Chinese Expert Consensus on the Clinical Diagnosis and Management of Statin Intolerance.

The clinical benefits of statins have well-established and recognized worldwide. Although statins are well-tolerated generally, however, the report of statin-related adverse event and statin intolerance are common in China, which results in insufficient use of statins and poor adherence. The main reason may be attributed to confusions or misconceptions in the clinical diagnosis and management in China, including the lack of unified definitions and diagnostic standards, broad grasp of diagnosis, and unscientific management strategies. Based on that, this consensus carefully summarized the statin-related gene polymorphism and statin usage issue among Chinese population, and comprehensively reviewed global research data on statin intolerance, referenced guidelines, and consensus literature on statin intolerance in foreign and different regions, proposes an appropriate and easy to implement statin intolerance definition as well as corresponding diagnostic criteria and management strategies for Chinese clinicians, in order to improve the clinical application of statin drugs and enhance the prevention and treatment level of atherosclerotic cardiovascular disease in China.

2023 China Guidelines for Lipid Management.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death among urban and rural residents in China, and elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for ASCVD. Considering the increasing burden of ASCVD, lipid management is of the utmost importance. In recent years, research on blood lipids has made breakthroughs around the world, hence a revision of China guidelines for lipid management is imperative, especially since the target lipid levels in the general population vary in respect to the risk of ASCVD. The level of LDL-C, which can be regarded as appropriate in a population without frisk factors, can be considered abnormal in people at high risk of developing ASCVD. As a result, the "Guidelines for the prevention and treatment of dyslipidemia" were adapted into the "China Guidelines for Lipid Management" (henceforth referred to as the new guidelines) by an Experts' committee after careful deliberation. The new guidelines still recommend LDL-C as the primary target for lipid control, with CVD risk stratification to determine its target value. These guidelines recommend that moderate intensity statin therapy in adjunct with a heart-healthy lifestyle, be used as an initial line of treatment, followed by cholesterol absorption inhibitors or/and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, as necessary. The new guidelines provide guidance for lipid management across various age groups, from children to the elderly. The aim of these guidelines is to comprehensively improve the management of lipids and promote the prevention and treatment of ASCVD by guiding clinical practice.

2023 Chinese guideline for lipid management.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death among urban and rural residents in China, and elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for ASCVD. Considering the increasing burden of ASCVD, lipid management is of the utmost importance. In recent years, research on blood lipids has made breakthroughs around the world, hence a revision of Chinese guideline for lipid management is imperative, especially since the target lipid levels in the general population vary in respect to the risk of ASCVD. The level of LDL-C, which can be regarded as appropriate in a population without frisk factors, can be considered abnormal in people at high risk of developing ASCVD. As a result, the "Guidelines for the prevention and treatment of dyslipidemia" were adapted into the "Chinese guideline for Lipid Management" (henceforth referred to as the new guidelines) by an Experts' committee after careful deliberation. The new guidelines still recommend LDL-C as the primary target for lipid control, with cardiovascular disease (CVD) risk stratification to determine its target value. These guidelines recommend that moderate intensity statin therapy in adjunct with a heart-healthy lifestyle, be used as an initial line of treatment, followed by cholesterol absorption inhibitors or/and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, as necessary. The new guidelines provide guidance for lipid management across various age groups, from children to the elderly. The aim of these guidelines is to comprehensively improve the management of lipids and promote the prevention and treatment of ASCVD by guiding clinical practice.

New insights into apolipoprotein A5 in controlling lipoprotein metabolism in obesity and the metabolic syndrome patients.

