The effect of glucagon-like peptide-1 receptor agonists on cardiac function and structure in patients with or without type 2 diabetes mellitus: An updated systematic review and meta-analysis.

AIMS: To conduct an updated systematic review and meta-analysis to evaluate the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with regard to cardiac function and structure in people with or without type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We conducted a systematic search using the PubMed, Embase and ClinicalTrials.gov online databases. The primary outcome of interest was changes in mitral inflow E-velocity to tissue Doppler e' velocity (E/e') ratio. Secondary outcomes included other indicators of cardiac reverse remodelling and functional capacity comprising changes in left ventricular mass (LVM), left ventricular global longitudinal strain, left ventricular end-diastolic volume, left ventricular end-systolic volume, left ventricular ejection fraction (LVEF), early to atrial mitral inflow velocity ratio, left atrial volume (LAV), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and 6-min walk test (6MWT) results. RESULTS: A total of 15 trials involving 898 patients were included in this analysis. GLP-1RAs significantly improved E/e' ratio (mean difference [MD] = -0.73; 95% confidence interval [CI] -1.34, -0.13), LVM (MD = -3.86 g; 95% CI -7.60, -0.12), LAV (MD = -8.20 mL; 95% CI -12.37, -4.04), NT-proBNP level (standardized MD = -0.27; 95% CI -0.47, -0.06), and 6MWT result (MD = +22.31 m; 95% CI 1.64, 42.99). However, GLP-1RAs had no effect on LVEF (MD = +0.31%; 95% CI -1.02, 1.64). CONCLUSIONS: In this systematic review and meta-analysis, GLP-1RAs were found to have a positive impact on left ventricle diastolic function, hypertrophy, and exercise capacity, but had no effect on systolic function.

Efficacy and Safety of Omega-3 Fatty Acids in the Prevention of Cardiovascular Disease: A Systematic Review and Meta-analysis.

BACKGROUND: It is widely accepted that omega-3 fatty acids are beneficial in the prevention of cardiovascular disease, but many large randomized controlled trial studies and meta-analyses have come to different conclusions. The evidence for omega-3 fatty acids supplementation to prevent cardiovascular disease remains insufficient. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of several types of omega-3 fatty acids supplements. METHODS: We comprehensively searched the online database and found 15 RCTs. The primary efficacy outcomes included major cardiovascular events, myocardial infarction, heart failure, atrial fibrillation, stroke, cardiovascular death, and all-cause death. The safety endpoints included gastrointestinal problems, bleeding-related disorders, and cancer. Subgroup analysis was conducted according to the main characteristics of the population, and the dose-response relationship of omega-3 fatty acids was evaluated by meta-regression. All results were calculated by the random effect model. Statistical heterogeneity was assessed using chi-square tests and quantified using I-square statistics. RESULTS: The incidence of major cardiovascular events (RR 0.95, 95%CI 0.91 to 0.99, P = 0.026), myocardial infarction (RR 0.90, 95%CI 0.83 to 0.98; P = 0.021), and cardiovascular death (RR 0.94, 95%CI 0.88 to 0.99; P = 0.028) was reduced in the omega-3 fatty acid group compared with the control group. An increased risk of atrial fibrillation (RR 1.25, 95%CI 1.10 to 1.41; P = 0.000) was observed in patients in the omega-3 fatty acid group. No statistical differences were observed between the two groups in heart failure, stroke, and all-cause death. For safety endpoints, there were no statistically significant differences between the two groups in gastrointestinal problems, bleeding-related disorders, and cancer. Subgroup analysis showed that the cardiovascular benefit of omega-3 fatty acids was primarily attributable to the prescription of EPA ethyl ester. Omega-3 fatty acids may reduce the risk of major cardiovascular events in patients with cardiovascular disease or risk factors, and reduce the risk of myocardial infarction in patients without cardiovascular disease; however, they may increase the risk of stroke in patients with myocardial infarction. In addition, prescription omega-3 acid ethyl ester has a good safety profile, and prescription EPA ethyl ester has a high risk of bleeding. CONCLUSION: Moderate evidence showed that the use of omega-3 fatty acids may reduce the risk of major cardiovascular events, myocardial infarction, and cardiovascular death. Compared to other types of omega-3 fatty acids supplements, we support the use of prescription EPA ethyl ester formulations for the prevention of cardiovascular disease, but the potential risk of atrial fibrillation and bleeding cannot be ignored. It is important to note that omega-3 fatty acids should be applied with caution in patients with previous myocardial infarction, which may increase the risk of stroke. Finally, omega-3 fatty acids are relatively safe and in general do not increase gastrointestinal problems, bleeding-related disorders, or cancer, but attention needs to be paid to the risk of bleeding with prescription EPA ethyl ester formulations.

