TAK-676: A Novel Stimulator of Interferon Genes (STING) Agonist Promoting Durable IFN-dependent Antitumor Immunity in Preclinical Studies.

Oncology therapies targeting the immune system have improved patient outcomes across a wide range of tumor types, but resistance due to an inadequate T-cell response in a suppressive tumor microenvironment (TME) remains a significant problem. New therapies that activate an innate immune response and relieve this suppression may be beneficial to overcome this hurdle. TAK-676 is a synthetic novel stimulator of interferon genes (STING) agonist designed for intravenous administration. Here we demonstrate that TAK-676 dose-dependently triggers activation of the STING signaling pathway and activation of type I interferons. Furthermore, we show that TAK-676 is a highly potent modulator of both the innate and adaptive immune system and that it promotes the activation of dendritic cells, natural killer cells, and T cells in preclinical models. In syngeneic murine tumor models in vivo, TAK-676 induces dose-dependent cytokine responses and increases the activation and proliferation of immune cells within the TME and tumor-associated lymphoid tissue. We also demonstrate that TAK-676 dosing results in significant STING-dependent antitumor activity, including complete regressions and durable memory T-cell immunity. We show that TAK-676 is well tolerated, exhibits dose-proportional pharmacokinetics in plasma, and exhibits higher exposure in tumor. The intravenous administration of TAK-676 provides potential treatment benefit in a broad range of tumor types. Further study of TAK-676 in first-in-human phase I trials is ongoing. Significance: TAK-676 is a novel systemic STING agonist demonstrating robust activation of innate and adaptive immune activity resulting in durable antitumor responses within multiple syngeneic tumor models. Clinical investigation of TAK-676 is ongoing.

Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route.

Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.

MAP3K11/GDF15 axis is a critical driver of cancer cachexia.

BACKGROUND: Cancer associated cachexia affects the majority of cancer patients during the course of the disease and thought to be directly responsible for about a quarter of all cancer deaths. Current evidence suggests that a pro-inflammatory state may be associated with this syndrome although the molecular mechanisms responsible for the development of cachexia are poorly understood. The purpose of this work was the identification of key drivers of cancer cachexia that could provide a potential point of intervention for the treatment and/or prevention of this syndrome. METHODS: Genetically engineered and xenograft tumour models were used to dissect the molecular mechanisms driving cancer cachexia. Cytokine profiling from the plasma of cachectic and non-cachectic cancer patients and mouse models was utilized to correlate circulating cytokine levels with the cachexia phenotype. RESULTS: Utilizing engineered tumour models we identified MAP3K11/GDF15 pathway activation as a potent inducer of cancer cachexia. Increased expression and high circulating levels of GDF15 acted as a key mediator of this process. In animal models, tumour-produced GDF15 was sufficient to trigger the cachexia phenotype. Elevated GDF15 circulating levels correlated with the onset and progression of cachexia in animal models and in patients with cancer. Inhibition of GDF15 biological activity with a specific antibody reversed body weight loss and restored muscle and fat tissue mass in several cachectic animal models regardless of their complex secreted cytokine profile. CONCLUSIONS: The combination of correlative observations, gain of function, and loss of function experiments validated GDF15 as a key driver of cancer cachexia and as a potential therapeutic target for the treatment and/or prevention of this syndrome.

Decreased left atrial strain parameters are correlated with prolonged total atrial conduction time in lone atrial fibrillation.

To investigate left atrium (LA) strain properties of patients with lone atrial fibrillation (LAF) and to assess relationships between LA strain parameters and total atrial conduction time measured with tissue Doppler imaging (PA-TDI). The study population consisted of 53 patients with LAF. The control group was comprised of 50 normal volunteers. Conventional echocardiography indices were measured. Mitral annular velocities and PA-TDI were assessed with TDI. Two-dimensional speckle-tracking echocardiography (2D-STE) was used to assess LA segmental strain and strain rate. Compared with the control group, PA-TDI was significantly prolonged and LA myocardial Ss, SRs, Sa, and SRa were significantly decreased in the LAF group (all P < 0.001). In the control group, LA myocardial Ss (γ = -0.486, P < 0.01), SRs (γ = -0.436, P < 0.01), and Sa (γ = -0.360, P < 0.05) were correlated negatively with PA-TDI. LA myocardial SRa (γ = 0.377, P < 0.01) was correlated positively with PA-TDI. In the LAF group, LA myocardial Ss (γ = -0.429, P < 0.01), SRs (γ = -0.468, P < 0.01), and Sa (γ = -0.380, P < 0.05) were also correlated negatively, and SRa (γ = 0.390, P < 0.01) was correlated positively, with PA-TDI. Multivariate logistic regression identified PA-TDI as the only predictor of AF onset (OR 1.39; 95 % CI 1.02-1.54; P < 0.01). LA strain parameters were decreased and PA-TDI was prolonged in patients with LAF. Structural remodeling of the LA, assessed by 2D-STE, was correlated with electrical remodeling, determined by PA-TDI. Prolonged PA-TDI was independently associated with AF onset.