Apolipoprotein A5 (apoA5) has been identified to play an important role in lipid metabolism, specifically in triglyceride (TG) and TG-rich lipoproteins (TRLs) metabolism. Numerous evidence has demonstrated for an association between apoA5 and the increased risk of obesity and metabolic syndrome, but the mechanism remains to be fully elucidated. Recently, several studies verified that apoA5 could significantly reduce plasma TG level by stimulating lipoprotein lipase (LPL) activity, and the intracellular role of apoA5 has also been proved since apoA5 is associated with cytoplasmic lipid droplets (LDs) and affects intrahepatic TG accumulation. Furthermore, since adipocytes provide the largest storage depot for TG and play a crucial role in the development of obesity, we could infer that apoA5 also acts as a novel regulator to modulate TG storage in adipocytes. In this review, we focus on the association of gene and protein of apoA5 with obesity and metabolic syndrome, and provide new insights into the physiological role of apoA5 in humans, giving a potential therapeutic target for obesity and associated disorders.

New insights into ANGPLT3 in controlling lipoprotein metabolism and risk of cardiovascular diseases.

Dyslipidemia, characterized by elevation of plasma low density lipoprotein cholesterol (LDL-C), triglyceride (TG) and reduction of plasma high density lipoprotein cholesterol (HDL-C), has been verified as a causal risk factor for cardiovascular diseases (CVD), leading to a high mortality rate in general population. It is important to understand the molecular metabolism underlying dyslipidemia in order to reduce the risk and to develop effective therapeutic approaches against CVD. ANGPTL3 (human) or Angptl3 (mouse), one member of the angiopoietin-like protein (ANGPTL) family, has been identified as an important regulator of lipid metabolism by inhibiting LPL and EL activity. Results have demonstrated that inactivation of Angptl3 in mice could obviously reduce the level of TG, LDL-C and the atherosclerotic lesion size, leading to a lower risk for dyslipidemia and CVD. Additionally, in humans, carriers with homozygous LOF mutations in ANGPTL3 have lower plasma LDL-C, TG levels and lower risk of atherosclerosis compared to the non-carriers. Here, we collect the latest data and results, giving a new insight into the important role of ANGPTL3 in controlling lipoprotein metabolism. Finally, we introduce two update reports on the antisense oligonucleotide and monoclonal antibody-based inactivation of ANGPTL3 in human clinical trials, to identify that ANGPTL3 could be a novel and effective target for the treatment of dyslipidemia and CVD.

Combined use of metformin and atorvastatin attenuates atherosclerosis in rabbits fed a high-cholesterol diet.

Statins are widely used to reduce cardiovascular risk. Unfortunately, some patients still experience cardiovascular events though prescribed with high-intensity statins. Metformin, an anti-diabetic drug, was reported to possess anti-atherosclerotic effects. Therefore, the experiments were designed to evaluate whether combined use of metformin and atorvastatin can achieve additional benefits. In rabbits fed a high-cholesterol diet, we evaluated the effects of the combination therapy on atherosclerotic plaques, lipid profiles, blood glucose levels, liver and kidney functions. Effects of combination therapy on cholesterol efflux and the expression of related transporters were studied in vitro. Our results showed that the combination therapy induced a more significant decrease in atherosclerotic lesion area than atorvastatin without additional lipid-lowering effect. The combination therapy significantly increased the percentage of large high-density lipoprotein subfraction. The intravenous glucose tolerance test showed that atorvastatin-treated rabbits had an increased area under the curve for time-dependent glucose levels after a bolus injection of glucose, which was completely reversed by metformin treatment. In cultured macrophages, co-treatment with metformin and atorvastatin promoted cholesterol efflux and up-regulated expression of ATP-binding cassette transporters A1 and G1. Taken together, our results suggest that atorvastatin/metformin combination therapy may achieve additional anti-atherosclerotic benefits likely through increasing cholesterol efflux in macrophages.

MG132 Induces Expression of Monocyte Chemotactic Protein-Induced Protein 1 in Vascular Smooth Muscle Cells.

