Presence of cystic duct stone is a risk for postoperative retained stones in patients with acute cholecystitis.

PURPOSE: Retained stones (RS) in the common bile duct (CBD) are one of the major problems after laparoscopic cholecystectomy and usually require endoscopic treatment. However, few reports have investigated risk factors for the development of RS in the CBD. METHODS: A total of 325 patients with acute cholecystitis underwent laparoscopic cholecystectomy at our hospital between January 2013 and Jury 2021. Patient characteristics, including radiographic factors and perioperative outcomes, were reviewed, and perioperative factors predicting RS in the CBD were investigated. RESULTS: RS in the CBD were developed in 34 patients. All 34 patients were treated endoscopically. ASA-PS class 3 or more (p = 0.029, odds ratio = 2.601), subtotal cholecystectomy performance (p = 0.004, odds ratio = 3.783) and the presence of cystic duct stones (p < 0.001, odds ratio = 11.759) were found by logistic regression analysis to be independent risk factors for developing RS in the CBD. Cystic duct stones were preoperatively detected in 60 patients. Of these, 21 cases were not detected on magnetic resonance cholangiopancreatography (MRCP) but on CT, while 15 cases were not detected on CT but on MRCP. CONCLUSIONS: The presence of cystic duct stones on preoperative CT or MRCP is a crucial risk factor for developing RS in the CBD. Both CT and MRCP are useful to avoid overlooking cystic duct stones.

Prediction of extensive necrotic change in acute gangrenous cholecystitis.

PURPOSE: Gangrenous cholecystitis (GC) is a severe type of acute cholecystitis that implies higher mortality and morbidity rates than uncomplicated cholecystitis. The characteristics of GC are various for each case. However, preoperative predictors of GC with extensive necrotic change have not been investigated well. METHODS: A total of 239 patients who were pathologically diagnosed with GC underwent laparoscopic cholecystectomy at our hospital between January 2013 and December 2021. Of these, 135 patients were included in this study and were subdivided into the extensive necrosis group (patients with necrotic change extending to the neck of the gallbladder, n = 18) and the control group (patients with necrotic change limited to the fundus or body, not extending to the neck, n = 117) according to each operation video. Patient characteristics and perioperative factors predicting extensive necrotic change were investigated. RESULTS: Pericholecystic fat stranding (83.3 vs. 53.8%, p = 0.018) and absence of wall enhancement on preoperative CT images (50.0 vs. 24.7%, p = 0.026) were significantly associated with extensive necrosis. Seven of 18 patients in the extensive necrosis group showed necrotic changes beyond the infundibulum. The absence of wall enhancement on preoperative CT images (71.4 vs. 28.8%, p = 0.018) was significantly associated with necrotic changes beyond the infundibulum. CONCLUSIONS: Pericholecystic fat stranding and absence of wall enhancement on preoperative enhanced CT are predictors of extensive necrotic change in patients with GC. In addition, the absence of wall enhancement also predicts the presence of necrotic changes beyond the infundibulum.

Generation of Transgenic Mice that Conditionally Overexpress Tenascin-C.

Tenascin-C (TNC) is an extracellular matrix glycoprotein that is expressed during embryogenesis. It is not expressed in normal adults, but is up-regulated under pathological conditions. Although TNC knockout mice do not show a distinct phenotype, analyses of disease models using TNC knockout mice combined with in vitro experiments revealed the diverse functions of TNC. Since high TNC levels often predict a poor prognosis in various clinical settings, we developed a transgenic mouse that overexpresses TNC through Cre recombinase-mediated activation. Genomic walking showed that the transgene was integrated into and truncated the Atp8a2 gene. While homozygous transgenic mice showed a severe neurological phenotype, heterozygous mice were viable, fertile, and did not exhibit any distinct abnormalities. Breeding hemizygous mice with Nkx2.5 promoter-Cre or α-myosin heavy chain promoter Cre mice induced the heart-specific overexpression of TNC in embryos and adults. TNC-overexpressing mouse hearts did not have distinct histological or functional abnormalities. However, the expression of proinflammatory cytokines/chemokines was significantly up-regulated and mortality rates during the acute stage after myocardial infarction were significantly higher than those of the controls. Our novel transgenic mouse may be applied to investigations on the role of TNC overexpression in vivo in various tissue/organ pathologies using different Cre donors.

Does early surgery imply a critical risk for patients with Grade III acute cholecystitis?