A rare case of tricuspid valve thrombus with acute pulmonary embolism.

The development of thrombus on the tricuspid valve is very rare. This report describes a case of acute pulmonary embolism (PE) with a mass on the tricuspid valve in a normal heart, detected by bedside transthoracic echocardiography (TTE). After successful surgical management, the histopathological examination revealed the mass from the tricuspid valve to be mixed thrombus. The early use of bedside TTE can facilitate the prompt diagnosis and aggressive therapy when PE is suspected.

[Effect of spironolactone on L-arginine/iNOS/NO pathway of aortic adventitia in spontaneously hypertensive rats].

OBJECTIVE: Adventitia plays an important role in vascular injury diseases. Nitric oxide (NO) from inducible nitric oxide synthase (iNOS) is involved in many cardiovascular diseases. iNOS/NO pathway is activated in aorta of spontaneously hypertensive rats (SHRs). The role of aldosterone in L-arginine (L-Arg)/iNOS/NO pathway of aortic adventitia is uncertain. We investigated the effect of aldosterone antagonist spironolactone on adventitial L-Arg/iNOS/NO pathway in SHRs. METHODS: Twenty male SHR (10 weeks old, 220-280 g) were randomly divided into 2 groups (10 in each): untreated or treated with the aldosterone receptor antagonist, spironolactone (20 mg/kg per day) for 6 weeks. Age-matched Wistar-Kyoto rats (WKY) were used as control. Systolic blood pressure (tail-cuff method) was measured weekly. Six weeks later, the rats were sacrificed. The whole aorta was collected and aortic adventitia was isolated. iNOS activity, [(3)H]-L-Arg transport assay of aortic adventitia were carried out by isotope-labeled L-arginine conversion rate measurement, and measurement of nitrate/nitrite (NOx), an index of NO production of aortic adventitia was assayed with the Griess reaction. RESULTS: iNOS activity, [(3)H]-L-Arg transport and NO production were greatly increased in aortic adventitia of SHR [(12.55 +/- 2.27) pmol x mg(-1) x min(-1), (0.88 +/- 0.19) pmol x mg(-1) x min(-1) and (2.07 +/- 0.39) micromol/L)] compare versus WKY [(5.96 +/- 1.87) pmol x mg(-1) x min(-1), (0.51 +/- 0.15) pmolxmg(-1) x min(-1) and (1.55 +/- 0.32) micromol/L, P < 0.01], and decreased significantly by spironolactone treatment [(8.32 +/- 1.84) pmol x mg(-1) x min(-1), (0.61 +/- 0.15) pmol x mg(-1) x min(-1) and (1.64 +/- 0.27) micromol/L, P < 0.01]. CONCLUSION: L-Arg/iNOS/NO is activated in aortic adventitia of SHR. Spironolactone can inhibit the activation of L-Arg/iNOS/NO pathway. Aldosterone may play an important role in some cardiovascular diseases such as atherosclerosis through iNOS/NO pathway.