Dapagliflozin alleviates cardiac fibrosis through suppressing EndMT and fibroblast activation via AMPKα/TGF-ß/Smad signalling in type 2 diabetic rats.

Diabetic cardiomyopathy (DCM) is one of the leading causes of heart failure in patients with diabetes mellitus, with limited effective treatments. The cardioprotective effects of sodium-glucose cotransporter 2(SGLT2) inhibitors have been supported by amounts of clinical trials, which largely fills the gap. However, the underlying mechanism still needs to be further explored, especially in terms of its protection against cardiac fibrosis, a crucial pathophysiological process during the development of DCM. Besides, endothelial-to-mesenchymal transition (EndMT) has been reported to play a pivotal role in fibroblast multiplication and cardiac fibrosis. This study aimed to evaluate the effect of SGLT2 inhibitor dapagliflozin (DAPA) on DCM especially for cardiac fibrosis and explore the underlying mechanism. In vivo, the model of type 2 diabetic rats was built with high-fat feeding and streptozotocin injection. Untreated diabetic rats showed cardiac dysfunction, increased myocardial fibrosis and EndMT, which was attenuated after treatment with DAPA and metformin. In vitro, HUVECs and primary cardiac fibroblasts were treated with DAPA and exposed to high glucose (HG). HG-induced EndMT in HUVECs and collagen secretion of fibroblasts were markedly inhibited by DAPA. Up-regulation of TGF-ß/Smad signalling and activity inhibition of AMPKα were also reversed by DAPA treatment. Then, AMPKα siRNA and compound C abrogated the anti-EndMT effects of DAPA in HUVECs. From above all, our study implied that DAPA can protect against DCM and myocardial fibrosis through suppressing fibroblast activation and EndMT via AMPKα-mediated inhibition of TGF-ß/Smad signalling.

Inhibition of PHLPP1 ameliorates cardiac dysfunction via activation of the PI3K/Akt/mTOR signalling pathway in diabetic cardiomyopathy.

BACKGROUND: Pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase 1 (PHLPP1) is a kind of serine/threonine phosphatase, whose dysregulation is accompanied with numerous human diseases. However, its role in diabetic cardiomyopathy remains unclear. We explored the underlying function and mechanism of PHLPP1 in diabetic cardiomyopathy (DCM). METHOD: In vivo, Type 1 diabetic rats were induced by intraperitoneal injection of 60 mg/kg streptozotocin (STZ). Lentivirus-mediated short hairpin RNA (shRNA) was used to knock down the expression of PHLPP1. In vitro, primary neonatal rat cardiomyocytes and H9C2 cells were incubated in 5.5 mmol/L glucose (normal glucose, NG) or 33.3 mmol/L glucose (high glucose, HG). PHLPP1 expression was inhibited by PHLPP1-siRNA to probe into the function of PHLPP1 in high glucose-induced apoptosis in H9c2 cells. RESULTS: Diabetic rats showed up-regulated PHLPP1 expression, left ventricular dysfunction, increased myocardial apoptosis and fibrosis. PHLPP1 inhibition alleviated cardiac dysfunction. Additionally, PHLPP1 inhibition significantly reduced HG-induced apoptosis and restored PI3K/AKT/mTOR pathway activity in H9c2 cells. Furthermore, pretreatment with LY294002, an inhibitor of PI3K/Akt/mTOR pathway, abolished the anti-apoptotic effect of PHLPP1 inhibition. CONCLUSION: Our study indicated that PHLPP1 inhibition alleviated cardiac dysfunction via activating the PI3K/Akt/mTOR signalling pathway in DCM. Therefore, PHLPP1 may be a novel therapeutic target for human DCM.

WISP1 alleviates lipid deposition in macrophages via the PPARγ/CD36 pathway in the plaque formation of atherosclerosis.

