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Original Research: Critical Care Medicine |

Myocardial Dysfunction in Severe Sepsis and Septic ShockInflammatory Cytokines and Myocardial Dysfunction: No Correlation With Inflammatory Cytokines in Real-life Clinical Setting FREE TO VIEW

Giora Landesberg, MD, DSc; Phillip D. Levin, MA, BChir; Dan Gilon, MD; Sergey Goodman, MD; Milena Georgieva, MD; Charles Weissman, MD; Allan S. Jaffe, MD; Charles L. Sprung, MD, FCCP; Vivian Barak, PhD
Author and Funding Information

From the Departments of Anesthesiology and Critical Care Medicine (Drs Landesberg, Levin, Goodman, Georgieva, Weissman, and Sprung), the Department of Cardiology (Dr Gilon), and the Immunology Laboratory (Dr Barak), Hadassah – Hebrew University Medical Center, Jerusalem, Israel; and the Cardiovascular Department of Laboratory Medicine and Pathology (Dr Jaffe), Mayo Clinic, Rochester, MN.

CORRESPONDENCE TO: Giora Landesberg, MD, DSc, Department of Anesthesiology and Critical Care Medicine, Hadassah – Hebrew University Medical Center, Jerusalem 91120, Israel; e-mail: giora.lan@mail.huji.ac.il


FUNDING/SUPPORT: This study was funded in major part by the International Anesthesia Research Association (IARS) 2006 Clinical Scholar Research Award (CSRA) and in part by a grant from Hadassah Hospital.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(1):93-102. doi:10.1378/chest.14-2259
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BACKGROUND:  In vitro studies suggested that circulating inflammatory cytokines cause septic myocardial dysfunction. However, no in vivo clinical study has investigated whether serum inflammatory cytokine concentrations correlate with septic myocardial dysfunction.

METHODS:  Repeated echocardiograms and concurrent serum inflammatory cytokines (IL-1β, IL-6, IL-8, IL-10, IL-18, tumor necrosis factor-α, and monocyte chemoattractant protein-1) and cardiac biomarkers (high-sensitivity [hs] troponin-T and N-terminal pro-B-type natriuretic peptide [NT-proBNP]) were examined in 105 patients with severe sepsis and septic shock. Cytokines and biomarkers were tested for correlations with systolic and diastolic dysfunction, sepsis severity, and mortality.

RESULTS:  Systolic dysfunction defined as reduced left ventricular ejection fraction (LVEF) < 50% or < 55% and diastolic dysfunction defined as e′-wave < 8 cm/s on tissue-Doppler imaging (TDI) or E/e′-ratio were found in 13 (12%), 24 (23%), 53 (50%), and 26 (25%) patients, respectively. Forty-four patients (42%) died in-hospital. All cytokines, except IL-1, correlated with Sequential Organ Failure Assessment and APACHE (Acute Physiology and Chronic Health Evaluation) II scores, and all cytokines predicted mortality. IL-10 and IL-18 independently predicted mortality among cytokines (OR = 3.1 and 28.3, P = .006 and < 0.0001). However, none of the cytokines correlated with LVEF, end-diastolic volume index (EDVI), stroke-volume index (SVI), or s′-wave and e′-wave velocities on TDI (Pearson linear and Spearman rank [ρ] nonlinear correlations). Similarly, no differences were found in cytokine concentrations between patients dichotomized to high vs low LVEF, EDVI, SVI, s′-wave, or e′-wave (Mann-Whitney U tests). In contrast, NT-proBNP strongly correlated with both reduced LVEF and reduced e′-wave velocity, and hs-troponin-T correlated mainly with reduced e′-wave.

CONCLUSIONS:  Unlike cardiac biomarkers, none of the measured inflammatory cytokines correlates with systolic or diastolic myocardial dysfunction in severe sepsis or septic shock.

