Tzung-Dau Wang

Efficacy of fenofibrate and simvastatin on endothelial function and inflammatory markers in patients with combined hyperlipidemia: relations with baseline lipid profiles

Given that combination therapy with statin plus fibrate confers a risk of myopathy, it is worthwhile to determine whether statin or fibrate monotherapy is associated with greater clinical benefit in individuals with combined hyperlipidemia. In this randomized double-blind study, we compared the efficacy of simvastatin and fenofibrate on indexes of endothelial function (flow-mediated dilation (FMD) of the brachial artery) and inflammatory markers (plasma high-sensitivity C-reactive protein (CRP), interleukin-1 beta (IL-1 beta), soluble CD40, and soluble CD40 ligand (sCD40L) levels), as surrogate indicators of future coronary heart disease (CHD), in patients with combined hyperlipidemia. A total of 70 patients with plasma triglyceride levels between 200 and 500 mg/dl and total cholesterol levels of >200 mg/dl were randomly assigned to receive either simvastatin (20 mg/day) (n=35) or micronized fenofibrate (200 mg/day) (n=35) for 8 weeks. Treatment with simvastatin was associated with significantly greater reduction of total cholesterol and low-density lipoprotein cholesterol (LDL-C), while the decrease in triglycerides was significantly greater in patients receiving fenofibrate. Both fenofibrate and simvastatin markedly reduced plasma levels of high-sensitivity CRP, IL-1 beta, and sCD40L, and improved endothelium-dependent FMD without mutual differences. The changes in plasma inflammatory markers did not correlate with baseline clinical characteristics in both groups. However, the improvement in FMD with fenofibrate treatment correlated inversely with baseline high-density lipoprotein cholesterol (HDL-C) levels, whereas the improvement in FMD with simvastatin treatment was positively related to HDL-C levels. Accordingly, in the subgroup with a baseline HDL-C of < or =40 mg/dl, only fenofibrate significantly improved the endothelium-dependent FMD. On the other hand, in the subgroup with HDL-C >40 mg/dl, only treatment with simvastatin achieved significant improvement in FMD. The data here indicate that in patients with combined hyperlipidemia, both fenofibrate and simvastatin have comparative beneficial effects on various inflammatory markers and differential beneficial effects on endothelial function according to baseline HDL-C levels. These findings should be validated by additional prospective studies, in which patients are stratified by baseline HDL-C prior to randomization.

Relations of Epicardial Adipose Tissue Measured by Multidetector Computed Tomography to Components of the Metabolic Syndrome Are Region-Specific and Independent of Anthropometric Indexes and Intraabdominal Visceral Fat

CONTEXT Epicardial adipose tissue (EAT) is a metabolically active visceral fat depot. Its distribution is asymmetrical and primarily concentrated in the grooves. To date, it remains unclear which measurement of EAT best reflects its metabolic risk. OBJECTIVE We aimed to examine the correlations between various multidetector computed tomographic measurements of EAT, metabolic syndrome components, and plasma levels of high-sensitivity C-reactive protein and adipokines. DESIGN, SETTING, AND PARTICIPANTS This study included 148 consecutive patients undergoing multidetector computed tomography prior to diagnostic coronary angiography. Thickness in the grooved segments, cross-sectional areas, and total volume of EAT were measured. The cross-sectional areas of sc and visceral abdominal fat depots were additionally measured in 70 randomly selected patients. RESULTS Thickness of EAT in the left atrioventricular groove was the only EAT measurement significantly correlated with all three metabolic syndrome components (blood pressure, lipid, and glucose components) and plasma levels of resistin and high-sensitivity C-reactive protein after age and gender adjustments. The association between left atrioventricular groove thickness and increasing number of metabolic syndrome components remained significant after additional adjustments for body mass index, waist circumference, and intraabdominal visceral fat area. By using the receiver operating characteristic analysis, the optimal cutoff point for left atrioventricular groove thickness to predict the presence of at least two metabolic syndrome components was 12.4 mm. CONCLUSIONS A simple measurement of EAT thickness in the left atrioventricular groove may provide a more accurate assessment of metabolic risk associated with EAT, which could not be accounted for by anthropometric indexes and intraabdominal visceral fat.

Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.

Genome-wide association studies (GWAS) have identified ∼100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10−4 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.

Circulating levels of markers of inflammation and endothelial activation are increased in men with chronic spinal cord injury.

BACKGROUND/PURPOSE Accelerated atherogenesis is often seen in individuals with chronic spinal cord injury (SCI). However, the mechanisms contributing to this phenomenon remain unclear. This study aimed to evaluate whether SCI per se is associated with a low-grade chronic inflammatory state and endothelial activation, both of which are well-documented prerequisites for atherogenesis. METHODS Serum levels of markers of inflammation (C-reactive protein [CRP], interleukin-6, and soluble CD40 ligand) and endothelial activation (endothelin-1, soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 [sVCAM-1]) were measured in SCI patients with CRP levels < 10 mg/L and with no evidence of active infection. Sixty-two men with traumatic neurologically complete SCI (20 tetraplegics and 42 paraplegics) and 29 age-matched male controls were enrolled. RESULTS Compared with able-bodied controls, subjects with SCI had a significantly lower body mass index (BMI) (-7%) and significantly lower serum levels of albumin (-10%), creatinine (-20%), low-density lipoprotein cholesterol (-10%), and high-density lipoprotein (HDL) cholesterol (-25%), and showed a trend toward higher fasting insulin levels. Irrespective of injury level and duration, subjects with SCI had significantly higher serum levels, compared to able-bodied controls, of CRP (mean, 4.0 +/- 2.7 mg/L vs. 1.4 +/- 1.1 mg/L), interleukin-6 (median, 2.5 pg/mL vs. 0.4 pg/mL; range, 1.5-3.6 pg/mL vs. 0.2-0.5 pg/mL), endothelin-1 (mean, 1.3 +/- 0.4 pg/mL vs. 0.9 +/- 0.3 pg/mL), and sVCAM-1 (mean, 1170 +/- 318 ng/mL vs. 542 +/- 318 ng/mL). The serum levels of all four factors correlated negatively with levels of serum albumin, creatinine and HDL cholesterol, but not with BMI or fasting insulin levels. In multivariate analyses, SCI was the only factor that was independently associated with increased serum levels of CRP, interleukin-6, endothelin-1 and sVCAM-1 after adjustment for confounding factors such as serum albumin and creatinine levels and parameters of dyslipidemia and insulin resistance. CONCLUSION In this study, we have, for the first time, demonstrated that SCI per se is associated with a low-grade chronic inflammatory state and endothelial activation, which may partly explain the increased atherogenic risk in patients with long-standing SCI.

Association of epicardial adipose tissue with coronary atherosclerosis is region-specific and independent of conventional risk factors and intra-abdominal adiposity

OBJECTIVE To elucidate which measurement of epicardial adipose tissue (EAT) best reflects its atherogenic risk, we examined the associations between different EAT measurements and various atherosclerotic parameters of the entire coronary tree and individual coronary arteries. METHODS This study included 224 consecutive patients underwent multidetector computed tomography before diagnostic coronary angiography. Regional thickness, cross-sectional areas, and total volume of EAT were measured. Four atherosclerotic parameters, including severity score, extent score, calcium volume score, and number of coronary arteries with ≥50% luminal stenosis, of the entire coronary tree and individual coronary arteries were assessed. RESULTS Both total EAT volume and thickness of EAT in the left atrioventricular groove were unanimously associated with the presence of coronary atherosclerosis dichotomously defined by the 4 scoring systems. However, only EAT thickness in the left atrioventricular groove, but not total EAT volume, was significantly associated with all 4 parameters of coronary atherosclerosis in a dose-dependent manner, even after adjustments for conventional risk factors, body-mass index, waist circumference, C-reactive protein, and intra-abdominal visceral fat area. Using the receiver-operating-characteristic analysis, 12.2mm was the optimal cutoff point for left atrioventricular groove thickness to predict the presence of significant coronary stenosis (≥50% diameter stenosis). Among the three coronary arteries, left atrioventricular groove thickness was most strongly correlated with ≥50% diameter stenosis in the embedded left circumflex artery by multivariate regression model. CONCLUSIONS Thickness of EAT in the left atrioventricular groove provides a more accurate assessment of its atherogenic risk and is therefore a better coronary risk factor than total EAT volume.

