Smooth muscle cell fate decisions decipher a high-resolution heterogeneity within atherosclerosis molecular subtypes.

BACKGROUND: Mounting evidence has revealed the dynamic variations in the cellular status and phenotype of the smooth muscle cell (SMC) are vital for shaping the atherosclerotic plaque microenvironment and ultimately mapping onto heterogeneous clinical outcomes in coronary artery disease. Currently, the underlying clinical significance of SMC evolutions remains unexplored in atherosclerosis. METHODS: The dissociated cells from diseased segments within the right coronary artery of four cardiac transplant recipients and 1070 bulk samples with atherosclerosis from six bulk cohorts were retrieved. Following the SMC fate trajectory reconstruction, the MOVICS algorithm integrating the nearest template prediction was used to develop a stable and robust molecular classification. Subsequently, multi-dimensional potential biological implications, molecular features, and cell landscape heterogeneity among distinct clusters were decoded. RESULTS: We proposed an SMC cell fate decision signature (SCFDS)-based atherosclerosis stratification system and identified three SCFDS subtypes (C1-C3) with distinguishing features: (i) C1 (DNA-damage repair type), elevated base excision repair (BER), DNA replication, as well as oxidative phosphorylation status. (ii) C2 (immune-activated type), stronger immune activation, hyper-inflammatory state, the complex as well as varied lesion microenvironment, advanced stage, the most severe degree of coronary stenosis severity. (iii) C3 (stromal-rich type), abundant fibrous content, stronger ECM metabolism, immune-suppressed microenvironment. CONCLUSIONS: This study uncovered atherosclerosis complex cellular heterogeneity and a differentiated hierarchy of cell populations underlying SMC. The novel high-resolution stratification system could improve clinical outcomes and facilitate individualized management.

Circulating exosomes repair endothelial cell damage by delivering miR-193a-5p.

Circulating exosomes delivering microRNAs are involved in the occurrence and development of cardiovascular diseases. How are the circulating exosomes involved in the repair of endothelial injury in acute myocardial infarction (AMI) convalescence (3-7 days) was still not clear. In this study, circulating exosomes from AMI patients (AMI-Exo) and healthy controls (Normal-Exo) were extracted. In vitro and in vivo, our study showed that circulating exosomes protected endothelial cells (HUVECs) from oxidative stress damage; meanwhile, Normal-Exo showed better protective effects. Through the application of related inhibitors, we found that circulating exosomes shuttled between HUVECs via dynamin. Microarry analysis and qRT-PCR of circulating exosomes showed higher expression of miR-193a-5p in Normal-Exo. Our study showed that miR-193a-5p was the key factor on protecting endothelial cells in vitro and in vivo. Bioinformatics analyses found that activin A receptor type I (ACVR1) was the potential downstream target of miR-193a-5p, which was confirmed by ACVR1 expression and dual-luciferase report. Inhibitor of ACVR1 showed similar protective effects as miR-193a-5p. While overexpression of ACVR1 could attenuate protective effects of miR-193a-5p. To sum up, these findings suggest that circulating exosomes could shuttle between cells through dynamin and deliver miR-193a-5p to protect endothelial cells from oxidative stress damage via ACVR1.

Genome-Wide Association and Functional Studies Identify SCML4 and THSD7A as Novel Susceptibility Genes for Coronary Artery Disease.

OBJECTIVE: The genetic contribution to coronary artery disease (CAD) remains largely unclear. We combined genetic screening with functional characterizations to identify novel loci and candidate genes for CAD. APPROACH AND RESULTS: We performed genome-wide screening followed by multicenter validation in 8 cohorts consisting of 21 828 participants of Han ethnicity and identified 3 novel intragenic SNPs (single nucleotide polymorphisms), rs9486729 (SCML4 [Scm polycomb group protein-like 4]; odds ratio, 1.25; 95% CI, 1.17-1.34; P=3.51×10-11), rs17165136 (THSD7A [thrombospondin type 1 domain-containing 7A]; odds ratio 1.28; 95% CI, 1.21-1.35; P<1.00×10-25), and rs852787 (DAB1 [disabled-1]; odds ratio, 1.29; 95% CI, 1.21-1.38; P=2.02×10-14), associated with CAD with genome-wide significance. The risk allele of rs9486729 and protective allele of rs17165136 were associated with the decreased expression of their host genes, SCML4 and THSD7A, respectively, whereas rs852787 did not have transcriptional effects on any gene. Knockdown of SCML4 activated endothelial cells by increasing the expression of IL-6, E-selectin, and ICAM and weakened their antiapoptotic activity, whereas the knockdown of THSD7A had little effect on these endothelial cell functions but attenuated monocyte adhesion via decreasing the expression of ICAM, L-selectin, and ITGB2. We further showed that inhibiting the expression of SCML4 exacerbated endothelial dysfunction and vascular remodeling in a rat model with partial carotid ligation. CONCLUSIONS: We identify 3 novel loci associated with CAD and show that 2 genes, SCML4 and THSD7A, make functional contributions to atherosclerosis. How rs852787 and its host gene DAB1 are linked to CAD needs further studies.

