Ivermectin ameliorates acute myocarditis via the inhibition of importin-mediated nuclear translocation of NF-κB/p65.

BACKGROUND: Myocarditis is an important clinical issue which lacks specific treatment by now. Ivermectin (IVM) is an inhibitor of importin α/ß-mediated nuclear translocation. This study aimed to explore the therapeutic effects of IVM on acute myocarditis. METHODS: Mouse models of coxsackie B3 virus (CVB3) infection-induced myocarditis and experimental autoimmune myocarditis (EAM) were established to evaluate the effects of IVM. Cardiac functions were evaluated by echocardiography and Millar catheter. Cardiac inflammatory infiltration was assessed by histological staining. Cytometric bead array and quantitative real-time PCR were used to detect the levels of pro-inflammatory cytokines. The macrophages and their M1/M2 polarization were analyzed via flow cytometry. Protein expression and binding were detected by co-immunoprecipitation, Western blotting and histological staining. The underlying mechanism was verified in vitro using CVB3-infected RAW264.7 macrophages. Cyclic polypeptide (cTN50) was synthesized to selectively inhibit the nuclear translocation of NF-κB/p65, and CVB3-infected RAW264.7 cells were treated with cTN50. RESULTS: Increased expression of importin ß was observed in both models. IVM treatment improved cardiac functions and reduced the cardiac inflammation associated with CVB3-myocarditis and EAM. Furthermore, the pro-inflammatory cytokine (IL-1ß/IL-6/TNF-α) levels were downregulated via the inhibition of the nuclear translocation of NF-κB/p65 in macrophages. IVM and cTN50 treatment also inhibited the nuclear translocation of NF-κB/p65 and downregulated the expression of pro-inflammatory cytokines in RAW264.7 macrophages. CONCLUSIONS: Ivermectin inhibits the nuclear translocation of NF-κB/p65 and the expression of major pro-inflammatory cytokines in myocarditis. The therapeutic effects of IVM on viral and non-viral myocarditis models suggest its potential application in the treatment of acute myocarditis.

Prognostic Value of Elevated Levels of Plasma N-Acetylneuraminic Acid in Patients With Heart Failure.

BACKGROUND: Cardiac sialylation is involved in a variety of physiological processes in the heart. Altered sialylation has been implicated in heart failure (HF) mice. However, its role in patients with HF is unclear, and the potential effect of modulation of cardiac sialylation is worth exploring. METHODS: We first assessed the association between plasma N-acetylneuraminic acid levels and the incidence of adverse cardiovascular events in patients with HF over a median follow-up period of 2 years. Next, immunoblot analysis and lectin histochemistry were performed in cardiac tissue to determine the expression levels of neuraminidases and the extent of cardiac desialylation. Finally, the therapeutic impact of a neuraminidase inhibitor was evaluated in animal models of HF. RESULTS: Among 1699 patients with HF, 464 (27%) died of cardiovascular-related deaths or underwent heart transplantation. We found that the elevated plasma N-acetylneuraminic acid level was independently associated with a higher risk of incident cardiovascular death and heart transplantation (third tertile adjusted hazard ratio, 2.11 [95% CI, 1.67-2.66], P<0.001). In addition, in cardiac tissues from patients with HF, neuraminidase expression was upregulated, accompanied by desialylation. Treatment with oseltamivir, a neuraminidase inhibitor, in HF mice infused with isoproterenol and angiotensin II significantly inhibited desialylation and ameliorated cardiac dysfunction. CONCLUSIONS: This study uncovered a significant association between elevated plasma N-acetylneuraminic acid level and an increased risk of a poor clinical outcome in patients with HF. Our data support the notion that desialylation represents an important contributor to the progression of HF, and neuraminidase inhibition may be a potential therapeutic strategy for HF.

Zero-fluoroscopy permanent pacemaker implantation using Ensite NavX system: Clinical viability or fanciful technique?

