Mechanistic insights into the anti-restenotic effects of HSP27 and HO1 modulated by reconstituted HDL on neointimal hyperplasia.

High-density lipoprotein (HDL) therapy has demonstrated beneficial effects in acute stroke and acute myocardial infarction models by reducing infarct size. In this study, we investigated the inhibitory effects of reconstituted HDL (rHDL) on neointimal hyperplasia and elucidated its underlying mechanism using a balloon injury rat model. Our finding revealed a significant 37% reduction in the intima to media ratio in the arteries treated with 80 mg/kg rHDL compared to those subjected to injury alone (p < 0.05), indicating a specific inhibition of neointimal hyperplasia. In vivo analysis further supported the positive effects of rHDL by demonstrating a reduction in smooth muscle cell (SMC) proliferation and an increase in endothelial cell (EC) proliferation. Additionally, rHDL treatment led to decreased infiltration of leukocytes and downregulated the expression of matrix metallopeptidase 9 (MMP9) in the neointimal area. Notably, rHDL administration resulted in decreased expression of VCAM1 and HIF1α, alongside increased expression of heme oxygenase 1 (HO1) and heat shock protein 27 (HSP27). Overexpression of HSP27 and HO1 effectively inhibited SMC proliferation. Moreover, rHDL-mediated suppression of injury-induced HIF1α coincided with upregulation of HSP27. Interestingly, HSP27 and HO1 had varying effects on the expression of chemokine receptors and rHDL did not exert significant effect on chemokine receptor expression in THP1 cells. These findings underscore the distinct roles of HSP27 and HO1 as potential regulatory factors in the progression of restenosis. Collectively, our study demonstrates that rHDL exerts a potent anti-neointimal hyperplasia effect by reducing leukocytes infiltration and SMC proliferation while promoting EC proliferation.

Integrated Analysis of Two Probucol Trials for the Secondary Prevention of Atherosclerotic Cardiovascular Events: PROSPECTIVE and IMPACT.

AIMS: In this study, we integrated two randomized control trials, PROSPECTIVE and IMPACT, to address the effect of probucol on cerebrocardiovascular events and carotid intima-media thickness (IMT) in Japanese, Korean, and Chinese patients with coronary artery disease (CAD). METHODS: A total of 1,025 patients from the PROSPECTIVE and IMPACT studies were enrolled. The time to the first major adverse cerebrocardiovascular event, in addition to carotid IMT and lipid levels, was compared between the control and probucol groups. RESULTS: In the integrated analysis, the adjusted hazard ratio (HR) and 95% confidence interval (CI) were 0.67 and 0.44-1.03, respectively, indicating a tendency to show the effect of probucol on cerebrocardiovascular events in secondary prevention. We also found no significant differences between the control and probucol groups in the mean IMT of the carotid arteries and its changes. However, we found a significant decrease in cerebrocardiovascular events in patients with reduced levels of HDL cholesterol (HDL-C) (≥ 6.25 mg/dL) compared with those with levels ＜6.25 mg/dL (p=0.024), without any increase in adverse events such as severe ventricular arrhythmias. CONCLUSION: We demonstrated a marginal effect of probucol on cerebrocardiovascular events in Asian patients with CAD, with reasonable safety profiles. A larger study may be needed to support the effect of probucol for cardiovascular prevention.

Effect of Probucol and/or Cilostazol on Carotid Intima Media Thickness in Patients with Coronary Heart Disease: A Randomized, Multicenter, Multinational Study.

AIM: In a prospective randomized multinational open blinded endpoint study, the long-term effects of probucol or probucol and cilostazol with statin on carotid mean intima media thickness (IMT) were evaluated for the first time. METHODS: Hypercholesterolemic patients with coronary artery disease were randomized to three groups and received study drugs for 3 years: the control with statin alone; the probucol group with statin and probucol; and the combo group with statin, probucol, and cilostazol. Primary efficacy endpoint was changes of mean carotid IMT at 3 years. Biomarkers, major adverse cerebro-cardiovascular events (MACCEs) and safety were secondary endpoints. RESULTS: Two hundred eighty-one patients were randomized into three groups. All three groups showed significant regression of carotid IMT at 3 years compared with baseline. Decrease in mean carotid IMT was significantly greater in the combo group than in the control group at 1 year. However, there were no significant differences in changes of mean carotid IMT between groups at 3 years (control; -0.12±0.36 mm vs. probucol; -0.11 ±0.32 mm vs. combo; -0.16±0.38 mm). MACCEs were frequent in the control group, but the difference was not significant (control; 10.8% vs. probucol; 4.4% vs. combo; 6.9%, p=0.35). Probucol and cilostazol were well tolerated in long-term treatment without serious drug-related adverse reactions. CONCLUSION: Probucol or probucol and cilostazol with statin did not reduce carotid IMT in comparison with statin alone in this study. However, the clinical outcome of probucol-based treatment with current standard statin treatment may need further studies.

