Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation.

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new pharmacological tools that regulate metabolic reprogramming in VSMCs for treatment of atherosclerosis. The effects of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, have been broadly investigated in highly proliferative cells; however, it is unclear whether DON inhibits proliferation of VSMCs and neointima formation. Here, we investigated the effects of DON on neointima formation in vivo as well as proliferation and migration of VSMCs in vitro. DON simultaneously inhibited FBS- or PDGF-stimulated glycolysis and glutaminolysis as well as mammalian target of rapamycin complex I activity in growth factor-stimulated VSMCs, and thereby suppressed their proliferation and migration. Furthermore, a DON-derived prodrug, named JHU-083, significantly attenuated carotid artery ligation-induced neointima formation in mice. Our results suggest that treatment with a glutamine antagonist is a promising approach to prevent progression of atherosclerosis and restenosis.

Smart Care Based on Telemonitoring and Telemedicine for Type 2 Diabetes Care: Multi-Center Randomized Controlled Trial.

BACKGROUND: This study was performed to determine the effectiveness of the Smart Care service on glucose control based on telemedicine and telemonitoring compared with conventional treatment in patients with type 2 diabetes. MATERIALS AND METHODS: This 24-week prospective multi-center randomized controlled trial involved 338 adult patients with type 2 diabetes at four university hospitals in South Korea. The patients were randomly assigned to a control group (group A, n = 113), a telemonitoring group (group B, n = 113), or a telemedicine group (group C, n = 112). Patients in the telemonitoring group visited the outpatient clinic regularly, accompanied by an additional telemonitoring service that included remote glucose monitoring with automated patient decision support by text. Remote glucose monitoring was identical in the telemedicine group, but assessment by outpatient visits was replaced by video conferencing with an endocrinologist. RESULTS: The adjusted net reductions in HbA1c concentration after 24 weeks were similar in the conventional, telemonitoring, and telemedicine groups (-0.66% ± 1.03% vs. -0.66% ± 1.09% vs. -0.81% ± 1.05%; p > 0.05 for each pairwise comparison). Fasting glucose concentrations were lower in the telemonitoring and telemedicine groups than in the conventional group. Rates of hypoglycemia were lower in the telemedicine group than in the other two groups, and compliance with medication was better in the telemonitoring and telemedicine than in the conventional group. No serious adverse events were associated with telemedicine. CONCLUSIONS: Telehealthcare was as effective as conventional care at improving glycemia in patients with type 2 diabetes without serious adverse effects.

Lactate dehydrogenase-A is indispensable for vascular smooth muscle cell proliferation and migration.

The proliferation and migration of vascular smooth muscle cells (VSMCs) have been implicated in the pathogenesis of atherosclerosis. Increased aerobic glycolysis is a key feature of cellular phenotypes including cancer and immune cells. However, the role of aerobic glycolysis in the atherogenic phenotype of VSMCs remains largely unknown. Here, we investigated the role of lactate dehydrogenase-A (LDHA), which is a key enzyme for glycolysis, in the proliferation and migration of VSMCs. Activation of primary rat VSMCs with fetal bovine serum (FBS) or platelet-derived growth factor (PDGF) increased their proliferation and migration, glycolytic activity, and expression of LDHA. Wound healing and transwell migration assays demonstrated that small interfering RNA-mediated knockdown of LDHA and pharmacological inhibition of LDHA by oxamate both effectively inhibited VSMC proliferation and migration. Inhibition of LDHA activity by oxamate reduced PDGF-stimulated glucose uptake, lactate production, and ATP production. Taken together, this study shows that enhanced glycolysis in PDGF- or FBS-stimulated VSMCs plays an important role in their proliferation and migration and suggests that LDHA is a potential therapeutic target to prevent vessel lumen constriction during the course of atherosclerosis and restenosis.

Alpha lipoic acid induces hepatic fibroblast growth factor 21 expression via up-regulation of CREBH.

