The lncRNA ADAMTS9-AS1/miR-185-5p/KAT7 ceRNA network inhibits cardiomyocyte hypertrophy in hypertrophic obstructive cardiomyopathy.

Hypertrophic obstructive cardiomyopathy (HOCM) is a well-recognized inherited cardiac disease. This study was conducted to explore the role of lncRNA ADAMTS9 antisense RNA 1 (ADAMTS9-AS1) in HOCM-induced cardiomyocyte hypertrophy. The serum of HOCM patients was collected. AC16 cells were treated with isoproterenol (ISO) and transfected with oe-ADAMTS9-AS1 vector, miR-185-5p mimic, and lysine acetyltransferase 7 (KAT7) specific small interfering RNA. lncRNA ADAMTS9-AS1, miR-185-5p, KAT7, brain natriuretic peptide (BNP), and atrial natriuretic peptide (ANP) in the serum or cells were determine by qRT-PCR or Western blot assay. Cell surface area was observed by Texas Red-Phalloidin staining. Subcellular localization of lncRNA ADAMTS9-AS1 was tested by nuclear/cytoplasmic fractionation assay, with RNA pull-down and dual-luciferase assay to validate gene interactions. lncRNA ADAMTS9-AS1 was downregulated in the serum of HOCM patients and ISO-treated AC16 cells. lncRNA ADAMTS9-AS1 overexpression inhibited ISO-induced cardiomyocyte hypertrophy and reduced levels of ANP and BNP. lncRNA ADAMTS9- AS1 was located in cytoplasm and inhibited miR-185-5p expression through targeted binding. miR-185-5p bound to KAT7 3'UTR and inhibited KAT7 expression. miR-185-5p overexpression and KAT7 knockdown both neutralized the inhibitory role of lncRNA ADAMTS9-AS1 in cardiomyocyte hypertrophy. Overall, lncRNA ADAMTS9-AS competitively bound to miR-185-5p to up-regulate KAT7 and thus inhibited cardiomyocyte hypertrophy.

DNA methylome and transcriptome profiling reveal key electrophysiology and immune dysregulation in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease. However, a detailed DNA methylation (DNAme) landscape has not yet been elucidated. Our study combined DNAme and transcriptome profiles for HCM myocardium and identify aberrant DNAme associated with altered myocardial function in HCM. The transcription of methylation-related genes did not significantly differ between HCM and normal myocardium. Nevertheless, the former had an altered DNAme profile compared with the latter. The hypermethylated and hypomethylated sites in HCM tissues had chromosomal distributions and functional enrichment of correlated genes differing from those of their normal tissue counterparts. The GO analysis of network underlying the genes correlated with DNAme alteration and differentially expressed genes (DEGs) shows functional clusters centred on immune cell function and muscle system processes. In KEGG analysis, only the calcium signalling pathway was enriched either by the genes correlated with changes in DNAme or DEGs. The protein-protein interactions (PPI) underlying the genes altered at both the DNAme and transcriptional highlighted two important functional clusters. One of these was related to the immune response and had the estrogen receptor-encoding ESR1 gene as its node. The other cluster comprised cardiac electrophysiology-related genes. Intelliectin-1 (ITLN1), a component of the innate immune system, was transcriptionally downregulated in HCM and had a hypermethylated site within 1500 bp upstream of the ITLN1 transcription start site. Estimates of immune infiltration demonstrated a relative decline in immune cell population diversity in HCM. A combination of DNAme and transcriptome profiles may help identify and develop new therapeutic targets for HCM.

Differential Expression of LOXL1-AS1 in Coronary Heart Disease and its Regulatory Mechanism in ox-LDL-Induced Human Coronary Artery Endothelial Cell Pyroptosis.

