A novel mouse model of calcific aortic valve stenosis

Background:Calcific aortic valve stenosis(CAVS)is one of the most challenging heart diseases in clinical with rapidly increasing prevalence.However,study of the mecha-nism and treatment of CAVS is hampered by the lack of suitable,robust and efficient models that develop hemodynamically significant stenosis and typical calcium deposi-tion.Here,we aim to establish a mouse model to mimic the development and features of CAVS.Methods:The model was established via aortic valve wire injury(AVWI)combined with vitamin D subcutaneous injected in wild type C57/BL6 mice.Serial transthoracic echocardiography was applied to evaluate aortic jet peak velocity and mean gradi-ent.Histopathological specimens were collected and examined in respect of valve thickening,calcium deposition,collagen accumulation,osteogenic differentiation and inflammation.Results:Serial transthoracic echocardiography revealed that aortic jet peak velocity and mean gradient increased from 7 days post model establishment in a time depend-ent manner and tended to be stable at 28 days.Compared with the sham group,sim-ple AVWI or the vitamin D group,the hybrid model group showed typical pathological features of CAVS,including hemodynamic alterations,increased aortic valve thicken-ing,calcium deposition,collagen accumulation at 28 days.In addition,osteogenic dif-ferentiation,fibrosis and inflammation,which play critical roles in the development of CAVS,were observed in the hybrid model.Conclusions:We established a novel mouse model of CAVS that could be induced efficiently,robustly and economically,and without genetic intervention.It provides a fast track to explore the underlying mechanisms of CAVS and to identify more effec-tive pharmacological targets.

Exogeneous metal ions as therapeutic agents in cardiovascular disease and their delivery strategies

Metal ions participate in many metabolic processes in the human body,and their homeostasis is crucial for life.In cardiovascular diseases(CVDs),the equilibriums of metal ions are frequently interrupted,which are related to a variety of disturbances of physiological processes leading to abnormal cardiac functions.Exogenous supplement of metal ions has the potential to work as therapeutic strategies for the treatment of CVDs.Compared with other therapeutic drugs,metal ions possess broad availability,good stability and safety and diverse drug delivery strategies.The delivery strategies of metal ions are important to exert their ther-apeutic effects and reduce the potential toxic side effects for cardiovascular applications,which are also receiving increasing attention.Controllable local delivery strategies for metal ions based on various biomaterials are constantly being designed.In this review,we comprehensively summarized the positive roles of metal ions in the treatment of cVDs from three aspects:protecting cells from oxidative stress,inducing angiogenesis,and adjusting the functions of ion channels.In addition,we introduced the transferability of metal ions in vascular reconstruction and cardiac tissue repair,as well as the currently available engineered strategies for the precise delivery of metal ions,such as integrated with nanoparticles,hydrogels and scaffolds.

Engineered M2 macrophage-derived extracellular vesicles with platelet membrane fusion for targeted therapy of atherosclerosis

Atherosclerosis is featured as chronic low-grade inflammation in the arteries,which leads to the formation of plaques rich in lipids.M_(2)macrophage-derived extracellular vesicles(M_(2)EV)have significant potential for anti-atherosclerotic therapy.However,their therapeutic effectiveness has been hindered by their limited targeting capability in vivo.The objective of this study was to create the P-M_(2)EV(platelet membrane-modified M_(2)EV)using the membrane fusion technique in order to imitate the interaction between platelets and macrophages.P-M_(2)EV exhibited excellent physicochemical properties,and microRNA(miRNA)-sequencing revealed that the extrusion process had no detrimental effects on miRNAs carried by the nanocarriers.Remarkably,miR-99a-5p was identified as the miRNA with the highest expression level,which targeted the mRNA of Homeobox A1(HOXA1)and effectively suppressed the formation of foam cells in vitro.In an atherosclerotic low-density lipoprotein receptor-deficient(Ldlr^(-/-))mouse model,the intravenous injection of P-M_(2)EV showed enhanced targeting and greater infiltration into atherosclerotic plaques compared to regular extracellular vesicles.Crucially,P-M_(2)EV successfully suppressed the progression of atherosclerosis without causing systemic toxicity.The findings demonstrated a biomimetic platelet-mimic system that holds great promise for the treatment of atherosclerosis in clinical settings.

Induction of thoracic aortic dissection: a mini-review of β-aminopropionitrile-related mouse models

Thoracic aortic dissection(TAD)is one of the most lethal aortic diseases due to its acute onset,rapid progress,and high rate of aortic rupture.The pathogenesis of TAD is not completely understood.In this mini-review,we introduce three emerging experimental mouse TAD models usingβ-aminopropionitrile(BAPN)alone,BAPN for a prolonged duration(four weeks)and then with added infusion of angiotensinⅡ(AngⅡ),or co-administration of BAPN and AngⅡchronically.We aim to provide insights into appropriate application of these three mouse models,thereby enhancing the understanding of the molecular mechanisms of TAD.

