Exercise-mediated regulation of autophagy in the cardiovascular system

Cardiovascular disease is the leading cause of human death worldwide. Autophagy is an evolutionarily conserved degradation pathway,which is a highly conserved cellular degradation process in which lysosomes decompose their own organelles and recycle the resulting macromolecules.Autophagy is critical in maintaining cardiovascular homeostasis and function, and excessive or insufficient autophagy or autophagic flux can lead to cardiovascular disease. Enormous evidence indicates that exercise training plays a beneficial role in the prevention and treatment of cardiovascular diseases. The regulation of autophagy during exercise is a bidirectional process. For cardiovascular disease caused by either insufficient or excessive autophagy, exercise training restores normal autophagy function and delays the progression of cardiovascular disease.An in-depth exploration and discussion of exercise-mediated regulation of autophagy in the cardiovascular system can broaden our view about the prevention of various autophagy-related diseases through exercise training. In this article, we review autophagy and its related signaling pathways,as well as autophagy-dependent beneficial effects of exercise in cardiovascular system.

Animal exercise studies in cardiovascular research:Current knowledge and optimal design--A position paper of the Committee on Cardiac Rehabilitation,Chinese Medical Doctors’Association

Growing evidence has demonstrated exercise as an effective way to promote cardiovascular health and protect against cardiovascular diseases However,the underlying mechanisms of the beneficial effects of exercise have yet to be elucidated.Animal exercise studies are widely used to investigate the key mechanisms of exercise-induced cardiovascular protection.However,standardized procedures and well-established evaluation indicators for animal exercise models are needed to guide researchers in carrying out effective,high-quality animal studies using exercise to prevent and treat cardiovascular diseases.In our review,we present the commonly used animal exercise models in cardiovascular research and propose a set of standard procedures for exercise training,emphasizing the appropriate measurements and analysis in these chronic exercise models.We also provide recommendations for optimal design of animal exercise studies in cardiovascular research,including the choice of exercise models,control of exercise protocols,exercise at different stages of disease,and other considerations,such as age,sex,and genetic background.We hope that this position paper will promote basic research on exercise-induced cardiovascular protection and pave the way for successful translation of exercise studies from bench to bedside in the prevention and treatment of cardiovascular diseases.

Exercise sustains the hallmarks of health

Exercise has long been known for its active role in improving physical fitness and sustaining health.Regular moderate-intensity exercise improves all aspects of human health and is widely accepted as a preventative and therapeutic strategy for various diseases.It is well-documented that exercise maintains and restores homeostasis at the organismal,tissue,cellular,and molecular levels to stimulate positive physiological adaptations that consequently protect against various pathological conditions.Here we mainly summarize how moderate-intensity exercise affects the major hallmarks of health,including the integrity of barriers,containment of local perturbations,recycling and turnover,integration of circuitries,rhythmic oscillations,homeostatic resilience,hormetic regulation,as well as repair and regeneration.Furthermore,we summarize the current understanding of the mechanisms responsible for beneficial adaptations in response to exercise.This review aimed at providing a comprehensive summary of the vital biological mechanisms through which moderate-intensity exercise maintains health and opens a window for its application in other health interventions.We hope that continuing investigation in this field will further increase our understanding of the processes involved in the positive role of moderate-intensity exercise and thus get us closer to the identification of new therapeutics that improve quality of life.

Perspectives of genetic management strategy for inherited cardiovascular diseases in China

Inherited cardiovascular diseases(CVDs)threaten human health and pose an enormous economic burden worldwide.Genetic alteration is a major risk factor for many CVDs.These disorders are usually controlled by a pair of alleles,affecting offspring according to the Mendelian principle,regardless of isolated primary damage or secondary injury from other syndromes or deficiency.To date,there are hundreds of inherited CVDs.With advances in nextgeneration sequencing(NGS)technologies,rapid and accurate molecular diagnosis of patients with inherited CVDs is clinically practical.Besides,great improvements have been made in recent years,and targeted therapy and assist devices have been used in clinical practice.Yet there is still no totally efficient strategy for dealing with inherited CVDs.Accordingly.

