&

Septic Cardiomyopathy: From Basics

to Management Choices
Nidhruv Ravikumara,1,
Mohammed Arbaaz Sayed, BSca,1,
Chanaradh James Poonsupha,1, Rijuvani Sehgala,1,
Manasi Mahesh Shirkea,1, and
Amer Harky, MSc, MRCSb,c,d,e,1
From the a School of Medicine, Queen’s university Belfast, Belfast, UK, b Department of Cardiotho-
racic Surgery, Liverpool Heart and Chest Hospital, Liverpool, UK, c Department of Congenital Car-
diac Surgery, Alder Hey Children Hospital, Liverpool, UK, d Liverpool Centre for Cardiovascular
Science, University of Liverpool and Livepool Heart and Chest Hospital, Liverpool, UK and e School
of Medicine, Faculty of Health and life Science, University of Liverpool, Liverpool, UK.

Abstract: Septic cardiomyopathy (SCM) is increas-

ingly recognized as a potential complication of septic
shock; it is understood to be a reversible left ventricu-
lar systolic dysfunction. The presence of SCM in septic
shock, in previous studies, infer a poorer prognosis as
it significantly increases the mortality rate of patients
to 70%-90% and its incidence varies from 18% to
40% of septic shock patients. The pathogenesis is
unclear, but believed to be a combination of bacterial
toxins, cytokines, nitric oxide, and cardiac mitochon-
drial dysfunction, that depresses intrinsic cardiac con-
tractility. The presence of SCM can be diagnosed in
patients using a bedside transthoracic echocardiogram
which typically shows left ventricular ejection fraction
<45% and right ventricular dilatation. For manage-
ment, levosimendan provides a good hemodynamic
response without increasing cardiac oxygen demand
when compared to dobutamine, while more invasive
techniques such as extracorporeal membrane

1
All authors contributed equally.
The authors declare that they have no known competing financial interests or personal relationships that
could have appeared to influence the work reported in this paper.
Curr Probl Cardiol 2021;46:100767
0146-2806/$
see front matter
https://doi.org/10.1016/j.cpcardiol.2020.100767

Curr Probl Cardiol, April 2021 1

 oxygenation, and intra-aortic balloon pulsation are
being explored as well as potential rescue strategies
for patients with severe SCM. (Curr Probl Cardiol
2021;46:100767.)

Introduction

&
S
epsis has recently been redefined in 2016 as a “life-threatening
organ dysfunction caused by a dysregulation of the host response
to infection.” Consequently, septic shock, a subset of sepsis has
been defined as hypotension and lactic acid levels >2 mmol/L after ade-
quate fluid resuscitation; requiring systemic vasopressors to maintain a
systolic blood pressure >90 mm Hg.1 It is a type of distributive shock;
occurs due to a dysregulated immune response to infection leading to a
systemic cytokine release and resultant vasodilatation and fluid leak from
the capillaries and arterioles. These inflammatory cytokines through
varying mechanisms of action, which will be later discussed in this
review, can cause an acute transient “stunning” of the cardiac myo-
cardium, recently recognized as septic cardiomyopathy (SCM). These
features were first described in 19852 where serial radionuclide cin-
eangiographic scans were performed on a cohort of patients with sep-
tic shock and it was found that up to half of these patients had
moderate to severe (left ventricular ejection fraction [LVEF] <40%).
In this literature review, we will discuss the pathophysiology, risk
factors, diagnosis, and potential approaches in the management of
SCM.

Literature Search
A comprehensive literature search of PubMed, Scopus, Embase, and
Google Scholar resources was done to identify articles which discussed
pathophysiology, diagnosis and management of SCM. Keywords used
were “Sepsis induced Cardiomyopathy,” “Septic Cardiomyopathy,” and
“Sepsis induced Cardiac dysfunction.” The search terms were used as
keywords and in combination as MeSH terms: “sepsis,” “myocardial dys-
function,”and “echocardiography” to maximize the output from literature
findings. In conjunction to this manual search of reviews and other rele-
vant studies was conducted. The relevant articles are cited and referenced
within each section separately. Only studies published in English were
taken into consideration and no limits were placed on publication time of
the article.