Evaluation of Safety and Efficacy of Qinming8631 DR Implantable Cardiac Pacemaker in Chinese Patients： A Prospective, Multicenter, Randomized Controlled Trial of the First Domestically Developed Pacemaker of China

Background：High cost of imported pacemakers is a main obstacle for Chinese patients suffering from bradyarrhythmia,and a domestically developed pacemaker will help lower the burden.This study aimed to evaluate the safety and efficacy ofQinming8631 DR （Qinming Medical,Baoji,China）,the first domestically developed dual-chamber pacemaker of China,compared with a commercially available pacemaker Talos DR （Biotronik,Berlin,Germany） in Chinese patients.Methods：A prospective randomized trial was conducted at 14 centers in China.Participants were randomized into trial （Qinming8631 DR） and control （Talos DR） groups.Parameters of the pacing systems were collected immediately after device implantation and during follow-ups.The effective pacing rate at 6-month follow-up was recorded as the primary end point.Electrical properties,magnet response,single-and double-pole polarity conversion,rate response function,and adverse events of the pacing system were analyzed.The Cochran-Mantel-Haenszel Chi-square test,paired t-test,and Wilcoxon signed-rank test were used for measuring primary qualitative outcomes and comparing normally and abnormally distributed measurement data.Results：A total of 225 patients with a diagnosis ofbradyarrhythmia and eligible for this study were randomly enrolled into the trial （n =113） and control （n =112） groups.They underwent successful pacemaker implantation with acceptable postoperative pacing threshold and sensitivity.Effective pacing rates of trial and control groups were comparable both in the full analysis set and the per protocol set （81.4% vs.79.5%,P =0.712 and 95.4% vs.89.5%,P =0.143,respectively）.In both data sets,noninferiority of the trial group was above the predefined noninferiority limit（-9.5%）.Conclusions：This study established the noninferiority ofQinming8631 DR to Talos DR.The safety and efficacy ofQinming8631 DR pacemaker were comparable to those of Talos DR in treating patients with cardiac bradyarrhythmia.

Cardiac Piezo1 Exacerbates Lethal Ventricular Arrhythmogenesis by Linking Mechanical Stress with Ca^(2+) Handling After Myocardial Infarction

Ventricular arrhythmogenesis is a key cause of sudden cardiac death following myocardial infarction(MI).Accumulating data show that ischemia,sympathetic activation,and inflammation contribute to arrhythmogenesis.However,the role and mechanisms of abnormal mechanical stress in ventricular arrhythmia following MI remain undefined.We aimed to examine the impact of increased mechanical stress and identify the role of the key sensor Piezo1 in ventricular arrhythmogenesis in MI.Concomitant with increased ventricular pressure,Piezo1,as a newly recognized mechano-sensitive cation channel,was the most up-regulated mechanosensor in the myocardium of patients with advanced heart failure.Piezo1 was mainly located at the intercalated discs and T-tubules of cardiomyocytes,which are responsible for intracellular calcium homeostasis and intercellular communication.

Nano-hydroxyapatite accelerates vascular calcification via lysosome impairment and autophagy dysfunction in smooth muscle cells

Vascular calcification(VC)is a common characteristic of aging,diabetes,chronic renal failure,and atherosclerosis.The basic component of VC is hydroxyapatite(HAp).Nano-sized HAp(nHAp)has been identified to play an essential role in the development of pathological calcification of vasculature.However,whether nHAp can induce calcification in vivo and the mechanism of nHAp in the progression of VC remains unclear.We discovered that nHAp existed both in vascular smooth muscle cells(VSMCs)and their extracellular matrix(ECM)in the calcified arteries from patients.Synthetic nHAp had similar morphological and chemical properties as natural nHAp recovered from calcified artery.nHAp stimulated osteogenic differentiation and accelerated mineralization of VSMCs in vitro.Synthetic nHAp could also directly induce VC in vivo.Mechanistically,nHAp was internalized into lysosome,which impaired lysosome vacuolar H+-ATPase for its acidification,therefore blocked autophagic flux in VSMCs.Lysosomal re-acidification by cyclic-3′,5′-adenosine monophosphate(cAMP)significantly enhanced autophagic degradation and attenuated nHAp-induced calcification.The accumulated autophagosomes and autolysosomes were converted into calcium-containing exosomes which were secreted into ECM and accelerated vascular calcium deposit.Inhibition of exosome release in VSMCs decreased calcium deposition.Altogether,our results demonstrated a repressive effect of nHAp on lysosomal acidification,which inhibited autophagic degradation and promoted a conversion of the accumulated autophagic vacuoles into exosomes that were loaded with undissolved nHAp,Ca^(2+),Pi and ALP.These exosomes bud off the plasma membrane,deposit within ECM,and form calcium nodules.Vascular calcification was thus accelerated by nHAP through blockage of autophagic flux in VSMCs.