Lipid deposition in macrophages plays an important role in atherosclerosis. The WNT1-inducible signalling pathway protein 1(WISP1) can promote proliferation and migration of smooth muscle cells. Its expression is up-regulated in obesity, which is associated with atherosclerosis, but the effect of WISP1 on atherosclerosis remains unclear. Thus, the objective of our study was to elucidate the role of WISP and its mechanism of action in atherosclerosis via in vivo and in vitro experiments. In our experiment, ApoE-/- mice were divided into 5 groups: control, high-fat diet (HFD), null lentivirus (HFD + NC), lentivirus WISP1 (HFD + IvWISP1) and WISP1-shRNA (HFD + shWISP1). Oil Red O staining, immunofluorescence and immunohistochemistry of the aortic sinuses were conducted. Macrophages (RAW264.7 cell lines and peritoneal macrophages) were stimulated with 50 µg/mL oxidized low-density lipoprotein (ox-LDL); then, the reactive oxygen species (ROS) level was measured. Oil Red O staining and Dil-ox-LDL (ox-LDL with Dil dye) uptake measurements were used to test lipid deposition of peritoneal macrophages. WISP1, CD36, SR-A and PPARγ expression levels were measured via Western blotting and ELISA. The results showed that HFD mice had increased WISP1, CD36 and SR-A levels. The plaque lesion area increased when WISP1 was down-regulated, and lipid uptake and foam cell formation were inhibited when WISP1 was up-regulated. Treatment of RAW264.7 cell lines with ox-LDL increased WISP1 expression via activation of the Wnt5a/ß-catenin pathway, whereas ROS inhibition reduced WISP1 expression. Moreover, WISP1 down-regulated CD36 and SR-A expression, and Oil Red O staining and Dil-ox-LDL uptake measurement showed that WISP1 down-regulated lipid deposition in macrophages. These results clearly demonstrate that WISP1 is activated by ox-LDL at high ROS levels and can alleviate lipid deposition in atherosclerosis through the PPARγ/CD36 pathway.

Nicorandil alleviates apoptosis in diabetic cardiomyopathy through PI3K/Akt pathway.

Nicorandil exerts myocardial protection through its antihypoxia and antioxidant effects. Here, we investigated whether it plays an anti-apoptotic role in diabetic cardiomyopathy. Sprague-Dawley rats were fed with high-fat diet; then single intraperitoneal injection of streptozotocin was performed. Rats with fasting blood glucose (FBG) higher than 11.1 mmol/L were selected as models. Eight weeks after the models were built, rats were treated with nicorandil (7.5 mg/kg day and 15 mg/kg day respectively) for 4 weeks. H9c2 cardiomyocytes were treated with nicorandil and then stimulated with high glucose (33.3 mmol/L). TUNEL assay and level of bcl-2, bax and caspase-3 were measured. 5-HD was used to inhibit nicorandil. Also, PI3K inhibitor (Miltefosine) and mTOR inhibitor (rapamycin) were used to inhibit PI3K/Akt pathway. The results revealed that nicorandil (both 7.5 mg/kg day and 15mg/kg day) treatment can increase the level of NO in the serum and eNOS in the heart of diabetic rats compared with the untreated diabetic group. Nicorandil can also improve relieve cardiac dysfunction and reduce the level of apoptosis. In vitro experiments, nicorandil (100 µmol) can attenuate the level of apoptosis stimulated by high glucose significantly in H9C2 cardiomyocyte compared with the untreated group. The effect of nicorandil on apoptosis was blocked by 5-HD, and it was accompanied with inhibition of the phosphorylation of PI3K, Akt, eNOS, and mTOR. After inhibition of PI3K/Akt pathway, the protective effect of nicorandil is restrained. These results verified that as a NO donor, nicorandil can also inhibit apoptosis in diabetic cardiomyopathy which is mediated by PI3K/Akt pathway.

AIM2 regulates vascular smooth muscle cell migration in atherosclerosis.

BACKGROUND: Atherosclerosis (AS) is a common pathological basis of various cardiovascular and cerebrovascular diseases. Plaque formation is initiated and triggered by vascular smooth musclecells (VSMCs) migration in vascular wall, which gradually aggravates atherosclerosis progression. Absent in melanoma 2 (AIM2), a member of HIN-200 family, plays an important role in activating inflammasome. However, the role of AIM2 in atherosclerotic plaque progression outside of the inflammasome has not yet been reported. METHODS: The potential effect and the underlying mechanism of AIM2 were investigated in apoliporotein E-deficient (ApoE-/-) mice. Murine AIM2 lentivirus, shRNA-AIM2 lentivirus and null lentivirus were constructed and injected intravenously into ApoE-/- mice, which were fed on a high fat diet. The specific mechanism of AIM2 in vascular smooth cells (VSMCs) was explored in vitro. RESULTS: Results showed the aortic atherosclerotic lesion area was larger with AIM2 over-expression, and the number of smooth muscle cells was enhanced in line with the increased AIM2 levels. AIM2 overexpression also induced the increasing expression of MMP2. In vitro studies revealed that different levels of ox-LDL increased AIM2 expression in a time-dependent manner. Transwell showed that AIM2 mediated migration in VSMCs. The expression of AIM2 can be inhibited when the ROS inhibitor was used. Additionally, the overexpression and inhibition of AIM2 significantly affects HG-induced migration and TGF-ß/SMAD signaling pathway in VSMCs. CONCLUSION: Thus, we demonstrated that AIM2 could promote the progression of atherosclerotic plaque by increasing migration in VSMCs.

AIM2 accelerates the atherosclerotic plaque progressions in ApoE-/- mice.