BACKGROUND: For patients with Grade III acute cholecystitis (AC), several factors have been proposed in the 2018 Tokyo guidelines as caution signs in performing early surgery. However, these factors have not been externally validated in detail. METHODS: This retrospective study examined 35 patients who had been diagnosed with Grade III AC and treated with laparoscopic cholecystectomy between January 2008 and July 2019. The patients were allocated into an early group (patients who underwent surgery within 7 days of admission, n = 28) and a delayed group (patients who underwent surgery at least 8 days after admission, n = 7). Comparisons were made between these groups. RESULTS: No patients died. Significantly more patients required a conversion to open surgery (0% vs 28.5%, P = .003) or conversion to subtotal cholecystectomy (25.0% vs 71.4%, P = .020) in the delayed group than in the early group, and the total length of postoperative stay was significantly longer in the delayed group (11.4 vs 27.2 days, P = .001). The presence of negative predictive factors or risk factors listed in the 2018 Tokyo guidelines was not associated with death or postoperative complications. CONCLUSIONS: Early surgery was considered appropriate and feasible for select patients who had Grade III AC and preoperative risk factors.

Does preoperative MRCP imaging predict risk for conversion to subtotal cholecystectomy in patients with acute cholecystitis?

BACKGROUND: Subtotal cholecystectomy (SC) is a useful procedure for avoiding bile duct injury in patients with difficult gallbladder. However, risk factors for conversion to SC, especially preoperative magnetic resonance cholangiopancreatography (MRCP) findings that predict conversion to SC, have not been investigated in detail. METHODS: A total of 290 patients with acute cholecystitis who underwent laparoscopic cholecystectomy at our hospital between November 2011 and March 2020 were included. Patient characteristics and perioperative outcomes were reviewed, and preoperative clinical factors predicting conversion to SC were investigated. RESULTS: Forty-three patients underwent SC, whereas the remaining 247 patients underwent total cholecystectomy. An American Society of Anesthesiologists (ASA) score of 3 or greater (p = 0.011), surgery on or after 9 days from symptom onset (p < 0.001), obscuration of the gallbladder wall around the neck on MRCP images (p = 0.010) and disruption of the common hepatic duct on MRCP images (p < 0.001) were significantly associated with conversion to SC. Logistic regression analyses revealed that an ASA score of 3 or greater (odds ratio = 2.667, p = 0.020), surgery on or after 9 days from symptom onset (odds ratio = 4.229, p < 0.001) and disruption of the common hepatic duct on MRCP images (odds ratio = 4.478, p = 0.002) were independent predictors for conversion to SC. CONCLUSIONS: Early surgery yielded a lower risk for conversion to SC. Disruption of the common hepatic duct on preoperative MRCP images is associated with a risk for conversion to SC.

Risk factors for postoperative bile leak in patients who underwent subtotal cholecystectomy.

BACKGROUND: Subtotal cholecystectomy (SC) is a procedure for avoiding the risk of bile duct injury, especially in patients with difficult gallbladders. However, recent meta-analyses have demonstrated that SC is associated with a relatively high incidence of postoperative bile leak. To our knowledge, there have been no reports that have investigated risk factors for postoperative bile leak. METHODS: A total of 76 patients underwent reconstituting SC at our hospital between January 2005 and July 2019. Patient characteristics and perioperative outcomes were reviewed, and risk factors for postoperative bile leak were investigated. In addition, in patients with acute cholecystitis (AC) (n = 60), subgroup analyses were performed. RESULTS: Bile leak developed in 11 patients with AC (18.3%), while no patients with chronic cholecystitis developed bile leak (p = 0.064). Patients with AC who underwent surgery 10 days or later from onset developed postoperative bile leak significantly more frequently than those who underwent surgery within 10 days (38.0 vs 7.6%, p = 0.003). Patients with AC who underwent gallbladder stump closure with suturing developed postoperative bile leak significantly more frequently than those who underwent ligation (37.5 vs 11.3%, p = 0.020). In the patients with AC, surgery after 10 days from onset (p = 0.022, odds ratio = 5.85) was found by logistic regression analysis to be an independent risk factor for developing postoperative bile leak. CONCLUSION: Early surgery yielded a lower incidence of postoperative bile leak in patients who underwent SC. Surgery during the subacute phase was considered to imply a higher risk for developing bile leak than surgery during the acute and chronic phases.

Calculus left in remnant gallbladder cause long-term complications in patients undergoing subtotal cholecystectomy.