Monocyte chemoattractant protein-1 (MCP-1) has been reported to induce the expression of monocyte chemotactic protein-induced protein 1 (MCPIP1), which undergoes ubiquitination degradation. Therefore, we predict that in vascular smooth muscle (VSMCs), MCPIP1 may be induced by MCP-1 and undergo degradation, which can be inhibited by the proteasome inhibitor, MG132. Our results showed that treatment of human VSMCs with MCP-1 did not increase the expression of MCPIP1. Treatment with MG132, however, elevated MCPIP1 protein levels through stimulation of the gene transcription, but not through increasing protein stability. MCPIP1 expression induced by MG132 was inhibited by α-amanitin inhibition of gene transcription or cycloheximide inhibition of protein synthesis. Our further studies showed that MCPIP1 expression induced by MG132 was inhibited by the inhibitors of AKT and p38 kinase, suggesting a role of the AKT-p38 pathway in MG132 effects. We also found that treatment with MG132 induces apoptosis, but overexpression of MCPIP1 inhibited bromodeoxyuridine (BrdU) incorporation of human VSMCs without induction of significant apoptosis. In summary, MCPIP1 expression is induced by MG132 likely through activation of the AKT-p38 pathway. MCPIP1 inhibits SMC proliferation without induction of apoptosis. J. Cell. Physiol. 232: 122-128, 2017. © 2016 Wiley Periodicals, Inc.

Increased sortilin and its independent effect on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) in statin-naive patients with coronary artery disease.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to play a crucial role in the metabolism of low density lipoprotein receptor (LDLR). Sortilin, encoded by the dyslipidemia-related gene SORT1, is also an important regulator of lipoprotein metabolism. Animal studies have shown the potential role of sortilin in regulating secretion of PCSK9. However, the data for the relationship between serum sortilin and circulating PCSK9 in CAD patients are scarce. METHODS: Eighty subjects were classified into a CAD group (n=43) and a non-CAD group (n=37) according to their clinical conditions and the results of coronary angiography (CAG). Serum PCSK9 and sortilin levels were measured with enzyme-linked immunosorbent assays. RESULTS: CAD patients had markedly greater PCSK9 concentrations than controls [247.0(218.6317.4) vs 226.6(181.6270.3) ng/ml, P=0.007]. Moreover, serum PCSK9 levels were still higher in patients not receiving statin therapy, as compared with those in the control group [261.8(216.0,315.8) vs 221.0(176.8260.7)ng/ml, P=0.003]. Circulating sortilin tended to be higher in CAD patients than in non-CAD subjects, yet the difference is significant only between the statin-naive CAD patients and controls [4.96(4.38,6.57) vs 4.28(2.96,5.03) ng/ml, P=0.032]. Serum PCSK9 concentrations were positively associated with sortilin levels(r=0.37, P=0.001,n=80). Stratified analysis showed that there was stronger correlation between PCSK9 and sortilin in non-statin group (r=0.41, P=0.001,n=60) as well as in the non-CAD group (r=0.47, P=0.004,n=37) , whereas the correlation between them was disappeared in statin group and CAD group. Using stepwise multiple regression analysis with adjustment for age, gender, LDL-cholesterol, smoking and CAD, we found that the correlation between serum sortilin and PCSK9 levels remained significant in all subjects (P=0.01) as well as in statin-naive group (P=0.03). CONCLUSION: Both circulating PCSK9 and sortilin levels are elevated in CAD patients. PCSK9 was independent related to sortilin, but their correlation was affected by the use of statin therapy.

A case report of a giant right ventricular outflow tract in a young man.

