Septic cardiomyopathy: characteristics, evaluation, and mechanism : Emergency and Critical Care Medicine

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Septic cardiomyopathy: characteristics, evaluation, and mechanism

Xue, Wanlina,b,c; Pang, Jiaojiaob,c,d; Liu, Jiaoe; Wang, Haoa,b,c; Guo, Haipenga,b,c,d,,∗; Chen, Yuguob,c,d,∗

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Emergency and Critical Care Medicine: September 2022 - Volume 2 - Issue 3 - p 135-147
doi: 10.1097/EC9.0000000000000060
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Abstract

Introduction

Sepsis is a life-threatening organ dysfunction caused by the body's dysfunctional response to infection.[1] Although significant breakthroughs 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 pathophysiology includes inflammatory reaction, immune dysfunction, and coagulation 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] In 1951, Waisbren[8] was the first to describe cardiac dysfunction 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 present, 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 cardiomyopathy, 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 activation 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 controversial 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 diagnostic 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 radionuclide 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, the left ventricular ejection fraction (LVEF) was initially low, which was 0.40 (SD, 0.04) (reference range, 0.45–0.55), and gradually increased to 0.55 (SD, 0.05) within 7 to 10 days. The 13 survivors originally 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 sepsis 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 compliance 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 ventricle 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 dilatation may be related to increased left ventricular compliance. A subsequent study compared the end-diastolic volume index (EDVI) between patients with septic shock and the control group (the control group included 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 patients 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 excessive 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 catecholamines, 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 ventricle, 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 common 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 cardiomyopathy and hypertrophic cardiomyopathy, which usually have a long history and slow progression, should be excluded.[15] Therefore, 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 characteristics, 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 understanding.[37] Therefore, it is necessary to identify and deal with septic 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 syndrome,[38] including depression or elevation of ST segment, appearance 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 cardiomyopathy. There is no specific ECG manifestation for septic cardiomyopathy; 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 hemodynamic disorder needs intensive care echocardiography.[43,44] Bedside target-guided echocardiographic evaluation in patients with sepsis usually provides the first evidence of septic cardiomyopathy.[45] Although echocardiography is one of the primary methods for diagnosing septic cardiomyopathy and evaluating the myocardial function, there is no single diagnostic parameter currently.[15]

Left ventricular ejection fraction. Left ventricular ejection fraction can be used to measure cardiac systolic dysfunction, and it is also one of the indicators initially identified to describe septic cardiomyopathy.[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 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 measure 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 evaluates 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' myocardial performance index (MPI) was evaluated by transthoracic echocardiography, 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 systolic excursion has the advantages of easy availability and repeatability, 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 difference, 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 independent 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 outcome 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 addition, 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 insufficiency.[18] The flow velocity of mitral annulus in early diastole (e′) and the ratio of the mitral annulus velocity to mitral annulus velocity (E/e′) are the key indicators of left ventricular diastolic insufficiency[48]; e′ is the first choice to evaluate diastolic function. The lower the value, the worse the diastolic function.[60] A systematic review 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 pulmonary hypertension.[64,65] Tricuspid annular plane of systolic excursion (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 increased mortality in critically ill patients.[67] However, a 2020 study recruited 24 patients who were admitted to the emergency department 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 develop 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 disease severity, but specific diseases cannot be identified.[75]

Other biomarkers

In recent years, studies have found that some new biomarkers can be used to predict septic myocardial dysfunction and prognosis, such as heart-type fatty acid–binding protein and pregnancy-associated plasma protein A.[76,77] However, the predictive 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 echocardiography of septic cardiomyopathy.

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

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.

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 increased macrophage infiltration, larger and longer cells, and increased expression of TNF-1; (2) lipid accumulation in myocardial cells of patients with sepsis; (3) diffuse distribution of myosin and myosin, myosin fragmentation, and myolysis; and (4) significantly increased expression of inducible NO synthase (iNOS) and nitrotyrosine in cardiomyocytes and interstitial macrophages in patients with sepsis.[85]

In terms of pathophysiology, septic cardiomyopathy has a complex pathophysiological process, and one of its basic characteristics is obvious reversibility. Many studies have pointed out that the cardiac function of patients can recover to the level before the disease.[11,16,86,87] Based on the hypothesis of the early animal experimental model, septic cardiomyopathy is similar to coronary artery disease, which is caused by decreased coronary blood flow and cardiomyocyte 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 instead 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 molecules function through different signal transduction pathways and activate positive and negative feedback circuits in the immune system.[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 molecules),[94] and lipopolysaccharide as potential pathogenic factors of septic cardiomyopathy. The injury of inflammatory factors will change the endothelial permeability,[95] leading to uneven microvascular 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 metabolism, imbalance of calcium homeostasis in cardiomyocytes, and so on (Fig. 1).[12,97]

F1
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 O2 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; O2 , superoxide; PAMPs, pathogen-associated molecular patterns; PGN, peptide polysaccharides; TNF-α, tumor necrosis factor α; UCP, uncoupling protein.