BACKGROUND: There have been only a few reports that describe the long-term outcomes of Subtotal cholecystectomy (SC). METHODS: A total of 59 patients underwent "reconstituting" SC at our hospital between January 2005 and July 2017. In the 59 patients, risk factors for long-term complications were analyzed. In addition, in the patients with acute cholecystitis (AC), perioperative and long-term clinical factors were compared for patients who underwent SC (n = 48) and those who underwent total cholecystectomy (n = 378). RESULTS: In the 59 patients who underwent SC, long-term complication developed in 14 (23.7%), including residual calculus in the common bile duct (n = 12), remnant cholecystitis (n = 1), and persistent severe inflammatory response (n = 1). Postoperative magnetic resonance image was performed in 35/59 patients (59.3%) who underwent SC. In these 35 patients, the size of the remnant gallbladder calculated by magnetic resonance cholangiopancreatography was significantly associated with the occurrence of long-term complications (p = 0.009). In the patients with AC, regarding long-term complications, the incidence of residual calculus in the common bile duct (16.6 versus 0.7%) was significantly higher in the SC group. CONCLUSIONS: SC was associated with a relatively high incidence of long-term complications associated with remnant calculus.

Outcomes of early versus delayed laparoscopic cholecystectomy for acute cholecystitis performed at a single institution.

INTRODUCTION: Debate continues regarding the clinical outcomes of early laparoscopic cholecystectomy (ELC) versus delayed laparoscopic cholecystectomy (DLC) for acute cholecystitis (AC). The aim of this retrospective study was to compare clinical outcomes of ELC and DLC. METHODS: This study consisted of 465 patients who had undergone laparoscopic cholecystectomy for AC between January 2000 and February 2017. Patients were divided between an ELC group (patients who underwent laparoscopic cholecystectomy within 6 days of symptom onset, n = 288) and a DLC group (patients who underwent laparoscopic cholecystectomy at least 7 days from symptom onset, n = 177), and clinical outcomes were compared. RESULTS: Operation time (105 vs 124 min), length of postoperative hospital stay (4 vs 4 days), conversion rate (1.3% vs 10.7%), bile leak (0.3% vs 3.3%), residual calculus (2.4% vs 6.7%), and readmission (1.0% vs 6.7%) were significantly better in the ELC group. A history of upper abdominal surgery, grade II or grade III AC, preoperative percutaneous transhepatic gallbladder drainage, and time between symptom onset and surgery of more than 7 days were independent risk factors for conversion. CONCLUSIONS: ELC for AC yields more favorable clinical outcomes than DLC.

Is postponed laparoscopic cholecystectomy justified for acute cholecystitis appearing early after onset?

INTRODUCTION: Early laparoscopic cholecystectomy (ELC) is considered the standard treatment for acute cholecystitis for patients who can tolerate surgery. The ideal time for performing ELC is reported to be 72 h from onset. However, many patients undergo surgery on or after the fourth day from onset, even if they presented early after onset. A few reports have investigated the feasibility and disadvantages of this so-called "postponed laparoscopic cholecystectomy" (PLC). METHODS: This study consisted of 215 patients who had undergone laparoscopic cholecystectomy for acute cholecystitis within 6 days of onset between July 2006 and December 2017. Patients were divided into an ELC group (patients who underwent LC within 3 days of symptom onset, n = 172) and a PLC group (patients who underwent LC 4-6 days from symptom onset and on or after 3 days from admission, n = 43). Comparisons were made between these groups. RESULTS: Perioperative outcomes between the PLC and ELC groups were not significantly different, except for the requirement of subtotal cholecystectomy (SC) (16.2% vs 5.2%, P = 0.013). In the PLC group, persistent fever after admission was significantly associated with the need for SC (P = 0.036). CONCLUSIONS: PLC for acute cholecystitis performed within 6 days of onset gave acceptable perioperative outcomes, except for an increased requirement for SC. Surgeons should keep in mind that PLC may increase the need for SC. A persistent fever after admission may be a risk factor for SC in the PLC group.

Tenascin-C accelerates adverse ventricular remodelling after myocardial infarction by modulating macrophage polarization.