An enquiry based on a standardised questionnaire into knowledge, awareness and preferences concerning the care of familial hypercholesterolaemia among primary care physicians in the Asia-Pacific region: the "Ten Countries Study".

OBJECTIVE: To determine physicians' knowledge, awareness and preferences regarding the care of familial hypercholesterolaemia (FH) in the Asia-Pacific region. SETTING: A formal questionnaire was anonymously completed by physicians from different countries/regions in the Asia-Pacific. The survey sought responses relating to general familiarity, awareness of management guidelines, identification (clinical characteristics and lipid profile), prevalence and inheritance, extent of elevation in risk of cardiovascular disease (CVD) and practice on screening and treatment. PARTICIPANTS: Practising community physicians from Australia, Japan, Malaysia, South Korea, Philippines, Hong Kong, China, Vietnam and Taiwan were recruited to complete the questionnaire, with the UK as the international benchmark. PRIMARY OUTCOME: An assessment and comparison of the knowledge, awareness and preferences of FH among physicians in 10 different countries/regions. RESULTS: 1078 physicians completed the questionnaire from the Asia-Pacific region; only 34% considered themselves to be familiar with FH. 72% correctly described FH and 65% identified the typical lipid profile, with a higher proportion of physicians from Japan and China selecting the correct FH definition and lipid profile compared with those from Vietnam and Philippines. However, less than half of the physician were aware of national or international management guidelines; this was significantly worse than physicians from the UK (35% vs 61%, p<0.001). Knowledge of prevalence (24%), inheritability (41%) and CVD risk (9%) of FH were also suboptimal. The majority of the physicians considered laboratory interpretative commenting as being useful (81%) and statin therapy as an appropriate cholesterol-lowering therapy (89%) for FH management. CONCLUSIONS: The study identified important gaps, which are readily addressable, in the awareness and knowledge of FH among physicians in the region. Implementation of country-specific guidelines and extensive work in FH education and awareness programmes are imperative to improve the care of FH in the region.

Genome-based exome sequencing analysis identifies GYG1, DIS3L and DDRGK1 are associated with myocardial infarction in Koreans.

Myocardial infarction (MI) is a complex disease caused by combination of genetic and environmental factors. Although genome-wide association studies (GWAS) identified more than 46 risk loci which are associated with coronary artery disease and MI, most of the genetic variability inMI still remains undefined. Here, we screened the susceptibility loci for MI using exome sequencing and validated candidate variants in replication sets. We identified that three genes (GYG1, DIS3L and DDRGK1) were associated with MI at the discovery and replication stages. Further research will be required to determine the functional association of these genes with MI risk, and these associations have to be confirmed in other ethnic populations.

Translational Research for Improving the Care of Familial Hypercholesterolemia: The "Ten Countries Study" and Beyond.

Familial hypercholesterolemia (FH) is the most common and serious form of inherited hyperlipidaemia. Dominantly inherited with high penetrance, untreated FH leads to premature death from coronary artery disease due to accelerated atherosclerosis from birth. Despite its importance, there is still a major shortfall in awareness, detection and treatment of FH worldwide. International models of care for FH have recently been published, but their effective implementation requires the garnering of more knowledge about the condition. The "Ten Countries Study" aims to investigate diagnostic, epidemiological and service aspects, as well as physician practices and patient experiences of FH in several countries in the Asia-Pacific Region and the Southern Hemisphere. Five observational studies are being undertaken that will systematically investigate the following aspects of FH: the phenotypic predictors of low-density lipoprotein receptor mutations, the point prevalence in available community populations, current knowledge and clinical practices among primary care physicians, availability and utilisation of services and facilities, and patient perceptions and personal experiences of the condition. The information gathered will inform better clinical practice and will enable the development of country-specific models of care for FH.

Valsartan 160 mg/Amlodipine 5 mg Combination Therapy versus Amlodipine 10 mg in Hypertensive Patients with Inadequate Response to Amlodipine 5 mg Monotherapy.

