Association of trimethylamine N-Oxide with cardiovascular and all-cause mortality in hemodialysis patients.

BACKGROUND: Trimethylamine-N-Oxide (TMAO) is a proatherogenic and prothrombotic metabolite. Our study examined the association of plasma TMAO level with cardiovascular and all-cause mortality in hemodialysis (HD) patients. METHODS: Patients who were at least 18 years-old and received HD for at least 6 months were enrolled within 6 months. Patients with coronary heart disease, congestive heart failure, arrhythmia, or stroke within 3 months before study onset were excluded. The primary endpoints were cardiovascular and all-cause death, and the secondary endpoint was cerebrovascular death. RESULTS: We recruited 252 patients and divided them into a high-TMAO group (>4.73 µg/mL) and a low-TMAO group (≤4.73 µg/mL). The median follow-up time was 73.4 months (interquartile range: 42.9, 108). A total of 123 patients died, 39 from cardiovascular disease, 19 from cerebrovascular disease, and 65 from other causes. Kaplan-Meier analysis indicated that the high-TMAO group had a greater incidence of cardiovascular death (Log-Rank: p = 0.006) and all-cause death (Log-Rank: p < 0.001). Cox regression analysis showed that high TMAO level was significantly associated with cardiovascular and all-cause mortality. After adjustment for confounding, this association remained significant for cardiovascular mortality (TMAO as a continuous variable: HR: 1.18, 95%CI: 1.07, 1.294, p < 0.001; TMAO as a dichotomous variable: HR: 3.44, 95%CI: 1.68, 7.08, p < 0.001) and all-cause mortality (TMAO as a continuous variable: HR: 1.14, 95%CI: 1.08, 1.21, p < 0.001; TMAO as a dichotomous variable: HR: 2.54, 95%CI: 1.71, 3.76, p < 0.001). CONCLUSIONS: High plasma TMAO level is significantly and independently associated with cardiovascular and all-cause mortality in HD patients.

[Role of triggering receptor expressed on myeloid cells-1 on coxsackievirus B3-induced inflammation and cardiomyocyte injury].

OBJECTIVE: To determine the expression of TREM-1 (triggering receptor expressed on myeloid cells-1) in macrophages after coxsackievirus B3 (CVB3) infection and the cardiomyocytes viability after culturing with supernatant of macrophages in the absence and presence of TREM-1 inhibitor LP-17 to explore if TREM-1 is involved in the pathogenesis of CVB3 infection induced inflammation and cardiomyocytes injury. METHODS: TREM-1 mRNA and TREM-1 and DAP-12 protein expression in macrophages were detected by Real-time PCR at 0, 1, 4, 8 and 12 h and by Western blot at 0, 16, 24 and 48 h post CVB3 infection. TNF-α secretion of macrophages was measure by ELISA, vitality and the apoptosis degree of cardiomyocytes was assessed by CCK8 and Annexin V-FITC after the cardiomyocytes were cultured with the supernatant of macrophages in normal control group, CVB3 infection group and LP-17 pretreated CVB3 infection group. RESULTS: TREM-1 mRNA expression was significantly upregulated at 4, 8, and 12 h (peaked at 8 h) and TREM-1 protein expression was significantly upregulated at 16 and 24 h and returned to baseline level at 48 h after CVB3 infection. The protein expression of DAP-12, a direct downstream signaling molecule of TREM-1, also significantly increased at 24 and 48 h post CVB3 infection (P < 0.01). Level of macrophages secreted TNF-α post CVB3 infection was significantly reduced in LP-17 pretreated cells (P < 0.01), LP-17 pretreatment also significantly improved viability and significantly reduced apoptosis of cardiomyocytes cultured with supernatant of CVB3 infected macrophages (P < 0.01). CONCLUSION: TREM-1 might be an important mediator post CVB3 infection and a major player on inducing excess macrophages-related inflammation and resulting in an indirect injury to cardiomyocytes.

[Association between expression of chromogranin A and myocardial fibrosis in patients with dilated cardiomyopathy].

OBJECTIVE: To observe the possible correlation between expression of chromogranin A (CGA) and myocardial fibrosis and investigate the potential role of CGA in the development of myocardial fibrosis in patients with dilated cardiomyopathy (DCM). METHODS: Surgical myocardial specimen from 10 DCM patients underwent successful orthotopic cardiac transplantation, and 3 normal myocardial specimen from brain-dead organ donors were obtained. CGA-mRNA, COLI-mRNA, COLIII-mRNA and ADAMTS-1-mRNA were analyzed by real-time PCR. The location and expression of CGA were assessed by immunohistochemistry(INH)with anti-CGA antibody. The collagen specific picrosirius red staining was applied on transversal myocardial slides and the collagen volume fraction (CVF) was calculated. The correlation between CGA and CVF was analyzed. RESULTS: Cytoplasmic expression of CGA assessed by INH showed large amount of strong positive granules densely arranged in the epicardial and endocardial myocardiocytes in DCM specimen while there was only few sparse granules in the normal myocardium (P < 0.05). CVF was significantly higher in DCM myocardial specimen than that in normal specimen (P < 0.001). CGA-mRNA was significantly correlated with COLI-mRNA (r = 0.729), COLIII-mRNA (r = 0.95) and ADAMTS-1-mRNA (r = 0.665, all P < 0.05). Moreover, collagen deposition location was almost identical with the strong positive expression location of CGA. CONCLUSION: We demonstrated for the first time that the deposition of CGA was related with the myocardial fibrosis in DCM heart, therefore, CGA might play an important role by influencing myocardial remodeling and fibrosis in DCM patients.