- Academic Editor
†These authors contributed equally.
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis-induced myocardial dysfunction represents reversible myocardial dysfunction which ultimately results in left ventricular dilatation or both, with consequent loss of contractility. Studies on septic cardiomyopathy report a wide range of prevalence ranging from 10% to 70%. Myocardial damage occurs as a result of weakened myocardial circulation, direct myocardial depression, and mitochondrial dysfunction. Mitochondrial dysfunction is the leading problem in the development of septic cardiomyopathy and includes oxidative phosphorylation, production of reactive oxygen radicals, reprogramming of energy metabolism, and mitophagy. Echocardiography provides several possibilities for the diagnosis of septic cardiomyopathy. Systolic and diastolic dysfunction of left ventricular is present in 50–60% of patients with sepsis. Right ventricular dysfunction is present in 50–55% of cases, while isolated right ventricular dysfunction is present in 47% of cases. Left ventricle (LV) diastolic dysfunction is very common in septic shock, and it represents an early biomarker, it has prognostic significance. Right ventricular dysfunction associated with sepsis patients with worse early prognosis. Global longitudinal stress and magnetic resonance imaging (MRI) of the heart are sufficiently sensitive methods, but at the same time MRI of the heart is difficult to access in intensive care units, especially when dealing with critically ill patients. Previous research has identified two biomarkers as a result of the integrated mitochondrial response to stress, and these are fibroblast growth factor-21 (FGF-21) and growth differentiation factor-15 (GDF-15). Both of the mentioned biomarkers can be easily quantified in serum or plasma, but they are difficult to be specific in patients with multiple comorbidities. Mitochondrial dysfunction is also associated with reduced levels of miRNA (microRNA), some research showed significance of miRNA in sepsis-induced myocardial dysfunction, but further research is needed to determine the clinical significance of these molecules in septic cardiomyopathy. Therapeutic options in the treatment of septic cardiomyopathy are not specific, and include the optimization of hemodynamic parameters and the use of antibiotic thera-pies with targeted action. Future research aims to find mechanisms of targeted action on the initial mechanisms of the development of septic cardiomyopathy.
Sepsis-induced myocardial dysfunction represents reversible myocardial dysfunction which ultimately results in left ventricular dilatation or both, with consequent loss of contractility. Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection [1]. The current definition of sepsis emphasizes the presence of organ dysfunction. Cardiac dysfunction caused by inflammation and systemic redistribution of blood volume plays a key role in this but worsens with reduced tissue oxygen utilization [2]. According to the research that has been done so far, there are two basic mechanisms that lead to myocardial dysfunction in sepsis; on the one hand, it is a consequence of the direct action of the pathogen, and on the other hand, the activation of the host’s immune system [3, 4]. From a pathophysiological point of view, myocardial damage occurs as a result of weakened myocardial circulation, direct myocardial depression, and mitochondrial dysfunction [4]. All three mechanisms intertwine with each other at the same time. Although all three mechanisms are equally important, recent studies emphasize that mitochondrial dysfunction is the key factor in the development of cardiac dysfunction.
This review paper aims to present the mechanisms of the development of cardiac dysfunction of the myocardium, diagnostic methods, and potential therapeutic goals with an emphasis on mitochondrial dysfunction.
In 1921, E. Romberg first described septic cardiomyopathy as “septic acute
myocarditis” in his Textbook of Heart and Vascular Diseases [5]. In 1967, McLean
et al., [6] by conducting a clinical trail, described diagnostic criteria for detecting heart failure as part of sepsis included a low cardiac index (CI). In 1984, Parker
et al. [7] using radionuclide angiography, defined septic cardiomyopathy
as reversible myocardial depression due to sepsis and septic shock, defined as a
reduced left ventricular ejection fraction (LVEF
From a pathophysiological point of view, the mechanism of development of
myocardial dysfunction in sepsis occurs as a result of direct depression of the
myocardium, weakened myocardial circulation, and mitochondrial dysfunction.
Direct myocardial depression is a consequence of the pathogen’s direct harmful
effects, activation of the host’s immune system itself, with consequent damaging
effects primarily of prostaglandins, nitric oxide, and finally apoptosis [4].