OBJECTIVE: Coronary heart disease (CHD) is a notable contributor to the burden of human health. Dysregulated long non-coding RNAs (lncRNAs) are implicated in the pathogenesis of CHD. This study investigated the expression pattern of lncRNA LOXL1-AS1 in CHD and its regulatory mechanism in oxidized low-density lipoprotein (ox-LDL)-induced human coronary artery endothelial cell (HCAEC) pyroptosis. METHODS: Serum was collected from 62 CHD patients and 62 healthy volunteers for the detection of LOXL1-AS1 expression. The value of LOXL1-AS1 in CHD diagnosis and major cardiovascular adverse event (MACE) prediction was analyzed using the ROC curve. LOXL1-AS1, miR-16-5p, and SNX16 expressions in ox-LDL-treated HCAECs were determined using RT-qPCR. NLPR3, cleaved-caspase-1, and GSDMD-N protein levels were measured using Western blot. IL-1ß and IL-18 concentrations were measured using ELISA. The binding relationships between LOXL1-AS1 and miR-16-5p and miR-16-5p and SNX16 were verified. Functional rescue experiment was performed to verify the role of miR-16-5p in HCAEC pyroptosis. RESULTS: LOXL1-AS1 was highly expressed in CHD patients. LOXL1-AS1 had diagnostic value for CHD and predictive value for MACE occurrence. ox-LDL-treated HCAECs showed reduced viability, increased IL-1ß and IL-18 concentrations, and elevated NLPR3, cleaved-caspase-1, and GSDMD-N levels. LOXL1-AS1 silencing promoted cell viability and reduced pyroptosis. LOXL1-AS1 bound to miR-16-5p and miR-16-5p targeted SNX16. Inhibition of miR-16-5p reversed the inhibitory effect of LOXL1-AS1 silencing on HCAEC pyroptosis. CONCLUSION: LOXL1-AS1 was elevated in CHD patients with a good diagnostic value for CHD and predictive value for MACE. LOXL1-AS1 downregulated miR-16-5p expression by binding to miR-16-5p to enhance ox-LDL-induced HCAEC pyroptosis, which may be associated with upregulation of SNX16 transcription.

Underlying mechanisms of saphenous vein graft stenosis after coronary artery bypass caused by clipping of the side branches: an experimental study.

Background: Saphenous veins are regular bypass conduits selected in non-left anterior descending artery (LAD) coronary artery bypass graft (CABG) surgery. Despite the technical errors, acute thrombosis, intimal hyperplasia and arteriosclerosis which could lead to saphenous vein graft (SVG) failure, the metal-clipping-related SVG failure is unique and rare. This study was conducted to investigate the clinical and underlying mechanisms of the metal-clipping-related SVG failure. Methods: We collected 6 typical cases of the metal-clipping-related SVG failure in 41 patients who were diagnosed graft stenosis by coronary angiograph after CABG in the Department of Cardiology, Beijing Anzhen Hospital, from January 2020 to September 2021. Furthermore, we built an in vitro model to verify the identical intravascular ultrasound (IVUS) pattern of metal clip. Results: There were 6 in 41 cases of SVG stenosis caused by clipping of the side branches. We found that the stenosis of SVG caused by metal clipping mostly occurred at the corner and multipole clipping points. In this situation, great resistance could be felt when pushing the instruments through the stenosis and crystallized cholesterol was rarely caught by the distal protection device. We verified the similar IVUS pattern of metal clip at the side-branches of SVG in vitro. Conclusions: The metal-clipping-related stenosis may lead to SVG failure. The stenosis of SVG caused by metal clipping mostly occurred at the corner and multipole clipping points. IVUS showed great modality for clarification.

The role and the signal pathways of Yes-associated protein 2 in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous myocardial disease characterized by myocardial hypertrophy, myocardial mechanical and electrical activity obstacles. This study aimed to explore the relationship between YAP2 (Yes-associated protein 2) and HCM and clarify a signaling path about the pathogenesis of HCM. Our study confirms that YAP2 can promote myocardial cell hypertrophy at the molecular level (myocardial lineage cell H9C2), organ level (clinical specimens of human HCM), and an animal model (a mouse model of HCM with cardiac-specific transgenic and knockout YAP2). The detailed molecular mechanisms linking YAP2 to cardiomyocyte hypertrophy and HCM were investigated. This study proved that YAP2, as the final reaction factor in Hippo pathways, influences Akt1 activity to affect the downstream genes, which participate in the formation of HCM by promoting myocardial cell proliferation and cardiac hypertrophy.

The expansion of no-touch harvesting sequential vein graft after off-pump coronary artery bypass grafting.

BACKGROUND AND AIM OF THE STUDY: Many studies support that the no-touch (NT) procedure can improve the patency rate of vein grafts. However, it is not clear that the sequential vein graft early expansion in the NT technique during off-pump coronary artery bypass grafting (CABG). This study will explore this issue. METHODS: This was a prospective single-center randomized controlled clinical trial. A total of 100 patients undergoing off-pump CABG with the sequential saphenous graft were randomly assigned to two groups: the NT and conventional (CON) groups. Perioperative and postoperative data were collected during the hospital stay. The mean diameter of sequential grafts was measured using cardiac computed tomography angiography 3 months after the operation. RESULTS: There was a significant difference in the average diameter of sequential grafts between the two groups (NT: [2.98 ± 0.42], CON: [3.26 ± 0.51], p = .005). There was no difference in occlusion of sequential venous grafts between the two groups (NT: 4/48 [8.3%], CON: 5/49 [10.2%], p = 1.000). There were differences in surgery time between the two groups (NT: 220 [188,240], CON: 190 [175,230], p = .009). CONCLUSIONS: The sequential graft early expansion in the NT technique is not as pronounced as that in the conventional technique, which may have a long-term protective effect on the grafts.