2 Curr Probl Cardiol, April 2021

Pathophysiology

Characteristics
The characteristics of SCM include, depressed ejection fraction, ability to
recover cardiac function within 7-10 days, and left ventricular dilatation.3
Ventricular dilatation occurs mainly due to increased left ventricular compli-
ance. Parker et al. conducted a study and reported decreased ejection fraction
and increased end-diastolic volume in septic shock survivors demonstrating
an extreme increase in ventricular (left) diastolic volume indicating increased
compliance of the ventricles.2 Furthermore, depressed ejection fraction was
proved in this study by reporting that the systolic and diastolic volumes at
the end were increased but there was also elevated stroke volume and cardiac
index that was identified in the septic shock survivors. The cohort of the
study was small; however, the results show that decreased ejection fraction
could have been a result of ventricular dilatation instead of stroke volume. It
was also demonstrated that the right and left ventricular ejection fractions
were depressed in patients with septic shock.4

Pathogenesis and Role of Inflammatory Mediators

Primary myocardial depressant factors include substances such as
cytokines, nitric oxide, the complement system, and lipopolysaccharides
(LPS), which are involved in actively suppressing the heart.5 Inflamma-
tory cytokines play a major role in the pathogenesis of this condition.
However, this remains in the exploration stage. Furthermore, the activa-
tion of Toll-like receptors and nuclear factor kappa B are responsible for
the pathogenesis of SCM. There are also other factors like mitochondrial
dysfunction and exosomes in cardiac myocytes that are responsible for
the development of SCM.

Cytokines. The role of chemical mediators has been long established as a

major causative agent of SCM. Tumor necrosis factor (TNF), released from
activated macrophages, is an essential mediator of endotoxin-induced septic
shock. Recent research has shown that it is also released by cardiac myo-
cytes.6 Another type of cytokine that plays a role in septic induced cardiomy-
opathy is interleukin-1 (IL-1). These are synthesized by macrophages,
monocytes, and neutrophils in response to circulating TNFs. Interleukin-1
depresses cardiac contractility; through the stimulation of nitric oxide. Inter-
leukin- 6 (IL-6) is also a proinflammatory cytokine that has been shown to
take part in the pathogenesis of sepsis. Overall, cytokines play an important

Curr Probl Cardiol, April 2021 3

role in the early reduction in cardiac contractility. However, they alone do
not explain the prolonged duration of myocardial dysfunction during sepsis,
unless they cause the release of other factors that interfere or alter myocardial
function, such as prostanoids or nitric oxide.7

Prostanoids. These are a product of cyclooxygenase enzymes from

arachidonic acid. Increased levels of prostanoids like thromboxane and
prostacyclin, which have the potential to irregulate coronary autoregula-
tion have been observed in septic patients.8

Nitric Oxide. Nitric oxide is produced by oxidation of L-arginine by Nitric

oxide synthase which is expressed in cardiac myocytes. Sepsis is responsi-
ble for the expression of nitric oxide synthase in the myocardium.9
This further result in increased nitric oxide production that contributes
to myocardial dysfunction. Nitric oxide synthase is of 3 subtypes, which
are, neuronal nitric oxide synthase, inducible nitric oxide synthase
(iNOS), and endothelial nitric oxide synthase. In the human body, neutro-
phils express iNOS. Invasion of bacteria leads to activation of TLRs, this
causes elevated inflammatory mediators (cytokines, chemokines). These
overstimulate the neutrophils and cause the expression of iNOS and
thereby increase the production of nitric oxide. Experiments have shown
that the production of nitric oxide due to iNOS can impair cardiac func-
tion, such as decreased sensitivity of myocardium to calcium ions.9

Role of Exosomes on Cardiac Function in Sepsis

Exosomes are extracellular vesicles that contain constituents (protein,
DNA, and RNA) of cells that secrete them.10 They originate from leukocytes,
platelets, and dendritic cells. Their role in SCM is considered from 2 mecha-
nisms that are exosomal nicotinamide adenine dinucleotide phosphate
(NADPH). A study has proved that exosomes can cause vascular apoptosis
and myocardial dysfunction by mechanisms associated with inflammation. In
patients with sepsis, increased exosomes that contain nicotinamide adenine
dinucleotide phosphate oxidase subunits similar to phagocytes in blood help
produce Reactive Oxygen Species (ROS). Thereby, inhibiting the secretion
of platelet exosomes would be beneficial for patients suffering from sepsis.10

Mitochondrial Mechanism of Dysfunction

In patients with sepsis, mitochondrial dysfunction plays a crucial role
in affecting the prognosis and development of myocardial dysfunction.

