ObjectiveTo investigate the mechanism of Huazhuo Jiedu Huoxue Tongluo prescription in alleviating cerebral ischemia-reperfusion injury via regulating nerve cell autophagy based on c-Jun N-terminal kinase（JNK）signaling pathway . MethodSixty SD rats were randomly divided into 6 groups： sham group， middle cerebral artery occlusion/reperfusion （MCAO/R） group （model group）， Huazhuo Jiedu Huoxue Tongluo prescription group ［traditional Chinese medicine （TCM） group（25.0 g·kg^-1）］， JNK inhibitor SP600125 （SP） group（5 mg·kg^-1）， TCM+SP group and JNK agonist Anisomycin （Ani） group（15 mg·kg^-1）. After 24 h of modeling， TCM group and TCM+SP group were given TCM decoction （ig） for 3 consecutive days， and the other groups were given equal volume of normal saline （ig）. Neurological deficit was evaluated by neurological function score and cerebral infarct volume was determined by 2，3，5-triphenyltetrazole chloride （TTC） staining. Hematoxylin-eosin （HE） staining and Nissl staining were used to observe the structural changes of brain tissue and the damage of neurons， respectively. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay （TUNEL） was performed to detect cell apoptosis. The ultrastructure of autophagosomes was observed by transmission electron microscope. Western blot was employed to detect the protein expressions of microtubule-associated protein 1 light chain 3A/B （LC3A/B）， autophagy related 5 （Atg5）， the ortholog of yeast Atg6 （Beclin1）， p62， B-cell lymphoma 2 （Bcl-2）， JNK， phosphorylated （p）-JNK and c-Jun in brain tissue. The mRNA expressions of LC3A/B， Beclin1， p62， Atg5， Bcl-2， JNK and c-Jun were detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. ResultCompared with the sham group， the model group had elevated neurological deficit score （P<0.05）， enlarged cerebral infarct volume （P<0.05）and typical infarction manifestations formed in hippocampal region and its surrounding brain tissue. In addition， there were a large number of neuronal cell degeneration， necrosis， liquefaction， nucleus pyknosis and deep staining， and inflammatory cell infiltration in the cortex in the model group， and severe swelling of mitochondria， lysosomes， autophagosomes and autophagolysosomes were clearly seen under electron microscope. TUNEL positive cells were increased （P<0.05）， and cell apoptosis was severe. The nuclear membrane and nucleolus of neurons in brain tissue were blurred with discontinuous processes， and Nissl bodies in cytoplasm were stained light with reduced number. Western blot revealed that the model group had up-regulated protein expressions of LC3A/B， Beclin1， Atg5， JNK， p-JNK and c-Jun in brain tissue （P<0.05）， while down-regulated protein expressions of p62 and Bcl-2 （P<0.05）as compared with the sham group. Real-time PCR indicated that the mRNA expressions of LC3A/B， Beclin1， Atg5， JNK and c-Jun in the model group were higher （P<0.05） while the mRNA expressions of p62 and Bcl-2 were lower （P<0.05） than those in the sham group. Compared with the conditions in model group， the neurological deficit scores of TCM， SP and TCM+SP groups were lowered （P<0.05）， and the cerebral infarct volume was reduced （P<0.05）， with improved pathological status of brain tissue， especially in the TCM group. Furthermore， there were abundant and basically normal mitochondrial cristae， slightly dilated endoplasmic reticulum， slightly swollen golgi apparatus， slightly fused nuclear membrane， and few visible lysosomes， autophagosomes and autophagolysosomes. TUNEL positive cells were decreased （P<0.05）， displaying reduced apoptosis， especially in the TCM group. The nucleolus and nuclear membrane of neurons in brain tissue were discernible， and Nissl bodies in cytoplasm was reduced to a certain degree as compared with those in the model group. Western blot showed a decrease in the protein expressions of LC3A/B， Beclin1， Atg5， JNK， p-JNK and c-Jun in the TCM group ，the SP group，and the TCM+SP group（P<0.05），while an increase in the protein expressions of p62 in the TCM group and SP group（P<0.05），and an increase in the protein expressions of Bcl-2 in the TCM group and TCM+SP group. By Real-time PCR， the mRNA expressions of LC3A， LC3B， Beclin1， Atg5， JNK and c-Jun had a down-regulation（P<0.05） while the mRNA expression of p62 a up-regulation in the TCM group ，the SP group，and the TCM+SP group（P<0.05），and the mRNA expression of Bcl-2 a up-regulation in the TCM group and the TCM+SP group（P<0.05）.Scores of the Ani group were raised （P<0.05）， and