Sleep disorders in patients with multiple sclerosis in China.

BACKGROUND: Poor sleep is common in patients with multiple sclerosis (MS). This study assessed the prevalence of poor sleep and investigated the potential impact factors that influence sleep quality of patients with MS. METHODS: A cross-sectional self-report survey of 231 patients with MS and 265 sex- and age-matched controls was conducted. Good sleepers and poor sleepers were separated by their global score on the Pittsburgh Sleep Quality Index (PSQI). Sociodemographic parameters, such as age, gender, and marital status, and clinical-demographic parameters, such as excessive daytime sleepiness (measured by the Epworth Sleepiness Scale), snoring, insomnia, obstructive sleep apnea, drugs, pain, depression, fatigue, and quality of life, were registered. Clinical and sociodemographic parameters were compared between patients with MS and controls and between good and poor sleepers among patients with MS. RESULTS: The prevalence of poor sleep in patients with MS was 64.9. Univariate analysis found that gender (p < 0.001), antidepressant drugs (p < 0.001), insomnia (p < 0.001), fatigue (p < 0.001), Epworth Sleepiness Scale (ESS) (p < 0.001), pain (p < 0.001), and depression (p < 0.001) were associated with sleep disorders. Multivariate analysis revealed that female gender, antidepressant drug treatment, and a high psychological burden of MS may be risk factors for poor sleep among patients with MS. CONCLUSIONS: Poor sleep is more common in patients with MS than in the general population. Sleep disorders should routinely be evaluated in patients with MS to improve the quality of sleep among them.

An epidemiologic study of restless legs syndrome among Chinese children and adolescents.

To determine the prevalence of restless legs syndrome (RLS) in Chinese children and adolescents as well as the impact of the disorder on 8-11 and 12-17 years old. This population-based study was conducted in five primary schools and seven high schools, which were randomly selected in Henan province, China. A total of 6792 students aged 8-17 years old were given a questionnaire that included the adult diagnostic criteria of RLS proposed by the International Restless Legs Study Group. Subjects who answered "yes" to all four questions were selected for a face-to-face interview to confirm RLS diagnosis. Individuals with definite RLS were then administered another questionnaire to survey RLS symptoms and perceived consequences. The prevalence of definite RLS in Chinese children and adolescents was 2.2 % (141/6437), with a prevalence of 1.8 % in the 8-11 years old age group and 2.4 % in the 12-17 years old age group. RLS was found to be more prevalent in females (2.7 %) than in males (1.7 %) (P = 0.008), and the prevalence of RLS was determined to increase with age. Sleep disturbance was the most common symptom of RLS in children and adolescents. Various consequences were attributed to RLS, with participants reporting that they dreaded the arrival of evening/night most frequently, followed by the description that RLS had a negative impact on mood. These data suggest that RLS is prevalent in Chinese children and adolescents, and that those affected by this disorder suffer from disruptions to sleep and daytime function.

Restless legs syndrome and hypertension in Chinese pregnant women.

Hypertension is a common complication of pregnancy, and studies show that pregnant women are more likely to suffer from restless legs syndrome (RLS). Pregnant women with hypertension and RLS often experience disrupted sleep patterns because of activation of the nervous system. The present study aimed to clarify the relationship between hypertension and RLS in pregnant women, and their impact on sleep. We enrolled 3,781 pregnant women who were admitted at our hospital for delivery between May 2011 and May 2014. The face-to-face questionnaire used to gather data included the International RLS Study Group criteria for diagnosis, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and hypertension diagnosis. Depending on the time of occurrence of hypertension, it was divided into two different types: pregnancy-induced hypertension and chronic hypertension in pregnancy. Out of 3,781 patients, 453 fulfilled the diagnostic criteria for RLS and 486 met the diagnostic criteria for hypertension. Among patients with RLS, prophylactic iron supplementation was less frequently taken during pregnancy. Pregnancy-induced hypertension, rather than chronic hypertension in pregnancy, was found to be more frequent in patients with RLS; pregnant women with RLS had higher PSQI and ESS scores than pregnant controls. In our study, RLS was frequent in pregnant women, especially in those without prophylactic iron supplementation. Patients with RLS described more serious sleep disruption and excessive daytime sleepiness (EDS). In addition, pregnancy-induced hypertension was more common in patients with RLS.

