Sang-Hyun Ihm

Relation between C-reactive protein, homocysteine levels, fibrinogen, and lipoprotein levels and leukocyte and platelet counts, and 10-year risk for cardiovascular disease among healthy adults in the USA.

The association between systemic inflammation and the estimated 10-year risk for coronary artery disease (CAD) according to the Framingham risk score is largely unknown. In this study, 6,371 participants in the Third National Health and Nutrition Examination Survey (NHANES III) aged 40 to 79 years, who had no histories of heart attack, stroke, peripheral artery disease, or diabetes mellitus, were categorized into groups at low (<10%), intermediate (10% to 20%), and high (>20%) risk according to 10-year risk for CAD, calculated using the Framingham risk score modified by the National Cholesterol Education Program Adult Treatment Panel III. After adjustments for age, gender, race, body mass index, and co-morbidities, participants at high risk were more likely to have elevated circulating C-reactive protein levels (>/=2.2 mg/L: adjusted odds ratio [OR] 1.61, 95% confidence interval [CI] 1.30 to 2.01, p <0.0001; >10.0 mg/L: OR 1.41, 95% CI 1.03 to 1.93, p = 0.034). The high-risk group had circulating fibrinogen, homocysteine, leukocyte, and platelet levels that were 20.98 mg/dl (95% CI 12.53 to 29.43, p <0.0001), 1.54 mumol/L (95% CI 0.76 to 2.32, p = 0.002), 0.90 mumol/L (95% CI 0.36 to 1.43, p = 0.001), 910/microl (95% CI 670 to 1,160, p <0.0001), and 10,220/microl (95% CI 2,830 to 17,610, p <0.0001) higher, respectively, than in those in the low-risk group. There was also a dose-dependent increase in circulating levels of inflammatory markers across the categories of CAD risk. In conclusion, these findings indicate that low-grade systemic inflammation and hyperhomocysteinemia were present in participants with high 10-year risk for CAD.

The Glu298Asp polymorphism in the endothelial nitric oxide synthase gene is strongly associated with coronary spasm.

Background Coronary spasm seems to be associated with coronary nitric oxide deficiency. Objectives We investigated whether the Glu298Asp polymorphism in the endothelial nitric oxide synthase (eNOS) gene is a definite risk factor for coronary spasm and whether diffuse spasm involving normal‐looking coronary artery correlates significantly with the Glu298Asp polymorphism, in contrast with focal spasm superimposed on an atherosclerotic plaque. Methods A polymerase chain reaction followed by restriction fragment length polymorphism analysis was performed in 118 control participants and in 102 patients with variant angina and a similar degree of atherosclerotic burden. Patients with coronary spasm were divided into diffuse spasm and focal spasm subgroups according to morphological criteria. Results There was a significantly higher incidence of the Glu298Asp polymorphism in the coronary spasm group than in the control group (21.5% compared with 8.5%, P =0.006). Multiple logistic regression analysis using risk factors and the Glu298Asp polymorphism showed that the most important predictive factor for coronary spasm was the Glu298Asp polymorphism (odds ratio 2.83, 95% confidence interval 1.25‐6.41, P = 0.009). The diffuse spasm subgroup had a significantly higher frequency of the Glu298Asp polymorphism than the control group (25.9% compared with 8.5%, P = 0.002). However, the focal spasm subgroup did not differ from the control group in the frequency of Glu298Asp polymorphism. Conclusion The Glu298Asp polymorphism in the eNOS gene is a definite risk factor for coronary spasm, especially for diffuse coronary spasm. This result supports the notion that diffuse coronary spasm is significantly associated with endothelial dysfunction, in contrast to focal spasm. Coron Artery Dis 14:293‐299

Catechin prevents endothelial dysfunction in the prediabetic stage of OLETF rats by reducing vascular NADPH oxidase activity and expression.

OBJECTIVES In the prediabetic stage, hyperinsulinemia or insulin resistance is thought to be closely associated with oxidative stress, which is also the main contributor of endothelial dysfunction. Clinical studies have indicated that regular intake of green tea reduces the risk of cardiovascular diseases. This study examined whether catechin prevents endothelial dysfunction and hyperglycemia in the prediabetic stage of a type 2 diabetic (T2D) rat, the Otsuka Long-Evans Tokushima Fatty (OLETF) model. METHODS AND RESULTS 30 OLETF rats, 13 week-old, were randomized into two equal groups for daily treatment with either catechin (30 mg/kg/day), Catechin-OLETF) or saline for 12 weeks. Intraperitoneal glucose tolerance tests and blood pressure measurements were performed at 13 and 25 weeks. Ex vivo vascular relaxation was assessed in organ chambers, vascular superoxide anion production by dihydroethidine, vascular NADPH oxidase activity by lucigenin, and expression by immunohistochemistry. Catechin significantly reduced blood pressure (OLETF vs. Catechin-OLETF; 138+/-16 mmHg vs. 126+/-16 mmHg, p=0.013), fasting sugar (129+/-11 mg/dL vs. 118+/-9 mg/dL, p=0.02) and the insulin level (2.13+/-1.29 ng/mL vs. 0.53+/-0.27 ng/mL, p=0.004). In the aorta of Catechin-OLETF at 25 weeks, endothelium-dependent relaxations were significantly improved and NADPH oxidase activity in aortic rings was markedly decreased compared with those of OLETF. Catechin reduced vascular reactive oxygen species formation in the aorta and suppressed the expression of p22phox and p47phox NADPH oxidase subunits. CONCLUSIONS Intake of catechin normalized blood pressure and prevented endothelial dysfunction and insulin resistance in the prediabetic stage. Prevention of vascular oxidative stress by inhibiting NADPH oxidase expression and activity is likely to contribute to the beneficial effect on the vascular system.