Analysis of risk factors of low cardiac output syndrome after congenital heart disease operation: what can we do.

BACKGROUND: It's necessary to analyze the related risk factors and complications of low cardiac output syndrome (LCOS) after operation in children with congenital heart disease (CHD), to elucidate the management strategy of LCOS. METHODS: CHD children admitted to the department of cardiology in our hospital from January 15, 2019 to October 31, 2020 were included. The personal and clinical data of CHD children with LCOS and without LCOS were collected and compared. Logistic regression analyses were conducted to identify the risk factors of postoperative LCOS. Besides, the complication and mortality of LCOS and no LCOS patients were compared. RESULTS: A total of 283 CHD patients were included, the incidence of postoperative LCOS in CHD patients was 12.37%. There were significant differences in the age, preoperative oxygen saturation, two-way ventricular shunt, duration of CPB and postoperative residual shunt between two groups (all p < 0.05). Logistic regression analyses indicated that age ≤ 4y(OR2.426, 95%CI1.044 ~ 4.149), preoperative oxygen saturation ≤ 93%(OR2.175, 95%CI1.182 ~ 5.033), two-way ventricular shunt (OR3.994, 95%CI1.247 ~ 6.797), duration of CPB ≥ 60 min(OR2.172, 95%CI1.002 ~ 4.309), postoperative residual shunt (OR1.487, 95%CI1.093 ~ 2.383) were the independent risk factors of LCOS in patients with CHD (all p < 0.05). There were significant differences in the acute liver injury, acute kidney injury, pulmonary infection, tracheotomy, duration of mechanical ventilation, length of ICU stay and mortality (all p < 0.05), no significant difference in the 24 h drainage was found(p = 0.095). CONCLUSION: LCOS after CHD is common, more attentions should be paid to those patients with age ≤ 4y, preoperative oxygen saturation ≤ 93%, two-way ventricular shunt, duration of CPB ≥ 60 min, postoperative residual shunt to improve the prognosis of CHD patients.

No-Touch Sequential Saphenous Venous Harvesting Technique in Off-Pump Bypass Surgery: A Retrospective Study.

BACKGROUND: In the mid-1990s, the Swedish expert team proposed saphenous vein graft (SVG) harvesting with pedicle tissue. The short-term and long-term patency rates of the great saphenous vein obtained by the no-touch (NT) were higher than those obtained by the conventional (CON). In the past, NT harvesting was mainly used in on-pump coronary artery bypass grafting (CABG), and vein grafts were mostly single vein grafts. In this study, we retrospectively analyzed the safety and effectiveness of sequential vein grafts using NT harvesting in off-pump CABG. METHODS: From 2017 to 2019, a total of 505 patients were included in the study. There were 150 patients in the NT group and 355 patients in the CON group. After applying propensity score matching (1:1 matching), 148 patients were included in each group. Baseline data, graft patency, post-operative complications, leg wound complications and 1-year major adverse cardiac and cerebrovascular events (MACCEs) were compared between the two groups. RESULTS: There was no significant difference in the patency rate of sequential venous grafts between the two groups 1 year after the operation either before [NT: 7.1% (10/141) vs. CON: 11.5% (38/331), p = 0.149) or after matching (NT: 7.1% (10/140) vs. CON: 7.3% (9/124), p = 0.971]. There was no significant difference in the composite clinical endpoint between the two groups either before [NT: 3 (2.3%) vs. CON: 9 (2.8%), p = 1.000] or after matching [NT: 3 (2.3%) vs. CON: 3 (2.5%), p = 1.000]. There were differences in leg wound complications between the two groups both before [NT: 9 (6.9%) vs. CON: 6 (1.9%), p = 0.007] and after matching [NT: 9 (6.9%) vs. CON: 2 (1.7%), p = 0.043]. CONCLUSIONS: The application of the NT harvesting in off-pump CABG with sequential vein grafts is safe and effective. NT method has disadvantages in leg wound.

Preparation of Nano Zinc Particles and Evaluation of Its Application in Mouse Myocardial Infarction Model.