Cardiac fibrosis in diabetic rats: regulation and mechanism of activation of the PPARgamma signal pathway.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily which affects organic fibrosis. The aims of the study were to approach the effects of activation of the PPARgamma signal pathway on cardiac fibrosis in diabetic rats, and also the effects on cardiac remodeling and function. Type 1 diabetic models were used in the study. All the animals were divided into 3 groups: I: control group; II: diabetic group; III: diabetes+Pioglitazone (Piog, a PPARgamma ligand) administration group. After 14 weeks of feeding, general condition, fibrosis indices, echocardiography and interventricular pressures parameters were detected. At the 14th week, compared with group I, the hydroxyproline concentration in group II significantly increased, and CO I and III distribution was more obvious by sirius red staining. Reduction of LVSP (left ventricular systolic pressure) and increase of LVEDP (left ventricular end-diastolic pressure) were also significant in group II. But these situations were changed by the administration of Piog in group III. Furthermore, results of RT-PCR and immunohistochemistry showed that Piog administration reduced angiotensin II type 1 receptor (AT1-R) expression in diabetic models. Hence, activation of the PPARgamma signal pathway could repress cardiac fibrosis in diabetic rats, and partly improve cardiac remodeling and function by down-regulating activity of RAS at the receptor level.

Relationship between integrated backscatter and atrial fibrosis in patients with and without atrial fibrillation who are undergoing coronary bypass surgery.

OBJECTIVE: The purpose of this study was to investigate the relationship between the integrated backscatter (IBS) and atrial fibrosis, with and without atrial fibrillation (AF), in patients who are undergoing coronary bypass grafting (CABG). METHODS: A total of 74 patients (18 preoperative AF, 56 sinus rhythm [SR]) with coronary artery disease undergoing CABG were included. The IBS of the left atrium (LA) posterior wall was acquired from transthoracic echocardiographic examination before surgery. Samples from the LA appendage were collected after opening the pericardium and quantitative assessment of atrial fibrosis was performed with collagen volume fraction (CVF). Postoperative AF was monitored with electrocardiographic telemetry in-hospital. RESULTS: There was a positive relationship between age, IBS of the left atrial posterior wall indexed by pericardium (IBS%), and CVF by multivariate linear regression analysis (r = 0.612, p = 0.034; r = 0.887, p < 0.001 respectively). The value of IBS%, LA dimension (LAD), and CVF values were higher in patients with preoperative AF than in patients with preoperative SR (p < 0.001, p < 0.01, p < 0.001, respectively). The value of age, IBS%, and CVF in patients with postoperative AF were higher than in patients without postoperative AF (p = 0.029, p < 0.001, p = 0.001 respectively). CONCLUSIONS: IBS of the LA posterior wall indexed by pericardium provides an objective quantitative measure of atrial fibrosis and correlates with postoperative AF in patients undergoing CABG surgery.

Relation of Hemoglobin A1c to myocardial acoustic densitometry and left ventricular diastolic function in patients with Type 2 diabetes mellitus and without evident heart disease.

AIM: The aim of the study was to detect the echocardiographic sensitive indexes for prediction of the subclinical cardiac dysfunction and to evaluate the relation between Hemoglobin A1c (HbA1c) and myocardial acoustic densitometry as well as cardiac function. METHODS: Fifty DM2 patients (48.5+/-8.6 years) without evident heart disease and 50 age- and sex-matched normal controls (47.6+/-8.8 years) were enrolled. Conventional echocardiography, tissue Doppler imaging and acoustic densitometry of both groups were measured. HbA1c of DM2 patients were determined. RESULTS: There were no significant differences in systolic indexes between the two groups. Mean LV myocardial early diastolic velocity Em and Em/Am were lower in DM group than control group. Mean LV myocardial late diastolic velocity Am and E/Em were higher in DM group than control group. IVS-IBS% and LVPW-IBS% were higher in DM group than control group. IVS-CVIB and LVPW-CVIB were lower in DM group than control group. HbA1c was negatively correlated with E/A (gamma=-0.310, P<0.05), Em (gamma=-0.409, P<0.01), Em/Am (gamma=-0.380, P<0.01) and positively correlated with E/Em (gamma=0.488, P<0.01). Significant positive correlation was present between HbA1c and IVS-IBS% (gamma=0.679, P<0.01), LVPW-IBS% (gamma=0.666, P<0.01). CONCLUSIONS: The diastolic dysfunction and abnormal myocardial acoustic densitometry exist before the systolic function damage in DM2 patients. Tissue Doppler imaging and ultrasonic integrated backscatter can be used as sensitive means for early assessing myocardial histological changes in DM2 patients. HbA1c is related with both diastolic dysfunction and acoustic densitometry.