Myocardial stunning after cerebral infarction

Myocardial stunning has not been described in patients with cerebrovascular accidents. We present a patient in whom inferior wall hypokinesis, ST-segment elevations and Q waves developed after acute right hemisphere ischemic stroke. Total recovery ensued within 5 days. Coronary vasospasm induced by stroke-related sympathetic surge might be the cause of this cardiac event.

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP–CAD associations (P < 5 × 10−8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

Cardioprotective effect of therapeutic hypothermia for postresuscitation myocardial dysfunction.

Mild-to-moderate therapeutic hypothermia after resuscitation from cardiac arrest is neuroprotective, but its effect on postresuscitation myocardial dysfunction is not clear. We hypothesized that therapeutic hypothermia is cardioprotective in postresuscitation. Male adult Wistar rats underwent asphyxia-induced cardiac arrest and manual resuscitation with epinephrine. Therapeutic hypothermia is induced immediately after successful resuscitation and the return of spontaneous circulation (ROSC). One hour after ROSC, the rats achieved a target temperature of 30°C to 31°C, which was maintained for 1.5 h and then transitioned to the passive rewarming process in the hypothermia group. A temperature between 36.5°C and 37.5°C was maintained in the normothermia group. Echocardiography revealed that hypothermia resulted in significantly better systolic function of fractional shortening in 60 and 120 min after ROSC (both P < 0.05). The benefit of cardioprotection was also confirmed by the general linear mixed-models analysis of dP/dt, which revealed significantly better systolic function in positive dP/dtR(40) and diastolic function in maximal negative dP/dt (both P < 0.001). The 4-h and 3-day survival analyses both revealed better outcomes in the hypothermia groups in the log-rank test (P < 0.001 for the 4-h analysis, and P < 0.05 for the 3-day analysis). Serum level of heart-type, fatty acid-binding protein at 4 h after resuscitation as the myocardium damage marker was also significantly lower in the hypothermia group (52.4 ng/mL vs 186.5 ng/mL in the normothermia group; P < 0.05). Western blotting of myocardium showed that myocardial Akt and ERK1/2 were more activated in the hypothermia group 2 h after spontaneous circulation returned. In conclusion, postresuscitation mild-to-moderate therapeutic hypothermic is cardioprotective in the asphyxia-induced cardiac arrest animal model. It stabilizes hemodynamics, improves short-term survival, and decreases myocardial damage. The cardioprotective effect is associated with Akt and ERK1/2 activation in signal transduction.

Increased cardiomyocyte apoptosis following ischemia and reperfusion in diet-induced hypercholesterolemia: relation to Bcl-2 and Bax proteins and caspase-3 activity.

