10.1042/
BST20060232
[169] Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane
permeabilization in cell death. Physiol Rev. 2007;87(1):99–163. doi:
10.1152/physrev.00013.2006
147
www.eccmjournal.org
[170] Ballard-Croft C, Maass DL, Sikes PJ, Horton JW. Sepsis and burn
complicated by sepsis alter cardiac transporter expression. Burns.
2007;33(1):72–80. doi:10.1016/j.burns.2006.06.009
[171] Avlas O, Fallach R, Shainberg A, Porat E, Hochhauser E. Toll-like
receptor 4 stimulation initiates an inflammatory response that
decreases cardiomyocyte contractility. Antioxid Redox Signal. 2011;
15(7):1895–1909. doi:10.1089/ars.2010.3728
[172] Gioannini TL, Weiss JP. Regulation of interactions of gram-negative
bacterial endotoxins with mammalian cells. Immunol Res. 2007;39
(1–3):249–260. doi:10.1007/s12026-007-0069-0
[173] Chaudhry H, Zhou J, Zhong Y, et al. Role of cytokines as a
double-edged sword in sepsis. In Vivo. 2013;27(6):669–684.
[174] Ward PA, Guo RF, Riedemann NC. Manipulation of the complement
system for benefit in sepsis. Crit Care Res Pract. 2012;2012:427607.
doi:10.1155/2012/427607
[175] Fattahi F, Ward PA. Complement and sepsis-induced heart dysfunction.
Mol Immunol. 2017;84:57–64. doi:10.1016/j.molimm.2016.11.012
[176] Fattahi F, Kalbitz M, Malan EA, et al. Complement-induced activation
of MAPKs and Akt during sepsis: role in cardiac dysfunction. FASEB J.
2017;31(9):4129–4139. doi:10.1096/fj.201700140R
[177] Liu Y, Shepherd EG, Nelin LD. MAPK phosphatases—regulating the immune
response. Nat Rev Immunol. 2007;7(3):202–212. doi:10.1038/nri2035
[178] Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways
mediated by ERK, JNK, and p38 protein kinases. Science. 2002;298
(5600):1911–1912. doi:10.1126/science.1072682
[179] Mockridge JW, Marber MS, Heads RJ. Activation of Akt during
simulated ischemia/reperfusion in cardiac myocytes. Biochem Biophys
Res Commun. 2000;270(3):947–952. doi:10.1006/bbrc.2000.2522
[180] Zheng G, Pan M, Jin W, Jin G, Huang Y. MicroRNA-135a is up-regulated
and aggravates myocardial depression in sepsis via regulating p38 MAPK/
NF-κB pathway. Int Immunopharmacol. 2017;45:6–12. doi:10.1016/
j.intimp.2017.01.029
[181] Karki R, Sharma BR, Tuladhar S, et al. Synergism of TNF-alpha and
IFN-gamma triggers inflammatory cell death, tissue damage, and
mortality in SARS-CoV-2 infection and cytokine shock syndromes.
Cell 2021;184(1):149–168.e17. doi:10.1016/j.cell.2020.11.025
How to cite this article: Xue W, Pang J, Liu J, Wang H, Guo H, Chen Y. Septic cardiomy-
opathy: characteristics, evaluation, and mechanism. Emerg Crit Care Med. 2022;2
(3):135–147. doi: 10.1097/EC9.0000000000000060