infarct volume was increased significantly， with aggravated neuronal cell necrosis and obvious inflammatory infiltration. Moreover， there were neuronal nuclear membrane fusion with abnormal protrusion， increased heterochromatin aggregation in edge， severe mitochondrial swelling， endoplasmic reticulum expansion， increased lysosomes， increased intracytoplasmic vesicles， and visible autophagosomes and autophagolysosomes. TUNEL positive cells were increased （P<0.05）， representing severe apoptosis. The number of Nissl bodies dropped with light staining， and the nucleolus and nuclear membrane were blurred. Real-time PCR found that the mNRA expressions of Atg5， c-Jun， JNK were up-regulated （P<0.05），while Beclin1， p62， Bcl-2 were were down-regulated in the Ani group （P<0.05）. Compared with the TCM group and SP group，the protein expressions of LC3A/B， Beclin1， Atg5， JNK， p-JNK， c-Jun were decreased，and p62， Bcl-2 were increased in the Ani group（P<0.05）. Compared with the TCM group，the mRNA expressions of JNK mRNA had a down-regulation in the SP group and TCM+SP group，while LC3A， LC3B， Atg5， c-Jun， JNK had an up-regulation（P<0.05） and Bcl-2 had a down-regulation in the Ani group（P<0.05）. Compared with the SP group，the mRNA expressions of Atg5， c-Jun， JNK had an up-regulation（P<0.05）， and Beclin1， p62， Bcl-2 had a down-regulation in the Ani group（P<0.05）. ConclusionHuazhuo Jiedu Huoxue Tongluo prescription significantly up-regulates the protein and mRNA expressions of LC3A/B， Beclin1， Atg5， JNK， p-JNK and c-Jun， and down-regulates the protein and mRNA expressions of p62 and Bcl-2， suggesting that the prescription can inhibit autophagy through JNK signaling pathway to reduce ischemia/reperfusion injury in rats.

Objective:To detect the abnormal changes of myocardial blood perfusion in patients with hypertrophic cardiomyopathy(HCM) by myocardial contrast echocardiography (MCE) combined with adenosine stress test.Methods:Fifteen adult patients with HCM who were treated in Fuwai Central China Cardiovascular Hospital from May 2021 to March 2022 were prospectively selected as the HCM group, and eighteen healthy volunteers matched by gender, age and body surface area during the same period were chosen as the control group. All subjects underwent routine echocardiography, rest and adenosine stress MCE. The MCE images were analyzed by QLab software to obtain the myocardial perfusion parameters: peak signal intensity (A value), rising slope of the curve (β value) and A×β value, and the differences of above parameters between the two groups were compared.According to whether the end-diastolic wall thickness ≥12 mm, the myocardial segments in the HCM group were divided into hypertrophic segments and non-hypertrophic segments. The differences in myocardial perfusion parameters were compared among control group segments, hypertrophic segments and non-hypertrophic segments of the HCM group. The correlations of stress myocardial blood flow with maximal left ventricular wall thickness (MLVWT), left ventricular mass index (LVMI) and left atrial volume index (LAVI) in the HCM group were analyzed.Results:Compared with the control group, the A value, β value and A×β value of whole myocardium, hypertrophic segments and non-hypertrophic segments in the HCM group were significantly decreased in the rest and adenosine stress state, and the differences were statistically significant (all P<0.05). In the stress state, the A value, β value and A×β value of the hypertrophic segments were significantly lower than those in the non-hypertrophic segments in the HCM group, and the detection rate of abnormal perfusion segments in the HCM group was significantly higher than that in the rest state(all P<0.05). Compared with the control group, the myocardial blood flow reserve of whole myocardium, hypertrophic segments and non-hypertrophic segments in the HCM group were significantly decreased, and the differences were statistically significant(all P<0.05). The stress myocardial blood flow in the HCM group was negatively correlated with MLVWT, LVMI and LAVI ( r=-0.815, -0.805, -0.742; all P<0.05). Conclusions:Myocardial blood perfusion abnormalities can occur in both hypertrophic and non-hypertrophic myocardial segments in patients with HCM, and adenosine stress MCE can significantly improve the sensitivity of detecting myocardial perfusion abnormalities. The stress myocardial blood flow in patients with HCM is negatively correlated with MLVWT, LVMI and LAVI.