Excess protein O-GlcNAcylation and the progression of diabetic cardiomyopathy

We examined the role that enzymatic protein O-GlcNAcylation plays in the development of diabetic cardiomyopathy in a mouse model of Type 2 diabetes mellitus (DM2). Mice injected with low-dose streptozotocin and fed a high-fat diet developed mild hyperglycemia and obesity consistent with DM2. Studies were performed from 1 to 6 mo after initiating the DM2 protocol. After 1 mo, DM2 mice showed increased body weight, impaired fasting blood glucose, and hyperinsulinemia. Echocardiographic evaluation revealed left ventricular diastolic dysfunction by 2 mo and O-GlcNAcylation of several cardiac proteins and of nuclear transcription factor Sp1. By 4 mo, systolic dysfunction was observed and sarcoplasmic reticulum Ca(2+) ATPase expression decreased by 50%. Fibrosis was not observed at any timepoint in DM2 mice. Levels of the rate-limiting enzyme of the hexosamine biosynthetic pathway, glutamine:fructose-6-phosphate amidotransferase (GFAT) were increased as early as 2 mo. Fatty acids, which are elevated in DM2 mice, can possibly be linked to excessive protein O-GlcNAcylation levels, as cultured cardiac myocytes in normal glucose treated with oleic acid showed increased O-GlcNAcylation and GFAT levels. These data indicate that the early onset of diastolic dysfunction followed by the loss of systolic function, in the absence of cardiac hypertrophy or fibrosis, is associated with increased cardiac protein O-GlcNAcylation and increased O-GlcNAcylation levels of key calcium-handling proteins. A link between excessive protein O-GlcNAcylation and cardiac dysfunction is further supported by results showing that reducing O-GlcNAcylation by O-GlcNAcase overexpression improved cardiac function in the diabetic mouse. In addition, fatty acids play a role in stimulating excess O-GlcNAcylation. The nature and time course of changes observed in cardiac function suggest that protein O-GlcNAcylation plays a mechanistic role in the triggering of diabetic cardiomyopathy in DM2.

Decaffeinated green tea extract improves hypertension and insulin resistance in a rat model of metabolic syndrome

BACKGROUND Oxidative stress and endothelial dysfunction are closely associated with hypertension and insulin resistance (IR) in metabolic syndrome (MetS). It is still controversial whether green tea extract (GTE) may have blood pressure (BP) lowering effect. Decaffeinated GTE might be presumed to have strong antioxidative effect and BP-lowering effect as compared with catechins. Thus we investigated whether decaffeinated-GTE could attenuate hypertension and IR by improving endothelial dysfunction and reducing oxidative stress in a rat model of MetS. METHODS AND RESULTS 20 Otsuka Long-Evans Tokushima Fatty (OLETF) rats at 13 weeks old, MetS rats, were randomized into a saline treated group (OLETF; n = 10) and a group treated with decaffeinated-GTE (25 mg/kg/day) (GTE-OLETF; n = 10). Intraperitoneal glucose tolerance tests and BP measurements were performed at 13 and 25 weeks. Decaffeinated-GTE significantly reduced BP (OLETF vs. GTE-OLETF; 130 ± 7 vs. 121 ± 3 mmHg, p = 0.01), fasting/postprandial 2 h glucose (141 ± 18/159 ± 13 vs. 115 ± 7/132 ± 16 mg/dL, p = 0.009/0.002) and insulin levels (4.8 ± 2.3 vs. 2.4 ± 1.3 ng/mL, p < 0.001). Decaffeinated-GTE significantly reduced vascular reactive oxygen species (ROS) formation and NADPH oxidase activity, and improved endothelium dependent relaxation in the thoracic aorta of OLETF rats. Decaffeinated-GTE also suppressed the expression of p47 and p22phox (NADPH oxidase subunits) in the immunohistochemical staining, and stimulated phosphorylation of endothelial nitric oxide synthase (eNOS) and Akt in the immunoblotting of aortas. CONCLUSIONS Decaffeinated-GTE reduced the formation of ROS and NADPH oxidase activity and stimulated phosphorylation of eNOS and Akt in the aorta of a rat model of MetS, which resulted in improved endothelial dysfunction and IR, and eventually lowered BP.