BACKGROUND AND OBJECTIVES: When monotherapy is inadequate for blood pressure control, the next step is either to continue monotherapy in increased doses or to add another antihypertensive agent. However, direct comparison of double-dose monotherapy versus combination therapy has rarely been done. The objective of this study is to compare 10 mg of amlodipine with an amlodipine/valsartan 5/160 mg combination in patients whose blood pressure control is inadequate with amlodipine 5 mg. SUBJECTS AND METHODS: This study was conducted as a multicenter, open-label, randomized controlled trial. Men and women aged 20-80 who were diagnosed as having hypertension, who had been on amlodipine 5 mg monotherapy for at least 4 weeks, and whose daytime mean systolic blood pressure (SBP) ≥135 mmHg or diastolic blood pressure (DBP) ≥85 mmHg on 24-hour ambulatory blood pressure monitoring (ABPM) were randomized to amlodipine (A) 10 mg or amlodipine/valsartan (AV) 5/160 mg group. Follow-up 24-hour ABPM was done at 8 weeks after randomization. RESULTS: Baseline clinical characteristics did not differ between the 2 groups. Ambulatory blood pressure reduction was significantly greater in the AV group compared with the A group (daytime mean SBP change: -14±11 vs. -9±9 mmHg, p<0.001, 24-hour mean SBP change: -13±10 vs. -8±8 mmHg, p<0.0001). Drug-related adverse events also did not differ significantly (A:AV, 6.5 vs. 4.5 %, p=0.56). CONCLUSION: Amlodipine/valsartan 5/160 mg combination was more efficacious than amlodipine 10 mg in hypertensive patients in whom monotherapy of amlodipine 5 mg had failed.

Heterogeneous effects of association between blood pressure loci and coronary artery disease in east Asian individuals.

BACKGROUND: A coronary artery disease (CAD) association study of genetic loci previously identified as being associated with blood pressure (BP) was performed in east Asian populations. METHODS AND RESULTS: Nine single nucleotide polymorphisms (SNPs) from 9 candidate loci robustly confirmed to be associated with BP in east Asian people, were genotyped. Genotyping was done in up to 17,785 CAD case-control samples (6,522 cases and 11,263 controls). We then tested the associations with other metabolic traits (n≤17,900) and with type 2 diabetes (931 cases and 1,404 controls), and looked up the datasets in silico in other populations. Significant (adjusted P<0.05) CAD associations were found for 5 BP loci: 3 new CAD associations at FIGN,FGF5 and NPR3, and 2 previously reported ones at ATP2B1 and CNNM2. The strongest CAD association was detected at ATP2B1rs2681472 (P=1.7×10(-8)), in the direction inverted to what is generally recognized for BP in the epidemiological studies.CNNM2rs12413409 showed significant association with CAD (P=8.7×10(-7)) and BMI (P=3.5×10(-8), when meta-analyzed with 75,807 east Asian people). The genetic risk score combining BP-raising alleles at each of the SNPs was positively associated with CAD (P=0.011). CONCLUSIONS: A substantial proportion of genetic variants associated with BP were also associated with the risk of CAD in east Asian people, and there was some counter-evidence for causal inference.

Primo vascular system in human umbilical cord and placenta.

The primo vascular system (PVS) has been observed in various animals such as mice, rats, rabbits, dogs, swine, and cow, but not in humans. In this work, we report on the observation of a human PVS on both the epithelial fascia and inside the blood vessels of the umbilical cord (UC). The main morphological characteristics of the primo vessels (PVs) and primo nodes (PNs) from the human UC were in agreement with those of the PVS in various animal organs, including the thicknesses and the transparency of the PVs, the sizes of the PNs, the broken-line arrangement of the rod-shaped nuclei, the sparse distribution of nuclei, and the presence of hollow lumens in the central inner parts of the PNs. It was rather surprising that the human PV was not thicker than the PVs from small animals. The difference between the PVS and blood/lymph vessels was confirmed using immunofluorescence staining of von Willebrand factor, CD31, LYVE-1, and D2-40. The positive expression of the PVS to proliferating cell nuclear antigen, a cell-proliferation marker, was consistent with the recent finding of very small embryonic-like stem cells in the PVS of mice.

Lipid-lowering treatment practice patterns in korea: comparison with the data obtained from the CEPHEUS Pan-Asian study.