4 Curr Probl Cardiol, April 2021

 The primary role of the mitochondria in cardiomyocytes is to generate
high energy phosphates by the oxidation of fatty acids. NADH (reduced
nicotinamide adenine dinucleotide) and FADH2 (reduced flavin adenine
dinucleotide) are the main products which provide electrons into the elec-
tron transport chain of oxidative phosphorylation. The ultimate goal of
which is the generation of ATP which occurs upon reduction of O2 to
H2O2. The ATP produced in the mitochondria is utilized, primarily, to
maintain contractile function by myosin ATPases. It is also important to
note that the complete pool of ATP in the myocardial cells is turned over
every few seconds.11 This, thus, highlights the fact that ATP availability
needs to be maintained to preserve cardiac function.
Mitochondrial dysfunction thus is a widely discussed concept and
much emphasis is placed on its association with organ dysfunction in sep-
sis, particularly the heart.11 The main changes that occur in the mitochon-
dria upon the introduction of sepsis (illustrated in Figure) include: change
in mitochondrial structure (swelling, internal vesicle formation, and
abnormalities in cristae), mitochondrial DNA damage, increased mito-
chondrial permeability, and suppression of mitochondrial biogenesis.12
A study conducted by Takasu et al13 demonstrated the presence of
extensive mitochondrial injury associated with sepsis. A key finding of
the study included the occurrence of edema in the mitochondrial matrix.
This was associated with changes in the cristae and its collapse into small
myelin-like clusters. The cause of which was attributed to the influence
of cytokines such as TNF-a, and IL-1b.13

FIG. Mechanisms factores that cause mitochondrial and myocardial dysfunction as conse-
quence of species (Created with Borendeo.com).

Curr Probl Cardiol, April 2021 5

 Recent advancements in the field of molecular biology have enabled the
recognition of pathogen-associated molecular patterns and damage-associ-
ated molecular patterns (DAMPs) in the development of the disease. Mito-
chondrial DNA as a noteworthy DAMP has been the focus of recent
research.12 The recognition of mitochondrial DNA as a DAMP induces a
series of defense reactions. A study conducted by Bagirath et al demonstrated
elevated levels of mitochondrial DNA in patients with sepsis and conse-
quently accumulation of neutrophils.14 Increased levels of neutrophils are
suggestive of an inflammatory response that causes an uncontrolled and inap-
propriate response, leading to systemic capillary leak occurring due to vaso-
dilation and inflammation. This causes a buildup of interstitial fluid resulting
in decreased blood volume and reduced cardiac output. This is often coupled
with suppressed myocardial contractility and loss of vascular tone causing
myocardial depression. Moreover, tissue hypoperfusion often leads to low
oxygen supply to the mitochondria thus compromising the levels of ATP
which in turn triggers cell death pathways leading to cardiomyocyte death.14
Suliman et al15 postulated that mitochondrial damage upon activation by
bacterial toxins such as LPS, occurs due to the excess production of cyto-
kines and ROS, causing oxidation of mitochondrial DNA. The study demon-
strated that this oxidative stress caused a 3.8 Kb deletion of a GC-rich
section which contained the coding regions for cytochrome c oxidase subunit
1 (COX-1) and NADH dehydrogenase. In vivo studies also suggested that
accumulation of this deletion caused a sharp decline in the mitochondrial
mRNA transcript levels.15 These, thus, have a drastic effect on the oxidative
phosphorylation pathway, causing the downregulation of ATP generation.
Under normal conditions, the mitochondria may univalently reduce O2
to O2
during oxidative phosphorylation as a normal metabolite. How-
ever, in septic circumstances, the levels of these ROS increase drastically
which can cause reversible and irreversible toxic modifications to biomo-
lecules. Along with the production of ROS, excessive release of nitric
oxide and inflammatory cytokines simultaneously occur.11
According to the chemiosmotic model of energy transduction, to allow
protons to be pumped across the inner mitochondrial membrane by the
electron transport chain, the membrane must maintain its impermeable
nature. In septic conditions, a membrane permeability transition often
occurs through a voltage- and Ca2+- dependant channel situated in the
inner mitochondrial membrane and is termed as mitochondrial permeabil-
ity transition pore. This is due to a Ca2+ overload induced by endotoxe-
mia.11 Hassoun et al16 conducted a study in mice to determine the
mechanism of this overload and its effect on the mitochondrial and myo-
cardial dysfunction. The study proved that bacterial toxin, LPS, caused a

