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Objective:To investigate the role and mechanism of microRNA-499 (miR-499) regulating α-myosin heavy chain (α-MHC) and β-myosin heavy chain (β-MHC) gene axis in septic myocardial dysfunction (SMD) and its significance.Methods:Sixty healthy adult male Sprague-Dawley (SD) rats were divided into phosphate buffered saline (PBS) control group (PBS group), lipopolysaccharide (LPS) induced SMD model group (LPS group), miR-499 agonist pretreatment group (agomir+LPS group), and miR-499 inhibitor pretreatment group (antagomir+LPS group) by random number table, with 15 rats in each group. SMD rat model was reproduced by intraperitoneal injection of LPS 10 mg/kg. The PBS group was intraperitoneally injected with the same amount of PBS. The two pretreatment groups were injected with agomir 30 mg/kg or antagomir 80 mg/kg through the caudal vein for 3 days, once a day. PBS group and LPS group were not pretreated. Echocardiography was detected 5 hours after LPS injection, and relevant indexes were recorded. The expression of miR-499 in plasma and myocardial tissue was detected by real-time quantitative polymerase chain reaction (qPCR). Western blotting was used to detect the protein expressions of α-MHC and β-MHC in myocardial tissue. Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of heart failure, was measured by electrochemiluminescence.Results:Compared with the PBS group, the rats in LPS group were depressed. Additionally, LPS down-regulated the level of miR-499 in plasma and myocardial tissue, decreased α-MHC expression in myocardial tissue and up-regulated the expression of β-MHC. Echocardiography showed that left ventricular ejection fraction (LVEF), left ventricle fractional shortening (LVFS), cardiac output (CO), stroke volume (SV) and heart rate (HR) decreased by 49.1%, 59.2%, 48.8%, 39.4% and 15.9%, respectively, and the level of plasma NT-proBNP increased significantly in LPS group, indicating that LPS could induce cardiac dysfunction in rats. Compared with the LPS group, after pretreatment with agomir to overexpress the miR-499, LVEF and LVFS were significantly increased [LVEF: 0.662±0.020 vs. 0.323±0.024, LVFS: (36.16±1.43)% vs. (20.20±1.32)%, both P < 0.01], which suggested that the cardiac function of rats was improved in agomir+LPS group. At the same time, pretreatment with agomir significantly down-regulated the β-MHC protein expression (β-MHC/GAPDH: 0.74±0.04 vs. 2.97±0.34, P < 0.01), significantly up-regulated α-MHC protein expression (α-MHC/GAPDH: 1.59±0.05 vs. 0.74±0.14, P < 0.01), and significantly decreased the plasma NT-proBNP level (ng/L: 114.49±6.85 vs. 334.13±4.36, P < 0.01). After pretreatment with antagomir to inhibit the expression of miR-499, echocardiography showed that LVEF and LVFS were significantly lower than those in the LPS group [LVEF: 0.297±0.021 vs. 0.323±0.024, LVFS: (19.38±1.52)% vs. (21.20±1.32)%, both P < 0.01], which suggested that the cardiac function of rats was significantly inhibited. At the same time, pretreatment with antagomir significantly down-regulated α-MHC protein expression in myocardial tissue (α-MHC/GAPDH: 0.63±0.03 vs. 0.74±0.14, P < 0.01), significantly up-regulated β-MHC protein expression (β-MHC/GAPDH: 3.03±0.47 vs. 2.97±0.34, P < 0.01), and significantly increased the level of plasma NT-proBNP (ng/L: 373.91±4.23 vs. 334.13±4.36, P < 0.05). Conclusions:miR-499 could regulate the expression of α-MHC and β-MHC which improved cardiac dysfunction caused by sepsis. Targeted regulation of miR-499 expression may be an effective way to treat SMD.