Direct depression of the myocardium is a consequence of the reduction of
The host’s immune system recognizes the invasion of a pathogenic microorganism
by typically identifying pattern recognition receptors (PRRs), which bind to
patho-gen-associated molecular patterns (PAMPs). PAMP lipopolysaccharide (LPS),
lipo-teichoic acid and others are parts of microorganisms that play a role in
conquering the host. On the other hand, as a result of direct cell damage,
molecules called damage-associated molecular patterns (DAMPs) are released. DAMPs
represent ligands for PRRs that, when activated, promote nuclear translocation of
various transcription factors (e.g., nuclear factor kappa-light chain enhancer of
activated B cells (NF-
The most common pro-inflammatory cytokines released by macrophages in sepsis are
tumor necrosis factor (TNF)-
Nitric oxide is produced by cardiomyocytes via endothelial nitric oxide synthase (eNOS/NOS3) and has inotropic and relaxing effects in normal hemodynamics. It is also responsible for the metabolism and contractility of cardiomyocytes [22]. Under conditions of increased production or concentration of nitric oxide, it has a negative inotropic effect. Its effects are reflected in changes in calcium concentration within myocardial cells.
A study has found that high levels of endothelin-1 (ET-1) stimulate the release of inflammatory cytokines, which can have adverse effects on the myocardium. Increased expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) was detected in coronary endothelium and cardiomyocytes [23]. Studies have shown that the molecules have adverse effects on myocardial contractility. In vivo, in vitro, and human sepsis studies have shown that high histone levels are associated with a higher prevalence of emerging left ventricular dysfunction and new arrhythmias [24]. Circulating histones are also associated with sepsis severity and outcome.
The humoral immune response that is activated in sepsis results in the activation of complement proteins, such as complement C5a. Expression of the C5aR receptor on cardiomyocytes, complement C5a, mediates C5a-induced cardiodepression [25].
Cardiomyocyte apoptosis is a leading cause of sepsis-induced myocardial
depression and multiorgan dysfunction. Myocardial dysfunction often progresses
with cardiomyocyte apoptosis, after which the number of
About 70% of cardiac adenosine triphosphate (ATP) is produced by the oxidation of lipids, the rest is produced by the oxidation of glucose, and a smaller part also comes from the catabolism of lactate and ketone bodies. In sepsis, myocytes use glucose as their primary energy substrate, not fatty acids, which results in a detrimental effect on myocardial contractility, as occurs during post-ischemic hibernation of the myocardium [5].
Mitochondrial dysfunction is a leading problem in the development of septic cardiomyopathy, it involves oxidative phosphorylation, production of reactive oxygen radicals, reprogramming of energy metabolism and mitophagy. The role of mitochondrial dysfunction is shown by the results of research that compared the hearts of people who died of sepsis, with the hearts of people who undergo transplantation, and confirmed that hearts of patients who died from sepsis showed a significant decrease in the expression of genes related to mitochondrial ATP production [30].
Inflammation and oxidative stress change the structure of mitochondria with consequent development of edema, cytoplasmic accumulation of denatured proteins and development of lysosomal lesions [31, 32]. Such damage disrupts the respiratory chain with a decrease in ATP synthesis, release of calcium and proapoptotic proteins [33]. Previous research has described several mechanisms other than oxidative stress that lead to mitochondrial dysfunction, changes in structure, increased permeability of membranes, mitochondrial separation [34].
Major mechanisms leading to deranged oxidative phosphorylation in septic cardiomyopathy include altered cyclic adenosine monophosphate (cAMP)-dependent protein kinase A signaling, overproduction of reactive oxygen species (ROS) and NO, calcium overload, and reduced antioxidants within mitochondria [35, 36]. The resulting increased production of ROS and NO can lead to direct and indirect damage. Direct damage is oxidative or nitrosative, whereas indirect damage occurs through inhibition of oxidative phosphorylation complexes. Studies have shown that ROS and NO can inhibit mitochondrial complexes I and IV and increase their membrane permeability [37, 38]. Increased mitochondrial inducible nitric oxide synthase (iNOS) activation leads to increased mitochondrial peroxynitrite levels, which has been shown to play an important role in mitochondrial dysfunction during sepsis. Increased mitochondrial uncoupling protein (UCP) expression leads to a decrease in mitochondrial membrane potential and ATP synthesis and also results in proton release, thereby reducing ROS formation [39]. Another proposed mechanism for the development of mitochondrial dysfunction related to oxidative and nitrative stress is the activation of enzymes related to many cellular processes, including DNA repair [40].