Plaque formation is initiated and triggered by cell death in the vascular wall, which gradually leads to the progression of atherosclerosis. Pyroptosis is a newly discovered form of programmed cell death. Absent in melanoma 2 (AIM2), a member of the HIN-200 protein family, plays an important role in activating inflammasomes. However, the role and mechanism of AIM2 in atherosclerotic plaque progression has not been thoroughly elucidated to date. The effect of pyroptosis and the mechanism for this effect were investigated in apolipoprotein E-deficient (ApoE-/-) mice. AIM2 overexpression and inhibition were studied in ApoE-/- mice that were fed a high-fat diet. The specific role of AIM2 in vascular smooth muscle cells (VSMCs) was explored in vitro. The results showed that high fat diet increases the expression of AIM2, ICMA-1, GSDMD-N, which could be mediated by AIM2 expression. The plaque lesion area is lager with AIM2 overexpression. Moreover, TUNEL-positive cells were increased when AIM2 was overexpressed. With increased AIM2, macrophages were enhanced. In vitro studies showed that AIM2 and GSDMD-N expression correlated with ox-LDL levels in a concentration dependent manner. AIM2 expression is associated with NF-κB signaling activity and can be inhibited by NF-κB inhibitor. AIM2 mediated GSDMD activity through ASC, caspase1 pathway. EthD-III and TUNEL staining showed that AIM2 mediates pyroptosis in VSMCs. Our study suggests that AIM2 is not only a regular of inflammasome but also an active participant in atherosclerosis.

Prolyl hydroxylase 3 overexpression accelerates the progression of atherosclerosis in ApoE-/- mice.

PHD3 belongs to the family of 2-oxoglutarate and iron-dependent dioxygenases and is a critical regulator of HIF-1α. Its expression is increased in cardiovascular diseases such as cardiomyopathy, myocardial ischemia-reperfusion injury, and congestive heart failure. However, the association between PHD3 and atherosclerosis has not been clearly elucidated. In the present study, we investigated the potential effect and mechanism of PHD3 in apolipoprotein E-deficient (ApoE-/-) mice. Murine PHD3 lentivirus and shRNA -PHD3 lentivirus were constructed and injected intravenously into ApoE-/- mice fed on a high fat diet. The aortic atherosclerotic lesion area was larger with PHD3 over-expression. With increased PHD3 levels, macrophages and smooth muscle cells were enhanced. The apoptosis of atherosclerotic plaques revealed an increase when PHD3 was elevated. Furthermore, the expression of intercellular cell adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1(VCAM-1), monocyte chemotactic protein 1 (MCP-1), interleukin-1beta (IL-1ß) and tumor necrosis factor-α(TNF-α) were upregulated with PHD3 over-expression. In vitro, we explored the specific signaling pathway of PHD3 in HUVECs. PHD3 over-expression is associated with activation of ERK1/2 and JNK phosphorylation of MAPK signaling pathway. PHD3 inhibition decreased the apoptosis of HUVECs treated with ox-LDL (50 µg/ml). Our study suggests that PHD3 is not only a regulator of HIF-1α but also an active participant in atherogenesis.

HMGB1 mediates hyperglycaemia-induced cardiomyocyte apoptosis via ERK/Ets-1 signalling pathway.

Apoptosis is a key event involved in diabetic cardiomyopathy. The expression of high mobility group box 1 protein (HMGB1) is up-regulated in diabetic mice. However, the molecular mechanism of high glucose (HG)-induced cardiomyocyte apoptosis remains obscure. We aimed to determine the role of HMGB1 in HG-induced apoptosis of cardiomyocytes. Treating neonatal primary cardiomyocytes with HG increased cell apoptosis, which was accompanied by elevated levels of HMGB1. Inhibition of HMGB1 by short-hairpin RNA significantly decreased HG-induced cell apoptosis by reducing caspase-3 activation and ratio of Bcl2-associated X protein to B-cell lymphoma/leukemia-2 (bax/bcl-2). Furthermore, HG activated E26 transformation-specific sequence-1 (Ets-1), and HMGB1 inhibition attenuated HG-induced activation of Ets-1 via extracellular signal-regulated kinase 1/2 (ERK1/2) signalling. In addition, inhibition of Ets-1 significantly decreased HG-induced cardiomyocyte apoptosis. Similar results were observed in streptozotocin-treated diabetic mice. Inhibition of HMGB1 by short-hairpin RNA markedly decreased myocardial cell apoptosis and activation of ERK and Ets-1 in diabetic mice. In conclusion, inhibition of HMGB1 may protect against hyperglycaemia-induced cardiomyocyte apoptosis by down-regulating ERK-dependent activation of Ets-1.

Rosuvastatin alleviates diabetic cardiomyopathy by inhibiting NLRP3 inflammasome and MAPK pathways in a type 2 diabetes rat model.