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 dysfunction.[98] The progress from infection to sepsis has always been the focus of research, which is caused by pathogen-associated molecular patterns (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 molecular 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 triggers 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 interferon gene, TNF-α, and several ILs. If there is no early active treatment, it will further lead to multiple organ dysfunction.[104–106] Cardiomyocytes express TLR4, so PAMP binds not only the immune receptors on the surface of inflammatory cells but also the receptors on the surface of cardiomyocytes, which leads to the decrease in myocardial contractility and the occurrence of inflammation.[107] A study of healthy volunteers by Suffredini et al[108] showed that injection of endotoxin resulted in a decrease in LVEF and an increase in left ventricular end-diastolic volume.

A recent study showed that endotoxin could improve the biochemical indexes of inflammatory cell infiltration, cardiac dysfunction, 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 coronavirus 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 without nuclei. Yang et al[118] have demonstrated the role of HMGB1 as a proinflammatory cytokine in the immune response to tissue injury. In patients with sepsis, monocytes, neutrophils, and macrophages 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 crucial 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 effect on septic cardiomyopathy caused by LPS.[122] The specific mechanism 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 inflammation. Both aseptic and infectious tissue damage is related to the increased release of mtDNA.[123,124]

Myocardial inhibitory factor. In 1985, a study proved the existence of a myocardial inhibitory factor. Parrillo et al[125] incubated isolated rat cardiomyocytes with the serum of patients with septic shock, resulting in a decrease in the amplitude and speed of myocardial cell contraction, which further proved the existence of myocardial inhibitory 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 macrophages 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 synthesized 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 persistent myocardial dysfunction caused by sepsis, because TNF-α often reaches a peak within 48 hours after administration.[129] Besides, both TNF-α and IL-1β can induce the release of additional factors (such as NO), which in turn change myocardial function.[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 occurrence 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 proinflammatory 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 oxidative 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 glycoprotein located on the surface of the cell membrane and an integral part of the immune system,[15] which can distinguish different pathogens and cause an immune response quickly.[133] Toll-like receptors 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 kinase (MAPKs).[134] Various studies have identified the presentation of human TLRs, including the expression of TLR2, TLR4, and 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, resulting in cardiac insufficiency.[139] In addition, TLR4 regulates the oxidative stress of ryanodine receptor 2, resulting in increased sarcoplasmic reticulum calcium leakage in cardiomyocytes.[140] In an animal experimental model, inhibition of TLR4 has a specific protective effect on septic 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 proinflammatory factors such as TNF-α, IL-1, and IL-6 were significantly decreased 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 pathways 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 complement proteins. After the complement system is activated, the number of complement component 5 (C5) increases, and the final cleavage 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 essential complement receptor dependent enzymes in cardiomyocytes associated 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 cardiomyopathy by studying the effects of C5a on rat hearts in vivo and cultured cardiomyocytes in vitro during CLP-induced sepsis. CLP significantly reduced global left ventricular pressure, which could be reversed 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 dysfunction.[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 oxidative 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 reaction. Because the systolic and diastolic functions of the heart are maintained 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 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 making NO. However, when inflammation occurs, the invasion of bacteria will activate TLRs and lead to the release of cytokines and other substances and overstimulate neutrophils. Because neutrophils 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 cardiomyocytes to Ca2+ and causing damage to mitochondria.[151]

Nitric oxide reacts rapidly with superoxide (O2) to form a toxic product peroxynitrite anion (ONOO).[152] ONOO is a strong oxidant 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 capacity,[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 regenerate ATP from ADP. In general, some H+ is returned to the matrix 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 decisive factors in the story of ROS in mitochondria. However, in some cases, an increase in the level of uncoupling can reduce oxygen 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 associated 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 mitochondrial 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 increased 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 cytoplasm, and finally activated the apoptosis signal. Although apoptosis occurs in only a small number of cardiomyocytes, the activation of apoptotic pathway may lead to myocardial dysfunction.[168,169] Studies have shown that the cardiomyocytes of septic rats will have mitochondrial 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.

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 activation of intracellular signal pathways and lead to myocardial dysfunction (Fig. 2).

F2
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.

The pathogenesis of septic cardiomyopathy is very complex. Studies have shown that TLR4 is an essential mediator of innate immunity and inflammation and plays a crucial role in myocardial damage caused by sepsis.[11,171] Furthermore, it participates in signal transduction of specific antigens produced by pathogens and endotoxins, including 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 receptor mediates signal transduction to the homologous region of the Toll/IL-1 receptor, which is a highly conserved domain homologous to the intracellular domain of IL-1. After that, NF-κB is activated 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 cardiomyocytes, and the activated signal pathways will act on transcription factors, thus enhancing gene expression.[176] Mitogen-activated protein kinase often appears as an essential signaling pathway in different 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 members 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 phosphorylation of MAPKs (p38, ERK-1/2, and JNK-1/2) and Akt in 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 septic cardiomyopathy.

Other signal pathways are involved in the occurrence and development of septic cardiomyopathy. For example, miR-135a may mediate 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 mortality rate, because its pathogenesis is not completely clear. In this review, we discuss the characteristics, diagnostic methods, pathophysiology, 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 procedures, 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 approved 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 Program of Shandong Province (tsqn202103171). Project was funded by China Postdoctoral Science Foundation (2020T130072ZX) and Clinical 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 valuable comments on the manuscript.

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Keywords:

Echocardiography; Infection immunity; Mitochondrial dysfunction; Sepsis-induced cardiomyopathy; Septic cardiomyopathy

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