Nanometer zinc particles were synthesized by orthogonal test with manganese chloride, iron chloride and zinc sulfate as raw materials and NaOH as coprecipitating agent. The optimum synthesis conditions of coprecipitation method were obtained and the samples were characterized by various means. In this experiment, the SV, EF, FS, lvaws, lvawd, lvpws and lvpwd of left ventricle in mice with myocardial infarction were decreased, while the LVEDd, lveds and lvevs were increased in the environment exposed to ultrafine zinc nanoparticles, which proved that exposure to ultrafine zinc nanoparticles could lead to the enlargement of left ventricle, the thinning of ventricular wall, and the decrease of cardiac systolic and diastolic function. Further study on the heart tissue sections showed that the normal left ventricular myocardium of mice exposed to ultrafine zinc nanoparticles decreased, apoptotic cells increased, collagen content increased significantly, and myocardial fibrosis intensified. At the same time, WGA staining results of myocardial cell membrane showed that inhalation of ultra-fine nano zinc particles increased the size of myocardial infarction cells and disordered cell arrangement, which further proved that inhalation of ultra-fine nano zinc particles accelerated left ventricular pathological remodeling. The results of this study prove that the ultra-fine zinc nanoparticles in the air play an important role in the structural remodeling of myocardial infarction heart, and provide a theoretical basis for formulating targeted policies to control air pollution.

Soluble ST2, Galectin-3 and clinical prognosis of patients with hypertrophic cardiomyopathy undergoing ventricular septal myectomy: a correlation analysis.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common chromosomal abnormal heart disease. The pathophysiological mechanism of HCM is complex. Several studies have suggested that the level of Soluble ST2 (sST2) may be a biomarker of chronic systolic heart failure, however, the role of sST2 in HCM remains unclear. So we performed this study to analyze the role of Soluble ST2 (sST2), Galectin-3 (Gal-3) and its correlations with clinical prognosis of patients with hypertrophic cardiomyopathy (HCM) undergoing ventricular septal myectomy. METHODS: HCM patients who underwent modified Morrow surgery in our hospital during June 2016-June 2018 were included. We divided the patients into different groups stratified by sST2 and Gal-3 level. Besides, we included volunteers without heart disease for medical examination as normal controls. Biochemical analyses were conducted to identify the biomarkers difference. The predictive value of sST2 and Gal-3 on all-cause mortality was evaluated with Cox regression analysis. RESULTS: A total of 125 HCM patients were included in this present study. The sST2 and Gal-3 levels in HCM patients were significantly higher than that in control group (all P<0.001); there were significant differences in the incidence of all-cause mortality for HCM patients stratified by the sST2 and Gal-3 level; Cox univariate regression survival analysis showed that the hypertension (HR =1.19, 95% CI: 1.01-1.38), maximum wall thickness (HR =1.48, 95% CI: 1.04-1.98), Log sST2 (HR =1.02, 95% CI: 1.01-1.05), Log Gal-3 (HR =1.17, 95% CI: 1.09-1.32) were the predictors for all-cause mortality in patients with HCM, and Cox multivariate risk regression showed that maximum wall thickness was the independent predictors of all-cause mortality in patients with HCM (HR =1.63, 95% CI: 1.35-1.97). CONCLUSIONS: Even through sST2 and Gal-3 were not associated with clinical prognosis of patients with HCM undergoing ventricular septal myectomy, it may be involved in the progress of HCM, more studies are warranted to identify the potential mechanism and reverence value.

Atorvastatin reverses the dysfunction of human umbilical vein endothelial cells induced by angiotensin II.

Statins exert pleiotropic effects on endothelial cells, in addition to lowering cholesterol. This study evaluated angiotensin II (Ang II)-induced dysfunction in human umbilical vein endothelial cells (HUVECs), and the effects of atorvastatin (Ator) on induced HUVECs in vitro. The cytotoxicity of Ang II and Ator was determined by the MTT assay. A series of cellular responses were screened, including oxidative stress, cellular apoptosis, inflammatory response, autophagy, expression of endothelial nitric oxide synthase and the angiogenic function of HUVECs. Ator returned these cellular responses to a normal level. The present study also examined cellular organelle dysfunction. In HUVECs, Ang II triggered mitochondrial damage, as demonstrated by a decreased mitochondrial membrane potential, while Ator attenuated this Ang II-induced damage. The observed cellular dysfunction may cause endothelial senescence due to excessive cell injury. The current study examined several aging markers, which revealed that these disorders of cellular functions triggered endothelial senescence, which was delayed by Ator. Ator also suppressed Ang II-induced angiogenesis damage. The data presented in this study strongly suggested that Ang II induced a series of processes that lead to cellular dysfunction in HUVECs, including oxidative stress, inflammation, and mitochondrial damage, leading to apoptosis and endothelial senescence. However, Ator significantly reversed these effects and modulated intracellular stability. The present study indicated that Ator serves an antagonistic role against HUVEC dysfunction and may potentially prevent several diseases, including coronary disease and atherosclerosis, by maintaining cellular homeostasis.