Restless leg syndrome and multiple sclerosis: a case-control study in China.

BACKGROUND: As a common neurological movement disorder, restless leg syndrome (RLS) is often seen in patients with multiple sclerosis (MS). However, the relationship between RLS and MS is still unclear. This case-control study aimed to measure RLS prevalence and uncover its association with MS, as well as to identify possible associated risk factors. METHODS: Six hundred and ninety-five patients were randomly selected from a cohort of patients with MS at the Neurology Department of our hospital, and a group of age- and sex-matched healthy controls (n = 603) was enrolled from the general population. Using a face-to-face interview questionnaire, we collected data on RLS incidence in participants with or without MS. We further assessed sleep quality in all the participants. RESULTS: We found there to be a significantly higher prevalence of RLS among patients with MS compared to healthy controls (odds ratio [OR], 3.8; P < 0.001). Risk factors such as an older MS age at onset and a longer MS duration were significantly associated with the presence of RLS. Furthermore, patients with both MS and RLS were more likely to suffer from sleep complaints compared to patients with MS without RLS. CONCLUSIONS: RLS was significantly associated with MS and was found to have a significant impact on sleep quality, particularly in patients with MS.

Meteorin­like/meteorin­ß protects against cardiac dysfunction after myocardial infarction in mice by inhibiting autophagy.

Meteorin-ß (Metrnß) is a protein that is secreted by skeletal muscle and adipose tissue, and participates in cardiovascular diseases. However, its role in myocardial infarction (MI) has not been fully elucidated to date. The aim of the present study was to investigate the role and underlying mechanism of Metrnß in MI. In the present study, mice were subjected to left coronary ligation to induce a MI model before being injected with adeno-associated virus 9 (AAV9)-Metrnß to overexpress Metrnß. Mice were subjected to echocardiography and pressure-volume measurements 2 weeks after ligation. Cardiac injury was measured from the levels of cardiac troponin T and pro-inflammatory factors, which were detected using ELISA kits. Cardiac remodelling was determined from the cross-sectional areas detected using H&E and wheat germ agglutinin staining as well as from the transcriptional levels of hypertrophic and fibrosis markers detected using reverse transcription-quantitative PCR. Cardiac function was detected using echocardiography and pressure-volume measurements. In addition, H9c2 cardiomyocytes were transfected with Ad-Metrnß to overexpress Metrnß, before being exposed to hypoxia to induce ischaemic injury. Apoptosis was determined using TUNEL staining and caspase 3 activity. Cell inflammation was detected using ELISA assays for pro-inflammatory factors. Autophagy was detected using LC3 staining and assessing the protein level of LC3II using western blotting. H9c2 cells were also treated with rapamycin to induce autophagy. It was revealed that Metrnß expression was reduced in both mouse serum and heart tissue 2 weeks post-MI. Metrnß overexpression using AAV9-Metrnß delivery reduced the mortality rate, decreased the infarction size and reduced the extent of myocardial injury 2 weeks post-MI. Furthermore, Metrnß overexpression inhibited cardiac hypertrophy, fibrosis and inflammation post-MI. In ischaemic H9c2 cells, Metrnß overexpression using adenovirus also reduced cell injury, cell death and inflammatory response. Metrnß overexpression suppressed MI-induced autophagy in vitro. Following autophagy activation using rapamycin in vitro, the protective effects induced by Metrnß were reversed. Taken together, these results indicated that Metrnß could protect against cardiac dysfunction post-MI in mice by inhibiting autophagy.

Enhanced myofilament calcium sensitivity aggravates abnormal calcium handling and diastolic dysfunction in patient-specific induced pluripotent stem cell-derived cardiomyocytes with MYH7 mutation.

Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is frequently caused by mutations in the ß-cardiac myosin heavy chain gene (MYH7). Abnormal calcium handling and diastolic dysfunction are archetypical features of HCM caused by MYH7 gene mutations. However, the mechanism of how MYH7 mutations leads to these features remains unclear, which inhibits the development of effective therapies. Initially, cardiomyocytes were generated from induced pluripotent stem cells from an eight-year-old girl diagnosed with HCM carrying a MYH7(C.1063 G>A) heterozygous mutation(mutant-iPSC-CMs) and mutation-corrected isogenic iPSCs(control-iPSC-CMs) in the present study. Next, we compared phenotype of mutant-iPSC-CMs to that of control-iPSC-CMs, by assessing their morphology, hypertrophy-related genes expression, calcium handling, diastolic function and myofilament calcium sensitivity at days 15 and 40 respectively. Finally, to better understand increased myofilament Ca2+ sensitivity as a central mechanism of central pathogenicity in HCM, inhibition of calcium sensitivity with mavacamten can improveed cardiomyocyte hypertrophy. Mutant-iPSC-CMs exhibited enlarged areas, increased sarcomere disarray, enhanced expression of hypertrophy-related genes proteins, abnormal calcium handling, diastolic dysfunction and increased myofilament calcium sensitivity at day 40, but only significant increase in calcium sensitivity and mild diastolic dysfunction at day 15. Increased calcium sensitivity by levosimendan aggravates cardiomyocyte hypertrophy phenotypes such as expression of hypertrophy-related genes, abnormal calcium handling and diastolic dysfunction, while inhibition of calcium sensitivity significantly improves cardiomyocyte hypertrophy phenotypes in mutant-iPSC-CMs, suggesting increased myofilament calcium sensitivity is the primary mechanisms for MYH7 mutations pathogenesis. Our studies have uncovered a pathogenic mechanism of HCM caused by MYH7 gene mutations through which enhanced myofilament calcium sensitivity aggravates abnormal calcium handling and diastolic dysfunction. Correction of the myofilament calcium sensitivity was found to be an effective method for treating the development of HCM phenotype in vitro.

Severe fever with thrombocytopenia syndrome virus replicates in platelets and enhances platelet activation.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) infection causes an emerging hemorrhagic fever in East Asia with a high mortality rate. Thrombocytopenia is a consistent feature of SFTS illness, but the mechanism remains elusive. OBJECTIVES: We aimed to better understand the role of platelets in the pathophysiology of SFTSV infection, including the development of thrombocytopenia. METHODS: Using platelets from healthy volunteers and patients with SFTS, we evaluated the functional changes in platelets against SFTSV infection. We investigated the direct effect of glycoprotein VI on platelet-SFTSV interaction by quantitative real-time PCR, molecular docking, surface plasmon resonance spectrometry, flow cytometry, western blot, and platelet functional studies in vitro. Interactions of SFTSV and platelet-SFTSV complexes with macrophages were also determined by scanning electron microscope, quantitative real-time PCR, and flow cytometry. RESULTS: This study is the first to demonstrate that platelets are capable of harboring and producing SFTSV particles. Structural and functional studies found that SFTSVs bind platelet glycoprotein VI to potentiate platelet activation, including platelet aggregation, adenosine triphosphate release, spreading, clot retraction, coagulation, phosphatidylserine exposure, thrombus formation, and adherence. In vitro mechanistic studies highlighted that the interaction of platelets with human THP-1 cells promoted SFTSV clearance and suppressed cytokine production in macrophages. However, unwanted SFTSV replication in macrophages reciprocally aggravated SFTSV persistence in the circulation, which may contribute to thrombocytopenia and other complications during SFTSV infection. CONCLUSION: These findings together highlighted the pathophysiological role of platelets in initial intrinsic defense against SFTSV infections, as well as intertwined processes with host immunity, which can also lead to thrombocytopenia and poor prognosis.

Atherosclerotic plaque vulnerability quantification system for clinical and biological interpretability.

Acute myocardial infarction dominates coronary artery disease mortality. Identifying bio-signatures for plaque destabilization and rupture is important for preventing the transition from coronary stability to instability and the occurrence of thrombosis events. This computational systems biology study enrolled 2,235 samples from 22 independent bulks cohorts and 14 samples from two single-cell cohorts. A machine-learning integrative program containing nine learners was developed to generate a warning classifier linked to atherosclerotic plaque vulnerability signature (APVS). The classifier displays the reliable performance and robustness for distinguishing ST-elevation myocardial infarction from chronic coronary syndrome at presentation, and revealed higher accuracy to 33 pathogenic biomarkers. We also developed an APVS-based quantification system (APVSLevel) for comprehensively quantifying atherosclerotic plaque vulnerability, empowering early-warning capabilities, and accurate assessment of atherosclerosis severity. It unraveled the multidimensional dysregulated mechanisms at high resolution. This study provides a potential tool for macro-level differential diagnosis and evaluation of subtle genetic pathological changes in atherosclerosis.