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Objective: To evaluate the cardiac functional changes in hypertrophic cardiomyopathy(HCM) patients with β-myosin heavy chain gene (MYH7) mutations by three-dimensional (3D) speckle tracking imaging(3D-STI) and conventional echocardiography modalities, and then to explore the potential predictors of adverse cardiovascular events in these patients. Methods: A consecutive series of 192 HCM patients admitted in our center from October 2014 to October 2016 were genetically screened to identify MYH7 mutations in this retrospective study. A total of 43 HCM patients with MYH7 mutations were enrolled. The patients were divided into events group(n=13) and no event group(n=30) according to the presence or absence of adverse cardiovascular events(primary and secondary endpoints). All patients were followed up to January 2019 after comprehensive evaluation of 3D-STI, two-dimensional and Doppler echocardiography. The adverse cardiovascular events were recorded. Results: The median follow up time was 1 012 (812, 1 330) days. During follow-up, 13 patients (30.2%) reached endpoints: 6 cases of the primary endpoints(2 cases of sudden cardiac death(SCD), 3 cases of survival after defibrillation, and 1 case of appropriate implantable cardioverter-defibrillator(ICD) discharge); 7 cases of the second endpoints(5 cases of heart failure hospitalization, 1 case of syncope and cardioversion due to supraventricular tachycardia, and 1 case of end-stage HCM). Patients with adverse cardiovascular events had higher prevalence of syncope and risk of SCD, enlarged left atrial volume index(LAVI) and reduced 3D left ventricular global longitudinal train (3D-GLS), as compared to those without adverse events(all P<0.05). The multivariate Cox regression analysis showed that reduced 3D-GLS(HR=0.814, 95%CI 0.663-0.999, P=0.049) was an independent predictor for adverse cardiovascular events. The cutoff value of 3D-GLS≤13.67% was linked with significantly increased risk of adverse cardiovascular events in this patient cohort(AUC=0.753, 95%CI 0.558-0.948, sensitivity 86%, specificity 69%, P<0.05). The Kaplan-Meier analysis indicated that the patients with the 3D-GLS≤ 13.67% faced higher risk of death than those with 3D-GLS>13.67%. Conclusion: 3D-GLS is useful on predicting adverse cardiovascular events in HCM patients with MYH7 mutations.
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Humans , Cardiac Myosins/genetics , Cardiomyopathy, Hypertrophic/genetics , Echocardiography , Mutation , Myosin Heavy Chains/genetics , Predictive Value of Tests , Retrospective Studies , Risk FactorsABSTRACT
Objective To investigate the the molecular mechanism of telmisartan for myocardial remodeling in rats with renovascular hypertention. Methods The renovascular hypertensive myocardial hypertrophy model of rats were established by narrowing the left renal artery.The total of 45 mature male SD rats were divided into sham-operated group(n= 15),model control (n = 15 ) and telmisartan group ( n = 15 ) randomly. The rats in telmisartan group were treated with telmisartan (10 mg?kg-1?d-1 ) while those in the sham-operated and model control were reated with the same amounts of distilled water by intragastrical administration . At 8th week of administration, the myocardial structure and function were detected by ultrasonography.The blood pressure was measured by arterial catheterization and calculating the left ventricular mass index (LVMI) .The level of serum calcium and nerve phosphatase ( CaN) and the expression of β-myosin heavy chain ( β-MHC) mRNA were detected. Results The thickness of left ventricular,ejection fraction[(69.23± 1.09)% vs(73.77± 3.00)%], fractional shortening [(30.21±2.02)% vs(35.29±0.90)%],LVMI[(2.83±0.14) mg?g-1 vs(2.32±0.11) mg?g-1 ] were decreased,and the differences were statistically significant (P<0.05).The level of serum calcium and nerve phosphatase (CaN) and the expression of β-myosin heavy chain (β-MHC) mRNA were decreased in telmisartan treated rats,and the differences were statistically significant (P< 0.05) when compared with the model control group. Conclusion Telmisartan can improve the myocardial hypertrophy of renovascular hypertensive rats,and it may downregulate the expression of β-MHC by inactivating of the start signal CaN and its downstream signal pathway.
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Objective To identify the disease-causing gene mutation and investigate the genotypephenotype correlation in a Chinese pedigree with familial hypertrophic cardiomyopathy.Methods In this study we collected a large multigenerational Chinese family with FHCM.Total genome DNA was extracted from 67 subjects' peripheral leucocytes.The exons and boundary introns of MYH7 gene was amplified by PCR and directly sequenced by ABI PRISM 3700 DNA sequencer.Then,the mutation was examined.Results Fourteen family members had hypertrophic cardiomyopathy,including 4 deceased 2 of whom died from sudden death at young age.Analysis by echocardiography showed all the 10 living affected individuals have a maximal leftventricular-wall thickness of at least 13 mm.Three single nucleotide polymorphisms (SNP) which had been reported in NCBI SNP database,were found mutated.No mutation co-seperated with the disease was identified.Conclusion FHCM of this family was not caused by MYH7 mutation.Other genes should be screened to further identify the disease-causing gene mutation in hypertrophic cardiomyopathy.