Objective:To evaluate the right atrial volume and function abnormalities in patients with pulmonary hypertension (PH) by four-dimensional automatic quantitation technique, and to explore the application value of this technique in evaluating the risk stratification and World Health Organization functional class(WHO-FC) of PH patients.Methods:Eighty-four adult patients with PH diagnosed by right heart catheterization from April to October 2022 in Fuwai Central China Cardiovascular Hospital were consecutively enrolled as the PH group. All cases were divided into 3 groups according to the mean pulmonary arterial pressure (mPAP): mild PH group ( n=28), moderate PH group ( n=28), severe PH group ( n=28). Twenty-eight healthy volunteers matched by gender and age were included in the same period as the control group. The volume and strain parameters of the right atrium were obtained by analyzing the four-dimensional image of the right atrium using four-dimensional automatic quantitation technique, including right atrial minimum volume index (RAVImin), right atrial maximum volume index (RAVImax), right atrial presystolic volume index (RAVIpreA), right atrial ejection fraction (RAEF), right atrial passive ejection fraction (RAPEF), right atrial active ejection fraction, RAAEF, longitudinal strains of right atrial reserve, conduit and systolic period (RASr, RAScd, RASct), circumferential strains of right atrial reserve, conduit and systolic period (RASr-c, RAScd-c, RASct-c). The differences in right atrial parameters among four groups were compared.ROC curve was used to analyze the diagnostic efficiency of right atrial four-dimensional strain parameters for PH patients with WHO-FC≥Ⅲ. Pearson linear correlation analysis was used to investigate the relationships between RASr and right atrial area (RAA), NT-proBNP and tricuspid annular plane systolic excursion to pulmonary arterial systolic pressure ratio (TAPSE/sPAP). Results:①Compared with the control group, RAEF, RAPEF, RASr, RAScd, RASr-c, RAScd-c were significantly decreased in mild, moderate and severe PH groups; while RAAEF, RASct, RASct-c were significantly increased in mild PH group and significantly decreased in moderate and severe PH groups, and the differences were statistically significant (all P<0.05). RAVImin, RAVImax, RAVIpreA gradually increased among the control, mild PH, moderate PH and severe PH groups, and the differences were statistically significant (all P<0.05). RAEF, RAPEF, RAAEF, RASr, RAScd, RASct, RASr-c, RAScd-c, RASct-c were decreased successively among mild, moderate and severe PH groups, and the differences were statistically significant (all P<0.05). ②ROC curve showed that RASr had the highest diagnostic efficiency in PH patients with WHO-FC ≥Ⅲ, and the cut-off value was 20.5% (AUC=0.914, P<0.001). ③Correlation analysis showed that RASr was correlated with RAA, NT-proBNP and TAPSE/sPAP ( r=-0.803, -0.621, 0.739; all P<0.001). Conclusions:The degree of right atrial function impairment increased in patients with mild, moderate and severe PH in turn. RASr is the best predictor of WHO-FC ≥Ⅲ in patients with pulmonary hypertension and is a potential parameter for risk stratification in patients with PH.