BACKGROUND: Fluoroscopy is the imaging modality routinely used for cardiac device implantation and electrophysiological procedures. Due to the rising concern regarding the harmful effects of radiation exposure to both the patients and operation staffs, novel 3D mapping systems have been developed and implemented in electrophysiological procedure for the navigation of catheters inside the heart chambers. Their applicability in cardiac device implantation has been rarely reported. Our aim is to evaluate the feasibility and safety of permanent pacemaker implantation without fluoroscopy. METHODS AND RESULTS: From January 2012 to June 2016, six patients (50 ± 15 years, four of six were female, one of who was at the 25th week of gestation) who underwent permanent pacemaker implantation were included (zero-fluoroscopy group). Data from 20 consecutive cases of implantation performed under fluoroscopy guidance were chosen as a control group (fluoroscopy group). Total implantation procedure time for single-chamber pacemaker was 51.3 ± 13.1 minutes in the zero-fluoroscopy group and 42.6 ± 7.4 minutes in the fluoroscopy group (P  =  0.155). The implantation procedural time for a dual-chamber pacemaker was 88.3 ± 19.6 minutes and 67.3 ± 7.6 minutes in the zero-fluoroscopy and fluoroscopy groups (P  =  0.013), respectively. No complications were observed during the procedure and the follow-up in the two groups, and all pacemakers worked with satisfactory parameters. CONCLUSION: Ensite NavX system can be used as a reliable and safe zero-fluoroscopy approach for the implantation of single- or dual-chamber permanent pacemakers in specific patients, such as pregnant women or in extreme situations when the x-ray machine is not available.

MiR-30c-5p ameliorates hepatic steatosis in leptin receptor-deficient (db/db) mice via down-regulating FASN.

Approximately 15-40% of the general adult population suffers from non-alcoholic fatty liver disease (NAFLD) worldwide. However, no drug is currently licensed for its treatment. In this study, we observed a significant reduction of miR-30c-5p in the liver of leptin receptor-deficient (db/db) mice. Remarkably, recombinant adeno-associated virus (rAAV)-mediated delivery of miR-30c-5p was sufficient to attenuate triglyceride accumulation and hepatic steatosis in db/db mice. Through computational prediction, KEGG analysis and Ago2 co-immunoprecipitation, we identified that miR-30c-5p directly targeted fatty acid synthase, a key enzyme in fatty acid biosynthesis. Moreover, down-regulation of FASN by siRNA attenuated some key features of NAFLD, including decreased triglyceride accumulate and lipid deposition. Our findings reveal a new role of miR-30c-5p in counterbalancing fatty acid biosynthesis, which is sufficient to attenuate triglyceride accumulation and hepatic steatosis in db/db mice.

Short leukocyte telomere length is associated with aortic dissection.

BACKGROUND: Aortic dissection is an age-related and lethal vascular disease. Aging, which is associated with degeneration, is the major risk factor of aortic dissection. Telomeres are specialized DNA structures located at the end of eukaryotic chromosomes, the telomere length could be considered as an index of vascular aging. The purpose of present study was undertaken to investigate the relationship between the leukocyte telomere length and aortic dissection. METHODS AND RESULTS: Seventy-two patients with aortic dissection and seventy-two sex- and age-matched subjects without vascular diseases were collected. Leukocyte telomere length ratio (T/S ratio) was measured using a quantitative PCR method and analyzed. A significantly shorter leukocyte telomere length in the patients with aortic dissection was found compared to the controls, [median 1.02 (interquartile range {IQR}:0.83-1.37) vs median 1.63 [IQR: 1.18-2.51), p<0.001]. The telomere length in the control group showed a trend of inverse correlation with age (r=-0.226, p=0.056), however, there was no significant correlation in aortic dissection (r=0.062, p=0.607). The short leukocyte telomere length was associated with aortic dissection, even after adjustment for other risk factor (OR=0.214, 95% CI: 0.085-0.537). CONCLUSION: Leukocyte telomere length could be an independent predictor of aortic dissection. Measurement of the leukocyte telomere length may be valuable for patients with a high risk of aortic dissection.

Right coronary artery fistula to left ventricle complicated with huge coronary artery aneurysm.

Congenital coronary artery fistula (CAF) with huge coronary artery aneurysm is a very rare condition. In this paper, we describe a 26-year-old asymptomatic male patient with right coronary artery (RCA) to the left ventricle fistula with a huge coronary artery aneurysm which was diagnosed by multidetector computed tomography and coronary angiography. The patient received surgical treatment for coronary artery after diagnosis. Both RCA and a giant aneurysm were excised; surgical closure of CAF and coronary artery bypass grafting were performed on this patient. Two months after surgery, the enlarged left ventricle returned to normal as evaluated by echocardiography.