AIMS: Tenascin-C (TN-C) is an extracellular matrix protein undetected in the normal adult heart, but expressed in several heart diseases associated with inflammation. We previously reported that serum TN-C levels of myocardial infarction (MI) patients were elevated during the acute stage, and that patients with high peak TN-C levels were at high risk of left ventricular (LV) remodelling and poor outcome, suggesting that TN-C could play a significant role in the progression of ventricular remodelling. However, the detailed molecular mechanisms associated with this process remain unknown. We aimed to elucidate the role and underlying mechanisms associated with TN-C in adverse remodelling after MI. METHODS AND RESULTS: MI was induced by permanent ligation of the coronary artery of TN-C knockout (TN-C-KO) and wild type (WT) mice. In WT mice, TN-C was expressed at the borders between intact and necrotic areas, with a peak at 3 days post-MI and observed in the immediate vicinity of infiltrating macrophages. TN-C-KO mice were protected from ventricular adverse remodelling as evidenced by a higher LV ejection fraction as compared with WT mice (19.0 ± 6.3% vs. 10.6 ± 4.4%; P < 0.001) at 3 months post-MI. During the acute phase, flow-cytometric analyses showed a decrease in F4/80+CD206lowCD45+ M1 macrophages and an increase in F4/80+CD206highCD45+ M2 macrophages in the TN-C-KO heart. To clarify the role of TN-C on macrophage polarization, we examined the direct effect of TN-C on bone marrow-derived macrophages in culture, observing that TN-C promoted macrophage shifting into an M1 phenotype via Toll-like receptor 4 (TLR4). Under M2-skewing conditions, TN-C suppressed the expression of interferon regulatory factor 4, a key transcription factor that controls M2-macrophage polarization, via TLR4, thereby inhibiting M2 polarization. CONCLUSION: These results suggested that TN-C accelerates LV remodelling after MI, at least in part, by modulating M1/M2-macrophage polarization.

Teneligliptin Prevents Cardiomyocyte Hypertrophy, Fibrosis, and Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats.

BACKGROUND: We investigated the effects of the dipeptidyl peptidase 4 inhibitor teneligliptin on cardiac function and hemodynamics during heart failure in hypertensive model rats. METHODS AND RESULTS: Fifty-five male Dahl salt-sensitive rats were divided into 4 groups: control group (0.3% NaCl chow; n = 13), hypertension (HT) group (8% NaCl chow; n = 20), HT-early TNL group (8% NaCl chow and teneligliptin from 6 weeks; n = 10), and HT-late TNL group (8% NaCl chow and teneligliptin from 10 weeks; n = 12). Hemodynamic measurement and tissue analyses were performed at 18 weeks. In all of the HT groups, systolic blood pressures were similarly elevated (P = .66) and heart weights similarly increased (P = .36) with and without TNL administration. LV end-diastolic dimension was significantly enlarged only in the HT-early TNL group compared with the control group (P = .025). Histologic analysis showed less fibrosis (P = .008) and cardiomyocyte widths (P = .009) in the HT-early TNL group compared with the HT group. On hemodynamic analysis, only the HT group showed significant LV end-diastolic pressure elevation (P = .049) and lung congestion (P < .001) compared with the control group. CONCLUSIONS: These results suggest that teneligliptin prevents concentric LV hypertrophy, fibrosis, and development of congestive heart failure in Dahl salt-sensitive rats. Teneligliptin may inhibit pressure-overload hypertrophic adaption and result in LV eccentric hypertrophy with reduced LV ejection fraction.

Tokyo Guidelines 2018: surgical management of acute cholecystitis: safe steps in laparoscopic cholecystectomy for acute cholecystitis (with videos).

In some cases, laparoscopic cholecystectomy (LC) may be difficult to perform in patients with acute cholecystitis (AC) with severe inflammation and fibrosis. The Tokyo Guidelines 2018 (TG18) expand the indications for LC under difficult conditions for each level of severity of AC. As a result of expanding the indications for LC to treat AC, it is absolutely necessary to avoid any increase in bile duct injury (BDI), particularly vasculo-biliary injury (VBI), which is known to occur at a certain rate in LC. Since the Tokyo Guidelines 2013 (TG13), an attempt has been made to assess intraoperative findings as objective indicators of surgical difficulty; based on expert consensus on these difficulty indicators, bail-out procedures (including conversion to open cholecystectomy) have been indicated for cases in which LC for AC is difficult to perform. A bail-out procedure should be chosen if, when the Calot's triangle is appropriately retracted and used as a landmark, a critical view of safety (CVS) cannot be achieved because of the presence of nondissectable scarring or severe fibrosis. We propose standardized safe steps for LC to treat AC. To achieve a CVS, it is vital to dissect at a location above (on the ventral side of) the imaginary line connecting the base of the left medial section (Segment 4) and the roof of Rouvière's sulcus and to fulfill the three criteria of CVS before dividing any structures. Achieving a CVS prevents the misidentification of the cystic duct and the common bile duct, which are most commonly confused. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

Rev-erb agonist improves adverse cardiac remodeling and survival in myocardial infarction through an anti-inflammatory mechanism.