Model construction and clinical therapeutic potential of engineered cardiac organoids for cardiovascular diseases

Cardiovascular diseases cause significant morbidity and mortality worldwide.Engineered cardiac organoids are being developed and used to replicate cardiac tissues supporting cardiac morphogenesis and development.These organoids have applications in drug screening,cardiac disease models and regenerative medicine.Therefore,a thorough understanding of cardiac organoids and a comprehensive overview of their development are essential for cardiac tissue engineering.This review summarises different types of cardiac organoids used to explore cardiac function,including those based on co-culture,aggregation,scaffolds,and geometries.The self-assembly of monolayers,multilayers and aggravated cardiomyocytes forms biofunctional cell aggregates in cardiac organoids,elucidating the formation mechanism of scaffold-free cardiac organoids.In contrast,scaffolds such as decellularised extracellular matrices,three-dimensional hydrogels and bioprinting techniques provide a supportive framework for cardiac organoids,playing a crucial role in cardiac development.Different geometries are engineered to create cardiac organoids,facilitating the investigation of intrinsic communication between cardiac organoids and biomechanical pathways.Additionally,this review emphasises the relationship between cardiac organoids and the cardiac system,and evaluates their clinical applications.This review aims to provide valuable insights into the study of three-dimensional cardiac organoids and their clinical potential.

Diagnosis of interatrial block

In the 70＇s, we classified for the first time the blocks at the atrial level into interatrial blocks （IAB）, partial and advanced, and other types of atrial blocks including the concept of atrial aberrancy, and atrial dissociation.

Hemodynamic effects of propranolol with spironolactone in patients with variceal bleeds: A randomized controlled trial

AIM: To study the hemodynamic effects of spironolactone with propranolol vs propranolol alone in the secondary prophylaxis of variceal bleeding. METHODS: Thirty-five cirrhotics with variceal bleeding randomly received propranolol (n = 17: Group A) or spironolactone plus propranolol (n = 18: Group B). Hemodynamic assessment was performed at baseline and on the eighth day. RESULTS: Spironolactone with propranolol caused a greater reduction in the hepatic venous pressure gradient than propranolol alone (26.94% vs 10.2%; P < 0.01). Fourteen out of eighteen patients on the combination treatment had a reduction in hepatic venous pressure gradient to ≤ 12 mmHg or a 20% reduction from baseline in contrast to only six out of seventeen (6/17) on propranolol alone (P < 0.05). CONCLUSION: Spironolactone with propranolol results in a better response with a greater reduction in hepatic venous pressure gradient in the secondary prophylaxis of variceal bleeding. A greater number of patients may be protected by this combination therapy than by propranolol alone. Hence, this combination may be recommended for secondary prophylaxis in patients with variceal bleeding.

Exercise and cardiovascular protection:Update and future

Cardiovascular disease(CVD)is a major cause of mortality and morbidity worldwide.In China,it is estimated that 330 million people are CVD patients.With the rapid aging of populations around the world,the number of CVD patients and death due to CVD are continuously rising.1 Exercise and physical activity have been recognized as economical and effective ways to enhance cardiovascular health and reduce CVD.Pathways mediating the cardiovascular benefits of exercise are promising therapeutic targets for CVD.

Histopathology and Morphometric Analysis of the Internal Mammary Artery to Study the Incidence of Atherosclerosis and Its Associated Risk Factors

Background: The left internal mammary artery (IMA) is widely used as a conduit for coronary revascularization. The incidence of atherosclerosis is known to be lower in the IMA than in the coronary artery. The aim of this study was to evaluate the reliability of the use of the distal section of the IMA as an anastomotic site for bypass grafting and morphometric studies of IMA in patients with proven coronary artery disease and their associated risk factors. Methods: Patients who underwent Coronary Artery Bypass Graft (CABG) from June 2010 to November 2012 were chosen in this retrospective study and the discarded distal segments of the internal mammary artery were analyzed. The potential risk factors for atherosclerosis considered were age, sex, diabetes mellitus, history of cigarette smoking, hypertension and hypercholesterolemia. The samples were analyzed for the degree of intimal thickening and atherosclerosis by calculating the percentage of Luminal Narrowing, Intimal Thickness Index (ITI) and Intima-to-Media Ratio (IMR). Results: There were seven cases of intimal hyperplasia and two cases of focal medial and intimal hyperplasia with fatty streak and no cases of atherosclerosis and medial calcification. ITI was higher in males when compared to females. There was a strong relationship between IMR and smokers when compared to nonsmokers. Conclusion: In our study, when ITI was used as the dependent variable, diabetes was the most important factor. When IMR was used, the strongest predictor was hypercholesterolemia. There was a strong relationship between IMR and smokers when compared to nonsmokers.

