Wei-Chuan Tsai

Effects of oxidative stress on endothelial function after a high-fat meal

Postprandial lipaemia is known to cause endothelial dysfunction, but its underlying mechanism is still under debate. The present study was undertaken to investigate the effects of postprandial lipaemia on endothelial dysfunction and oxidative stress. We measured plasma glutathione peroxidase (GSH-Px), an antioxidant enzyme, and the urinary excretion of 8-epi-prostaglandin F2alpha (8-PGF2alpha), a free radical-catalysed product from the oxidative modification of arachidonic acid, in 16 healthy subjects (mean age, 30 +/- 5 years) without major coronary risk factors. Plasma high-sensitive C-reactive protein, soluble intercellular cell-adhesion molecule-1 and vascular cell-adhesion molecule-1 were also measured. High-resolution ultrasound was used to assess the flow-mediated vasodilatation (FMD) of the brachial artery. Blood and urine samples were collected before and 2, 4 and 6 h after a standard high-fat meal (3677 J, containing 50 g of fat). Serum triacylglycerol (triglyceride) increased and FMD decreased significantly after a high-fat meal. Plasma GSH-Px significantly decreased from 27.2 +/- 12.3 microg/ml to 25.7 +/- 11.8 microg/ml (P=0.022) 2 h after the meal, and urinary excretion of 8-PGF2alpha significantly increased from 1286 +/- 1401 pg/mg of creatinine to 2197 +/- 1343 pg/mg of creatinine (P=0.014) at 4 h after the meal. However, there were no significant changes in the levels of high-sensitive C-reactive protein and adhesion molecules after a high-fat meal. In conclusion, endothelial dysfunction was observed after consuming a high-fat meal and is associated with augmented oxidative stress manifested by the depletion of serum antioxidant enzymes and increased excretion of oxidative modification products.

A Genome-Wide Association Study Reveals a Quantitative Trait Locus of Adiponectin on CDH13 That Predicts Cardiometabolic Outcomes

OBJECTIVE The plasma adiponectin level, a potential upstream and internal facet of metabolic and cardiovascular diseases, has a reasonably high heritability. Whether other novel genes influence the variation in adiponectin level and the roles of these genetic variants on subsequent clinical outcomes has not been thoroughly investigated. Therefore, we aimed not only to identify genetic variants modulating plasma adiponectin levels but also to investigate whether these variants are associated with adiponectin-related metabolic traits and cardiovascular diseases. RESEARCH DESIGN AND METHODS We conducted a genome-wide association study (GWAS) to identify quantitative trait loci (QTL) associated with high molecular weight forms of adiponectin levels by genotyping 382 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 SNP chips. The culpable single nucleotide polymorphism (SNP) variants responsible for lowered adiponectin were then confirmed in another 559 YOH subjects, and the association of these SNP variants with the risk of metabolic syndrome (MS), type 2 diabetes mellitus (T2DM), and ischemic stroke was examined in an independent community–based prospective cohort, the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS, n = 3,350). RESULTS The SNP (rs4783244) most significantly associated with adiponectin levels was located in intron 1 of the T-cadherin (CDH13) gene in the first stage (P = 7.57 × 10−9). We replicated and confirmed the association between rs4783244 and plasma adiponectin levels in an additional 559 YOH subjects (P = 5.70 × 10−17). This SNP was further associated with the risk of MS (odds ratio [OR] = 1.42, P = 0.027), T2DM in men (OR = 3.25, P = 0.026), and ischemic stroke (OR = 2.13, P = 0.002) in the CVDFACTS. CONCLUSIONS These findings indicated the role of T-cadherin in modulating adiponectin levels and the involvement of CDH13 or adiponectin in the development of cardiometabolic diseases.