Rev-erb α, known as nuclear receptor 1D1 (NR1D1), regulates circadian rhythm, modulates glucose and lipid metabolism, and inflammatory response. However, little is known about the effect of Rev-erb agonist on the progression of myocardial infarction (MI) and heart failure. To investigate it, wild-type male mice underwent sham-operation or permanent ligation of the left anterior descending coronary artery to create MI model. Rev-erb agonist SR9009 (100 mg/kg/day) or vehicle was intraperitoneally administered. Echocardiography was performed to evaluate cardiac function 1 week after surgery. The gene and protein expression levels in the left ventricles (LVs) were determined with real-time PCR, western blotting, and immunofluorescence. Moreover, immune cell infiltration into the LVs was analyzed by flow cytometry. Survival rate and reduced LV function were significantly improved by the treatment with SR9009 after MI. The expression level and plasma concentration of brain natriuretic peptide were significantly lower in MI mice treated with SR9009 (MI+SR) than in MI mice treated with vehicle (MI+V). Moreover, the mRNA expression levels of inflammatory-related molecules such as Il6, Mcp1, Ly6g, Cd11b, matrix metallopeptidase (Mmp)9, and the protein expression levels of phosphorylated NF-κB p65, phosphorylated ERK, and phosphorylated p38 were also significantly lower in MI+SR than in MI+V. Immunofluorescence intensity for MMP-9 was enhanced in the LVs, but was less so in MI+SR than in MI+V. Furthermore, infiltrations of neutrophils and proinflammatory macrophages in the LVs were dramatically increased in MI+V and were significantly suppressed in MI+SR. Rev-erb agonist SR9009 treatment inhibited post-MI mortality and improved cardiac function through modulating inflammation and remodeling process.

Strangulated gallbladder caused by a tip of the omentum attached to the abdominal wall: a case report.

Strangulation of the gallbladder associated with the omentum is extremely rare and, to our knowledge, only two cases have been previously reported. The patient was a 91-year-old female who presented to our emergency room with a chief complaint of upper abdominal pain. Computed tomography imaging revealed a gourd-shaped gallbladder with biphasic appearance divided clearly at the body. In the fundus side, the wall of the gallbladder was oedematous and thickened, while the neck side was intact. On the second day after onset, a laparoscopic cholecystectomy was performed. A tip of the omentum encircling the gallbladder was adhered to the abdominal wall and was strangling the gallbladder. By cutting the omentum at the attachment site, the strangulation was released. Laparoscopic cholecystectomy was performed, and the patient was discharged with an uneventful course. We experienced an extremely rare case of strangulated gallbladder caused by a tip of the omentum attached to the abdominal wall.

Loss of MURC/Cavin-4 induces JNK and MMP-9 activity enhancement in vascular smooth muscle cells and exacerbates abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is relatively common in elderly patients with atherosclerosis. MURC (muscle-restricted coiled-coil protein)/Cavin-4 modulating the caveolae function of muscle cells is expressed in cardiomyocytes, skeletal muscle cells and smooth muscle cells. Here, we show a novel functional role of MURC/Cavin-4 in vascular smooth muscle cells (VSMCs) and AAA development. Both wild-type (WT) and MURC/Cavin-4 knockout (MURC-/-) mice subjected to periaortic application of CaCl2 developed AAAs. Six weeks after CaCl2 treatment, internal and external aortic diameters were significantly increased in MURC-/- AAAs compared with WT AAAs, which were accompanied by advanced fibrosis in the tunica media of MURC-/- AAAs. The activity of JNK and matrix metalloproteinase (MMP) -2 and -9 were increased in MURC-/- AAAs compared with WT AAAs at 5 days after CaCl2 treatment. At 6 weeks after CaCl2 treatment, MURC-/- AAAs exhibited attenuated JNK activity compared with WT AAAs. There was no difference in the activity of MMP-2 or -9 between saline and CaCl2 treatments. In MURC/Cavin-4-knockdown VSMCs, TNFα-induced activity of JNK and MMP-9 was enhanced compared with control VSMCs. Furthermore, WT, MURC-/-, apolipoprotein E-/- (ApoE-/-), and MURC/Cavin-4 and ApoE double-knockout (MURC-/-ApoE-/-) mice were subjected to angiotensin II (Ang II) infusion. In both ApoE-/- and MURC-/-ApoE-/- mice infused for 4 weeks with Ang II, AAAs were promoted. The internal aortic diameter was significantly increased in Ang II-infused MURC-/-ApoE-/- mice compared with Ang II-infused ApoE-/- mice. In MURC/Cavin-4-knockdown VSMCs, Ang II-induced activity of JNK and MMP-9 was enhanced compared with control VSMCs. Our results suggest that MURC/Cavin-4 in VSMCs modulates AAA progression at the early stage via the activation of JNK and MMP-9. MURC/Cavin-4 is a potential therapeutic target against AAA progression.