Establishment of a rat model with diet-induced coronary atherosclerosis

Coronary atherosclerotic disease is a serious disease in humans,but no suitable animal model is available currently for further studies.We used apolipoprotein E gene knockout（ApoE KO） rats to induce hypercholesterolemia through a special high cholesterol/bile salt diet（Paigen diet）,then analyzed aortic and coronaiy atherosclerosis lesions and the myocardial injury in order to establish a novel small animal model of coronary atherosclerosis.Plasma cholesterol of ApoE KO rats increased 7.6-fold compared with wild-type rats after 8 weeks on the Paigen diet.After 10 to 12 weeks of subsisting on the Paigen diet,ApoE KO rats developed mild aortic atherosclerosis with severe coronary atherosclerosis.Hematoxilyn and eosin staining showed that 11 out of 12 ApoE KO male rats had right coronary artery atherosclerosis,7 of them were〉70%occluded.Oil Red O（Lipid Stain）,Mac2 immuno-staining and Masson＇s tnchrome staining demonstrated substantial amounts of lipid,macrophages and collagen fibers in coronary atherosclerosis plaques.In addition,ApoE KO male rats had severe myocardial focal lesions with cholesterol ester as the main component in the lesions.In conclusion,ApoE KO rats developed severe hypercholesterolemia,coronary atherosclerosis and myocardial cholesterol ester deposition after subsisting on the Paigen diet and can be used as a novel animal model for studies on cholesterol metabolism and coronary atherosclerotic disease.

Animal models of coronary heart disease

Cardiovascular disease,predominantly coronary heart disease and stroke,leads to high morbidity and mortality not only in developed worlds but also in underdeveloped regions.The dominant pathologic foundation for cardiovascular disease is atherosclerosis and,as to coronary heart disease,coronary atherosclerosis and resulting lumen stenosis,even total occlusions.In translational research,several animals,such as mice,rabbits and pigs,have been used as disease models of human atherosclerosis and related cardiovascular disorders.However,coronary lesions are either naturally rare or hard to be fast induced in these models,hence,coronary heart disease induction mostly relies on surgical or pharmaceutical interventions with no or limited primary coronary lesions,thus unrepresentative of human coronary heart disease progression and pathology.In this review,we describe the progress of animal models of coronary heart disease following either spontaneous or diet-accelerated coronary lesions.

Impact of 1,25-(OH)_2D_3 on Left Ventricular Hypertrophy in Type 2 Diabetic Rats

Objective To investigate the impact of 1, 25-(OH)2D3 on left ventricular hypertrophy(LVH) in type 2 diabetic rats. Methods Type 2 diabetic mellitus(DM) model rats were established by intraperitoneally injecting with 30 mg/kg streptozotocin. After 8 weeks, 19 male rats were identified as diabetic with left ventricular hypertrophy(LVH) by ultrasound examination, and randomly assigned into three groups: untreated(DM-LVH, n=7), treated with insulin(DM-LVH+INS, n=6), and treated with 1, 25-(OH)2D3(DM-LVH+VD, n=6). Healthy male rats were used as the controls group(n=6). The fasting blood glucose and the insulin level were determined weekly. The left ventricular mass index, myocardial collagen content, collagen volume fraction, and 1, 25-(OH)2D3-receptor level were determined by 4 weeks later. Results In the DM-LVH model group, the insulin level was significantly decreased compared with the non-diabetic control group(P<0.05), whereas the blood glucose, left ventricular mass index, myocardial collagen content, collagen volume fraction, and 1, 25-(OH)2D3-receptor expression were significantly increased(all P<0.05). In the DM-LVH+INS and DM-LVH+VD groups, the insulin levels were significantly increased compared with the DM-LVH model group(P<0.05), whereas the other parameters were significantly decreased(all P<0.05). Conclusion 1, 25-(OH)2D3 could reverse LVH in diabetic rats and that the mechanism may involve stimulating insulin secretion and reducing blood glucose via direct up-regulation of 1, 25-(OH)2D3-receptor expression.

Coronary Artery Perforation Complicated With Acute Aortic Valve Regurgitation During Percutaneous Coronary Intervention:Report of Two Cases

CORONARY artery perforation catastrophic complication （CAP） is a rare, of percutaneous coronary intervention （PCI）. CAP during PCI procedure is invariably associated with high riskpatients with complex coronary artery disease such as coronary calcified lesions, multi-vessel lesions, coronary chronic total occlusion and so on,

Maternal inheritance of severe hypertriglyceridemia impairs glucose metabolism in offspring

Maternally inherited familial hypercholesterolemia（FH） impairs glucose metabolism and increases cardiovascular risks in the offspring to a greater degree than paternal inherited FH.However,it remains unknown whether hypertriglyceridemia affects glucose metabolism via inheritance.In this study,we sought to compare the impact of maternally and paternally inherited hypertriglyceridemia on glucose and lipid metabolism in mice.Apo CIII transgenic mice with severe hypertriglyceridemia were mated with non-transgenic control mice to obtain 4 types of offspring：maternal non-transgenic control and maternal transgenic offspring,and paternal control and paternal transgenic offspring.Plasma triglycerides（TG）,total cholesterol（TC）,fasting plasma glucose（FPG） and fasting insulin（FINS） were measured.Apo CIII overexpression caused severe hypertriglyceridemia,but the transgenic female mice had unaltered fertility with normal pregnancy and birth of pups.The 4 groups of offspring had similar birth weight and growth rate.The plasma TG of maternal and paternal transgenic offspring were nearly 40-fold higher than maternal and paternal control mice,but there was no difference in plasma TG between maternal and paternal transgenic offspring.Although the FPG of the 4 groups of animals had no difference,the maternal transgenic mice showed impaired glucose tolerance,increased FINS levels and higher homeostasis model assessment insulin resistance index（HOMA-IR） than the other 3 groups.In conclusion,maternally inherited hypertriglyceridemia in Apo CIII transgenic mice displayed impaired glucose tolerance,hyperinsulinemia and increased HOMA-R,while paternally inherited hypertriglyceridemia did not have such impacts.