Objective:To detect the abnormal changes of myocardial blood perfusion in patients with hypertrophic cardiomyopathy (HCM) by myocardial contrast echocardiography(MCE) combined with exercise stress test.Methods:Twenty-seven patients with clinically diagnozed of asymmetric HCM in Fuwai Central China Cardiovascular Hospital from May 2020 to April 2021 were selected as the HCM group, and 29 healthy subjects during the same period were selected as the control group. All patients underwent routine echocardiography, resting and exercise stress MCE. The myocardial perfusion parameters of each segment of interventricular septum in the 2 groups were quantitatively analyzed: the peak plateau intensity (A value), ascending slope of the curve(β value) and value of A×β. According to the end-diastolic myocardial thickness, the interventricular septum of the HCM group was divided into hypertrophic and non-hypertrophic segments, and the myocardial contrast parameters of the interventricular septum of the study group were compared with those of the control group. The myocardial blood flow reserve value of the two groups were calculated, and the correlation of myocardial blood flow reserve value with left ventricular mass index (LVMI) and left ventricular remodeling index (LVRI) were analyzed.Results:No matter at rest or under stress, the A value, β value and A×β value of ventricular septal hypertrophic and non-hypertrophic segments in the hypertrophic cardiomyopathy group were lower than those in the control group, and the differences were statistically significant (all P<0.05). Under stress, the A value, β value and A×β value of interventricular septal hypertrophic segments were lower than those in non-hypertrophic segments in the HCM group, and the differences were statistically significant (all P<0.05). The myocardial blood flow reserve in the HCM group was negatively correlated with LVMI and LVRI( r=-0.899, -0.676; all P<0.001). Conclusions:In patients with HCM under resting and exercise stress, microcirculation disorders were found in both hypertrophic and non-hypertrophic segments of the ventricular wall, and the myocardial blood flow reserve was negatively correlated with LVMI and LVRI.

Aortic Valve/surgery* ; Aortic Valve Stenosis/surgery* ; China/epidemiology* ; Heart Valve Prosthesis Implantation ; Humans ; Severity of Illness Index ; Treatment Outcome

BACKGROUND: The past decade has witnessed an ever-increasing momentum of transcatheter aortic valve replacement (TAVR) and a subsequent paradigm shift in the contemporary management of severe aortic stenosis (AS). We conducted a multi-centric TAVR registry based on Chinese patients (the China Aortic valve tRanscatheter Replacement registrY [CARRY]) to delineate the clinical characteristics and outcomes of Chinese patients who underwent TAVR and compare the results between different valve types in different Chinese regions. METHODS: CARRY is an all-comer registry of aortic valve disease patients undergoing TAVR across China and was designed as an observational study that retrospectively included all TAVR patients at each participating site. Seven hospitals in China participated in the CARRY, and 1204 patients from April 2012 to November 2020 were included. Categorical variables were compared using the chi-squared test, and continuous variables were analyzed using a t test or analysis of variance (ANOVA) test. The Kaplan-Meier curve was used to estimate the risk of adverse events during follow-up. RESULTS: The mean age of the patients was 73.8 ± 6.5 years and 57.2% were male. The median Society of Thoracic Surgeon-Predicted Risk of Mortality score was 6.0 (3.7-8.9). Regarding the aortic valve, the proportion of bicuspid aortic valve (BAV) was 48.5%. During the hospital stay, the stroke rate was 0.7%, and the incidence of high-degree atrioventricular block indicating permanent pacemaker implantation was 11.0%. The in-hospital all-cause mortality rate was 2.2%. After 1 year, the overall mortality rate was 4.5%. Compared to patients with tricuspid aortic valve (TAV), those with BAV had similar in-hospital complication rates, but a lower incidence of in-hospital mortality (1.4% vs. 3.3%) and 1 year mortality (2.3% vs. 5.8%). CONCLUSIONS: TAVR candidates in China were younger, higher proportion of BAV, and had lower rates of post-procedural complications and mortality than other international all-comer registries. Given the use of early generation valves in the majority of the population, patients with BAV had similar rates of complications, but lower mortality than those with TAV. These findings further propel the extension of TAVR in low-risk patients. TRIAL REGISTRATION https://www.chictr.org.cn/ (No. ChiCTR2000038526).