Mitochondrial function is maintained through a balance between fission, fusion, biogenesis, and autophagy [41]. Different signaling pathways enable interaction between mitochondria and the nucleus [42]. Mitochondria undergo various morphological changes during fission and fusion, which help maintain a healthy mitochondrial population. It achieves the aforementioned by facilitating the exchange of mitochondrial DNA, preserving the integrity of mitochondrial DNA. Fission and fusion processes are present in stressful conditions and have a key role in eliminating damaged mitochondria [43]. Proteins that play a role in fusion (mitofusin-2) and fission (dynamin-related protein-1) are associated with changes in mitochondrial membrane potentials and reduced oxygen consumption [44]. Mitophagy (autophagic degradation) and mitoptosis (programmed destruction) are processes by which deal with damaged mitochondria.
The most important function of macrophages is phagocytosis of both pathogens and apoptotic cells. Macrophage clearance of innate immune cells may also be impaired by increased IL-10 production from neutrophils and pyroptosis [45].
Establishing a diagnosis is a major challenge in establishing a diagnosis of septic cardiomyopathy. Due to insufficiently clear and specific criteria, it is difficult to distinguish heart failure from septic cardiomyopathy. Clinical findings suggestive of septic cardiomyopathy are “septic, cold extremities” phenotype, hemodynamic instability despite vasopressor therapy, failure to respond to preload challenge, cardiac arrhythmias, abnormal echocardiogram, low mixed venous oxygen saturation, and elevated cardiac troponins [46].
In contrast to serum biomarkers, echocardiography provides several possibilities
for the diagnosis of septic cardiomyopathy. The method is simple, available,
cheap, easily repeatable, and it can be performed “at the bedside” in
critically ill patients. Even though at the beginning it was considered that the
assessment of reduced LVEF would be sufficient for
establishing the diagnosis, the pseudo-normalization of LVEF in the case of reduced
preload in distributive shock represents a problem. LVEF is not a sensitive
indicator of myocardial contractility but reflects the relationship between LV
myocardial contractility and LV afterload. Considering the above, re-evaluation
should be done after initial volume replacement and vasopressor administration.
Systolic dysfunction of left ventricular is present in 50–60% of patients with
sepsis. A retrospective analysis in the intensive care unit, which analyzes the
data of echocardiographic findings made within 3 days of admission to the
hospital, showed that the largest number of patients had LVEF between 55% and
70%. At the same time, the highest in-hospital mortality was found in patients
with LVEF
Echocardiographic tools that can be used to demonstrate septic LV dysfunction
include the myocardial performance index (Tei index), which reflects the time
spent in isovolumetric contraction, lower values representing better function.
Mitral annular plane systolic excursion (MAPSE) can also play an important role
in the assessment function LV [48, 49]. Although not many studies have been
published so far investigating the role of MAPSE in the assessment of systolic
function in septic cardiomyopathy, Brault et al. [50] described in their
work a positive correlation of septal MAPSE
LV diastolic dysfunction is very common in septic shock, and it represents an
early biomarker, it has prognostic significance. Based on the 2016 recommendation
by the American Society of Echocardiography and the European Association of
Cardiovascular Imaging, LV diastolic dysfunction is defined based on left atrium
volume assessment (
It’s estimated that right ventricular dysfunction is present in 50–55% of
cases, while isolated right ventricular dysfunction is present in 47% of cases
[57, 58]. Right ventricular dysfunction is defined according: tricuspid annular
plane systolic excursion (TAPSE)
Strain imaging is a new method based on regional deformation of the myocardium. Global longitudinal strain (GLS) is the most commonly used parameter. Normal GLS for LV is more than –18% and for RV more than –22%. The values of the circumferential stress of the left ventricle at the three levels basal, middle and apex range from –22 to –35% [60]. GLS assessment is certainly desirable in subclinical, early assessment of myocardial damage as part of sepsis, the main disadvantage of such a sophisticated method is the difficult availability in the ICU. Studies have shown that worse GLS (less negative) is associated with higher mortality in patients with sepsis, and the same relationship was not established between mortality and LVEF [61].