Optimal time for human umbilical cord blood cell transplantation in rats with myocardial infarction.

BACKGROUND: Cell therapy for cardiac regeneration is still under investigation. To date there have been a limited number of studies describing the optimal time for cell injection. The present study aimed to examine the optimal time for human umbilical cord blood cells (HUCBCs) transplantation after myocardial infarction (MI). METHODS: The animals underwent MI by ligation of the left anterior descending coronary artery and received an intravenous injection of equal volumes of HUCBCs or phosphate buffered saline at days 1, 5, 10 and 30 after MI. HUCBCs were detected by immunostaining against human human leucocyte antigen (HLA). Cardiac function, histological analysis and measurement of vascular endothelial growth factor (VEGF) were performed 4 weeks after cell transplantation. RESULTS: HUCBCs transplantation could improve cardiac function in rats that received transplantation at 5 and 10 days after MI. The best benefit was achieved in rats that received cells at 10-day after MI. Survival of engrafted HUCBCs, angiogenesis and VEGF expression were more obvious in the 10-day transplantation group than in the other transplantation groups. No evidence of cardiomyocyte regeneration was detected in any transplanted rats. CONCLUSIONS: HUCBCs transplantation could improve cardiac function in rats that received HUCBCs at days 5 and 10 after MI with the optimal time for transplantation being 10 days post MI. Angiogenesis, but not cardiomyocyte regeneration, played a key role in the cardiac function improvement.

[Effects of carvedilol and metoprolol on cardiac fibrosis in rats with experimental myocardial infarction].

OBJECTIVE: To investigate the effects of carvedilol and metoprolol on cardiac fibrosis in rats with experimental myocardial infarction (MI). METHODS: MI was induced in male Sprague-Dawley rats by ligating the left coronary artery. Rats randomly received saline, carvedilol (10 mg.kg(-1).d(-1)) or metoprolol (20 mg.kg(-1).d(-1)) beginning at 4 weeks post MI for 8 weeks per gavage. Sham-operated rats serve as control. Collagen perivascular circumferential collagen area (PCVA), peri-coronary circumferential collagen area (VLCA) and interstitial collagen volume fraction (ICVF) as well as myocardial hydroxyproline content were determined after hemodynamic measurements at the study end. RESULTS: LVEDP were significantly lower and +/- dp/dt significantly higher in carvedilol and metoprolol treated MI rats than that in saline treated MI rats. Myocardial hydroxyproline, PCVA/VLCA ratio and ICVF were significantly reduced in metoprolol, more significantly reduced in carvedilol treated MI rats compared to saline treated MI rats (all P < 0.05). CONCLUSION: Metoprolol and carvedilol could decrease the concentration of hydroxyproline and ICVF in MI rats.

[The effect of radial artery on coronary bypass surgery in patients aged 65 years and older].

OBJECTIVE: To investigate the effect of autologous radial artery (RA) on coronary artery bypass grafting (CABG) in the elderly aged 65 years and older. METHODS: Three hundreds and twenty-two patients aged 65 years and older underwent CABG with autologous RA from January 2000 to March 2007. Peri-operative complication and mortality were observed and follow-up was performed. RESULTS: Three hundreds and forty-four RA grafts including 300 cases of single and 22 cases of bilateral RA were collected. The total number of distal anastomosis was 974, with the mean of (3.0 +/- 0.4). The mean of RA distal anastomosis was (1.1 +/- 0.4). There were 321 single, 16 Y or T composite and 7 sequential grafts of RA constructed. The distal end of RA was anastomosed to right coronary artery system for 234 times, to obtuse marginal for 95 times, to diagonal or intermediate ramous artery for 22 times. The proximal end of RA was anastomosed to aorta for 328 times, to left internal mammary artery for 9 times and to saphenous vein for 7 times. Only 13 patients manifested transient paresthesia in the area of radial aspect of thumb and no other complication occurred in the forearm. During hospitalization, 7 patients died. No patient died after the follow-up of (46.5 +/- 6.7) months. Seventy-three patients were performed with coronary angiography postoperatively. It was showed by coronary angiography that all RA conduits were patent after the duration of (47.5 +/- 11.2) months after CABG. CONCLUSION: Utilization of RA to CABG in the elderly is safe and effective.