Expect the Unexpected: A Unique Association of Bicuspid Aortic Valve, with Severe Aortic Stenosis and Dilation of Ascending Aorta, with Cervical Vagus Nerve Schwannoma

Hoarseness of voice is a common symptom of many laryngeal and extralaryngeal conditions. It is very crucial to identify the culprit behind it, keeping in mind all the various differentials. We re-port a case of a 35-year-old woman presenting with complaint of hoarseness of voice. Upon car-diac evaluation, the patient was diagnosed with bicuspid aortic valve, with severe aortic stenosis and dilation of ascending aorta. We suspected that the plausible reason for hoarseness of voice was compression of recurrent laryngeal nerve due to dilation of aorta, i.e., Ortner’s syndrome. But to our surprise, CT of aorta and neck revealed extensive elongated cervical vagus nerve schwannoma. Such type of association is unique and new to voluminous medical literature.

Meta-analysis of T-wave indices for risk stratification in myocardial infarction

Ventricular tachy-arrhythmias are the commonest cause of sudden cardiac death in patients with ischemie heart dis- ease. It is estimated that up to 20% patients with acute myocardial infarction suffer from these arrhythmias.There is a growing need for developing tools for risk as- sessment for sudden cardiac death （SCD） in this population.

Hypoxia Enhances the Therapeutic Potential of Superparamagnetic Iron Oxide-labeled Adipose-derived Stem Cells for Myocardial Infarction

Adipose-derived stem cells（ASCs） induce therapeutic angiogenesis due to pro-angiogenic cytokines secretion. Superparamagnetic iron oxide（SPIO） nanoparticles are critical for magnetic resonance（MR） tracking of implanted cells. Hypoxia is a powerful stimulus for angiogenic activity of ASCs. In this study, we investigated whether therapeutic potency could be enhanced by implantation of hypoxia-preconditioned SPIO-labeled ASCs（SPIOASCs） into the infarcted myocardium. ASCs and SPIOASCs were cultured under 2% O_2（hypoxia） or 95% air（normoxia）. Cells were intramyocardially injected into the infarcted myocardium after 48-h culture. We found that hypoxia culture increased the m RNA expression of hypoxia-inducible factor-1 alpha（HIF-1α） and vascular endothelial growth factor（VEGF） in ASCs and SPIOASCs. The VEGF protein in the conditioned medium was significantly higher in hypoxic ASCs and SPIOASCs than in normoxic ASCs and SPIOASCs. The capillary density and left ventricular contractile function in the infarcted myocardium were significantly higher 4 weeks after implantation with hypoxic ASCs and SPIOASCs than with normoxic ASCs and SPIOASCs. Improvement in the capillary density and left ventricle function didn＇t differ between hypoxic ASCs-transplanted rats and hypoxic SPIOASCs-transplanted rats. Hypoxic culture enhanced the angiogenic efficiency of ASCs. It was concluded that implantation of hypoxic ASCs or SPIOASCs promotes therapeutic angiogenesis and cardiac function recovery in the infarcted myocardium. SPIO labeling does not impact the beneficial effect of hypoxic ASCs.

The Effect of U50488 on the Cardiac Rhythm and Intracellular Calcium in the Rat Heart.

The effect of U50488, a selective K-opioid receptor agonist, on cardiac rhythm in the isolated perfused rat heart and intracellular calcium ([Ca2+] i) in the single ventricular myocyte were studied. The results showed that U50488 can induce arrhythmias dose-dependently in the isolated perfused rat heart and increase [ Ca2 + ] i in the single ventricular myocyte. The effect of U50488 can be blocked by a selectivek-receptor antagonist, nor-binaltorphimine. The arrhythmogenic effects and the increase of [ Ca2+]i induced by U50488 were blocked by U73122, neomycin and streptomycin, which are selective phospolipase C inhibitors, but not by U73433, the inactive structural analog of U73122. These results demonstrated that the arrhythmogenic effect of cardiac K-receptor is due to activation of phosphoinositol/Ca2+ pathway.