Figures in this Article

Sepsis is a dysregulated inflammatory overresponse of the immune system to the invasion of pathogenic organisms.1 Mortality from severe sepsis and septic shock is high (30%-40%) despite the best available treatments and is mostly the result of septic shock and multiorgan failure. The cardiovascular system plays a key role in the pathophysiology of septic shock, organ failure, and death. Since the first clinical demonstrations of septic myocardial depression in the 1980s and the observation that serum obtained from patients with septic shock depresses the contractility of isolated rat myocardial cells,2,3 numerous experimental in vitro studies attempted to explore the complex molecular-cellular inflammatory pathways potentially leading to septic myocardial dysfunction.4,5 In vitro studies showed that circulating inflammatory substances, specifically cytokines, possess cardiodepressant effects.6 Proinflammatory cytokines most intensively studied were tumor necrosis factor (TNF)-α, IL-1β, and IL-6.713 However, despite intensive laboratory efforts, the mechanisms responsible for septic myocardial dysfunction remain elusive, and the paucity of clinical evidence for an association of circulating cytokines with septic myocardial dysfunction is notable.

We have demonstrated that diastolic dysfunction is more common than systolic dysfunction and strongly predicts mortality in patients with severe sepsis and septic shock.14,15 In this study we aimed to investigate whether diastolic or systolic dysfunction on echocardiography in severe sepsis and septic shock can be explained by increased circulating inflammatory cytokine concentrations.

The final 105 patients included in our previously published echocardiography study14 composed the patient group for this study. As previously reported,14 after approval by the Institutional Review Board (Hadassah Medical Organization 0034-11-HMO), patients with severe sepsis and septic shock admitted to the general intensive care unit were enrolled. Severe sepsis was defined as the presence of (1) infection or serious clinical suspicion for infection, (2) at least two signs of systemic inflammatory response syndrome, and (3) at least one organ dysfunction.16 Septic shock was defined as severe sepsis and hypotension (systolic BP < 90 mm Hg) lasting > 1 h, not responding to fluids, and requiring vasopressor therapy.17 Excluded were patients with more than mild mitral and/or aortic valve disease (insufficiency or stenosis), patients with regional myocardial wall motion abnormality on echocardiography suggesting myocardial ischemia or infarction, and patients with poor quality echocardiographic images.

Echocardiography

As previously reported,14 all patients underwent two transthoracic echocardiography examinations using a Phillips Sonos 5500 machine and a S4 2-4 MHz probe. The first examination was as early as possible after admission to the ICU with the diagnosis of sepsis and the second was performed on the following day. All echocardiograms were performed by one experienced sonographer, and data were analyzed by two experts who were blinded to the treatment and outcome of the patients. Differences in interpretations were resolved by agreement. Measurements included left ventricular end-diastolic volume, left ventricular end-systolic volume, stroke volume, left ventricular ejection fraction (LVEF), peak mitral inflow E- and A-wave velocities, E-wave deceleration time, isovolumic relaxation time, and mitral inflow velocity of propagation. The systolic s′ and diastolic e′ and a′ peak velocities were obtained by tissue Doppler imaging (TDI) at both the septal and lateral mitral origins on four-chamber apical view, and the left ventricular (LV) filling index E/e′ ratio was calculated.18,19 Peak systolic tricuspid insufficiency gradient was measured. Echocardiography results were available for the treating physicians, but patients were not treated to reach any specific echocardiographic goal.

Blood samples were obtained in two different aliquots at the time of echocardiography. Samples were immediately centrifuged and serum stored at −70°C. One aliquot was used for measurements of the cardiac biomarkers: high-sensitivity (hs) troponin-T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (Elecsys Assays; Roche Diagnostics) and the other for measurements of cytokines: TNF-α, IL-1β, -6, -8, -10, and -18, and monocyte chemoattractant protein-1 (normal values: ≤ 20, ≤ 5, ≤ 6, ≤ 70, ≤ 10, 250, and 722 pg/mL, respectively). Cytokines were measured by solid phase enzyme-linked immunosorbent assay kits (R&D Systems, Inc). These particular cytokines were chosen because they were most frequently cited in the literature in relation to sepsis and to myocardial dysfunction.