Postinfarction myocardial scarring in mice: molecular MR imaging with use of a collagen-targeting contrast agent.

PURPOSE: To prospectively evaluate a gadolinium-based collagen-targeting contrast agent, EP-3533, for in vivo magnetic resonance (MR) imaging of myocardial fibrosis in a mouse model of healed myocardial infarction (MI). MATERIALS AND METHODS: All procedures were performed in accordance with protocols approved by the animal care and use committee. MI was induced in eight mice by means of occlusion of the left anterior descending coronary artery followed by reperfusion. Four MR examinations were performed in each animal: one examination before, one examination 1 day after, and two examinations 6 weeks after the MI. For the latter two examinations, electrocardiographically gated inversion-recovery gradient-echo MR images were acquired before and serially (every 5 minutes) after the intravenous injection of either gadopentetate dimeglumine or EP-3533. The image enhancement kinetic properties of the postinfarction scar, normal myocardium, and blood were compared. RESULTS: Dynamic T1-weighted MR imaging revealed the washout time constants for EP-3533 to be significantly longer than those for gadopentetate dimeglumine in regions of postinfarction scarring (mean, 194.8 minutes +/-116.8 [standard deviation] vs 25.5 minutes +/- 4.2; P < .05) and in normal myocardium (mean, 45.4 minutes +/- 16.7 vs 25.1 minutes +/- 9.7; P < .05). Findings on postmortem histologic sections stained for collagen correlated well with EP-3533-enhanced areas seen on inversion-recovery MR images. Fifty minutes after EP-3533 injection, the postinfarction scar tissue samples, as compared with the normal myocardium, had a twofold higher concentration of gadolinium. CONCLUSION: Use of the gadolinium-based collagen-targeting contrast agent, EP-3533, enabled in vivo molecular MR imaging of fibrosis in a mouse model of healed postinfarction myocardial scarring.

Down-regulation of the expression of angiotensin II type 1 receptor in neonatal rat cardiac fibroblast by activation of PPARgamma signal pathway.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is one of the hormone nuclear receptors. Recent data have shown that activation of PPARgamma signal pathway has many positive effects on cardiovascular system. The goals of this study were to determine whether PPARgamma activator affects cardiac fibrosis and the possible mechanisms. Cardiac fibroblasts (CFs) of SD neonate rats were used in the study. Cells were divided into 4 groups: I--control group; II--pioglitazone group (Piog--PPARgamma agonist); III--angiotensin II (Ang II) group; and IV--Piog + Ang II group (Piog plus angiotensin II). mRNA and protein expression of collagen type I, III and angiotensin II type 1 receptor (AT1-R) were tested by reverse transcription--polymerase chain reaction and Western blotting. With the inhibition of actinomycin D, we investigated the impacts of Piog on the stability of AT1-RmRNA. Compared with group I, the mRNA and protein expression of collagen type I, III and AT1-R were up-regulated in group III (P < 0.05). However with the effects of Piog in group IV, the expressions mentioned above were attenuated significantly (P < 0.05). With the effects of actinomycin D, AT1-RmRNA was reduced at the same degree in control and Piog groups at the same time points. These results indicated that treatment with Piog can attenuate Ang II-induced collagen synthesis in CFs through down-regulation of the AT1-R expression. With the intervention of actinomycin D, we suggested that PPARgamma agonist didn't affect the stability of AT1-RmRNA.

[Effects of aldosterone on inducible nitric oxide synthase/nitric oxide pathway in aortic adventitia].