It has been reported that apoptosis is a significant contributor to myocardial cell death as a result of reperfusion injury. However, whether the extent of cardiomyocyte apoptosis following ischemia and reperfusion varies in different pathophysiological backgrounds is still uncertain. In this study, we examined whether hypercholesterolemia increases the extent of myocardial reperfusion injury by aggravating cardiomyocyte apoptosis and the effects of hypercholesterolemia on the expression of Bcl-2 and Bax proteins and the activation of caspase-3. Twenty-eight male New Zealand white rabbits were fed standard chow (control, n=14) or chow supplemented with 1% cholesterol (hypercholesterolemic, n=14) for 8 wk. Anesthetized rabbits were then subjected to 30 min of left circumflex artery occlusion followed by 4 h of reperfusion. Apoptosis was identified as “DNA ladders” by gel electrophoresis and confirmed histologically using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. The infarct size (% of risk region) was significantly greater in hypercholesterolemic rabbits than in controls (39±6 vs. 23±2%, P=0.02). Very few TUNEL-positive cardiomyocytes could be identified in the nonischemic regions in both groups, consistent with an absence of DNA laddering. In contrast, TUNEL-positive cardiomyocytes were significantly displayed in the ischemic, nonnecrotic myocardium, and DNA ladder occurred in all animals. The percentage of TUNEL-positive cardiomyocytes in the ischemic nonnecrotic myocardium was significantly higher in hypercholesterolemic rabbits compared with controls (40±5 vs. 17±1%, P<0.001). Western blot analysis showed that, in the nonischemic myocardium, hypercholesterolemic rabbits exhibited an approximately 50% increase in the expression of Bcl-2 (P<0.05), but not Bax, than control rabbit. However, compared with controls, hypercholesterolemic rabbits exhibited a more pronounced decrease in the expression of Bcl-2 (42±4 vs. 26±2%, P<0.01) and a similar extent of increase in the expression of Bax in the ischemic myocardium. Furthermore, hypercholesterolemic rabbits were associated with a markedly increased activation of caspase-3 within the ischemic myocardium compared to control rabbits. This study demonstrates that although hypercholesterolemia is associated with an increased myocardial Bcl-2/Bax ratio at baseline, it still significantly exacerbates cardiac reperfusion injury, not only by increasing the infarct size but also by increasing the extent of cardiomyocyte apoptosis.

Attenuation of increased myocardial ischaemia-reperfusion injury conferred by hypercholesterolaemia through pharmacological inhibition of the caspase-1 cascade

Hypercholesterolaemia has been shown to be associated with greater myocardial ischaemia‐reperfusion injury, in which apoptosis and inflammation‐mediated necrosis both play a key role. Caspase‐1 is involved in the activation of both apoptosis and inflammation, through the intermediate of interleukin‐1β (IL‐1β). We herein examined whether pharmacological inhibition of the caspase‐1 cascade, using Ac‐Tyr‐Val‐Ala‐Asp‐CH2Cl (Ac‐YVAD.cmk), after myocardial ischaemia have greater protective effects on myocardial ischaemia‐reperfusion injury in diet‐induced hypercholesterolaemic rabbits. Male rabbits fed with standard chow or chow supplemented with 0.5% cholesterol and 10% coconut oil for 8 weeks were subjected to 30 min of left circumflex artery occlusion followed by 4 h of reperfusion. An intravenous bolus of Ac‐YVAD.cmk (1.6 mg kg−1) or vehicle was given 20 min after coronary occlusion. Postischaemic administration of Ac‐YVAD.cmk markedly decreased infarct size from 26±3% to 12±2% in normally fed rabbits (P=0.005) and from 41±6% to 14±2% in cholesterol‐fed rabbits (P<0.001). In the ischaemic non‐necrotic area, treatment with Ac‐YVAD.cmk markedly reduced the percentage of terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end labelling (TUNEL)‐positive cardiomyocytes from 15.5±0.8% to 2.2±0.1% in normally fed rabbits (P<0.001) and from 39.0±2.3% to 2.2±0.1% in cholesterol‐fed rabbits (P<0.001). Ac‐YVAD.cmk treatment resulted in a reduction not only of IL‐1β and caspase‐1, but also of caspase‐3 in the ischaemic myocardium in both normally fed and cholesterol‐fed rabbits. No differences in infarct size, the percentage of TUNEL‐positive cardiomyocytes, IL‐1β levels or activity of caspase‐1 and caspase‐3 were observed between Ac‐YVAD.cmk‐treated normally fed and cholesterol‐fed rabbits. This study demonstrates that injection of a selective caspase‐1 inhibitor after myocardial ischaemia markedly reduced the detrimental effect conferred by hypercholesterolaemia on myocardial ischaemia‐reperfusion injury by attenuating both necrotic as well as apoptotic cell death pathways through inhibition of IL‐1β production and activation of caspase‐1 and caspase‐3.