Evidence of a casual relationship between vitamin D deficiency and hypertension: a family-based study.

An association between vitamin D deficiency and hypertension has been observed in numerous studies. However, blood pressure improvements resulting from supplementation with vitamin D have been inconsistent. The causal relationship between vitamin D deficiency and hypertension is still unclear and was investigated in this family-based study. A total of 1370 individuals from both vitamin D deficiency and hypertension families were included. First, the heritability of vitamin D deficiency was estimated by the Falconer method. Second, SNPs (single nucleotide polymorphisms) of vitamin D metabolic and functional pathway genes associated with vitamin D deficiency were screened by a family-based association test, and the findings were further verified in nuclear families with vitamin D deficiency. Finally, a family-based association test was applied to investigate the association between selected SNPs associated with vitamin D deficiency and hypertension. The heritability of vitamin D deficiency was 50.4% in this family-based study. Allele C of rs3847987 was a risk factor for vitamin D deficiency (OR: 1.639, 95% CI: 1.170-2.297, P = 0.004). Furthermore, a family-based association of rs3847987 with hypertension was found in both additive and recessive models (P < 0.05). In addition, vitamin D deficiency was associated with hypertension (OR: 1.317, 95% CI: 1.022-1.698, P = 0.033). In conclusion, rs3847987 in the VDR gene was associated with both vitamin D deficiency and hypertension. Therefore, vitamin D deficiency may be a causal factor for hypertension.

Uncovering the genetic links of SARS-CoV-2 infections on heart failure co-morbidity by a systems biology approach.

AIMS: The co-morbidities contribute to the inferior prognosis of COVID-19 patients. Recent reports suggested that the higher co-morbidity rate between COVID-19 and heart failure (HF) leads to increased mortality. However, the common pathogenic mechanism between them remained elusive. Here, we aimed to reveal underlying molecule mechanisms and genetic correlation between COVID-19 and HF, providing a new perspective on current clinical management for patients with co-morbidity. METHODS: The gene expression profiles of HF (GSE26887) and COVID-19 (GSE147507) were retrieved from the GEO database. After identifying the common differentially expressed genes (|log2FC| > 1 and adjusted P < 0.05), integrated analyses were performed, namely, enrichment analyses, protein-protein interaction network, module construction, critical gene identification, and functional co-expression analysis. The performance of critical genes was validation combining hierarchical clustering, correlation, and principal component analysis in external datasets (GSE164805 and GSE9128). Potential transcription factors and miRNAs were obtained from the JASPER and RegNetwork repository used to construct co-regulatory networks. The candidate drug compounds in potential genetic link targets were further identified using the DSigDB database. RESULTS: The alteration of 12 genes was identified as a shared transcriptional signature, with the role of immune inflammatory pathway, especially Toll-like receptor, NF-kappa B, chemokine, and interleukin-related pathways that primarily emphasized in response to SARS-CoV-2 complicated with HF. Top 10 critical genes (TLR4, TLR2, CXCL8, IL10, STAT3, IL1B, TLR1, TP53, CCL20, and CXCL10) were identified from protein-protein interaction with topological algorithms. The unhealthy microbiota status and gut-heart axis in co-morbidity were identified as potential disease roads in bridging pathogenic mechanism, and lipopolysaccharide acts as a potential marker for monitoring HF during COVID-19. For transcriptional and post-transcriptional levels, regulation networks tightly coupling with both disorders were constructed, and significant regulator signatures with high interaction degree, especially FOXC1, STAT3, NF-κB1, miR-181, and miR-520, were detected to regulate common differentially expressed genes. According to genetic links targets, glutathione-based antioxidant strategy combined with muramyl dipeptide-based microbe-derived immunostimulatory therapies was identified as promising anti-COVID-19 and anti-HF therapeutics. CONCLUSIONS: This study identified shared transcriptomic and corresponding regulatory signatures as emerging therapeutic targets and detected a set of pharmacologic agents targeting genetic links. Our findings provided new insights for underlying pathogenic mechanisms between COVID-19 and HF.

The Functional Role of Lipoproteins in Atherosclerosis: Novel Directions for Diagnosis and Targeting Therapy.