AIM: The Pan-Asian CEPHEUS study assessed low-density lipoprotein cholesterol (LDL-C) goal attainment among patients under lipid-lowering therapy. We compared Korean and other Asian data in order to investigate international variations in clinical practice in the field of cardiology. METHODS: Hypercholesterolemic patients ≥18 years of age who had been on lipid-lowering treatment for ≥3 months were recruited from eight Asian countries. The lipid concentrations were measured, and demographic and other relevant data were collected. In addition, the cardiovascular risk was determined using criteria established in the updated 2004 NCEP guidelines. RESULTS: In Korea, 92 cardiologists enrolled 1,584 patients. The data of these patients were compared with those for 2,060 patients enrolled by 135 cardiologists from other Asian countries in the CEPHEUS study. The proportion of high-risk patients, frequency of use of more potent LDL-C-lowering regimens and rate of LDL-C goal attainment were significantly greater in the Korean subjects than those observed in the other Asian populations. In addition, the Korean patients were more likely to achieve the LDL-C target (odds ratio=1.37, 95% confidence interval 1.11-1.70) after adjusting for the LDL-C target level, use of potent LDL-C-lowering regimens, the baseline LDL-C level, age and systolic blood pressure. CONCLUSIONS: There was a significant difference in the goal attainment rate between Korea and the other Asian countries. Korean cardiologists appear to be relatively more aggressive with lipid-lowering treatment than other Asian cardiologists.

A novel molecular diagnostic marker for familial and early-onset coronary artery disease and myocardial infarction in the LRP8 gene.

BACKGROUND: Many single-nucleotide polymorphisms have been associated with coronary artery disease (CAD)/myocardial infarction (MI) by genome-wide association studies, but the diagnostic value of these variants is limited. Functional single-nucleotide polymorphism R952Q in LRP8 is associated with familial and early-onset CAD/MI. The objective of this study is to test whether fine mapping and haplotype analysis for single-nucleotide polymorphisms flanking R952Q may identify a haplotype that may serve as a molecular diagnostic marker for familial and early-onset CAD/MI. METHODS AND RESULTS: Five single-nucleotide polymorphisms (rs7546246, rs2297660, rs3737983, R952Q, and rs5177) were genotyped and analyzed in GeneQuest (381 patients with familial, early-onset CAD and 183 patients with MI versus 560 controls) and the Italian population (248 patients with familial MI versus 308 controls). One novel risk haplotype, TACGC, was found only in patients with CAD and MI but not in controls. It was significantly associated with CAD (P=7.4×10(-7)) and MI (P=2.2×10(-9)) in GeneQuest. The finding was replicated in the Italian cohort (P=0.041). Sib-transmission disequilibrium test analysis showed a significant association between haplotype TACGC and CAD in GeneQuest II (P=0.039). Haplotype TACGC was not present in a South Korean population of 611 patients with CAD and 294 normal controls. TACGC/TACGC homozygotes tended to develop CAD/MI earlier and showed higher low-density lipoprotein cholesterol levels than heterozygotes (P<0.05). CONCLUSIONS: The rare haplotype TACGC in LRP8 confers a significant risk of familial, early-onset CAD/MI. Because the risk haplotype exists only in patients with familial and early-onset CAD/MI, we propose that it may be a molecular diagnostic marker for diagnosis of familial, early-onset CAD/MI in some white populations.

Prediction of 4-year risk for coronary artery calcification using ensemble-based classification.

The progression of coronary artery calcification (CAC) has been regarded as an important risk factor of coronary artery disease (CAD), which is the biggest cause of death. Because CAC occurrence increases the risk of CAD by a factor of ten, the one whose coronary artery is calcified should pay more attention to the health management. However, performing the computerized tomography (CT) scan to check if coronary artery is calcified as a regular examination might be inefficient due to its high cost. Therefore, it is required to identify high risk persons who need regular follow-up checks of CAC or low risk ones who can avoid unnecessary CT scans. Due to this reason, we develop a 4-year prediction model for a new occurrence of CAC based on data collected by the regular health examination. We build the prediction model using ensemble-based methods to handle imbalanced dataset. Experimental results show that the developed prediction models provided a reasonable accuracy (AUC 75%), which is about 5% higher than the model built by the other imbalanced classification method.

Lipoteichoic acid isolated from Lactobacillus plantarum suppresses LPS-mediated atherosclerotic plaque inflammation.