PURPOSE: Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is important in inflammation of several diabetic complications. However, the potential role of NLRP3 inflammasome in the inflammatory process of diabetic cardiomyopathy (DCM) remains unclear. Although rosuvastatin (RSV) has an anti-inflammatory effect on some cardiovascular diseases, its influence on DCM is incompletely understood. We aimed to explore the effect on and underlying mechanism of RSV in DCM, and whether NLRP3 is a target for RSV. METHODS: Type 2 diabetes was induced in rat. The characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. The expression of factors was determined by real-time RT-PCR and western blot. Eight-week RSV treatment and NLRP3 gene silencing were used to investigate the effect and underlying target of RSV in DCM. RESULTS: Compared with controls, diabetic rats showed severe metabolic disorder, cardiac dysfunction, fibrosis, disorganized ultrastructure, and excessive activation of thioredoxin interacting/inhibiting protein (TXNIP, p < 0.05), NLRP3 inflammasome (NLRP3, p < 0.01; apoptosis-associated speck-like protein containing a caspase recruitment domain [ASC], p < 0.05; caspase-1, p < 0.01), interleukin-1ß (p < 0.01) and mitogen-activated protein kinases (MAPKs, all p < 0.01). Compared with diabetes alone, RSV ameliorated the overexpression of NLRP3 inflammasome (NLRP3, p < 0.05; ASC, p < 0.05; pro-caspase-1 p < 0.05, caspase-1 p20, p < 0.01) and MAPKs (all p < 0.05), which paralleled the cardiac protection of RSV. Silencing NLRP3 ameliorated cardiac remodeling and dysfunction. The beneficial effects of RSV in vehicle-treated rats were all abrogated in NLRP3-silenced rats. CONCLUSIONS: The beneficial effect of RSV on DCM depended on inhibited NLRP3 inflammasome, and correlated with suppression of the MAPKs.

Risk factors for long-term outcome of drug-eluting stenting in adults with early-onset coronary artery disease.

OBJECTIVE: We lack data on the long-term outcome of drug-eluting stenting in patients with early-onset coronary artery disease (CAD). Here, we investigated the association of traditional risk factors and major adverse cardiovascular events (MACEs) after drug-eluting stenting in patients with CAD who were < 50 years old. METHODS: We enrolled 437 consecutive CAD patients < 50 years old who underwent drug-eluting stenting and 132 subjects who were age- and sex-matched and angiographically shown to be disease free as controls. MACEs were analyzed in CAD patients for a median of 24 months [interquartile range 14-34 months]. RESULTS: Male patients accounted for 90.4% of cases. As compared with controls, patients with early-onset CAD had higher body mass index and rates of smoking, family history of CAD, and diabetes and hypercholesterolemia. During the hospital stay, 1 patient died, and the incidence of MACEs was 1.1%. At the end of follow-up, the overall death rate was 0.7%. MACEs were observed in 54 patients (12.4%). On Cox proportional hazard analyses, positive family history and diabetes were independent risk factors of MACEs (HR 2.61, 95% confidence interval 1.29-4.00, p = 0.002; and HR 2.48, 95% confidence interval 0.86-3.14, p = 0.004, respectively). CONCLUSIONS: Drug-eluting stenting is a reliable treatment for patients with early-onset CAD. Positive family history of CAD and diabetes are independent risk factors of adverse cardiovascular events in this subgroup of patients after drug-eluting stent implantation.

Association of nucleotide-binding oligomerization domain-like receptor 3 inflammasome and adverse clinical outcomes in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: The nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome is a multiprotein complex consisting of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1. In peripheral blood mononuclear cells (PBMCs), NLRP3 can activate interleukin-1ß (IL-1ß), important in the chronic inflammatory process of idiopathic dilated cardiomyopathy (IDCM). Therefore, the NLRP3 inflammasome in PBMCs may be involved in the pathogenesis of IDCM. We evaluated the association of circulating levels of NLRP3 inflammasome and cardiac function in patients with IDCM and 6-month rehospitalization. METHODS: We enrolled 54 patients with IDCM and 20 healthy volunteers and analyzed left ventricle ejection fraction (LVEF), electrocardiography findings and circulating levels of NLRP3, ASC, caspase-1, IL-1ß, N terminal-pro type B natriuretic peptide (NT-pro BNP) and blood values. Patients were followed up for 6 months. RESULTS: On admission and discharge, the circulating levels of NLRP3, ASC, caspase-1 and IL-1ß were higher in IDCM patients than healthy controls (all p<0.05). In patients, NLRP3 mRNA level was associated with LVEF, NT-pro BNP level and monocyte count (all p<0.05). LVEF at admission and mRNA levels of NLRP3 and IL-1ß at discharge were independent risk factors of 6-month rehospitalization for patients. High NLRP3 mRNA level was associated with cumulative rehospitalization rate (p<0.05). CONCLUSIONS: NLRP3 level in PBMCs may be associated with cardiac function and rehospitalization in IDCM patients.