Dyslipidemia, characterized by a high level of lipids (cholesterol, triglycerides, or both), can increase the risk of developing and progressing atherosclerosis. As atherosclerosis progresses, the number and severity of aterial plagues increases with greater risk of myocardial infarction, a major contributor to cardiovascular mortality. Atherosclerosis progresses in four phases, namely endothelial dysfunction, fatty streak formation, lesion progression and plaque rupture, and eventually thrombosis and arterial obstruction. With greater understanding of the pathological processes underlying atherosclerosis, researchers have identified that lipoproteins play a significant role in the development of atherosclerosis. In particular, apolipoprotein B (apoB)-containing lipoproteins have been shown to associate with atherosclerosis. Oxidized low-density lipoproteins (ox-LDLs) also contribute to the progression of atherosclerosis whereas high-density lipoproteins (HDL) contribute to the removal of cholesterol from macrophages thereby inhibiting the formation of foam cells. Given these known associations, lipoproteins may have potential as biomarkers for predicting risk associated with atherosclerotic plaques or may be targets as novel therapeutic agents. As such, the rapid development of drugs targeting lipoprotein metabolism may lead to novel treatments for atherosclerosis. A comprehensive review of lipoprotein function and their role in atherosclerosis, along with the latest development of lipoprotein targeted treatment, is timely. This review focuses on the functions of different lipoproteins and their involvement in atherosclerosis. Further, diagnostic and therapeutic potential are highlighted giving insight into novel lipoprotein-targetted approaches to treat atherosclerosis.

The hemoglobin glycation index predicts the risk of adverse cardiovascular events in coronary heart disease patients with type 2 diabetes mellitus.

Background: Previous studies have shown that the hemoglobin glycation index (HGI) can be used as a predictor of diabetic complications. However, limited information is currently available to indicate the correlation between HGI and comorbidity of coronary heart disease (CHD) and diabetes. This study aimed to evaluate the potential of HGI to predict major adverse cardiovascular events (MACEs) in CHD patients with type 2 diabetes mellitus (T2DM) undergoing percutaneous coronary intervention (PCI). Materials and methods: A total of 918 CHD patients with T2DM were enrolled in a 3-year retrospective cohort study, from December 2017 to December 2020 at the First Affiliated Hospital of Zhengzhou University. Data including fasting blood glucose (FPG/FBG) and glycated hemoglobin A1c (HbA1c) were collected. HGI was calculated as actual measured HbA1c minus predicted HbA1c. Three groups were further divided based on the levels of HGI, including low, medium, and high levels. Result: Kaplan Meier analysis indicated that elevated HGI was strongly associated with the occurence of MACE (log-rank P < 0.001). Multivariate Cox regression analysis revealed that elevated HGI was an independent risk factor for incident MACE in CHD patients with T2DM [adjusted hazard ratio (HR): 1.473; 95% confidence interval (CI): 1.365-1.589, P < 0.001]. Conclusions: Hemoglobin glycation index is an independent predictor of MACE events in CHD patients with T2DM. High HGI indicates a higher risk of MACE occurrence.

New Insights and Novel Therapeutic Potentials for Macrophages in Myocardial Infarction.

Cardiovascular disease (CVD) has long been the leading cause of death worldwide, and myocardial infarction (MI) accounts for the greatest proportion of CVD. Recent research has revealed that inflammation plays a major role in the pathogenesis of CVD and other manifestations of atherosclerosis. Overwhelming evidence supports the view that macrophages, as the basic cell component of the innate immune system, play a pivotal role in atherosclerosis initiation and progression. Limited but indispensable resident macrophages have been detected in the healthy heart; however, the number of cardiac macrophages significantly increases during cardiac injury. In the early period of initial cardiac damage (e.g., MI), numerous classically activated macrophages (M1) originating from the bone marrow and spleen are rapidly recruited to damaged sites, where they are responsible for cardiac remodeling. After the inflammatory stage, the macrophages shift toward an alternatively activated phenotype (M2) that promotes cardiac repair. In addition, extensive studies have shown the therapeutic potential of macrophages as targets, especially for emerging nanoparticle-mediated drug delivery systems. In the present review, we focused on the role of macrophages in the development and progression of MI, factors regulating macrophage activation and function, and the therapeutic potential of macrophages in MI.

Inhibition of Autophagy Prevents Panax Notoginseng Saponins (PNS) Protection on Cardiac Myocytes Against Endoplasmic Reticulum (ER) Stress-Induced Mitochondrial Injury, Ca2+ Homeostasis and Associated Apoptosis.

