Intramuscular expression of functional proteins is a promising strategy for therapeutic purposes. Previously, we developed an intramuscular gene delivery method by combining Pluronic L64 and optimized electropulse, which is among the most efficient methods to date. However, plasmid DNAs (pDNAs) in this method were not compressed, making them unstable and inefficient in vivo. We considered that a proper compression of pDNAs by an appropriate material should facilitate gene expression in this L64-electropulse system. Here, we reported our finding of such a material, Epigallocatechin gallate (EGCG), a natural compound in green teas, which could compress and protect pDNAs and significantly increase intramuscular gene expression in the L64-electropulse system. Meanwhile, we found that polyethylenimine (PEI) could also slightly improve exogenous gene expression in the optimal procedure. By analysing the characteristic differences between EGCG and PEI, we concluded that negatively charged materials with strong affinity to nucleic acids and/or other properties suitable for gene delivery, such as EGCG, are better alternatives than cationic materials (like PEI) for muscle-based gene delivery. The results revealed that a critical principle for material/pDNA complex benefitting intramuscular gene delivery/expression is to keep the complex negatively charged. This proof-of-concept study displays the breakthrough in compressing pDNAs and provides a principle and strategy to develop more efficient intramuscular gene delivery systems for therapeutic applications.

BACKGROUND:HF incurs high disease burden, and the effectiveness of known HF treatments is unsatisfactory. Therefore, seeking novel therapeutic target of HF is important. The present study aimed to investigate the role of the mitochondrial calcium uniporter (MCU) and its relationship with autophagy in overload-induced heart failure (HF).METHODS AND RESULTS:In both early-stage and end-stage of pressure overload-induced HF, MCU appeared up-regulated along with heart enlargement, increased microtubule-associated proteins 1A/1B light chain 3B (LC3B) II/I ratio and autophagosome content, damaged cardiac function, and ventricular asynchrony. However, sequestosome-1 (SQSTM1/p62) level decreased indicating blockaded autophagic flux. Seven-week administration of MCU inhibitor ruthenium red improved cardiac function and mitigated its pathological change. MCU inhibition maintained mitochondrial integrity, increased LC3B II/I ratio, up-regulated Parkin and Pink1, and down-regulated SQSTM1/p62. MCU inhibition also alleviated ventricular asynchrony of HF, and this might be related to connexin-43 up-regulation. In vitro study validated intervention on MCU leading to elevation of autophagy and mitophagy. MCU inhibition could partly prevent from excessive cellular enlargement induced by isoprenaline.CONCLUSIONS:In summary, MCU inhibition played an important role in pressure overload-induced heart failure through autophagy and mitophagy enhancement, and intervention on MCU offered cardioprotective effects. To our knowledge, the role of MCU in HF and its relationship with autophagy and mitophagy are firstly disclosed. Moreover, our study suggests that MCU inhibition could be explored as a novel therapeutic concept in HF.

Long-term RVP could bring adverse problems to cardiac electro-mechanics and result in inter- and intra-ventricular asynchrony, impaired labor force, and aggravation of cardiac function. HBRP including direct His bundle pacing and para-His bundle pacing was regarded as a novel physiological pacing pattern to avoid devastating cardiac function. This synthetic study was conducted to integratively and quantitatively evaluate the efficacy of His bundle related pacing (HBRP) in comparison with conventional right ventricular pacing (RVP).

Cardiac resynchronization therapy (CRT) threw lights on heart failure treatment, however, parts of patients showed nonresponse to CRT. Unfortunately, it lacks effective parameters to predict CRT non-response. In present study, we try to seek effective electro-echocardiographic predictors on CRT non-response. This is a retrospective study to review a total of 227 patients of dyssynchronous heart failure underwent CRT implantation. Logistic analysis was performed between CRT responders and CRT non-responders. The primary outcome was the occurrence of improved left ventricular ejection fraction 1 year after CRT implantation. We concluded that LVEDV > 255 mL ( OR = 2.236; 95 % CI, 1.016 – 4.923 ) rather than LVESV > 160 mL ( OR = 1.18; 95 % CI, 0.544 – 2.56 ) and TpTe/QTc > 0.203 ( OR = 5.206; 95 % CI, 1.89 – 14.34 ) significantly predicted CRT non-response. Oppositely, S wave > 5.7 cm/s ( OR = 0.242; 95 % CI, 0.089 – 0.657 ), E/A > 1 ( OR = 0.211; 95 % CI, 0.079 – 0.566 ), E’/A’ > 1 ( OR = 0.054; 95 % CI, 0.017 – 0.172 ), CLBBB ( OR = 0.141; 95 % CI, 0.048 – 0.409 ), and QRS duration >160 ms ( OR = 0.52; 95 % CI, 0.305 – 0.922 ) surprisingly predicted low-probability of CRT non-response.

Purpose Persistent left superior vena cava (PLSVC) is rare and often asymptomatic, which might cause difficulties in the implantation of cardiac implantable electronic devices (CIEDs). The aim of this study was to determine the prevalence of PLSVC and to study the clinical characteristics and significance of PLSVC in patients with CIED implantation. Methods Thirty-three patients with PLSVC were collected from 7047 CIED recipients over recent 10 years in our center. These 33 patients were divided into three groups: PLSVC in the absence of RSVC, with a pacemaker implantation (group A, n = 7); double superior vena cava (DSVC), having both PLSVC and RSVC, with a pacemaker or implantable cardioverter defibrillator (ICD) implantation (group B, n = 20); DSVC with a cardiac resynchronization therapy/cardiac resynchronization therapy defibrillator (CRT/CRT-D) implantation (group C, n = 6). The clinical characteristics, pacing parameters, and complications were collected and compared among three groups. Results The prevalence of PLSVC in our patients implanting CIEDs in the recent 10 years was 0.47%. Coronary sinus diameter, right atrium lead type (active or passive), right atrium lead location (right atrium appendage or lateral wall), right ventricle lead location (right ventricular apex or right ventricular outflow tract), and procedure duration were found to be significantly different among three groups, while the incidence of complications and pacing parameters was not significantly different among three groups during long-term follow-up. Conclusions Although the presence of PLSVC made the CIED implantation more challenging and might increase the complications related to the procedure, the pacing parameters were not likely to be affected during long-term follow-up.