Evidence of Left Ventricular Systolic Dysfunction Detected by Automated Function Imaging in Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction

BACKGROUND Left ventricular ejection fraction (LVEF) cannot reflect cardiac contractile function in patients with heart failure and preserved LVEF (HFPEF). LV systolic impairment is actually debated in HFPEF patients. Automated function imaging (AFI) is a novel algorithm of speckle-tracking echocardiography and efficiently to assess global LV peak systolic longitudinal strain (PSLS), an index for systolic function. The purpose of the study is to examine whether contractile function is impaired in HFPEF patients. METHODS AND RESULTS This study included 49 heart failure patients (23 with systolic dysfunction [SHF] and 26 with HFPEF), and 40 patients, matched for age, sex, as well as concomitant disease and without heart failure as controls. All patients underwent transthoracic echocardiography. LVEF was measured by Simpsons method. Two-dimensional speckle tracking imaging with AFI assessment was applied to measure longitudinal strain. LVEF was 66+/-5% in the controls, 63+/-8% in the HFPEF group (P=.14), and 34+/-10% in the SHF group (P < .001). The value of LV global PSLS (controls: -20%, HFPEF: -14%, SHF: -8%, P < .001) was significantly less negative in both heart failure groups. CONCLUSIONS Deteriorated LV systolic function is demonstrated by decreased global PSLS in HFPEF patients. AFI is an effective and facile method for assessing LV systolic abnormalities.

Genome-Wide Association Study of Young-Onset Hypertension in the Han Chinese Population of Taiwan

Young-onset hypertension has a stronger genetic component than late-onset counterpart; thus, the identification of genes related to its susceptibility is a critical issue for the prevention and management of this disease. We carried out a two-stage association scan to map young-onset hypertension susceptibility genes. The first-stage analysis, a genome-wide association study, analyzed 175 matched case-control pairs; the second-stage analysis, a confirmatory association study, verified the results at the first stage based on a total of 1,008 patients and 1,008 controls. Single-locus association tests, multilocus association tests and pair-wise gene-gene interaction tests were performed to identify young-onset hypertension susceptibility genes. After considering stringent adjustments of multiple testing, gene annotation and single-nucleotide polymorphism (SNP) quality, four SNPs from two SNP triplets with strong association signals (−log10(p)>7) and 13 SNPs from 8 interactive SNP pairs with strong interactive signals (−log10(p)>8) were carefully re-examined. The confirmatory study verified the association for a SNP quartet 219 kb and 495 kb downstream of LOC344371 (a hypothetical gene) and RASGRP3 on chromosome 2p22.3, respectively. The latter has been implicated in the abnormal vascular responsiveness to endothelin-1 and angiotensin II in diabetic-hypertensive rats. Intrinsic synergy involving IMPG1 on chromosome 6q14.2-q15 was also verified. IMPG1 encodes interphotoreceptor matrix proteoglycan 1 which has cation binding capacity. The genes are novel hypertension targets identified in this first genome-wide hypertension association study of the Han Chinese population.

G-33A Mutation in the Promoter Region of Thrombomodulin Gene and Its Association With Coronary Artery Disease and Plasma Soluble Thrombomodulin Levels

Thrombomodulin is an endothelial glycoprotein that decreases thrombin activity and activates protein C. A recent study has shown that G-33A promoter mutation of the thrombomodulin gene occurs particularly in Asians. In this study, we analyzed the distribution of G-33A mutation in the promoter region of the thrombomodulin gene in the Chinese population and determined whether the mutation might be a risk for coronary artery disease (CAD). In addition, the influence of this mutation on plasma soluble thrombomodulin levels in patients with CAD was also examined. We studied 320 consecutive patients (mean age 63 years; 73% men) with CAD and 200 age- and sex-matched control subjects. Screening for thrombomodulin G-33A promoter mutation was conducted using polymerase chain reaction, single-strand conformation polymorphism, and direct deoxyribonucleic acid sequencing. The frequency of the G-33A mutation (GA+AA genotypes) was significantly higher in the CAD group (23.8% vs 15.5%, odds ratio [OR] 1.70, p = 0.031). Multiple logistic regression analysis showed that the mutation was an independent risk factor (OR 1.81, p = 0.016) for CAD, as was hypertension (OR 1.44, p = 0.040), diabetes mellitus (OR 2.50, p <0.001), and smoking (OR 2.15, p <0.001). In CAD patients with GG genotype, the soluble thrombomodulin level increased with the extent of CAD (36 +/- 15 vs 47 +/- 18 vs 55 +/- 36 ng/ml in 1-, 2-, or 3-vessel CAD, p <0.001). However, in CAD patients with G-33A mutation, there was no difference between the levels of soluble thrombomodulin (39 +/- 17 vs 37 +/- 15 vs 42 +/- 18 ng/ml, p = NS) in 1-, 2-, or 3-vessel CAD. Our observations suggest that there is a significant association of the G-33A mutation in thrombomodulin gene with CAD, and this mutation may influence the soluble thrombomodulin levels in patients with CAD.