Clinical Data

All demographic, clinical, hemodynamic, respiratory and laboratory results, and therapies were prospectively collected. Admission APACHE (Acute Physiology and Chronic Health Evaluation) II score and daily Sequential Organ Failure Assessment (SOFA) were calculated on the days of echocardiography. In-hospital and up to 2 years mortality data were collected from the hospital’s registry continually updated by the Ministry of the Interior. LV systolic dysfunction was defined using two cutoffs levels: LVEF < 50% or LVEF < 55%. LV diastolic dysfunction was defined as peak septal e′-wave < 8 cm/s based on previous observation that these patients have significantly worse survival.14

Statistics

Student t-test, χ2, or Mann-Whitney U tests were used to compare the distributions of continuous and dichotomous variables. Normality of distribution of all continuous variables was explored by examining skewness, kurtosis, and Q-Q plots. Variables with skewed distributions (skewness or kurtosis > 2 or < −2) were log-transformed before further analysis. After log10 transformation, all biomarkers (cardiac and cytokines) had close to normal distribution with skewness or kurtosis > 2 or < −2. Pearson linear correlation and Spearman rank nonparametric correlation were used to assess correlations among all continuous variables. The main echocardiography parameters of systolic and diastolic dysfunction were also dichotomized, and the log-transformed cytokine and biomarker concentrations were compared for the dichotomized variables. Benjamini-Hochberg step-up false-discovery-rate method was used to adjust P values for multiple comparisons, and both adjusted and unadjusted P values were reported. Univariate and multivariate (backward stepwise selection method with probability for removal of 0.10) logistic regressions and Cox regression were used to determine the association of variables with in-hospital and overall time-tagged mortality, respectively. Kaplan-Meier log-rank test were used to compare survival curves. Because patients had two sets of echocardiograms and biomarkers, each patient’s clinical, biochemical, echocardiography, and biomarker data were averaged for the purpose of survival analyses (Tables 1, 2). However, for the purpose of all correlation analyses, the two sets of clinical, echocardiography, cytokine, and biomarker data of all patients were included. Statistical analyses were performed using SPSS 19.0 software (IBM) and WinPepi version 11.43.

Table Graphic Jump Location
TABLE 1 ]  Clinical, Echocardiographic, and Biomarker Data of Patients Who Died or Survived the Hospitalization

Data are presented as mean ± SD, median [interquartile range], or No. (%). APACHE = Acute Physiology and Chronic Health Evaluation; hs = high sensitivity; MCP = monocyte chemoattractant protein; NT-proBNP = N-terminal pro-B-type natriuretic peptide; Sao2 = arterial oxygen saturation; SOFA = Sequential Organ Failure Assessment; TDI = tissue Doppler imaging; TI = tricuspid incompetence; TNF = tumor necrosis factor.

Table Graphic Jump Location
TABLE 2 ]  Independent Variables Associated With In-Hospital Mortality

See Table 1 legend for expansion of abbreviations.

The study included 105 patients. There were 30 patients with severe sepsis and 75 with septic shock requiring vasoactive medications: norepinephrine in all 75 patients, epinephrine in 27, vasopressin in 18, and dopamine in eight patients. Epinephrine, dopamine, and vasopressin were added to patients’ medications if they remained in shock despite escalating doses of norepinephrine. At least one source of infection was identified in 99 patients (94%), and 51 (49%) had positive blood cultures. Hypotension (systolic BP < 90 mm Hg for > 1 h) occurred in 94 patients (89%). All patients were tracheally intubated and mechanically ventilated at the time of echocardiography. Fifty-four patients (51%) died during follow-up (12.5 ± 11.9 months), 44 (42%) died in-hospital, and 30 (29%) died in the ICU. Among patients with septic shock, 36 (48%) died in-hospital.