Aged ; Aged, 80 and over ; Aortic Valve/surgery* ; Aortic Valve Stenosis/surgery* ; Humans ; Male ; Registries ; Retrospective Studies ; Risk Factors ; Transcatheter Aortic Valve Replacement/adverse effects* ; Treatment Outcome

Objective: To investigate the effects of modified acidic fibroblast growth factor (MaFGF) mediated by nanoliposomes combined with ultrasound-targeted microbubble destruction (UTMD) on left ventricular systolic function in early diabetes mellitus(DM) rats. Methods: The nanoliposomes containing MaFGF(MaFGF-nlip) were prepared by reverse phase evaporation method. Among 60 male Sprague Dawley (SD) rats, 50 rats were randomly selected and were induced to be DM models by streptozotocin(STZ) through intraperitoneal injecting, the other 10 rats as control group. Then DM rats were randomly divided into 4 groups: DM model group, MaFGF solution group, MaFGF-nlip group and MaFGF-nlip+ UTMD group. After the successful induction of DM model, the intervention was performed twice a week.After 12 weeks of intervention, all rats underwent conventional echocardiography and velocity vector imaging (VVI). Left ventricular ejection fraction (LVEF) and left ventricular fraction shortening(LVFS) were measured by conventional echocardiography. The mean peak systolic radial velocity (Vs), radial strain (Sr) and radial strain rate (SRr) of six walls at the papillary muscle level were measured in left ventricular short-axis view by VVI. At last, myocardial tissue of all rats were stained with Sirius red to evaluate myocardial interstitial fibrosis. The level of myocardial apoptosis was evaluated by TUNEL staining, and the changes of myocardial ultrastructure were observed by transmission electron microscopy. Results: The prepared MaFGF-nlip were more rounded, evenly dispersed, and of good stability and high encapsulation efficiency. Twelve weeks later after intervention, LVEF, LVFS, Vs, Sr and SRr in the DM model group were significantly lower than those in the control group (all P<0.05). LVEF, LVFS, Vs, Sr and SRr in the MaFGF-nlip+ UTMD group were significantly higher than those of the DM model group and other intervention groups (all P<0.05). The results of Sirius red staining and Tunel staining showed that CVF and AI in the DM model group were significantly higher than those in the control group (all P<0.05). For MaFGF-nlip+ UTMD group, CVF and AI were significantly decreased compared with the DM model group and other intervention groups(all P<0.05). According to the results of transmission electron microscopy, compared with the DM model group, the improvement of myocardial ultrastructure was the most obvious in the MaFGF-nlip+ UTMD group. Conclusions MaFGF delivered by using nanoliposomes combined with UTMD can improve the left ventricular systolic function in diabetic rats by inhibiting the myocardium cardiac fibrosis and reducing the cardiomyocyte apoptosis.

Objective:To explore the clinical value of adenosine stress myocardial contrast echocardiography in detecting myocardial blood perfusion abnormalities in patients with type 2 diabetes mellitus.Methods:Twenty-six patients with type 2 diabetes mellitus clinically diagnosed from May 2019 to January 2020 in the endocrinology department of Fuwai Central China Cardiovascular Hospital and 28 healthy examinees with gender and age matched during the same period were enrolled. Routine echocardiography, rest and adenosine stress myocardial contrast echocardiography were performed, the plateau signal intensity(A value), curve rising slope(K value) and A×K value of the myocardial perfusion time-intensity curve were obtained by offline analysis. And general data such as age, gender, disease course, body mass index and glycated hemoglobin were collected, and results of the two groups were compared statistically.Results:In the rest state, the A value of the myocardial perfusion parameter in the diabetic group was not significantly different from that of the control group, both in whole and in segments ( P>0.05), while the K value and A×K value of the myocardial perfusion parameters in the diabetic group were significantly lower than those in the control group ( P<0.05). In the stress state, the A value, K value and A×K value of myocardial perfusion parameters in the diabetic group were significantly lower than those in the control group, both in whole and in segments ( P<0.05). The detection rate of myocardial perfusion abnormality in the stress state was significantly higher than that in the rest state, and the difference was statistically significant ( P<0.05). The myocardial blood flow reserve in the diabetic group was negatively correlated with the course of disease and the level of glycated hemoglobin ( r=-0.580, P=0.020; r=-0.481, P=0.013). Conclusions:Adenosine stress myocardial contrast echocardiography can be used for detection of left ventricular myocardial perfusion abnormalities in patients with type 2 diabetes mellitus, which has great clinical application value.