OBJECTIVE: To evaluate the effect and related mechanisms of aldosterone (ALD) on inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) production in aortic adventitia. METHODS: Aortic adventitias from SD rats were incubated for 6 hours with various protocols: buffer alone (control), ALD (10(-8) mol/L - 10(-6) mol/L), ALD + spironolactone (10(-5) mol/L, ALD + SP), ALD + RU486 (10(-5) mol/L), LPS 10 ng/ml (LPS), ALD + LPS (10 ng/ml), ALD + LPS + SP (10(-5) mol/L), and ALD + LPS + RU486. Nitrate/nitrite (NOx), an index of NO production, was measured by Greiss Reaction. iNOS activity was determined by isotope-labeled L-arginine convertion rate. RESULTS: (1) NOx production and iNOS activity were similar between ALD and control groups (P > 0.05). NOx production was significantly reduced while iNOS activity remained unchanged in the ALD (10(-6) mol/L) + SP group compared to ALD (10(-6) mol/L) group. NOx production by 10(-7) mol/L and 10(-6) mol/L ALD increased by 50.0% and 58.7% respectively (P < 0.01) and iNOS activity was also significantly increased (P < 0.01) in ALD + RU486 group than that in ALD group. (2) LPS significantly increased the NOx production and iNOS activity (P < 0.01) and these effects were not augmented by adding ALD to LPS (P > 0.05) and SP significantly blocked and RU486 significantly enhanced the effects by LSP and ALD on NOx production and iNOS activity (P < 0.05). CONCLUSION: Aldosterone has a dual effect on iNOS/NO through mineralocorticoid receptor and glucocorticoid receptor pathway.

[Efficacy of intravenous aspirin use in patients with acute coronary syndrome].

OBJECTIVE: To compare the efficacy of intravenous versus oral aspirin use in patients with acute coronary syndrome (ACS). METHODS: ACS patients were randomly treated with intravenous aspirin (300 mg/d, IA, n = 30), low oral aspirin (100 mg/d, OA1, n = 32) or high oral aspirin (300 mg/d, OA2, n = 33). Aspirin sensitivity was tested by optical platelet aggregation using adenosine diphosphate (ADP) and arachidonic acid (AA). The serum CD62p contents were examined by Flow cytometry. RESULTS: Platelet aggregation expressed as ratio of reduction of ADP and AA post various aspirin were similar among 3 groups [IA: ADP (12.0 +/- 10.4)%, AA (6.7 +/- 11.2)%; OA1: ADP (6.0 +/- 14.6)%, AA (6.9 +/- 12.3)%; OA2: ADP (9.4 +/- 16.6)%, AA (7.3 +/- 13.0)%, all P > 0.05]. CD62p decreasing level post various aspirin were also similar among groups [IA: (10.9 +/- 18.6)%, OA1: (9.0 +/- 11.8)%, OA2: (7.1 +/- 15.7)%, all P > 0.05]. Side-effects and MACE post various aspirin use were comparable among groups. CONCLUSION: Inhibiting efficacy on platelets function by intravenous aspirin (300 mg/d) was comparable to that of by oral aspirin (100 mg/d, 300 mg/d) in patients with acute coronary syndrome and could be used as an alternative route for patients who can't take oral aspirin.

[Protective effects of dexamethasone on myocardium in rats with sepsis].

OBJECTIVE: To investigate the changes in heart function and myocardial mechanics in murine sepsis model, and the mechanism of the protective effect of dexamethasone on heart. METHODS: Wistar rats were randomly divided into control group, lipopolysaccharide (LPS) group (4 mg/kg LPS intravenously), LPS+dexamethasone group (4 mg/kg LPS+2 mg/kg dexamethasone intravenously), with 32 rats in each group. A catheter was passed through right common carotid artery to the left cardiac ventricle. Function of the left ventricle was monitored, and blood was drawn at 0, 2, 4, 6 hours to detect concentrations of tumor necrosis factor-alpha (TNF-alpha), troponin T (TnT), with 8 rats for each time point. RESULTS: In sepsis rats, TnT increased significantly and could be lowered by dexamethasone [at 6 hours after the treatment (1.76+/-0.57) microg/L vs. (0.70+/-0.36) microg/L, P<0.01]. There were changes in left ventricular peak systolic pressure (LVPP) and maximum rate of intraventricular pressure rise/down (+/-dp/dt max) to certain extent, and increase in left ventricular end-diastolic pressure (LVEDP), but these changes could be ameliorated by using dexamethasone. TNF-alpha increased significantly in sepsis rats, but dexamethasone could lower its level [at 2 hours after the treatment (11.22+/-2.38) pmol/L vs. (7.62+/-3.21) pmol/L, P<0.01]. CONCLUSION: Myocardium is remarkably damaged in rats with sepsis. TNF-alpha could be regarded as one of the factors which could produce injury to myocardium. Dexamethasone could alleviate cardiac damage produced by endotoxin in sepsis model.