All patients had two echocardiography examinations and blood samples, except for three who died before their second examination. First examination was within 1.6 ± 1.7 days after admission with the diagnosis of sepsis, and the second was on the next working day. Echocardiography revealed LVEF < 50% (43% ± 6%), LVEF < 55% (48.9% ± 5.8%), and e′-wave < 8 cm/s (6.5 ± 1.6) or E/e′-ratio in 13 (12%), 24 (23%), 53 (50%), and 26 patients (25%), respectively, in at least one of the two examinations. Table 1 summarizes the variables significantly associated with in-hospital mortality. Sex, hypertension, diabetes mellitus, ischemic heart disease, positive blood cultures, heart rate, central venous pressure, lowest hemoglobin concentration, and lowest oxygen saturation that did not significantly predict mortality are not included. Figure 1 shows the survival curves of all patients divided into quartiles by serum cytokine concentrations. Table 2 summarizes the independent predictors of mortality within the following categories: age, severity scores, physiologic variables, echocardiography variables, cytokines, and cardiac biomarkers. All log-transformed cytokine concentrations, except IL-1, correlated with both SOFA and APACHE II scores calculated for the specific days of echocardiography and blood sampling (Table 3).

Figure Jump LinkFigure 1 –  Kaplan-Meier survival curves and log-rank tests for comparisons when all patients were grouped according to their cytokine serum concentrations. A, Patients with IL-1 concentrations above or below 5 pg/mL. B, Patients with different quartiles of IL-6 concentrations. C, Patients with different quartiles of IL-8 concentrations. D, Patients with different quartiles of IL-10 concentrations. E, Patients with different quartiles of IL-18 concentrations. F, Patients with different quartiles of TNFα concentrations. G, Patients with different quartiles of MCP-1 concentrations. MCP = monocyte chemoattractant protein; TNFα = tumor necrosis factor-α.Grahic Jump Location
Table Graphic Jump Location
TABLE 3 ]  Correlations of Cytokine and Cardiac Biomarker Concentrations With Sepsis Severity and Echocardiographic Parameters (Pearson Linear and Spearman rank [ρ] Nonlinear Correlation—the Stronger of the Two)

EDVI = end-diastolic volume index; LVEF = left ventricular ejection fraction; SVI = stroke volume index. See Table 1 legend for expansion of other abbreviations.

a 

P < 0.001.

b 

P < 0.05.

Cytokines, Cardiac Biomarkers, and the Heart

None of the log-transformed cytokine concentrations correlated with any of the echocardiography parameters of systolic or diastolic function: LVEF, end-diastolic volume index, stroke volume index (SVI), and s′-wave or e′-wave on TDI, by linear nonlinear correlations tests among continuous variables (Table 3). Correlation between cytokine concentrations and echocardiography parameters were even weaker when only patients with septic shock were included in the analyses. No differences in serum cytokine concentrations were found also when patients were dichotomized according to high vs low LVEF (50% or 55%), left ventricular end-diastolic volume index, SVI, or s′-wave or e′-wave velocities, using independent samples Mann-Whitney U tests (Table 4). In contrast, NT-proBNP strongly correlated with systolic and diastolic dysfunction, and hs-troponin-T significantly correlated mainly with diastolic dysfunction (Tables 3, 4). Patients were divided into three groups according to their myocardial function. Group N included 39 patients (37%) with normal systolic and diastolic function: LVEF > 50% (60% ± 6%) and e′-wave > 8 cm/s (11.2 ± 2.5). Group S included 13 patients (12%) with systolic dysfunction: LVEF ≤ 50% (43% ± 6%). Group D included 53 patients (50%) with isolated diastolic dysfunction: LVEF > 50% (62 ± 7) and e′-wave ≤ 8 cm/s (6.5 ± 1.6). No significant differences were found among the three groups in any of the cytokine concentrations (Fig 2). In contrast, significant differences were found among the groups in both NT-proBNP and hs-troponin-T concentrations (analysis of variance: F = 12.8 and 4.9, P < .001 and .010, respectively).