Left Ventricular Systolic Strain in Chronic Kidney Disease and Hemodialysis Patients

Background: The impact of chronic kidney disease (CKD) and hemodialysis on heart function is not fully understood. We aimed to investigate the influence of different stages of CKD and maintenance hemodialysis on heart function. Methods: One hundred fifty-three patients were categorized into 3 subgroups [56 without CKD as controls; 37 with moderate-advanced CKD, stages 3, 4 or 5, and 60 with end-stage renal disease (ESRD) undergoing maintenance hemodialysis]. Left ventricular (LV) function was assessed by conventional echocardiography and 2-dimensional speckle-tracking echocardiography with strain analysis (2D strain analysis). Results: There was no significant difference of gender, age and LV ejection fraction among groups. Compared with controls, global peak systolic longitudinal strain (GSl), circumferential strain and strain rate were decreased in the CKD group. Along with the decline of renal function, GSl deteriorated. Moreover, compared with moderate-advanced CKD patients, GSl, circumferential strain and strain rate were better in ESRD group receiving maintenance hemodialysis. Conclusions: Worsening renal function was associated with a reduction of systolic function, and could be quantified by 2D strain analysis. The hemodialysis patients have better LV systolic function than the moderate-advanced CKD patients.

Association of Left Ventricular Longitudinal Strain with Mortality among Stable Hemodialysis Patients with Preserved Left Ventricular Ejection Fraction

BACKGROUND AND OBJECTIVES Little is known about the optimal echocardiographic parameters for risk stratification in stable dialysis patients with preserved left ventricular ejection fraction (LVEF) (ejection fraction ≥ 50%). Left ventricular (LV) global peak systolic longitudinal strain (GLS) is the ratio of the maximal change in myocardial longitudinal length in systole to the original length and reliably and accurately assesses LV function. During systole, LV myocardium in the longitudinal direction shortens and GLS is represented by a negative value. The more negative value of GLS, the better the LV function is. This study hypothesized that subtle abnormalities of GLS are associated with an adverse prognosis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This prospective study collected clinical and echocardiographic data (including GLS) from 88 stable hemodialysis patients (mean age 67.0 ± 11.2 years; 35% men) with preserved LVEF. These patients were enrolled from December 2008 to January 2009 and were followed-up for 25.6 ± 9.9 months. The primary outcome was all-cause mortality. Multivariate Cox regression analysis was used to investigate risk factors for mortality. RESULTS The mortality group (n=24) had lower albumin levels, less negative GLS, and higher prevalence of coronary artery disease and diabetes mellitus than the survival group. Using a GLS cutoff value of -15%, the less negative GLS group (GLS ≥-15%) had a higher mortality rate. Cox regression analyses revealed that lower albumin level (hazard ratio, 0.16; 95% confidence interval, 0.05 to 0.53; P=0.003) and less negative GLS (hazard ratio, 3.57; 95% confidence interval, 1.41 to 9.04; P=0.01) were independent predictors of all-cause mortality. Furthermore, less negative GLS was associated with a higher cardiovascular death rate. CONCLUSIONS Less negative GLS is predictive of poor prognosis among stable hemodialysis patients with preserved LVEF.