MRI of the heart represents a method that is available regardless of the severity of the general condition because it deals with patients who are sedated, mechanically ventilated. Myocardial edema and inflammation are the leading features of septic cardiomyopathy, without the presence of focal fibrosis. Research has shown that in T2 sequences there is homogeneous enhancement of the myocardium, and after the application of gadolinium there was no late thickening of the myocardium [62]. The leading limiting factors for the application of cardiac MRI in daily practice are the duration of the examination in the situation, especially when dealing with hemodynamically unstable patients.
In septic patients, elevated cardiac troponin (cTn) correlates with a greater degree of left ventricular dysfunction, disease severity, and mortality. The measurement of cardiac biomarkers in the serum provides separate, but in combination with echocardiographic parameters, has it’s significance in establishing the diagnosis of septic cardiomyopathy [63]. A retrospective analysis showed that elevated levels of troponin T upon admission to the ICU are associated with increased in-hospital mortality, as well as 1-year mortality [64].
For NTproBNP, we cannot say for sure that it has a significance in diagnosis, but multicenter clinical studies have found that in patients with sepsis and septic shock, N-terminal pro-B-type natriuretic peptide (NTproBNP) and cTn were elevated in 97.4% and 84.5% of patients, respectively. The association of biomarkers with the development of septic shock and mortality was established [10].
Mitochondrial dysfunction of the heart has been studied in numerous animal models in vitro and in vivo. Detected mitochondrial changes include altered redox status and reduction of oxygen consumption, ATP generation, changes in mitochondrial membrane potential.
Since we have highlighted in an earlier part of our work the importance of mitochondrial dysfunction in the development of septic cardiomyopathy, it will certainly be important to find biomarkers that can objectify this damage. Blood lactate is the most commonly used marker of mitochondrial dysfunction, but it is not specific enough. Previous studies identified two biomarkers as a result of the integrated mitochondrial response to stress, fibroblast growth factor-21 (FGF-21) and growth differentiation factor-15 (GDF-15) [65]. Circulating GDF-15 is currently the best biomarker for diagnosing mitochondrial dysfunction. Studies have shown that GDF-15 expression can induce stress responses through regulation of activating transcription factor 4 [66]. GDF-15 was found to be significantly increased in skeletal muscle and serum of patients with mitochondrial dysfunction [67]. The study found that the increase in GDF-15 in patients’ serum was associated with the severity of organ damage and sepsis. Dynamic changes in GDF-15 may indicate good diagnostic and prognostic value. GDF-15 is thought to play a protective role in sepsis; it can enhance the phagocytic and bactericidal functions of macrophages [68].
FGF-21 is a growth factor that regulates lipid and glucose metabolism. Earlier studies proved the anti-inflammatory effect of FGF-21 in sepsis, thus explaining the protective mechanism. It maintains thermoregulation and preserves cardiovascular function during bacterial inflammation [69].
Both of the mentioned biomarkers can be easily quantified in serum or plasma using enzyme-linked immunosorbent assays (ELISA). FGF-21 and GDF-15 are new biomarkers, and more sensitive than lactate, which is routinely used. A disadvantage in both cases is that the specificity of these biomarkers for detecting mitochondrial dysfunction in multifactorial diseases has not yet been clarified.
Increasing evidence suggests that mitochondrial dysfunction is also associated with reduced levels of miRNAs [70]. miRNAs serve as regulators of gene expression in biological processes and cell signaling pathways. miRNAs are produced in cells, but extracellular miRNAs can also be present as stable molecules in plasma and body fluids. Due to this property, miRNAs can be used as serum biomarkers of sepsis [28]. Manetti et al. [28] their study showed that many miRNAs are involved in cardiac dysfunction caused by atherosclerosis and sepsis. miR-223 and miR-23b stand out, and further studies are needed to determine the clinical significance of these molecules in septic cardiomyopathy.