Table Graphic Jump Location
TABLE 4 ]  Comparisons of Inflammatory Cytokine and Cardiac Biomarker Concentrations Among Patients Dichotomized According to the Main Echocardiographic Parameters of Systolic and Diastolic Dysfunction

LVEDVI = left ventricular end-diastolic volume index; LVSVI = left ventricular stroke volume index. See Table 1 and 3 legends for expansion of other abbreviations.

a 

P values in parentheses are after Benjamini-Hochberg false discovery rate correction for multiple comparisons.

Figure Jump LinkFigure 2 –  Boxplots demonstrating the distribution of cytokines and cardiac biomarker serum concentrations in all patients divided into three groups: N = patients with normal left ventricular (LV) systolic function (left ventricular ejection fraction [LVEF] ≥ 50%) and no diastolic dysfunction (e′-wave > 8 cm/s); S = all patients with LV systolic dysfunction (LVEF < 50%); D = all patients with LV diastolic dysfunction (e′-wave < 8 cm/s). All cytokines and NT-proBNP concentrations are in log10(pg/mL), and hs-troponin-T is in log10(ng/mL). hs = high sensitivity; NT-proBNP = N-terminal pro-B-type natriuretic peptide. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

The main finding in the present study is that serum cytokine concentrations do not correlate with echocardiographic evidence of systolic or diastolic myocardial dysfunction or with LV dimensions, despite the fact that cytokines predict mortality and correlate with organ dysfunction and sepsis severity (APACHE II and SOFA scores). This is in contrast to concurrent cardiac biomarkers, hs-troponin-T and NT-proBNP, which predict mortality and correlate with diastolic and systolic myocardial dysfunction.

In 1985, Parrillo et al3 showed that sera obtained from patients with septic shock depress rat myocardial cell contractility in vitro, creating the concept of circulating myocardial depressant substance(s). Kumar et al9 demonstrated that human TNF-α and IL-1β synergistically depress rodent myocardial cells in vitro. Pathan et al13 showed using in vitro gene-expression profiling that IL-6 is the most probable factor causing myocardial depression in sera of children with meningococcal septic shock.6,13 Numerous other experimental studies suggested that cytokines cause myocardial dysfunction via mechanisms such as nitric oxide overproduction7 or calcium ion leakage from the sarcoplasmic reticulum.5,7,2022 However, no clinical study examined the association of circulating cytokine concentrations with myocardial dysfunction in patients. Bouhemad et al23 found transient diastolic dysfunction and increase in cytokine (TNF-α, IL-8, and IL-10) concentrations in patients with septic shock with troponin elevations, yet no correlation was shown between the cytokines and echocardiographic indexes of myocardial dysfunction.

The present study shows that circulating inflammatory cytokines are probably not the dominant causes of systolic or diastolic myocardial dysfunction in real-life sepsis. Rather, cytokines probably have a weaker clinical role in the pathophysiology of myocardial dysfunction than suggested by the in vitro experiments, or their mechanisms are more complex and indirect than can be detected by correlations between cytokine concentrations and myocardial dysfunction (eg, serum cytokine concentrations may be different than those adjacent to the myocardial cells, and their local biologic effects may be independent of the circulating concentrations). However, other explanations are also possible. The pathophysiology of septic myocardial dysfunction is far from being fully understood. Apoptosis in patients and animals who die of sepsis is found almost exclusively in lymphatic and GI epithelial cells and very little in other organs, including the heart.24,25 TNF-α and IL-1β, are not consistently high and may even be undetectable in patients with sepsis.2628 Although cytokines are considered the culprits, they are also beneficial in sepsis, and attempts to block TNF-α and IL-1β led to increased mortality.29,30 Nitric oxide, an important downstream mediator of cytokine inflammatory activity held responsible for vasodilatation and hypotension in septic shock, also has protective roles in cardiomyocyte survival.31,32 In addition, cardiac stimulation by inotropes may mask any cardiac dysfunction caused by the cytokines.33 Alternatively, the physiologic stress of critical illness and the accompanying sympathoadrenal stimulation in patients with even minor preexisting systolic or diastolic dysfunction may have a much stronger effect on observed myocardial dysfunction than the cytokines.