6 Curr Probl Cardiol, April 2021

leak of Ca2+ from the sarcoplasmic reticulum, along with reduced reup-
take. This was associated with increased mitochondrial
Ca2+.16 The opening of these pores causes a cascading effect of patholog-
ical changes in the myocardial cells. The primary effect observed in the
myocardial cells includes the activation of caspase proteins which even-
tually causes contractile dysfunction of cardiomyocytes.13
Mitochondrial biogenesis is a key component in the mass control of
mitochondria in the body. Physiologically it refers to the growth, divi-
sion, and generation of mitochondria to meet the metabolic needs of the
cell.12 Various factors are present to trigger mitochondrial biogenesis
which ultimately leads to the activation of peroxisome proliferator-acti-
vated receptor g coactivators (PGC), mainly PGC-1a and PGC-1b. These
factors influence the expression of genes that encode for proteins that
play a role in mitochondrial biogenesis.11 A study by Schilling et al dem-
onstrated that when mice were injected with LPS, PGC-1 coactivators
were readily suppressed. This caused metabolic derangements in cardiac
myocytes which led to decreased ventricular function.17

Risk Factors
The main risk factors of SCM include male sex, younger age, elevated
lactate levels, and a history of heart failure.18 Although the prevalence of
the disease is quite common, various studies were conducted to identify
these factors that influence the incidence of the condition. One such study
was conducted by Sato et al19 which aimed to determine the risk factors
associated with sepsis-induced cardiomyopathy. The study confirmed
that the main risk factors include male sex, younger age, higher lactate
levels, and a history of heart failure.

Echocardiography in Diagnosis and Prognosis

Echocardiography can aid the diagnosis of SCM through detecting
parameters such as LVEF, right ventricle dysfunction, myocardial perfor-
mance index (MPI), and global longitudinal strain (GLS) using speckle
tracking.3 Although echocardiography is amongst the key methods of
diagnosing SCM, there is currently no single-reliable universal diagnostic
parameter.5
Studies over the years have shown that the various echocardiographic
parameters utilized have different strengths and weaknesses. Left ventri-
cle systole is a key stage of the cardiac cycle investigated using echocar-
diography. Within this, LVEF is an extensively looked at parameter for
diagnosing SCM. Early studies such as those by Parker et al found that a

Curr Probl Cardiol, April 2021 7

lower mortality rate and hence better survival was seen in patients who
had a lower LVEF.2 Later studies provided evidence which conflicted
with the results of the earlier studies, for example, Juanzhen et al found
that there was no significant difference in initial LVEF between survivors
and nonsurvivors.20 In addition to this, a meta-analysis concluded that
survivors of septic shock did not have lower LVEF.21 An advantage of
using LVEF in the diagnosis of SCM is that it is easy to acquire and is
well known amongst clinicians. However, a limitation of LVEF is that it
lacks sensitivity and specificity.4
GLS is another echocardiographic method that looks at the left ven-
tricles during systole; it is independent of LVEF and is capable of predict-
ing cardiovascular outcomes and providing prognostic data.22 GLS is
derived using a method called speckle tracking echocardiography, a
lower GLS score is associated with higher mortality in patients with sep-
sis. A benefit of using GLS was that it was a better prognostic factor over
LVEF for determining LV systolic function.23 Limitations of using GLS
is that it requires good imaging quality, which may increase expenditure.
In addition to this, the replicability of this method is hindered by various
external influences such as artifacts and random noise, influencing the
reliability and accuracy of the results.24 Consequently, whilst there are
promising aspects of using GLS for the prognosis of SCM patients, larger
scale studies are required to confirm the prognostic value of this method.
Mitral annular plane systolic excursion (MAPSE) is another echocar-
diographic parameter used as a prognostic tool for SCM. According to a
2018 study, when compared to other echo parameters, MAPSE was the
only statistically significant predictor of mortality.25 Advantages of
MAPSE is that the results are easy to acquire and that the method shares
similarities with GLS except without needing to be performed with
speckle tracking or Doppler. In addition to this, MAPSE is easily repro-
ducible and capable of being a very useful measure of the systolic left
ventricular function used to assess SCM. A weakness of this method is
that regional wall motion abnormalities, as well as, calcifications and
prosthetic valves can hinder the accuracy of the results obtained.26
MPI, also known as the Tei index is a Doppler derived index that
assesses both systolic and diastolic function to give an indicator of car-
diac function. Calculated using the formula:
ventricular isometric systolic time þ ventricular isometric diastolic time
MPI ¼
ejection time