Endoplasmic reticulum (ER) stress is often closely linked to autophagy, hypoxia signaling, mitochondrial biogenesis and reactive oxygen species (ROS) responses. Understanding the interaction between ER stress, mitochondrial function and autophagy is of great importance to provide new mechanisms for the pathology, prevention and treatment of cardiovascular diseases. Our previous study has reported that Panax notoginseng saponins (PNS) protection against thapsigargin (TG)-induced ER stress response and associated cell apoptosis in cardiac myocytes is calcium dependent and mediated by ER Ca2+ release through RyR2. However, whether its protection upon ER stress and associated apoptosis is related to mitochondrial function and autophagy remains largely unknown. Here, we investigated the roles of PNS played in TG-induced mitochondrial function, ROS accumulation and autophagy. We also assessed its effects on Ca2+ homeostasis, ER stress response and associated cell death in the presence of autophagy inhibition. PNS-pretreated primary cultured neonatal rat cardiomyocytes were stimulated with TG to induce ER stress response. Mitochondrial potential (Δψm) was measured by JC-1. The general and mitochondrial ROS were measured by DCFH-DA and MitoSOX Red, respectively. Autophagy was evaluated by immunofluorescence of LC3, and immunoblots of LC3, p62, ATG7 and PINK1. In addition, mRFP-GFP-LC3 labeling was used to assess the autophagic influx. SiATG7 transfected H9c2 cells were generated to inhibit autophagy. Cytosolic and ER Ca2+ dynamics were investigated by calcium imaging. RyR2 oxidation was tested by oxyblot. Cell viability was examined by TUNEL assay. ER stress response and cell apoptosis were detected by immunoblots of BiP, CHOP, Cleaved Caspase-3 and Caspase-12. The results demonstrated that firstly, PNS protects against TG-induced mitochondrial injury and ROS accumulation. Secondly, PNS enhances autophagy in TG-induced cardiac myocytes. Thirdly, inhibition of autophagy diminishes PNS prevention of TG-induced mitochondrial injury, ROS accumulation and disruption of Ca2+ homeostasis. Last but not least, inhibition of autophagy abolishes PNS protection against TG-induced ER stress response and associated apoptosis. In summary, PNS protection against ER stress response and associated apoptosis is related to the regulation of mitochondrial injury and ROS overproduction via modulation of autophagy. These data provide new insights for molecular mechanisms of PNS as a potential preventive approach to the management of cardiovascular diseases.

ADS Score as a Novel Predictor of Outcomes in Patients Who Underwent Percutaneous Coronary Intervention.

Objectives: A novel AFR- albumin-derived neutrophil to lymphocyte ratio (dNLR) score (ADS) were reported to associate with clinical outcome in various malignancies, However, the relation between the ADS score and outcomes in coronary artery disease (CAD) patients after percutaneous coronary intervention (PCI) has not been investigated. Methods: Three thousand five hundred and sixty-one patients were divided into two groups according to ADS score: low group (ADS score <2; n = 2,682) and high group (ADS score ≥ 2; n = 879). Overall, there were 133 all-cause mortality (ACM) during the following up. The incidence of ACM in the low group is 2.7% (72/2,682) and high group is 6.9% (61/879). The ACM incidence was significantly higher in high group compared to that in the low group (P < 0.001). Cardiac mortality (CM) occurred in 82 patients: 44(1.6%) in the low group and 38 (4.3%) in the high group. There was significant difference in the CM incidence between the low group and high group (P < 0.001). Major adverse cardiac and cerebrovascular events (MACCE) occurred in 520 patients: 366 (13.6%) in the low group and 154 (17.5%) in the high group. There was significant difference in the MACCE incidence between the low group and high group (P = 0.005). Major adverse cardiac and events (MACE) occurred in 395 patients: 281(10.5%) in the low group and 114 (13.0%) in the high group. There was significant difference in the MACE incidence between the low group and high group (P = 0.041). The multivariate Cox proportional hazards model showed that ADS score was independently correlated with the ACM [adjusted HR = 2.031 (1.357-3.039), P = 0.001]; CM [adjusted HR = 1.883 (1.127-3.147), P = 0.016]; MACCE [adjusted HR = 1.352 (1.096-1.668), P = 0.005], and MACE [adjusted HR = 1.260 (0.987-1.608), P = 0.063]. Conclusion: The present study indicated that the ADS score was associated with long-term mortality, the MACCE, and the MACE in CAD patients underwent PCI.