Surgical Treatment for Hypertrophic Obstructive Cardiomyopathy with Concomitant Mitral Valve Abnormalities: A Cohort of 26 Cases.

BACKGROUND: We sought to analyze the pathological characteristics of hypertrophic obstructive cardiomyopathy (HOCM) with concomitant mitral valve abnormalities and to discuss the surgical treatment strategies. METHODS: The clinical data of 26 HOCM patients treated from January 2014 to March 2016 were retrospectively analyzed. There were 19 males and 7 females with a mean age of 47 ± 16 years (range, 10-70 years). Echocardiography showed HOCM, systolic anterior motion of the mitral apparatus, and concomitant mitral regurgitation. Modified Morrow procedure with expanded resection area was performed in 21 patients. Concomitant mitral valvuloplasty was performed in 4 patients, coronary artery bypass grafting was performed in one patient, and aortic valve replacement was performed in one patient. Echocardiography was performed intraoperatively at postoperative 1 week and at postoperative 1 year to evaluate the left ventricular obstruction and the mitral regurgitation. RESULTS: The left ventricular outflow tract gradient, left ventricular outflow tract velocity, septal thickness, and mitral regurgitation area decreased significantly at postoperative 1 week and 1 year in comparison with the baseline (all P < .001). The postoperative mitral regurgitation and systolic anterior motion of the mitral apparatus were completely abolished or significantly relieved. Only one patient had moderate mitral regurgitation of 7 cm2 after the surgery. At postoperative 1 year, all patients were asymptomatic, and the quality of life was significantly improved. The New York Heart Association (NYHA) class was I-II. Echocardiography showed good anatomy and function of the mitral valve. CONCLUSIONS: Concomitant mitral valve abnormality is not uncommon in HOCM. Septal myectomy can adequately expand the left ventricular outflow tract and abolish mitral regurgitation and systolic anterior motion of the mitral apparatus. Concomitant mitral valvuloplasty is indicated for severe congenital abnormalities or secondary lesions of the mitral valve, and the outcomes are satisfactory.

Comparison of Modified With Classic Morrow Septal Myectomy in Treating Hypertrophic Obstructive Cardiomyopathy.

This study aimed to compare the efficacy and safety of the classic Morrow septal myectomy with the modified procedure in treating hypertrophic obstructive cardiomyopathy (HOCM).A retrospective study was conducted to compare the outcomes of classic with modified Morrow septal myectomy in 42 patients treated from January 2005 to July 2011. Preoperative and postoperative ventricular septal thickness, left ventricular (LV) outflow tract velocity and gradient were measured echocardiographically.In both groups, the ventricular septal thickness, LV outflow tract velocity, and LV outflow tract gradient were significantly decreased after the operation. The modified Morrow procedure group, however, showed significantly greater reduction in these echocardiographic parameters than the classic procedure group. All patients in the modified procedure group were asymptomatic postoperatively with a postoperative transvalvular pressure gradient <30 mm Hg. In the classic procedure group, only 14 (87.5%) patients, however, were asymptomatic postoperatively with a postoperative transvalvular pressure gradient <30 mm Hg, and 2 patients still had severe LV outflow obstruction postoperatively.The modified Morrow septal myectomy is safe and effective in treating HOCM patients, and is superior to the classic procedure in reducing the LV outflow tract gradient and velocity, restoring normal anatomic atrioventricular size, and alleviating symptoms associated with HOCM.

PP1A-mediated dephosphorylation positively regulates YAP2 activity.

BACKGROUND: The Hippo/MST1 signaling pathway plays an important role in the regulation of cell proliferation and apoptosis. As a major downstream target of the Hippo/MST1 pathway, YAP2 (Yes-associated protein 2) functions as a transcriptional cofactor that has been implicated in many biological processes, including organ size control and cancer development. MST1/Lats kinase inhibits YAP2's nuclear accumulation and transcriptional activity through inducing the phosphorylation at serine 127 and the sequential association with 14-3-3 proteins. However, the dephosphorylation of YAP2 is not fully appreciated. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2. Inhibition of PP1 by okadiac acid (OA) increases the phosphorylation at serine 127 and cytoplasmic translocation of YAP2 proteins, thereby mitigating its transcription activity. PP1A expression enhances YAP2's pro-survival capability and YAP2 knockdown sensitizes ovarian cancer cells to cisplatin treatment. CONCLUSIONS/SIGNIFICANCE: Our findings define a novel molecular mechanism that YAP2 is positively regulated by PP1-mediated dephosphorylation in the cell survival.