Hepatic expression of fibroblast growth factor 21 (FGF21), one of the most promising therapeutic candidates for metabolic syndrome, is induced by multiple factors associated with fasting, including cyclic AMP response element-binding protein H (CREBH). Alpha lipoic acid (ALA), a naturally occurring thiol antioxidant, has been shown to induce metabolic changes that are similar to those induced by FGF21, including weight loss and increased energy expenditure. Here, we investigated the effect of ALA on hepatic FGF21 expression. ALA treatment enhanced CREBH and FGF21 mRNA expression and protein abundance in cultured hepatocytes. ALA increased FGF21 promoter activity by up-regulating CREBH expression and increasing CREBH binding to the FGF21 promoter, indicating that ALA up-regulates FGF21 at the transcriptional level. Moreover, inhibition of endogenous CREBH expression by siRNA attenuated ALA-induced FGF21 expression. Finally, treatment of mice with ALA enhanced fasting-induced up-regulation of CREBH and FGF21 in the liver and inhibited feeding-induced suppression of their expression. Consistently, ALA increased serum FGF21 levels in both fasted and fed mice. Collectively, these results indicate that ALA increases hepatic FGF21 expression via up-regulation of CREBH, identifying ALA as a novel positive regulator of FGF21.

Clusterin attenuates the development of renal fibrosis.

Upregulation of clusterin occurs in several renal diseases and models of nephrotoxicity, but whether this promotes injury or is a protective reaction to injury is unknown. Here, in the mouse unilateral ureteral obstruction model, obstruction markedly increased the expression of clusterin, plasminogen activator inhibitor-1 (PAI-1), type I collagen, and fibronectin. Compared with wild-type mice, clusterin-deficient mice exhibited higher levels of PAI-1, type I collagen, and fibronectin and accelerated renal fibrosis in response to obstruction. In cultured rat tubular epithelium-like cells, adenovirus-mediated overexpression of clusterin inhibited the expression of TGF-ß-stimulated PAI-1, type I collagen, and fibronectin. Clusterin inhibited TGF-ß-stimulated Smad3 activity via inhibition of Smad3 phosphorylation and its nuclear translocation. Moreover, intrarenal delivery of adenovirus-expressing clusterin upregulated expression of clusterin in tubular epithelium-like cells and attenuated obstruction-induced renal fibrosis. In conclusion, clusterin attenuates renal fibrosis in obstructive nephropathy. These results suggest that upregulation of clusterin during renal injury is a protective response against the development of renal fibrosis.

Novel Asian-Specific Visceral Adiposity Indices Are Associated with Chronic Kidney Disease in Korean Adults.

BACKGROUND: The Chinese visceral adiposity index (CVAI) and new visceral adiposity index (NVAI) are novel indices of visceral adiposity used to predict metabolic and cardiovascular diseases in Asian populations. However, the relationships of CVAI and NVAI with chronic kidney disease (CKD) have not been investigated. We aimed to characterize the relationships of CVAI and NVAI with the prevalence of CKD in Korean adults. METHODS: A total of 14,068 participants in the 7th Korea National Health and Nutrition Examination Survey (6,182 men and 7,886 women) were included. Receiver operating characteristic (ROC) analyses were employed to compare the associations between indices of adiposity and CKD, and a logistic regression model was used to characterize the relationships of CVAI and NVAI with CKD prevalence. RESULTS: The areas under the ROC curves for CVAI and NVAI were significantly larger than for the other indices, including the visceral adiposity index and lipid accumulation product, in both men and women (all P<0.001). In addition, high CVAI or NVAI was significantly associated with a high CKD prevalence in both men (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.31 to 3.48 in CVAI and OR, 6.47; 95% CI, 2.91 to 14.38 in NVAI, P<0.05) and women (OR, 4.87; 95% CI, 1.85 to 12.79 in CVAI and OR, 3.03; 95% CI, 1.35 to 6.82 in NVAI, P<0.05); this association remained significant after adjustment for multiple confounding factors in men and women. CONCLUSION: CVAI and NVAI are positively associated with CKD prevalence in a Korean population. CVAI and NVAI may be useful for the identification of CKD in Asian populations, including in Korea.

Asymmetric chorea as presenting symptom in Graves' disease.

Chorea is an involuntary movement disorder characterized by irregular, brief movements that flow from one body part to another in a non-stereotyped fashion. In rare instances, chorea is associated with autoimmune thyroid disease. Most of them have been related with Hashimoto's encephalopathy and few cases have been related with Graves' disease. Most reported cases have been in women with Graves' disease. We describe a 16-year-old male patient with asymmetric chorea as presenting symptom in Graves' disease. He had no family history of neurological disease. Brain imaging, laboratory findings and electroencephalogram demonstrated no abnormality except for thyroid dysfunction which was proved by thyroid function test, sonography and radioiodine uptake scan. Asymmetric chorea improved over months after anti-thyroid medications. This asymmetry could be explained by difference in increased hypersensitivity or by the difference in the number of dopamine receptors, and an asymmetrical breakdown of blood-brain barrier due to their genetic differences.