Limitations

All the patients with septic shock by definition were on inotropic medications potentially affecting systolic and diastolic functions33 and possibly affecting also serum cytokine concentrations.34,35 However, if inotropes were the confounding factor masking the effect of cytokines, then this study all the more so shows that serum cytokine concentrations are not the dominant factor determining systolic or diastolic myocardial dysfunctions in real-life severe sepsis and septic shock. We did not have baseline echocardiography examinations prior to the admission with sepsis. Although we excluded all patients with regional myocardial wall motion abnormalities suggesting significant coronary artery disease and all patients with significant valvular disease, we cannot tell whether the systolic or diastolic myocardial dysfunctions occurred de novo as a result of sepsis or if they reflect deterioration of preexisting cardiac abnormality.36

Although circulating inflammatory cytokine concentrations predict mortality and correlate with sepsis severity, they do not seem to have a dominant effect on systolic or diastolic myocardial dysfunction in real-life sepsis. Rather, the main causes for myocardial dysfunction in severe sepsis and septic shock should be searched for in other potential factors, such as preexisting disease and the response to acute physiologic-pharmacologic stimulations during sepsis.

Author contributions: G. L. is the guarantor of the manuscript. G. L. contributed to conception and design, analysis and interpretation of all data, and drafting the manuscript, approved the final version of the manuscript, and agreed with accuracy and integrity of all parts of the work; P. D. L. contributed to conception and design, decisions in patient enrollment, collection and interpretation of the data, and revising the manuscript, approved the final version of the manuscript, and agreed with accuracy and integrity of all parts of the work; D. G. contributed to conception and design regarding all echocardiography analyses, interpretation of echocardiography data, and revising the manuscript, approved the final version of the manuscript, and agreed with accuracy and integrity of all parts of the work; S. G. contributed to collection of patients and clinical data acquisition and critical revision of the manuscript, approved the final version of the manuscript, and agreed with accuracy and integrity of all parts of the work; M. G. contributed to acquisition and analysis of all echocardiography data and involvement in drafting the manuscript, approved the final version of the manuscript, and agreed with accuracy and integrity of all parts of the work; C. W. and C. L. S. contributed to conception and design and drafting the manuscript, approved the final version of the manuscript, and agreed with accuracy and integrity of all parts of the work; A. S. J. contributed to interpretation of the cardiac biomarker data and involvement in drafting the manuscript, approved the final version of the manuscript, and agreed with accuracy and integrity of all parts of the work; and V. B. contributed to conception and design mainly with respect to all cytokine collection, analyses and interpretation, and drafting the manuscript, approved the final version of the manuscript, and agreed with accuracy and integrity of all parts of the work.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Jaffe has in the past or presently consults for Beckman Coulter, Inc; Alere; Abbott; Radiometer Medical ApS; Roche Diagnostics; Ortho-Clinical Diagnostics; Critical Diagnostics; Siemens Corporation; theheart.org; and Amgen Inc. Drs Landesberg, Levin, Gilon, Goodman, Georgieva, Weissman, Sprung, and Barak have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