8 Curr Probl Cardiol, April 2021

 A 2019 study by Nizamuddin et al showed that a worsening MPI over the
24-hour study period was associated with statistically significant increased
90-day mortality in patients.27 Thus, a lower MPI could be used to indicate a
better prognosis and vice versa. Strength of using MPI is that the use of both
systolic and diastolic data allows the involvement of both phases in SCM
pathology to be looked at. Also, unlike ejection fraction measurement, MPI
is independent of preload, heart rate, and ventricular geometry.28 A weakness
of this method is that at present, there is limited validated research on this
method. Also, due to sepsis reducing LV afterload, there may be discrepan-
cies in MPI measurement, reducing the accuracy of the MPI measurement.
Consequently, further and larger scale trials should take place to determine
the prognostic value of MPI in SCM patients.27,28
By utilizing tissue Doppler imaging, the variables e’ and E/e’ have been
proposed to be reliable predictors of mortality by being a key measure of left
ventricular diastolic dysfunction. These indicate the ratio of early diastolic
septal mitral inflow velocity to early diastolic mitral annulus velocity. A
2017 meta-analysis by Sanfilippo et al found that in patients with septic
shock, there was a significant association between mortality and overall
lower e’ and higher E/e’ values.29 A strength of this method is that it could
give better prognostic predictions of hospital outcomes in septic shock
patients in comparison to cardiac biomarkers.34 A weakness of using E/e’, as
stated in a study by Lanspa et al. is that regional wall motion abnormalities,
mitral valve disease, age, mechanical ventilation, and pericardial disease are
factors that may affect the accuracy of E/e’.30
Tricuspid annular plane of systolic excursion (TAPSE) is an indirect
method of evaluating right ventricular function by describing apex to
base shortening.31 TAPSE is an easily obtainable and replicable measure
of right ventricular function. According to some studies, reduced TAPSE
has been associated with increased mortality in critically ill patients.32
However, a 2020 study by Lahham et al36 further evaluated the use of
TAPSE and showed that there was no significant relationship between
severe sepsis and TAPSE values. It is worth noting that this study used a
small sample size obtained via convenience sampling, this could lead to
selection bias, reducing the validity of the findings. Thus, further large-
scale randomized control trials are required to provide definitive data as
to the effectiveness of TAPSE as a prognostic tool of SCM.31
As seen from the various studies discussed, the findings of which are
summarized in Table; echocardiography is a widely used and crucial tool
in diagnosing and providing prognostic information through the various
echo-parameters. While LVEF is the most widely used, diagnosis remains
difficult as there are no unanimous diagnostic criteria for SCM.

Curr Probl Cardiol, April 2021 9

10

TABLE. Summary of echocardiographic variables that have been used to evaluate septic cardiomyopathy

Echo Study Study design/ N Measured outcome Results

parameter setting
Left ventricle EF Parker et al Single-center 20 To evaluate the cardiac The mean initial EF for
systole (1984)2 prospective cohort function in patients with survivors was 0.34 § 0.04.
study septic shock None of the survivors had an
EF below 0.4
Juanzhen et al Prospective, single 50 To evaluate prognostic Kaplan-Meier survival analysis
(2019)20 center, value of LVSD in pediatric of 28-day mortality
observational severe sepsis suggested no difference in
study severe sepsis with or without
LVSD
Huang et al Meta-analysis 762 The evaluation of Survivors vs non-survivors had
(2013)21 association between a no significant difference in
reduction in LVEF and an LVEF and LV dimensions
increased LV dimensions
with mortality in patients
with sepsis and septic
shock
GLS Chang et al Multicenter 111 The evaluation of both LV GLS can be used to provide an
(2015)23 prospective function and the independent prognosis of
Curr Probl Cardiol, April 2021

cohort study prognostic value of GLS in mortality in ICU. GLS -13%

patients with sepsis. ICU
and hospital mortality
were looked at as the
primary outcome
was seen in patients who
had higher rates of ICU
mortality
(continued on next page)
Curr Probl Cardiol, April 2021

TABLE. (continued)