An on-time power-aware scheduling scheme for medical sensor SoC-based WBAN systems.

The focus of many leading technologies in the field of medical sensor systems is on low power consumption and robust data transmission. For example, the implantable cardioverter-defibrillator (ICD), which is used to maintain the heart in a healthy state, requires a reliable wireless communication scheme with an extremely low duty-cycle, high bit rate, and energy-efficient media access protocols. Because such devices must be sustained for over 5 years without access to battery replacement, they must be designed to have extremely low power consumption in sleep mode. Here, an on-time, energy-efficient scheduling scheme is proposed that performs power adjustments to minimize the sleep-mode current. The novelty of this scheduler is that it increases the determinacy of power adjustment and the predictability of scheduling by employing non-pre-emptible dual priority scheduling. This predictable scheduling also guarantees the punctuality of important periodic tasks based on their serialization, by using their worst case execution time) and the power consumption optimization. The scheduler was embedded into a system on chip (SoC) developed to support the wireless body area network-a wakeup-radio and wakeup-timer for implantable medical devices. This scheduling system is validated by the experimental results of its performance when used with life-time extensions of ICD devices.

DN200434 Inhibits Vascular Smooth Muscle Cell Proliferation and Prevents Neointima Formation in Mice after Carotid Artery Ligation.

BACKGRUOUND: Excessive proliferation and migration of vascular smooth muscle cells (VSMCs), which contributes to the development of occlusive vascular diseases, requires elevated mitochondrial oxidative phosphorylation to meet the increased requirements for energy and anabolic precursors. Therefore, therapeutic strategies based on blockade of mitochondrial oxidative phosphorylation are considered promising for treatment of occlusive vascular diseases. Here, we investigated whether DN200434, an orally available estrogen receptor-related gamma inverse agonist, inhibits proliferation and migration of VSMCs and neointima formation by suppressing mitochondrial oxidative phosphorylation. METHODS: VSMCs were isolated from the thoracic aortas of 4-week-old Sprague-Dawley rats. Oxidative phosphorylation and the cell cycle were analyzed in fetal bovine serum (FBS)- or platelet-derived growth factor (PDGF)-stimulated VSMCs using a Seahorse XF-24 analyzer and flow cytometry, respectively. A model of neointimal hyperplasia was generated by ligating the left common carotid artery in male C57BL/6J mice. RESULTS: DN200434 inhibited mitochondrial respiration and mammalian target of rapamycin complex 1 activity and consequently suppressed FBS- or PDGF-stimulated proliferation and migration of VSMCs and cell cycle progression. Furthermore, DN200434 reduced carotid artery ligation-induced neointima formation in mice. CONCLUSION: Our data suggest that DN200434 is a therapeutic option to prevent the progression of atherosclerosis.

Relationship of 11ß-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase gene polymorphisms with metabolic syndrome and type 2 diabetes.

11ß-Hydroxysteroid dehydrogenase type 1 (HSD11B1), which converts inactive glucocorticoid to active glucocorticoid, plays a critical role in the pathogenesis of visceral obesity, metabolic syndrome, and diabetes. Hexose-6-phosphate dehydrogenase (H6PD) supplies a crucial cofactor, reduced nicotinamide adenine dinucleotide phosphate (NADPH), which allows HSD11B1 to maintain reductase activity. The association of common SNPs in HSD11B1 [IVS3-29G/T (rs12086634), IVS4-11120A/G (rs1000283)] and H6PD [R453Q (rs6688832), P554L (rs17368528)], either separately or combined, with type 2 diabetes and metabolic syndrome was examined in 427 Korean subjects with type 2 diabetes and in 358 nondiabetic Korean subjects. HSD11B1 polymorphisms (rs12086634 and rs1000283) were associated with metabolic syndrome among type 2 diabetic subjects and an H6PD polymorphism (rs17368528) was a risk factor for metabolic syndrome in nondiabetic subjects. However, no significant association of these SNPs with type 2 diabetes and metabolic syndrome was found after considering the multiple comparisons in the total study population. In conclusion, HSD11B1 and H6PD polymorphisms may not be associated with type 2 diabetes and metabolic syndrome. Further investigation of the role of these gene polymorphisms on the pathogenesis of metabolic syndrome is required.