APACHE

Acute Physiology and Chronic Health Evaluation

hs

high sensitivity

LV

left ventricular

LVEF

left ventricular ejection fraction

NT-proBNP

N-terminal pro-B-type natriuretic peptide

SOFA

Sequential Organ Failure Assessment

SVI

stroke volume index

TDI

tissue Doppler imaging

TNF

tumor necrosis factor

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Bergmann M, Gornikiewicz A, Sautner T, et al. Attenuation of catecholamine-induced immunosuppression in whole blood from patients with sepsis. Shock. 1999;12(6):421-427. [CrossRef] [PubMed]
 
Muthu K, Deng J, Gamelli R, Shankar R, Jones SB. Adrenergic modulation of cytokine release in bone marrow progenitor-derived macrophage following polymicrobial sepsis. J Neuroimmunol. 2005;158(1-2):50-57. [CrossRef] [PubMed]
 
Repessé X, Charron C, Vieillard-Baron A. Evaluation of left ventricular systolic function revisited in septic shock. Crit Care. 2013;17(4):164-166. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Kaplan-Meier survival curves and log-rank tests for comparisons when all patients were grouped according to their cytokine serum concentrations. A, Patients with IL-1 concentrations above or below 5 pg/mL. B, Patients with different quartiles of IL-6 concentrations. C, Patients with different quartiles of IL-8 concentrations. D, Patients with different quartiles of IL-10 concentrations. E, Patients with different quartiles of IL-18 concentrations. F, Patients with different quartiles of TNFα concentrations. G, Patients with different quartiles of MCP-1 concentrations. MCP = monocyte chemoattractant protein; TNFα = tumor necrosis factor-α.Grahic Jump Location
Figure Jump LinkFigure 2 –  Boxplots demonstrating the distribution of cytokines and cardiac biomarker serum concentrations in all patients divided into three groups: N = patients with normal left ventricular (LV) systolic function (left ventricular ejection fraction [LVEF] ≥ 50%) and no diastolic dysfunction (e′-wave > 8 cm/s); S = all patients with LV systolic dysfunction (LVEF < 50%); D = all patients with LV diastolic dysfunction (e′-wave < 8 cm/s). All cytokines and NT-proBNP concentrations are in log10(pg/mL), and hs-troponin-T is in log10(ng/mL). hs = high sensitivity; NT-proBNP = N-terminal pro-B-type natriuretic peptide. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Clinical, Echocardiographic, and Biomarker Data of Patients Who Died or Survived the Hospitalization

Data are presented as mean ± SD, median [interquartile range], or No. (%). APACHE = Acute Physiology and Chronic Health Evaluation; hs = high sensitivity; MCP = monocyte chemoattractant protein; NT-proBNP = N-terminal pro-B-type natriuretic peptide; Sao2 = arterial oxygen saturation; SOFA = Sequential Organ Failure Assessment; TDI = tissue Doppler imaging; TI = tricuspid incompetence; TNF = tumor necrosis factor.

Table Graphic Jump Location
TABLE 2 ]  Independent Variables Associated With In-Hospital Mortality

See Table 1 legend for expansion of abbreviations.

Table Graphic Jump Location
TABLE 3 ]  Correlations of Cytokine and Cardiac Biomarker Concentrations With Sepsis Severity and Echocardiographic Parameters (Pearson Linear and Spearman rank [ρ] Nonlinear Correlation—the Stronger of the Two)

EDVI = end-diastolic volume index; LVEF = left ventricular ejection fraction; SVI = stroke volume index. See Table 1 legend for expansion of other abbreviations.

a 

P < 0.001.

b 

P < 0.05.

Table Graphic Jump Location
TABLE 4 ]  Comparisons of Inflammatory Cytokine and Cardiac Biomarker Concentrations Among Patients Dichotomized According to the Main Echocardiographic Parameters of Systolic and Diastolic Dysfunction

LVEDVI = left ventricular end-diastolic volume index; LVSVI = left ventricular stroke volume index. See Table 1 and 3 legends for expansion of other abbreviations.

a 

P values in parentheses are after Benjamini-Hochberg false discovery rate correction for multiple comparisons.

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