Chronic inflammation plays an important role in atherogenesis. Experimental studies have demonstrated the accumulation of monocytes/macrophages in atherosclerotic plaques caused by inflammation. Here, we report the inhibitory effects of lipoteichoic acid (LTA) from Lactobacillus plantarum (pLTA) on atherosclerotic inflammation. pLTA inhibited the production of proinflammatory cytokines and nitric oxide in lipopolysaccharide (LPS)-stimulated cells and alleviated THP-1 cell adhesion to HUVEC by down-regulation of adhesion molecules such as intracellular adhesion molecule-1 (ICAM-I), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. The inhibitory effect of pLTA was mediated by inhibition of NF-κB and activation of MAP kinases. Inhibition of monocyte/macrophage infiltration to the arterial lumen was shown in pLTA-injected ApoE(-/-) mice, which was concurrent with inhibition of MMP-9 and preservation of CD31 production. The antiinflammatory effect mediated by pLTA decreased expression of atherosclerotic markers such as COX-2, Bax, and HSP27 and also cell surface receptors such as TLR4 and CCR7. Together, these results underscore the role of pLTA in suppressing atherosclerotic plaque inflammation and will help in identifying targets with therapeutic potential against pathogen-mediated atherogenesis.

Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: a collaborative meta-analysis.

OBJECTIVES: This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD. BACKGROUND: Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. METHODS: We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects. RESULTS: We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele. CONCLUSIONS: The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.

Peripheral artery disease in korean patients undergoing percutaneous coronary intervention: prevalence and association with coronary artery disease severity.

Peripheral artery disease (PAD) is an important marker for the risk stratification of patients with coronary artery disease (CAD). We investigated the prevalence of PAD in patients undergoing percutaneous coronary intervention (PCI) with CAD and the relationship between ankle-brachial pressure index (ABPI) and CAD severity. A total of 711 patients undergoing PCI for CAD from August 2009 to August 2011 were enrolled. PAD diagnosis was made using the ABPI. The prevalence of PAD was 12.8%. In PAD patients, mean values of right and left ABPI were 0.71 ± 0.15 and 0.73 ± 0.15. Patients with PAD had a higher prevalence of left main coronary disease (14.3% vs 5.8%, P = 0.003), more frequently had multivessel lesions (74.9% vs 52.1%, P < 0.001) and had higher SYNTAX score (18.2 ± 12.3 vs 13.1 ± 8.26, P = 0.002). Using multivariate analysis, we determined that left main CAD (OR, 2.954; 95% CI, 1.418-6.152, P = 0.004) and multivessel CAD (OR, 2.321; 95% CI, 1.363-3.953, P = 0.002) were both independently associated with PAD. We recommend that ABPI-based PAD screening should be implemented in all patients undergoing PCI with CAD, especially in severe cases.

Novel SCN3B mutation associated with brugada syndrome affects intracellular trafficking and function of Nav1.5.

BACKGROUND: Brugada syndrome (BrS) is characterized by specific alterations on ECG in the right precordial leads and associated with ventricular arrhythmia that may manifest as syncope or sudden cardiac death. The major causes of BrS are mutations in SCN5A for a large subunit of the sodium channel, Nav1.5, but a mutation in SCN3B for a small subunit of sodium channel, Navß3, has been recently reported in an American patient. METHODS AND RESULTS: A total of 181 unrelated BrS patients, 178 Japanese and 3 Koreans, who had no mutations in SCN5A, were examined for mutations in SCN3B by direct sequencing of all exons and adjacent introns. A mutation, Val110Ile, was identified in 3 of 178 (1.7%) Japanese patients, but was not found in 480 Japanese controls. The SCN3B mutation impaired the cytoplasmic trafficking of Nav1.5, the cell surface expression of which was decreased in transfected cells. Whole-cell patch clamp recordings of the transfected cells revealed that the sodium currents were significantly reduced by the SCN3B mutation. CONCLUSIONS: The Val110Ile mutation of SCN3B is a relatively common cause of SCN5A-negative BrS in Japan, which has a reduced sodium current because of the loss of cell surface expression of Nav1.5.

Carina shift versus plaque shift for aggravation of side branch ostial stenosis in bifurcation lesions: volumetric intravascular ultrasound analysis of both branches.