Impact of urgently initiated tele-prescription due to COVID-19 on glycemic control in patients with type 2 diabetes.

BACKGROUND/AIMS: Coronavirus disease 2019 (COVID-19) is a global pandemic that had affected more than 13,000 people in South Korea by July 2020. To prevent spread of COVID-19, tele-prescription was permitted temporarily. This study investigated the impact of tele-prescription on glycemic control in patients with type 2 diabetes. METHODS: Glycated hemoglobin (HbA1c) concentrations were retrospectively analyzed in patients with type 2 diabetes who were treated with tele-prescription because of COVID-19 and those who were treated by face-to-face care (non-tele-prescription group) enrolled at the same period of time. Mean HbA1c concentrations and mean change in HbA1c concentration (ΔHbA1c) were compared in these two groups. RESULTS: The mean HbA1c levels of patients were significantly higher after than before the tele-prescription period (7.46% ± 1.24% vs. 7.27% ± 1.13%, p < 0.05). Mean ΔHbA1c was significantly higher in the tele-prescription than in the non-tele-prescription group (0.19% ± 0.68% vs. 0.04% ± 0.95%, p < 0.05). HbA1c was significantly greater in patients taking fewer oral hypoglycemic agents, no insulin, fewer comorbidities (e.g., coronary artery disease, cerebrovascular accident, and diabetic neuropathy), and higher baseline HbA1c. CONCLUSION: Tele-prescription may worsen glycemic control in patients with type 2 diabetes during public health crises.

Year-Long Trend in Glycated Hemoglobin Levels in Patients with Type 2 Diabetes during the COVID-19 Pandemic.

It has been suggested that the coronavirus disease 2019 (COVID-19) pandemic has had a negative impact on glycemic control in patients with type 2 diabetes mellitus (T2DM). However, no study has examined yearly trends in glycated hemoglobin (HbA1c) levels after the start of the COVID-19 outbreak. Here, we performed a retrospective analysis of HbA1c concentrations during the early period of the COVID-19 outbreak (COVID-19 cohort) and then compared the yearly trend in the mean HbA1c level, along with fluctuations in HbA1c levels, with those during previous years (non-COVID-19 cohorts). We observed that the mean HbA1c level in patients with T2DM increased during the first 6 months of the COVID-19 outbreak. After 6 months, HbA1c levels in the COVID-19 cohort returned to levels seen in the non-COVID-19 cohorts. The data suggest that vulnerable patients with T2DM should be monitored closely during the early period of a pandemic to ensure they receive appropriate care.

Relationship between cardiovascular autonomic neuropathy and coronary artery calcification in patients with type 2 diabetes.

To test the hypothesis that cardiovascular autonomic neuropathy (CAN) in Type 2 diabetes is a risk factor of coronary artery calcification (CAC), in this cross-sectional study, 118 patients (60 males, 58 females) with type 2 diabetes mellitus were randomly selected from the diabetes clinic of Kyungpook National University Hospital, Daegu, Korea, between January, 2008 and September, 2008. The subjects, whose mean age was 56.9+/-1.1 years, were tested for CAN by Ewing's method which employs five non-invasive tests of autonomic function. The coronary calcium score (CCS) was determined by Multi Detector-row Computed Tomography (MDCT). Statistical analysis was performed by using SPSS 13.0 (SPSS, Inc., Chicago,-Illinois). CAN was found in 31/118 (26.3%) patients. Compared to the patients without CAN, the patients with CAN were significantly older and had significantly higher triglyceride levels, blood pressure, pulse pressure, fasting c-peptide levels, CAN scores, and log-transformed coronary calcium scores [ln(CCS+1)]. The CAN scores correlated positively with ln(CCS+1) values (r = 0.214; P = 0.028). Multiple regression analysis using ln(CCS+1) as a dependent variable showed that CAN score (beta coefficient 0.623, 95% CI 0.059 approximately 1.188, P = 0.031) associated independently with ln(CCS+1). In conclusion, CAN was associated independently with CAC, which suggests that CAN is a risk factor of coronary atherosclerosis in patients with type 2 diabetes. This may help to explain the excess cardiovascular mortality seen in diabetic patients with CAN.

Effects of message framing and health literacy on intention to perform diabetes self-care: A randomized controlled trial.