INTRODUCTION: Localized pericardium restriction is a rare disease and likely to be unrecognized owing to the atypical manifestation, even after diagnostic avenues are exhausted. Recognizing the red flags of the disease could timely spark a preliminary suspicion of the disease and thus contribute to the early application of relevant examinations. CASE PRESENTATION: We will here report a case of a 21-year-old young man with a giant right ventricular outflow tract. He was presented to our hospital for further evaluation of progressive right heart failure which had been previously diagnosed as cardiomyopathy. Unlike patients with right heart failure owing to the restrictive cardiomyopathy, our patient's tissue Doppler revealed an increased early diastolic septal mitral annular velocity. In addition, the disproportion between the severity of right heart failure and the degree of myocardial dysfunction could not be completely explained by other myocardial disease, suggesting that alternative diagnosis of the patient should be sought. Subsequently, cardiac computed tomography, which revealed the focally calcific pericardium encircling the left ventricle, gave us a clue to the diagnosis of localized constrictive pericarditis. Cardiac catheterization, showing the "dip and plateau" sign, further confirmed this diagnosis. The patient underwent successful pericardiectomy. Nowadays, he is able to undertake ordinary physical activity. CONCLUSION: Localized constrictive pericarditis should be suspected in patients for whom the severity of heart failure and deformity of heart might not be completely explained by valvular heart disease or myocardial disease.

The roles of autophagy in vascular smooth muscle cells.

Autophagy, which is an evolutionarily conserved mechanism and links to several cellular pathways, impacts vascular smooth muscle cells (VSMCs) survival and function. Activation of autophagy by intercellular and/or extracellular stimuli has protective effects on VSMCs against cell death, while on the contrary, overloading autophagy has been recognized as a deleterious process by excessive self-digestion. Alterations in autophagy has been documented in VSMC in response to various stimuli, resulting in modulation of VSMC functions, including proliferation, migration, matrix secretion, contraction/relaxation, and differentiation. Each of these changes in VSMC functions plays a critical role in the development of vascular diseases. Importantly, emerging evidence demonstrates that autophagy deficiency in VSMCs would contribute to atherosclerosis and restenosis, shedding novel light on therapeutic target of the vascular disorders. Herein, this review summarizes the recent progress associated with the roles of autophagy in VSMC and offers the perspectives to several challenges and future directions for further studies.

The unsolved mystery of apoA-I recycling in adipocyte.

As the major storage site for triglycerides and free cholesterol, adipose tissue plays a central role in energy metabolism. ApoA-I is the main constituent of HDL and plays an important role in removal of excess cholesterol from peripheral tissues. Recently, multiple studies have shown beneficial effects of apoA-I on adipose metabolism and function. ApoA-I was reported to improve insulin sensitivity and exert anti-inflammatory, anti-obesity effect in animal studies. Interestingly, Uptake and resecretion of apoA-I by adipocytes has been detected. However, the significance of apoA-I recycling by adipocytes is still not clear. This article reviewed methods used to study cellular recycling of apoA-I and summarized the current knowledge on the mechanisms involved in apoA-I uptake by adipocytes. Since the main function of apoA-I is to mediate reverse cholesterol transport from peripheral tissues, the role of apoA-I internalization and re-secretion by adipocytes in intracellular cholesterol transport under physiological and pathological conditions were discussed. In addition, findings on the correlation between apoA-I recycling and obesity were discussed. Finally, it was proposed that during intracellular transport, apoA-I-protein complex may acquire cargoes other than lipids and deliver regulatory information when they were resecreted into the plasma. Although apoA-I recycling by adipocytes is still an unsolved mystery, it's likely that it is more than a redundant pathway especially under pathological conditions.

TRPC3 channel confers cerebrovascular remodelling during hypertension via transactivation of EGF receptor signalling.