Echo Study Study design/ N Measured outcome Results

parameter setting
Sanfilippo et al Meta-analysis 794 To investigate the Significant association
(2018)22 prognostic value of GLS in between worse LV function
patients with sepsis/ and GLS values and
septic shock mortality. Lower GLS
associated with higher
mortality.
MAPSE Zhang et al. Case control 45 The evaluation MAPSE as MAPSE values were found to
(2017)26 study/ICU well as other parameters be significantly lower in
in patients with septic patients with sepsis vs non-
shock. Primary outcome sepsis patients
being sepsis.
Havaldar et al Prospective, single 58 To assess the sepsis MAPSE when combined with
(2018)25 center, induced cardiac APACHE II was a good
observational dysfunction by 2D predictor of mortality in
study echocardiography and patients with sepsis induced
troponin I cardiac dysfunction
MPI Nizamuddin et al Single-center 47 To evaluate whether there A decline in MPI over initial 24-
(2017)27 prospective was an association hour study period was
cohort study/ICU between a change in LV associated with statistically
MPI and 90-day mortality significant higher 90 day
in patients with severe mortality
sepsis.
(continued on next page)
11
12

TABLE. (continued)

Echo Study Study design/ N Measured outcome Results

parameter setting
Right ventricle TAPSE Lahham et al Prospective, 24 To evaluate the relationship There was no statistically
systolic (2020)31 observational, between RV dysfunction significant association
single center using TAPSE in patients between TAPSE levels and
study/ICU with concern for severe ICU admission or death.
sepsis and septic shock
Gajanana et al Single-center 120 To evaluate the prognostic Reduced TAPSE measurement
(2015)32 prospective value of TAPSE in critically (< 2.4 cm) was correlated
cohort study/ICU ill patients with increased in-hospital
mortality and a longer
hospital stay
EF, ejection fraction; GLS, Global longitudinal strain; LV, Left ventricle; LVSD, Left ventricular systolic dysfunction; MAPSE, Mitral annular plane of systolic excur-
sion; MPI, Myocardial performance; RV, Right ventricle; TAPSE, Tricuspid annular plane systolic excursion; TDI, Tissue Doppler imaging, E/e'.
Curr Probl Cardiol, April 2021
Management
Currently, there are no recommended guidelines or treatment strategy
for SCM, nor are there any specific disease-modifying medications avail-
able due to its multifactorial and ultimately unclear pathogenesis. How-
ever, various medical and nonmedical interventions have been suggested
and implemented by multiple clinical trials and retrospective studies as
well as patient case reviews; to varying degrees of success.

Infection Control
Management of SCM should concern the infection primarily; intrave-
nous broad-spectrum antibiotics coupled with identification of infection
source and prompt surgical intervention if indicated, such as the drainage
of any abscesses.

Medical Therapy
Appropriate fluid resuscitation is a vital firstline management of sepsis,
especially in order to maintain adequate intravascular volume for tissue
perfusion. Per contra, patients with SCM, although likely to benefit from
fluids in the initial stages are more susceptible and at greater risk of
developing fluid overload and consequentially, pulmonary edema due to
increased pulmonary microvascular permeability as well as the left ven-
tricular diastolic dysfunction from SCM; necessitating the need for ino-
tropic/vasopressor support.33
In septic shock, when the patient is unresponsive or shows insufficient
response to fluids; the first-choice vasopressor used worldwide to achieve
the Mean Arterial Pressure target of >65 mm Hg is noradrenaline.26 Nor-
adrenaline is an alpha-adrenergic agonist with little to no beta-adrenergic
activity, overall causing systemic vasoconstriction. It is important to note
however that noradrenaline administration through increasing the sys-
temic vascular resistance may “unmask” LV impairment in SCM by
increasing the cardiac preload.34
Interestingly, a 2011 paper35 demonstrated that Noradrenaline was not
effective in restoring hemodynamic stability in up to 20% of septic shock
patients; strongly suggesting that SCM, to a certain degree, was present
in these patients and increasing the systemic vascular resistance by nor-
adrenaline infusions paradoxically diminished cardiac output.
Infusion of inotropic agents such as dobutamine at 5 micrograms/kg/
min in addition to the standard noradrenaline and fluid resuscitation pro-
tocol was shown in a study to improve LVEF and the cardiac index by