AIMS: To evaluate the effect of positive and negative message framing in diabetes education on attitudes, perceived control, and behavioral intentions toward diabetes self-care, and to identify potential moderating effects of health literacy on message framing. METHODS: A total of 52 patients with type 2 diabetes that visited an ambulatory endocrinology wing at a university hospital in Korea were randomized into positive or negative message framing groups. Each group watched a 10-minute video that was either positively or negatively framed, accentuating desirable outcomes from good diabetes self-care in the former and undesirable outcomes from inadequate diabetes self-care in the latter. Two-way ANCOVA controlling for HbA1C was conducted to evaluate outcomes. RESULTS: Patients who watched the negatively framed message showed significantly more favorable attitudes and perceived control toward diabetes self-care than those who viewed the positively framed message. Message framing had significant indirect effects on behavioral intentions for diabetes self-care that were mediated by attitudes and perceived control. Conversely, no significant interaction effects were observed between health literacy level and message framing of these same markers. CONCLUSION: The use of negative message framing in diabetes education is a promising strategy for shaping favorable attitudes, beliefs, and intentions toward diabetes self-care behavior.

Melatonin inhibits vascular smooth muscle cell proliferation and apoptosis through upregulation of Sestrin2.

Excessive vascular smooth muscle cell (VSMC) proliferation contributes to the development of atherosclerosis and restenosis. Furthermore, apoptosis of VSMCs accelerates plaque rupture in the atherosclerotic vessels. Therefore, a strategy that regulates both VSMC proliferation and apoptosis is essential for the development of novel pharmacological tools for the treatment of atherosclerosis. Despite mounting evidence supporting the benefits of melatonin in diverse metabolic diseases, the role of melatonin in VSMC growth remains largely unknown. The present study revealed that melatonin inhibited both proliferation and apoptosis of primary cultured rat VSMCs. Melatonin induced mitochondrial energetic stress in VSMCs and subsequent induction of Sestrin2 via C/EBPß. Melatonin-induced Sestrin2 suppressed mTORC1 activity in VSMCs, contributing to suppression of VSMC proliferation. Additionally, melatonin-induced upregulation of Sestrin2 blocked apoptosis by preventing excessive ROS generation. The results demonstrated that melatonin controlled VSMC proliferation and apoptosis via Sestrin2-mediated inhibition of mTORC1 and ROS scavenging. Therefore, melatonin should be considered as a lead compound for therapies aimed at preventing vessel lumen constriction during the course of atherosclerosis and restenosis.

Evogliptin, a Dipeptidyl Peptidase-4 Inhibitor, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice.

Renal fibrosis is considered to be the final common outcome of chronic kidney disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors have demonstrated protective effects against diabetic kidney disease. However, the anti-fibrotic effect of evogliptin, a DPP-4 inhibitor, has not been studied. Here, we report the beneficial effects of evogliptin on unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Evogliptin attenuated UUO-induced renal atrophy and tubulointerstitial fibrosis. Immunohistochemistry and Western blotting demonstrated that evogliptin treatment inhibits pro-fibrotic gene expressions and extracellular matrix production. In vitro findings showed that the beneficial effects of evogliptin on renal fibrosis are mediated by inhibition of the transforming growth factor-ß/Smad3 signaling pathway. The present study demonstrates that evogliptin is protective against UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of kidney disease of non-diabetic origin.

Novel mutation of aquaporin-2 gene in a patient with congenital nephrogenic diabetes insipidus.

Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disease, characterized by an inability of the kidney to concentrate urine in response to vasopressin. Three different inheritance patterns have been described, i.e., the X-linked recessive form associated with arginine vasopressin V2 receptor (AVPR2) gene mutations, the autosomal recessive and dominant forms of CNDI associated with mutations in the aquaporin-2 (AQP2) gene encoding the vasopressin-regulated water channel of the renal collecting duct. Our case is an 18-year-old male patient who complained of severe polyuria since his infancy. But his developmental and growth status were normal. He was diagnosed as CNDI by water deprivation test and genomic DNA sequencing, which revealed high plasma AVP levels but persistently low urine osmolalities to 6 h-water deprivation and the novel missense mutation S216F in exon4 of the AQP2 gene. Immunohistochemistry of renal biopsied tissue revealed that most of the AQP2 labeling was seen intracellularly in a dotted pattern in the collecting duct principal cells. Immunoblotting of urine samples revealed significantly decreased urinary excretion of AQP2 (approximately 7% of normal control). Here, we report a new case of CNDI associated with the novel missense mutation of the AQP2 gene.