Association of Derived Neutrophil-To-Lymphocyte Ratio With Prognosis of Coronary Heart Disease After PCI.

Aims: The present study aimed to investigate the prognostic role of derived neutrophil-to-lymphocyte ratio (dNLR) in patients with coronary heart disease (CHD) after PCI. Methods: A total of 3,561 post-PCI patients with CHD were retrospectively enrolled in the CORFCHD-ZZ study from January 2013 to December 2017. The patients (3,462) were divided into three groups according to dNLR tertiles: the first tertile (dNLR < 1.36; n = 1,139), second tertile (1.36 ≥ dNLR < 1.96; n = 1,166), and third tertile(dNLR ≥ 1.96; n = 1,157). The mean follow-up time was 37.59 ± 22.24 months. The primary endpoint was defined as mortality (including all-cause death and cardiac death), and the secondary endpoint was major adverse cardiovascular events (MACEs) and major adverse cardiovascular and cerebrovascular events (MACCEs). Results: There were 2,644 patients with acute coronary syndrome (ACS) and 838 patients with chronic coronary syndrome (CCS) in the present study. In the total population, the all-cause mortality (ACM) and cardiac mortality (CM) incidence was significantly higher in the third tertile than in the first tertile [hazard risk (HR) = 1.8 (95% CI: 1.2-2.8), p = 0.006 and HR = 2.1 (95% CI: 1.23-3.8), p = 0.009, respectively]. Multivariate Cox regression analyses suggested that compared with the patients in the first tertile than those in the third tertile, the risk of ACM was increased 1.763 times (HR = 1.763, 95% CI: 1.133-2.743, p = 0.012), and the risk of CM was increased 1.763 times (HR = 1.961, 95% CI: 1.083-3.550, p = 0.026) in the higher dNLR group during the long-term follow-up. In both ACS patients and CCS patients, there were significant differences among the three groups in the incidence of ACM in univariate analysis. We also found that the incidence of CM was significantly different among the three groups in CCS patients in both univariate analysis (HR = 3.541, 95% CI: 1.154-10.863, p = 0.027) and multivariate analysis (HR = 3.136, 95% CI: 1.015-9.690, p = 0.047). Conclusion: The present study suggested that dNLR is an independent and novel predictor of mortality in CHD patients who underwent PCI.

Atorvastatin prevents left ventricular remodeling in spontaneously hypertensive rats.

Statins improve left ventricular (LV) remodeling in spontaneously hypertensive rats (SHRs). This study was designed to investigate the effects of atorvastatin administered in the early stage on LV remodeling in SHRs, and to explore the underlying mechanisms.Sixteen male 8-week-old SHRs were randomized to receive distilled water (SHR-DW) or atorvastatin (SHR-ATV) for 12 weeks. Age-matched male Wistar-Kyoto (WKY) rats gavaged with distilled water served as controls. LV remodeling was evaluated, myocardial CTGF expression levels were detected using Western blotting, and cardiomyocyte apoptosis was detected with the TUNEL method.Compared with WKY and SHR-DW, atorvastatin treatment significantly decreased systolic blood pressure in SHRs; atorvastatin significantly inhibited LV remodeling, as indicated by the reduced LV weight/body weight ratio (SHR-ATV: 4.0 ± 0.4 versus SHR-DW: 4.7 ± 0.4 mg/g, P < 0.05), cardiomyocyte diameter (SHR-ATV: 16.2 ± 2.8 versus SHR-DW: 19.0 ± 1.0 µm, P < 0.05), and interstitial fibrosis (SHR-ATV: 3.3 ± 2.1 versus SHR-DW: 4.5 ± 1.8%, P < 0.05). Compared with WKY, myocardial CTGF expression was significantly increased and cardiomyocyte apoptosis decreased in SHRs. Compared with the SHR-DW group, atorvastatin treatment significantly inhibited myocardial CTGF expression (SHR-ATV: 0.69 ± 0.21 versus SHR-DW: 1.12 ± 0.27, P < 0.05) and induced cardiomyocyte apoptosis in SHRs (SHR-ATV: 5.2 ± 0.6 versus SHR-DW: 1.9 ± 0.3%, P < 0.05).The results indicate that early-stage administration of atorvastatin effectively prevented LV remodeling in SHRs, and that inhibition of myocardial CTGF expression and induction of cardiomyocyte apoptosis may be the underlying mechanisms.