Curr Probl Cardiol, April 2021 13

30%35,36 while having no statistically significant effect on the Mean
Arterial Pressure. A more recent study, using metaregression analysis
done by Naedeem et al37 showed that the use of dobutamine in septic
shock patients improved cardiac index.
Levosimendan, a calcium sensitizer, and ATP-dependent potassium
channel opener, originally indicated to treat acutely decompensated heart
failure, has a unique ability to increase calcium sensitivity in troponin C
of cardiac myocyte’s myofilaments; exerting inotropic support without
increasing cardiac oxygen demand; in theory, improving both right ven-
tricular and LV function. Levosimendan has been shown in multiple stud-
ies to significantly improve LVEF and cardiac output.38,39 One particular
trial (Meng et al 2016)40 evaluated the use of Levosimendan against
Dobutamine in patients with septic shock. The results were overwhelm-
ingly in favor of Levosimendan. The Levosimendan-treated group had
higher stroke volumes and cardiac indexes while also lowered biomarkers
of myocardial injury (Brain natriuretic peptide and Troponin I) more than
when compared to the dobutamine-treated cohort.41,42

Nonmedical Therapy
Venoarterial extracorporeal membrane oxygenation is often consid-
ered a viable rescue option for septic shock patients further complicated
by SCM. A retrospective study by Vogel et al43 concluded that patients
who underwent Venoarterial extracorporeal membrane oxygenation with
SCM had a survival rate of 75%. Although larger scale cohort studies
would need to be conducted to evaluate its full efficacy and feasibility, it
is considered as a suitable treatment option in a section of the population
with respiratory and cardiac failure coupled with septic shock and SCM.
Intra-aortic balloon counterpulsation44 has also been shown in patient
reports to be very effective in severe SCM because it reduces after-load
and increases coronary blood flow. Unfortunately, only patient case
reviews exist discussing the use of intra-aortic balloon counterpulsation
in SCM; limiting our evaluation of its true efficacy.

Future Directions
When it comes to emerging potential treatments for SCM, there is a
range of recent promising literature. A 2020 study by Gao et al45 looked
at Schistosoma japonicum cystatin (Sj-Cys), a cysteine protease inhibitor
that induces regulatory T-cells and has a potential role in reducing inflam-
mation seen in sepsis and thus sepsis-induced cardiac dysfunction. By

14 Curr Probl Cardiol, April 2021

inducing sepsis-induced myocardial injury in mice, followed by Sj-Cys
treatment, echocardiography was used to examine LV function. The lev-
els of cardiac biomarkers of injury, as well as pathological changes, pro-
inflammatory cytokine levels, and macrophages, were studied. Results
showed that following Sj-Cys, the injury to cardiac tissue improved, and
immune cell infiltration was reduced. Cardiac injury biomarkers were
reduced, and cardiac function was improved (by showing improved
LVEF).45 Therefore, the fact that Sj-Cys had protective roles against sep-
tic induced cardiac dysfunction, and reduced damage-causing excessive
inflammation in sepsis, could suggest a potential agent for the prevention
and treatment of SCM.
Zhong, J. et al46 were the first to look at the potential of melatonin in
the treatment of SCM. Through this study, it was discovered mitochon-
drial and inflammatory damage, and endoplasmic reticulum stress was
associated with LPS-induced SCM. Receptor-interacting protein kinase 3
(Ripk3) was found to be a key causal agent, with its upregulation being a
key upstream mediator of SCM. Ripk3 expression was associated with
impaired cardiac function, increased inflammatory response, and cardio-
myocyte death. Through the use of mice models, this study was able to
find melatonin as an inhibitor of Ripk3, thus attenuating the downstream
Ripk3 effects by reversing mitochondrial damage, ameliorating ER
stress, and preventing cardiomyocyte destruction, and thus preventing the
changes which result in the cardiac dysfunction seen in SCM.

Conclusions
Up to date clinical studies have, to an extent, proved the causes and
diagnosis of SCM, however, there is more research needed in terms of
management of the disease. Presently, there are no specific treatment
plans or drugs for the treatment of SCM due to the multifactorial nature
of the disease and uncertainty regarding the pathogenesis. Research in
the field has shown that the disease occurs due to a combination of bacte-
rial toxins, release of inflammatory mediators, and cardiac mitochondrial
dysfunction. It is still too early to establish a definite treatment for SCM,
however, the future is promising.

Human Studies
No ethical approval required as no patient information was shared

Curr Probl Cardiol, April 2021 15

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