Objective To investigate the protective effects of left ventricular myocardial perfusion after delivery of acidic fibroblast growth factor (aFGF) in rats with diabetic cardiomyopathy (DCM) by using ultrasound‐targeted microbubble destruction ( UTMD ) with real‐time myocardial contrast echocardiography( RT‐MCE) . Methods Among 64 male SD rats ,52 rats were randomly selected and were induced DCM by streptozotocin through intraperitoneal injecting ,the other rats as normal control group . DCM rats were randomly divided into the DCM model group ,aFGF only group ,SonoVue‐aFGF group and the SonoVue‐aFGF+ UTMD group in this study . The aFGF only group rats were injected with aFGF solution through tail vein ,the SonoVue‐aFGF group were injected with SonoVue‐aFGF solution through tail vein and SonoVue‐aFGF+ UTMD group rats were injected with SonoVue‐aFGF solution through tail vein and using UTMD simultaneously . All rats underwent conventional echocardiography and RT‐MCE exams before and 4 weeks after intervention . Left ventricular ejection fraction ( LVEF) and left ventricular fraction shortening( LVFS ) were measured by conventional echocardiography . The plateau intensity ( A ) ,initial slope of the curve (β) and myocardial blood flow ( A ×β) of left ventricular anterior wall at the papillary muscle level were measured in left ventricular short‐axis view by RT‐MCE . Results Before intervention , LVEF and LVFS in the DCM model group ,aFGF only group ,SonoVue‐aFGF group and the SonoVue‐aFGF+UTMD group were significantly lower than in the normal control group ( P <0 .01) .During 4 weeks after intervention ,LVEF and LVFS in the aFGF only group ,SonoVue‐aFGF group and the SonoVue‐aFGF+UTMD group were slightly increased than those in the DCM model group ,but no statistically significant differences were found ( P > 0 .05) ,however A and A × β in the SonoVue‐aFGF+ UTMD group were significantly increased than those in the DCM model group( P < 0 .01) . Compared with the same group before intervention ,A and A ×βin the SonoVue‐aFGF+UTMD group were higher ( P <0 .05) and these in the DCM model group were lower during four weeks after intervention ( P < 0 .05) . Conclusions Acidic fibroblast growth factor delivered by using UTMD can improve the left ventricular myocardial perfusion in diabetic cardiomyopathy rats .

Objective To assess the improvements of left ventricular systolic function by three‐dimensional speckle tracking imaging ( 3D‐STI) in type 2 diabetes mellitus ( T2DM ) patients after short‐term insulin pump intensive therapy . Methods Thirty‐five T2DM patients complicated with microangiopathy and thirty‐two healthy volunteers were studied ,underwent the dynamic image of the four‐chamber view ,three‐dimensional images of left ventricle were obtained for all the individuals . The left ventricular global longitudinal strain ( LVGLS) ,left ventricular global circumferential strain ( LVGCS) ,left ventricular ejection fraction (LVEF) ,peak basal and apical rotation (LV‐ProtB ,LV‐ProtA) ,peak LV twist ( LV‐tw ) were calculated using TomTec software .After insulin pump intensive therapy for two weeks ,all the indexes were reexamined in T2DM patients . Results Compared with control group ,the LVGLS , LVGCS ,LV‐tw and LV‐ProtA were significantly decreased in diabetes mellitus group before and after treatment ( P < 0 .01 or P < 0 .05) . Compared with diabetes mellitus patients before treatment ,the LVGLS ,LVGCS had significant higher level after treatment( P <0 .05) . The LVGLS ,LVGCS ,LV‐tw and LV‐ProtA were significantly correlated with LVEF in type 2 diabetes mellitus patients and normal controls . Conclusions Insulin pump intensive treatment could improve left ventricular systolic function in type 2 diabetes patients complicated with microangiopathy . 3D‐STI can be sensitive to accurately assess the therapeutic effect and has the important clinical value .