Increased Aortic Stiffness and Attenuated Lysyl Oxidase Activity in Obesity

Objective—One potential mechanism through which obesity exerts adverse effects on the vascular system is by increasing aortic stiffness, a change known to be predictive of increased cardiovascular mortality. The aim of this study was to investigate the pathophysiology that links obesity to aortic stiffening. Approach and Results—Obese (ob/ob) mice were used to examine physical, morphological, and molecular changes in the aorta in response to obesity. ob/ob mice had increased aortic pulse wave velocity and tissue rigidity. ob/ob aorta exhibited decreases of lysyl oxidase (LOX) activity and cross-linked elastin, and increases of elastin fragmentation and elastolytic activity. The aortas of ob/ob mice were surrounded by a significant amount of proinflammatory and pro-oxidative perivascular adipose tissue. In vitro studies revealed that the conditioned medium from differentiated adipocytes or the perivascular adipose tissue of ob/ob mice attenuated LOX activity. Furthermore, inhibition of LOX in wild-type lean mice caused elastin fragmentation and induced a significant increase in pulse wave velocity. Finally, we found that obese humans had stiffer arteries and lower serum LOX levels than do normal-weight humans. Conclusion—Our results demonstrated that obesity resulted in aortic stiffening in both humans and mice, and established a causal relationship between LOX downregulation and aortic stiffening in obesity.

Diagnostic Value of Segmental Longitudinal Strain by Automated Function Imaging in Coronary Artery Disease without Left Ventricular Dysfunction

BACKGROUND The aim of this study was to investigate the role of segmental longitudinal strain for the diagnosis of coronary artery disease (CAD) assessed by automated function imaging. METHODS One hundred fifty-two subjects (mean age, 63 ± 12 years; 77 men) referred for assessment of cardiac function under suspicion of CAD were recruited for this study. Patients with left ventricular dysfunction or with acute coronary syndromes were excluded. RESULTS Peak systolic global longitudinal strain (GLS) was significantly decreased in patients with CAD. Peak segmental longitudinal strain difference (LSD) and its ratio to peak systolic GLS were significant higher in patients with CAD. The areas under receiver operating characteristic curves for the diagnosis of CAD were 0.813 for peak systolic GLS, 0.851 for the number of abnormal segments, 0.805 for peak segmental LSD, and 0.862 for the ratio of peak segmental LSD to peak systolic GLS. Using 1.0 as a cutoff point for the ratio of peak segmental LSD to peak systolic GLS, sensitivity was 77.3% and specificity 79.2%. CONCLUSIONS This study suggests that it may be possible to assess CAD with strain by automated function imaging, but further larger scale studies are needed to confirm this.

Prognostic significance of elevated hemostatic markers in patients with acute myocardial infarction.

OBJECTIVES The purpose of this study was to determine whether the elevated levels of hemostatic markers in the early phase of myocardial infarction may serve as risk factors for subsequent cardiac mortality. BACKGROUND Increased plasma hemostatic markers were noted in acute myocardial infarction, indicating that the blood coagulation system is highly activated in those patients. However, there are few clinical data concerning the association between the elevated hemostatic markers and survival in patients with myocardial infarction. METHODS Blood samples were obtained from 64 patients (mean age 67 +/- 11 years; 49 male) with acute myocardial infarction within 12 h after the onset of symptoms and before the initiation of any antithrombotic treatment. We measured plasma concentrations of fibrinopeptide A (FPA), prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) using the enzyme-linked immunosorbent assay method, and examined the associations between the level of these markers and survival with Cox proportional hazards models. RESULTS The follow-up time was 27 +/- 17 months, and 19 patients died of cardiac causes during the follow-up. Univariate survival analysis identified Killip class IV (hazard ratio 4.86; 95% confidence interval [CI] 1.55-15.19), left ventricular ejection fraction (hazard ratio 0.94; 95% CI 0.90-0.99), FPA (hazard ratio 1.54; 95% CI 1.13-2.10), F1+2 (hazard ratio 2.03; 95% CI 1.17-3.53) and TAT (hazard ratio 1.88; 95% CI 1.27-2.79) as significant factors associated with cardiac mortality. In multivariate analyses, only FPA level (hazard ratio 1.84; 95% CI 1.03-3.30) and left ventricular ejection fraction (hazard ratio 0.93; 95% CI 0.88-0.98) were independent predictors of cardiac mortality. CONCLUSIONS Elevated FPA in the early phase of myocardial infarction identifies patients with increased risk for subsequent cardiac death. This association appears to be independent of residual left ventricular function after infarction.