AIMS: Ionic perturbation in vascular smooth muscle cells contributes to cerebrovascular remodelling in the setting of hypertension, but the role of transient receptor potential (TRP) channel superfamily remains unknown. The present study was conducted to define the contribution of TRP channels to cerebrovascular remodelling. METHODS AND RESULTS: By integrating quantitative PCR, western blotting, patch clamping, and Ca(2+) imaging, we identified TRP channel, subfamily canonical, member 3 (TRPC3) as the channel subtype most considerably elevated in basilar arteries of two-kidney, two-clip stroke-prone hypertensive rats. Importantly, administration of pyrazole 3 (Pyr3), a TRPC3 channel blocker, attenuated cerebrovascular remodelling. During hypertension, epidermal growth factor receptor (EGFR) was transactivated, as evidenced by marked EGFR phosphorylation, increased pro-HB-EGF shedding, and elevated activity of ADAM17 (HB-EGF sheddase). ADAM17 activity was increased owing to enhanced activation rather than elevated expression. Remarkably, Pyr3 treatment suppressed EGFR transactivation in hypertension. In proliferating basilar artery smooth muscle cells or basilar arteries of hypertensive rats, co-immunoprecipitation assay revealed an interaction between TRPC3 and ADAM17 upon Ang II stimulation. CONCLUSION: Collectively, we demonstrated that enhanced EGFR transactivation, due to increased TRPC3 expression and functional coupling of TRPC3/ADAM17, resulted in cerebrovascular remodelling. Therefore, TRPC3-induced EGFR transactivation may be therapeutically exploited to prevent hypertension-induced cerebrovascular remodelling.

Novel mutations of low-density lipoprotein receptor gene in China patients with familial hypercholesterolemia.

Familial hypercholesterolaemia (FH) is an autosomal dominant genetic disorder, associated with elevated level of serum low-density lipoprotein-cholesterol (LDL-C), which can lead to premature cardiovascular disease (CVD). Mutations in low density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) have been identified to be the underlying cause of this disease. Genetic research of FH has already been extensively studied all over the world. However, reports of FH mutations in the Chinese population are still limited. In this paper, 20 unrelated FH families were enrolled to detect the candidate gene variants in Chinese FH population by DNA direct sequencing. We identified 12 LDLR variants in 13 FH probands. Importantly, we first reported two unique mutations (c.2000_2000 delG/p.C667LfsX6 and c.605T>C/p.F202S) in LDLR gene. Our discoveries expand the spectrum of LDLR mutations and contribute to the genetic diagnosis and counseling for FH patients.

Myocyte Enhancer Factor 2A Regulates Hydrogen Peroxide-Induced Senescence of Vascular Smooth Muscle Cells Via microRNA-143.

Myocyte enhancer factor 2A (MEF2A) is involved in vascular smooth muscle cell (VSMC) proliferation, migration, and senescence. MicroRNA-143/145 (miR-143/145), which may be regulated by MEF2A, is known to promote cellular senescence. We hypothesized that MEF2A may promote VSMC senescence via miR-143/145. VSMC senescence was induced by hydrogen peroxide (H(2)O(2)), followed by detection using a senescence-associated ß-galactosidase staining kit. The MEF2A protein, mRNA, and miR-143/145 levels in VSMCs were detected using Western blot analysis and SYBR green real-time quantitative PCR, respectively. We further manipulated the expression levels of MEF2A and miR-143 through viral or transient transfection. VSMC proliferation and migration were determined by methylthiazolyldiphenyl-tetrazolium bromide and Millicell chamber, respectively. Both MEF2A and miR-143, but not miRNA-145, were up-regulated in senescent VSMCs. Overexpression of either MEF2A or miR-143 significantly enhanced VSMC senescence, but reduced proliferation and migration. MEF2A knockdown or miR-143 inhibitor suppressed cellular senescence and increased proliferation and migration. We further revealed AKT signaling as a potential miR-143 target, and an induction of miR-143 expression by MEF2A via KLF2. Additionally, overexpression of MEF2A and miR-143 resulted in synergistic effects on promotion of senescence, and MEF2A knockdown and miR-143 reduction by inhibitor had synergistic inhibitory effects. Finally, MEF2A barely promoted VSMC senescence when miR-143 was inhibited, and miR-143 overexpression antagonized the inhibitory effect of MEF2A knockdown on VSMC senescence. Our results revealed a link and interaction between MEF2A and miR-143 and suggested a potential mechanism for MEF2A to regulate H(2)O(2) -induced VSMC senescence.