Finerenone attenuates myocardial apoptosis, metabolic disturbance and myocardial fibrosis in type 2 diabetes mellitus.

BACKGROUND: Finerenone is a third-generation mineralocorticoid receptor antagonists, which has shown good cardiac function improvement in patients with type 2 diabetes in large-scale clinical trials. However, its specific role in diabetic cardiomyopathy remains unclear. We explored the potential functions and mechanisms of finerenone in diabetic cardiomyopathy. METHODS: The type 2 diabetic rat model was induced by high-fat diet and low-dose streptozotocin (n = 6, each group). Next the drug group was treated with finerenone (1 mg/kg/day) for 8 weeks. Then we detected the cardiac structure and function and relevant indicators. Neonatal rat cardiomyocytes were used for in vitro culture to determine the direct effect of finerenone on cardiomyocytes stimulated by high glucose and high fatty acid. RESULTS: Compared with the control group, rats in the type 2 diabetes group exhibited hyperglycemia, hyperlipidemia, and impaired cardiac function. Myocardium showed increased fibrosis and apoptosis. Finerenone attenuated these impairments without changing blood glucose levels. In neonatal rat cardiomyocytes, the stimulation of high concentrations of palmitic acid increased fatty acid uptake, as well as increased reactive oxygen species and apoptosis. Finerenone significantly improved fatty acid metabolism, reduced cellular inflammation levels, and decreased apoptosis. CONCLUSIONS: By blocking the mineralocorticoid receptor, finerenone attenuates cardiac steatosis, myocardial fibrosis and apoptosis, and subsequent myocardial remodeling and diastolic dysfunction in type II diabetic rats.

Effects of rosuvastatin and atorvastatin on renal function: meta-analysis.

BACKGROUND: Several clinical trials have reported inconsistent findings for the effects of rosuvastatin (RSV) and atorvastatin (ATV) on renal function. The aim of this meta-analysis was to investigate the effects of these 2 statins on glomerular filtration rate (GFR) and proteinuria respectively, and determine which is better. METHODS AND RESULTS: PubMed, CENTRAL, Web of Knowledge, and ClinicalTrials.gov website were searched for randomized controlled trials. Eligible studies reported GFR and/or proteinuria during treatment with RSV or ATV compared with control (placebo, no statins, or usual care), or RSV compared with ATV head to head. Trials that enrolled dialysis participants and teenagers were excluded. Statistical heterogeneity was assessed using the I(2) statistic, and pooled results using the random-effects model. The standardized mean differences (SMD) and ratio of means (ROM) were measured, respectively, to analyze GFR and proteinuria. Sixteen trials with a total number of 24,278 participants were identified. Compared with control, changes in the SMD of GFR were 0.04 (95% confidence interval [CI]: 0.01-0.07) and 0.59 (95%CI: 0.12-1.06) for RSV and ATV, respectively. The ROMs of proteinuria were 0.59 (95%CI: 0.46-0.74) for RSV vs. the control group, and 1.23 (95%CI: 1.05-1.43) in the head-to-head comparison. CONCLUSIONS: Both RSV and ATV improve GFR, and ATV seems to be more effective in reducing proteinuria. The validity and clinical significance require high-quality intensive studies with composite clinic endpoints of kidney and death.

Effects of HMG-CoA reductase inhibitor on experimental autoimmune myocarditis.

PURPOSE: Myocarditis is an acute inflammatory disease of the heart and is often a precursor of dilated cardiomyopathy. Experimental autoimmune myocarditis (EAM) has been used as a model for human myocarditis. The purpose of this study was to investigate the therapeutic role of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, rosuvastatin, on the development of EAM. METHODS: Experimental autoimmune myocarditis was induced in BALB/c mice by immunization with murine cardiac α-myosin heavy chain (MyHc-α(614-629) [Ac-SLKLMATLFSTYASAD-OH]). High-dose (10 mg/kg/day) or low-dose (1 mg/kg/day) rosuvastatin or vehicle was administered orally by gastric gavage to mice with EAM from day 0 to day 21 after immunization. On day 21 after immunization, echocardiography was carried out and the severity of myocarditis was detected by histopathological evaluation. Levels of serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 were measured by ELISA. Histopathology was performed using haematoxylin and eosin. With apoptosis examined by Tunel, the expression of active caspase-3 in myocardium was investigated by immunohistochemistry. RESULTS: Rosuvastatin attenuated the histopathological severity of myocarditis. Cardiac function was improved in the two rosuvastatin-treated groups compared to the non-treated EAM group (LVFS: high-dose rosuvastatin group [group H], 0.38 ± 0.10%; low-dose rosuvastatin group [group L], 0.34 ± 0.06%; non-treated EAM group [group N], 0.29 ± 0.07%. LVEF: group H, 0.80 ± 0.09%; group L, 0.71 ± 0.07%; group N, 0.68 ± 0.07%). Furthermore, treatment with rosuvastatin decreased the expression levels of TNF-α (group H, 65.19 ± 7.06 pg/ml; group L, 108.20 ± 5.28 pg/ml; group N, 239.34 ± 11.65 pg/ml) and IL-6 (group H, 14.33 ± 2.15 pg/ml; group L, 19.67 ± 3.04 pg/ml; group N, 40.39 ± 7.17 pg/ml). The rates of expression of active Caspase-3 and myocardial apoptosis were positively correlated with the scores for myocardial pathology. CONCLUSIONS: These results demonstrate that administration of rosuvastatin can ameliorate EAM progression, inhibit apoptosis of cardiomyocytes, and preserve cardiac output, and they also suggest rosuvastatin may be a promising novel therapeutic strategy for the clinical treatment of myocarditis.