Antagonists to endothelin receptor type B promote apoptosis in human pulmonary arterial smooth muscle cells.

AIMS: Vascular remodeling results from aberrations in the balance between cell proliferation and death, which is seen in the obstructive vasculature of pulmonary arterial hypertension (PAH). Endothelin (ET)-1 has a potent proliferative activity on vascular smooth muscle cells, and ET receptor inhibitors are used to treat PAH; however, it remains unclear whether ET receptor inhibition contributes to the apoptosis of pulmonary arterial smooth muscle cells (PASMCs), another cause of pulmonary vascular remodeling. MAIN METHODS: Cultured human PASMCs were treated with the ETA receptor antagonist BQ-123 (100µM), or the ETB antagonist A-192621 (1-100µM) or BQ-788 (1-100µM) for 48h. The cells were then incubated for another 24h with or without doxorubicin (DOX, 1µM), an anthracyclin antitumor antibiotic that promotes p53-mediated apoptosis. Cell viability and apoptosis were evaluated by MTT assays, caspase-3/7 activity assays, and Western blots for cleaved caspase-3 expression. KEY FINDINGS: The viability of PASMCs was significantly decreased by A-192621 and BQ-788, in a dose-dependent manner. A-192621 and BQ-788 significantly increased the caspase-3/7 activity and cleaved caspase-3 expression in PASMCs. The PASMCs' susceptibility to DOX-induced apoptosis was significantly higher in the presence of A-192621 and BQ-788 than with vehicle. However, BQ-123 did not affect these parameters. SIGNIFICANCE: Blockade of the ETB receptor increases the extent of apoptosis and susceptibility to DOX-induced apoptosis in PASMCs. Apoptosis caused by ETB receptor blockade in PASMCs may be one of the mechanisms by which vascular remodeling is reduced in ET receptor inhibitor-based PAH treatments.

Tenascin-C aggravates autoimmune myocarditis via dendritic cell activation and Th17 cell differentiation.

BACKGROUND: Tenascin-C (TN-C), an extracellular matrix glycoprotein, appears at several important steps of cardiac development in the embryo, but is sparse in the normal adult heart. TN-C re-expresses under pathological conditions including myocarditis, and is closely associated with tissue injury and inflammation in both experimental and clinical settings. However, the pathophysiological role of TN-C in the development of myocarditis is not clear. We examined how TN-C affects the initiation of experimental autoimmune myocarditis, immunologically. METHODS AND RESULTS: A model of experimental autoimmune myocarditis was established in BALB/c mice by immunization with murine α-myosin heavy chains. We found that TN-C knockout mice were protected from severe myocarditis compared to wild-type mice. TN-C induced synthesis of proinflammatory cytokines, including interleukin (IL)-6, in dendritic cells via activation of a Toll-like receptor 4, which led to T-helper (Th)17 cell differentiation and exacerbated the myocardial inflammation. In the transfer experiment, dendritic cells loaded with cardiac myosin peptide acquired the functional capacity to induce myocarditis when stimulated with TN-C; however, TN-C-stimulated dendritic cells generated from Toll-like receptor 4 knockout mice did not induce myocarditis in recipients. CONCLUSIONS: Our results demonstrated that TN-C aggravates autoimmune myocarditis by driving the dendritic cell activation and Th17 differentiation via Toll-like receptor 4. The blockade of Toll-like receptor 4-mediated signaling to inhibit the proinflammatory effects of TN-C could be a promising therapeutic strategy against autoimmune myocarditis.