Prevalence of homoplasmic/heteroplasmic mtDNA (mitochondrial DNA) mutations, SLSMD (single large deletion of mtDNA), MLSMD (multiple large deletion of mtDNA) in blood are probably not very sensitive biomarkers, but can be specific. Identification of mutations in blood can be a strong indicator of mitochondrial damage. Molecular tests for mtDNA can represent an attractive alternative to performing cellular tests [71].
The main goals of treatment in septic cardiomyopathy are based on the
optimization of hemodynamic parameters (fluid replacement, use of inotropes and
vasopressors, alternative renal methods, mechanical ventilation) and the use of
targeted antibiotic therapy. Treatment should begin with volume supplementation
of 20 mL/kg to increase preload and thus cardiac output (CO). Volume replacement
in the initial stage is extremely important, as later complications of pulmonary
edema may occur due to increased pulmonary microcirculatory permeability and
vasodilation [62]. Current international guidelines for sepsis treatment
recommend “hemodynamic monitoring” [72]. In this setting, echocardiography
plays a key role, helping to differentiate between hypovolemic patients and
volume overloaded patients. Norepinephrine, an alpha and beta agonist, is the
vasopressor of choice in patients with sepsis and can cause hypotension despite
adequate volume compensation [73]. Current guidelines support the use of
dobutamine in the presence of myocardial dysfunction, such as elevated filling
pressures and low cardiac output or signs of sustained hypoperfusion [71]. Taking
catecholamines increases the risk of developing cardiac arrhythmias. Due to its
mechanism of action, levosimendan has a more favorable inotropic effect that is
independent of
Myocardial dysfunction is only one of the organ dysfunctions that can be present in patients with sepsis, and its presence is associated with a worse prognosis. In this review, it was shown that the mechanism of development of septic cardiomyopathy is complex and includes a series of procedures that will lead to cardiomyocyte damage. In particular, we developed mitochondrial dysfunction. Mitochondrial dysfunction is one of the key mechanisms in the development of septic cardiomyopathy. Current knowledge suggests that GDF-15 and FGF-21 would be good markers of mitochondrial dysfunction. Advances in diagnostic methods, primarily echocardiography, have made it possible to detect abnormalities, but the methods are not specific enough, and because of the above, future research should focus on biomarkers that, in addition to available diagnostic methods, will enable early recognition and targeted treatment. When we talk about echocardiography, as we described in the paper, there are a number of modalities that can detect dysfunction of the myocardium, left or right ventricle, but it is certainly necessary to find additional biomarkers that, in combination with existing imaging methods, will enable a simpler assessment and final diagnosis. Previous studies have confirmed that the assessment of LV diastolic dysfunction correlates better with the prognosis and mortality of patients with sepsis compared to LVEF. Among the other methods, it is necessary to single out GLS, which proved to be a good predictor of subclinical signs of myocardial dysfunction, but the main drawback is the difficult availability in the ICU. Previous research has been conducted primarily on animal models, so certainly research in real clinical practice will provide a new perspective in the diagnosis and treatment of cardiomyopathy caused by sepsis. Septic cardiomyopathy will represent a challenge to many researchers in the future, both in the diagnostic and the therapeutic approach.
IL, DM, LZ, KSR, SCV and LM designed the research study. SCV, DL, and ŽBĆ data analysis. LZ, LK, IL and LM assessment and results. IL, LM wrote the manuscript. DL, LK, ŽBC assisted in the writing of the manuscript and made substantial contributions to the editing of the manuscript. IL, DM, KSR, SCV and LM contributed to editorial changes in the manuscript. IL, LM, DM, LZ, KSR, SCV, DL, LK, ŽBC have been involved in drafting the manuscript or reviewing it critically for important intellectual content. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
Not applicable.
This work was supported by the Faculty of Medicine, University J. J Strossmayera Osijek, Croatia, is part of scientific project IP28 “Myocardial dysfunction in patients with sepsis”.
This research received no external funding.
The authors declare no conflict of interest.
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