BACKGROUND: Although carina shift and plaque shift are suggested as mechanisms of side branch ostial (SBo) compromise after main vessel (MV) stenting in bifurcation lesions, there are few direct evidence. Our purpose was to confirm the mechanism of SBo compromise after MV stent implantation. METHODS AND RESULTS: Intravascular ultrasound images of both MV and SB before procedure and immediately after MV stenting were evaluated in 44 bifurcation lesions. Three 5 mm segments of interest were volumetrically analyzed: the proximal MV, distal MV, and SBo. SBo compromise was defined as a lumen volume decrease, carina shift as a vessel volume decrease, and plaque shift as a plaque volume increase in the SBo segment after MV stenting. The vessel volume increased, and the plaque volume decreased significantly in the proximal MV and distal MV. In contrast, in the SBo, the vessel volume decreased (53.0±17.5 mm(3) versus 50.4±16.2 mm(3); P<0.001), with the accompanying small increase in plaque volume (23.0±9.8 mm(3) versus 23.4±9.8 mm(3); P<0.001). The SBo compromise was significantly correlated with the carina shift (r=0.941; P<0.001), but not with the plaque shift (r=-0.019, P=0.90). Distal MV lumen volume increase was significantly correlated with SBo compromise (r=0.555; P<0.001) and carina shift (r=0.557; P<0.001), but not plaque shift (r=-0.228; P=0.14). CONCLUSIONS: Our study indicates that carina shift, not plaque shift, is the major mechanism of SBo compromise after MV stent implantation, and the carina shift is primarily influenced by distal MV lumen expansion.

A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5.

BACKGROUND: Mutations in genes including SCN5A encoding the α-subunit of the cardiac sodium channel (hNav1.5) cause Brugada syndrome via altered function of cardiac ion channels, but more than two-thirds of Brugada syndrome remains pathogenetically elusive. T-tubules and sarcoplasmic reticulum are essential in excitation of cardiomyocytes, and sarcolemmal membrane-associated protein (SLMAP) is a protein of unknown function localizing at T-tubules and sarcoplasmic reticulum. METHODS AND RESULTS: We analyzed 190 unrelated Brugada syndrome patients for mutations in SLMAP. Two missense mutations, Val269Ile and Glu710Ala, were found in heterozygous state in 2 patients but were not found in healthy individuals. Membrane surface expression of hNav1.5 in the transfected cells was affected by the mutations, and silencing of mutant SLMAP by small interfering RNA rescued the surface expression of hNav1.5. Whole-cell patch-clamp recordings of hNav1.5-expressing cells transfected with mutant SLMAP confirmed the reduced hNav1.5 current. CONCLUSIONS: The mutations in SLMAP may cause Brugada syndrome via modulating the intracellular trafficking of hNav1.5 channel.

Simvastatin and losartan differentially and synergistically inhibit atherosclerosis in apolipoprotein e(-/-) mice.

BACKGROUND AND OBJECTIVES: Since statins and angiotensin receptor blockers are a frequently prescribed combination in patients with atherosclerotic cardiovascular diseases, we tested the interactive effects of simvastatin and losartan on atherosclerosis in apolipoprotein E (apoE)(-/-) mice. MATERIALS AND METHODS: Apolipoprotein E(-/-) mice were fed a high-fat, high-cholesterol (HFHC) diet for 12 weeks, with and without simvastatin (40 mg/kg) and/or losartan (20 mg/kg). The mice were divided into 5 groups and were fed as follows: regular chow (control diet, n=5), HFHC diet (n=6), HFHC diet with losartan (n=6), HFHC diet with simvastatin (n=6), and HFHC diet with both losartan and simvastatin (n=6). RESULTS: Losartan treatment in apoE(-/-) mice significantly decreased atherosclerotic lesion areas in whole aortic strips stained with Oil Red O. The plaque area measured at the aortic sinus level was reduced significantly by 17% (HFHC; 346830.9±52915.8 µm(2) vs. HFHC plus losartan; 255965.3±74057.7 µm(2), p<0.05) in the losartan-treated group. Simvastatin and simvastatin plus losartan treatments reduced macrophage infiltration into lesions by 33% (HFHC; 183575.6±43211.2 µm(2) vs. HFHC plus simvastatin; 120556.0±39282.8 µm(2), p<0.05) and 44% (HFHC; 183575.6±43211.2 µm(2) vs. HFHC plus simvastatin and losartan; 103229.0±8473.3 µm(2), p<0.001, respectively). In mice fed the HFHC diet alone, the smooth muscle cell layer in the aortic media was almost undetectable. In mice co-treated with losartan and simvastatin, the smooth muscle layer was more than 60% preserved (p<0.05). Given alone, losartan showed a slightly stronger effect than simvastatin; however, treatment with losartan plus simvastatin induced a greater inhibitory effect on atherosclerosis than either drug given alone. Serum lipid profiles did not differ significantly among the groups. CONCLUSION: Losartan displayed anti-atherosclerotic effects in apoE(-/-) mice that were equivalent to or greater than the effects of simvastatin. Combined treatment with these drugs had greater effect than either drug alone.