SGLT-2 inhibitors on prognosis and health-related quality of life in patients with heart failure and preserved ejection fraction: A systematic review and meta-analysis.

Background: Heart failure with preserved ejection fraction (HFpEF) is becoming the main subtype of heart failure, but lacks proven effective therapies. Sodium-glucose cotransporter-2 (SGLT-2) inhibitor, a new kind of oral glucose-lowering agent, shows a great effect on improving cardiovascular outcomes. Based on the results of current RCTs, we perform this meta-analysis to illustrate the therapeutic impact of SGLT2i in HFpEF patients. Methods: We systematically searched the online database and 10 RCTs were involved. The primary outcome was the prognosis outcome of HFpEF patients, including a composite outcome of cardiovascular (CV) death and hospitalization for heart failure (HHF), CV mortality, HHF, and all-cause mortality. Main secondary outcomes included improvement of KCCQ-TSS (Kansas City Cardiomyopathy Questionnaire and total symptom score) and 6-Minute Walk Test (6MWT). All pooled results were calculated by the random-effects model. Statistical heterogeneity was assessed using the chi-squared test and was quantified using the I-squared statistic. Results: Ten RCTs comprising 10,334 patients were involved in. Incidence of composite outcome was reduced in SGLT-2 inhibitor group compared with placebo (HR: 0.78, 95% CI: 0.69-0.88, p = 0.00). Improvement of KCCQ-TSS was also more pronounced in the SGLT-2 inhibitor group (MD: 2.74, 95% CI: 1.30-4.18, p = 0.00). No statistical difference was observed in 6MWT. Conclusion: Treating HFpEF patients with SGLT-2 inhibitors is associated with reducing the composite outcome of CV death and HHF and improving health-related quality of life. Further studies with more evidence are in need to confirm this conclusion.

Comparison of efficacy and safety between VKAs and DOACs in patients with atrial fibrillation after transcatheter aortic valve replacement: A systematic review and meta-analysis.

In the past decade, direct oral anticoagulants (DOACs) have proven to be the best option for patients with nonvalvular atrial fibrillation. Nevertheless, evidence for the use of DOACs for anticoagulation in valvular atrial fibrillation, particularly after aortic valve replacement, remains inadequate. Thus, we conducted a meta-analysis to compare the efficacy and safety of vitamin K antagonists (VKAs) and DOACs in patients with atrial fibrillation after transcatheter aortic valve replacement (TAVR). We conducted a comprehensive search of online databases, and 11 studies were included in the final analysis. The primary endpoint was all-cause mortality. Secondary endpoints included stroke and cardiovascular death. The safe endpoint is major and/or life-threatening bleeding. Subgroup analysis was conducted according to the different follow-up time of each study. Random-effects models were used for all outcomes. Statistical heterogeneity was assessed using χ2 tests and quantified using I2  statistics. Patients in the DOACs group had a significantly lower risk of all-cause mortality compared with patients in the VKAs group (relative risk [RR]: 1.20, 95% confidence interval [CI]: 1.01-1.43, p = .04). This benefit may be greater with longer follow-up. In a subgroup analysis based on the length of follow-up, a significantly lower risk of all-cause mortality was found in the DOACs group in the subgroup with a follow-up time of >12 months (RR: 1.50, 95% CI: 1.07-2.09, p = .001). There were no significant differences between the two groups in cardiovascular death, stroke, and major and/or life-threatening bleeding. For patients with atrial fibrillation after TAVR, the use of DOACs may be superior to VKAs, and the benefit may be greater with longer follow-up. The anticoagulant strategy for atrial fibrillation after TAVR is a valuable direction for future research.