Glucotoxicity in the INS-1 rat insulinoma cell line is mediated by the orphan nuclear receptor small heterodimer partner.

Prolonged elevations of glucose concentration have deleterious effects on beta-cell function. One of the hallmarks of such glucotoxicity is a reduction in insulin gene expression, resulting from decreased insulin promoter activity. Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that inhibits nuclear receptor signaling in diverse metabolic pathways. In this study, we found that sustained culture of INS-1 cells at high glucose concentrations leads to an increase in SHP mRNA expression, followed by a decrease in insulin gene expression. Inhibition of endogenous SHP gene expression by small interfering RNA partially restored high-glucose-induced suppression of the insulin gene. Adenovirus-mediated overexpression of SHP in INS-1 cells impaired glucose-stimulated insulin secretion as well as insulin gene expression. SHP downregulates insulin gene expression via two mechanisms: by downregulating PDX-1 and MafA gene expression and by inhibiting p300-mediated pancreatic duodenal homeobox factor 1-and BETA2-dependent transcriptional activity from the insulin promoter. Finally, the pancreatic islets of diabetic OLETF rats express SHP mRNA at higher levels than the islets from LETO rats. These results collectively suggest that SHP plays an important role in the development of beta-cell dysfunction induced by glucotoxicity.

Serum Levels of PCSK9 Are Associated with Coronary Angiographic Severity in Patients with Acute Coronary Syndrome.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that promotes degradation of the low density lipoprotein receptor. PCSK9 has emerged as a target for lipid-lowering therapy, but the predictive value of the serum level of PCSK9 for the severity of coronary disease is largely unknown. METHODS: From December 2009 to July 2012, 121 individuals who underwent coronary angiography (CAG) because of clinically suspected acute coronary syndrome were enrolled in this study. Serum levels of PCSK9 and metabolic parameters were measured. SYNTAX (SYNergy between percutaneous coronary intervention with [paclitaxel-eluting] TAXUS stent and cardiac surgery) and GRACE (Global Registry of Acute Coronary Events) scores were calculated. RESULTS: Individuals with CAG lesions (n=100) had significantly higher levels of PCSK9 than those without lesions (n=21). The study population was stratified into three groups according to serum levels of PCSK9. The odds radio for occurrence of one or more CAG lesions was significantly higher in the group with the highest level of PCSK9 (odds ratio, 7.468; P=0.011) than in the group with the lowest level of PCSK9. Serum PCSK9 was positively associated with the number of involved coronary arteries. Multivariable linear regression indicated that levels of PCSK9 were positively correlated with GRACE risk scores and SYNTAX scores. CONCLUSION: Serum PCSK9 concentrations are higher in patients with coronary artery lesions, and are associated with SYNTAX and GRACE scores, suggesting that PCSK9 is a potential biomarker of the severity of coronary artery disease.

Serum Levels of PCSK9 Are Associated with Coronary Angiographic Severity in Patients with Acute Coronary Syndrome.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that promotes degradation of the low density lipoprotein receptor. PCSK9 has emerged as a target for lipid-lowering therapy, but the predictive value of the serum level of PCSK9 for the severity of coronary disease is largely unknown. METHODS: From December 2009 to July 2012, 121 individuals who underwent coronary angiography (CAG) because of clinically suspected acute coronary syndrome were enrolled in this study. Serum levels of PCSK9 and metabolic parameters were measured. SYNTAX (SYNergy between percutaneous coronary intervention with [paclitaxel-eluting] TAXUS stent and cardiac surgery) and GRACE (Global Registry of Acute Coronary Events) scores were calculated. RESULTS: Individuals with CAG lesions (n=100) had significantly higher levels of PCSK9 than those without lesions (n=21). The study population was stratified into three groups according to serum levels of PCSK9. The odds radio for occurrence of one or more CAG lesions was significantly higher in the group with the highest level of PCSK9 (odds ratio, 7.468; P=0.011) than in the group with the lowest level of PCSK9. Serum PCSK9 was positively associated with the number of involved coronary arteries. Multivariable linear regression indicated that levels of PCSK9 were positively correlated with GRACE risk scores and SYNTAX scores. CONCLUSION: Serum PCSK9 concentrations are higher in patients with coronary artery lesions, and are associated with SYNTAX and GRACE scores, suggesting that PCSK9 is a potential biomarker of the severity of coronary artery disease.