WNT1-inducible signalling pathway protein 1 stabilizes atherosclerotic plaques in apolipoprotein-E-deficient mice via the focal adhesion kinase/mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase pathway.

BACKGROUND: The migration, proliferation and apoptosis of vascular smooth muscle cells (VSMCs) are critical for plaque stability. WNT-inducible signalling pathway protein-1 (WISP1), a member of the CCN family of extracellular matrix proteins, can expedite the migration and proliferation of VSMCs. However, its underlying mechanism and relationship with atherosclerosis remain elusive. The relationship between WISP1 and apoptosis of VSMCs has not been determined previously. METHOD: In the study, we aimed to investigate the relationship between WISP1 and plaque stability and its related mechanism.ApoE-/- mice were divided following groups: the null lentivirus (NC), lentivirus WISP1 (IvWISP1) and WISP1-shRNA (shWISP1) groups. Immunofluorescence, Oil Red O and Masson's staining of the carotid arteries were performed. Transwell wound healing assay, CCK8 assay, and TdT-mediated dUTP nick-end labeling (TUNEL) staining were performed using VSMCs. The levels of WISP1, P38, C-Jun N-terminal kinase, extracellular signal-regulated kinase (ERK), mitogen-activated extracellular signal-regulated kinase (MEK), focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K), Akt (also known as PKB, protein kinase B), mammalian target of rapamycin (mTOR), cleaved caspase3, Bcl2 and Bax were detected by western blotting. RESULTS: The relative area of lipids and monocytes/macrophages in the shWISP1 group increased compared with that of the NC group. However, the relative area of smooth muscle cell and collagen in the IvWISP1 group increased compared with that in the NC group. Therefore, WISP1 could stabilize atherosclerotic plaques. Besides, WISP1 accelerate the migration and proliferation of VSMCs via integrin α5ß1 and FAK/MEK/ERK signalling pathways. In addition, WISP1 can inhibit the apoptosis of VSMCs via the PI3K/Akt/mTOR pathway. CONCLUSION: WISP1 not only inhibits the apoptosis of VSMCs via the PI3K/Akt/mTOR pathway but also enhances the migration and proliferation of VSMCs via the integrin α5ß1 and FAK/MEK/ERK pathways. Therefore, WISP1 could enhance the stability of atherosclerotic plaques.

Effect of evolocumab on the progression of intraplaque neovascularization of the carotid based on contrast-enhanced ultrasonography (EPIC study): A prospective single-arm, open-label study.

Background and Purpose: The aim of this study was to explore the effect of half a year of evolocumab plus moderate-intensity statin treatment on carotid intraplaque neovascularization (IPN) and blood lipid levels. Methods: A total of 31 patients with 33 carotid plaques who received evolocumab plus statin treatment were included. Blood lipid levels, B-mode ultrasound and contrast-enhanced ultrasonography (CEUS) at baseline and after half a year of evolocumab plus statin therapy were collected. The area under the curve (AUC) reflected the total amount of acoustic developer entering the plaque or lumen within the 180 s measurement period. The enhanced intensity reflected the peak blood flow intensity during the monitoring period, and the contrast agent area reflected the area of vessels in the plaques. Results: Except for high-density lipoprotein cholesterol (HDL-c), all other lipid indices decreased. Compared with baseline, low-density lipoprotein cholesterol (LDL-c) decreased by approximately 57% (p < 0.001); total cholesterol (TC) decreased by approximately 34% (p < 0.001); small dense low-density lipoprotein (sd-LDL) decreased by approximately 52% (p < 0.001); and HDL-c increased by approximately 20% (p < 0.001). B-mode ultrasonography showed that the length and thickness of the plaque and the hypoechoic area ratio were reduced (p < 0.05). The plaque area, calcified area ratio, and lumen cross-sectional area changed little (p > 0.05). CEUS revealed that the area under the curve of plaque/lumen [AUC (P/L)] decreased from 0.27 ± 0.13 to 0.19 ± 0.11 (p < 0.001). The enhanced intensity ratio of plaque/lumen [intensity ratio (P/L)] decreased from 0.37 ± 0.16 to 0.31 ± 0.14 (p = 0.009). The contrast agent area in plaque/area of plaque decreased from 19.20 ± 13.23 to 12.66 ± 9.59 (p = 0.003). The neovascularization score decreased from 2.64 ± 0.54 to 2.06 ± 0.86 (p < 0.001). Subgroup analysis based on statin duration (<6 months and ≥6 months) showed that there was no significant difference in the AUC (P/L) or intensity ratio (P/L) at baseline or after half a year of evolocumab treatment. Conclusion: This study found that evolocumab combined with moderate-intensity statins significantly improved the blood lipid profile and reduced carotid IPN. Clinical Trial Registration: https://www.clinicaltrials.gov; identifier: NCT04423406.