Noninvasive Assessment of Myocardial Inflammation by Cardiovascular Magnetic Resonance in a Rat Model of Experimental Autoimmune Myocarditis

Background— Limited availability of noninvasive and biologically precise diagnostic tools poses a challenge for the evaluation and management of patients with myocarditis. Methods and Results— The feasibility of cardiovascular magnetic resonance (CMR) imaging with magneto-fluorescent nanoparticles (MNPs) for detection of myocarditis and its effectiveness in discriminating inflammation grades were assessed in experimental autoimmune myocarditis (EAM) (n=65) and control (n=10) rats. After undergoing CMR, rats were administered with MNPs, followed by a second CMR 24 hours later. Head-to-head comparison of MNP-CMR with T2-weighted, early and late gadolinium enhancement CMR was performed in additional EAM (n=10) and control (n=5) rats. Contrast-to-noise ratios were measured and compared between groups. Flow cytometry and microscopy demonstrated that infiltrating inflammatory cells engulfed MNPs, resulting in altered myocardial T2* effect. Changes in contrast-to-noise ratio between pre- and post-MNP CMR were significantly greater in EAM rats (1.08±0.10 versus 0.48±0.20; P<0.001). In addition, contrast-to-noise ratio measurement in MNP-CMR clearly detected the extent of inflammation (P<0.001) except for mild inflammation. Compared with conventional CMR, MNP-CMR provided better image contrast (CNR change 8% versus 46%, P<0.001) and detectability of focal myocardial inflammation. Notably, MNP-CMR successfully tracked the evolution of myocardial inflammation in the same EAM rats. Conclusions— Magneto-fluorescent nanoparticle CMR permitted effective visualization of myocardial inflammatory cellular infiltrates and distinction of the extent of inflammation compared with conventional CMR in a preclinical model of EAM. Magneto-fluorescent nanoparticle CMR performs best in EAM rats with at least moderate inflammatory response.

Metabolically obese status with normal weight is associated with both the prevalence and severity of angiographic coronary artery disease

OBJECTIVE We evaluated prevalence and severity of angiographic coronary artery disease (CAD) according to groups by metabolically obese (MO) and/or weight status. MATERIAL/METHODS Normal weight was defined as body mass index (BMI, kg/m²)<25 and obesity was defined as BMI≥25. The MO was determined using the National Cholesterol Education Program-Adult Treatment Panel III classification with Korean-specific cutoffs for abdominal obesity. Therefore, a total of 856 subjects were categorized as follows: (1) metabolically healthy and normal weight (MHNW); (2) metabolically obese but normal weight (MONW); (3) metabolically healthy but obese (MHO); and (4) metabolically abnormally obese (MAO). The presence of obstructive lesion≥50% of coronary artery was considered as an angiographic CAD and the Gensini scoring system was used for the severity. RESULTS MONW or MO showed a higher prevalence of CAD than MHNW or non-MO after adjustment for age and sex, respectively (MONW, odds ratio [OR]=1.69, 95% confidence interval [CI]: 1.13-2.51 and MO, OR=1.44, 95% CI: 1.09-1.91). In subjects without diabetes mellitus (DM), MONW or MO showed a marginally higher prevalence of CAD (MONW, OR=1.58, 95% CI: 0.96-2.61 and MO, OR=1.41, 95% CI: 0.96-2.08). MONW was independently associated with a higher severity of angiographic CAD than MHNW after age, sex, glomerular filtration rate, smoking status, high sensitive C-reactive protein, and use of anti-platelet and anti-angina drugs (β=0.118, P=0.005). And MO was associated with a higher severity of angiographic CAD than non-MO after adjustment for age and sex (β=0.077, P=0.024). The above associations were also consistent in subjects without DM (MONW, β=0.147, P=0.003 and MO, β=0.129, P=0.005). CONCLUSIONS MONW or MO is associated with both the prevalence and severity of angiographic CAD after adjustment for age and sex and MONW is independently associated with the severity of angiographic CAD irrespective of DM. Therefore, subjects with MO but normal weight (MONW) should be carefully examined for angiographic CAD.

Relationship between erythropoietin resistance index and left ventricular mass and function and cardiovascular events in patients on chronic hemodialysis

The response to erythropoietin (EPO) treatment varies considerably in individual patients on chronic hemodialysis. The EPO resistance index (ERI) has been considered useful to assess the EPO resistance and can be easily calculated in the clinic. The aim of this study was to investigate the association between ERI and left ventricular mass (LVM) and function and to determine whether ERI was associated with cardiovascular events in patients on hemodialysis. This study was designed prospectively. Clinical, laboratory, and echocardiographic variables were assessed in 72 patients on hemodialysis. The ERI was determined as the weekly weight‐adjusted dose of EPO (U/kg/week) divided by hemoglobin concentration (g/dL). Patients were divided into three groups by tertiles of ERI. Patients with higher tertiles of ERI had a higher LVM index and lower LV ejection fraction compared with those with lower tertiles of ERI (P = 0.019 and P = 0.030, respectively). The median follow‐up period was 53 months. The Kaplan–Meier plot showed increased frequency of cardiovascular events in patients with higher tertiles of ERI, compared with those with lower tertiles of ERI (P = 0.011, log‐rank test). The multivariate Cox proportional hazard models showed that the ERI was the significant independent predictor of cardiovascular events (HR 3.00, 95% CI, 1.04–8.62, P = 0.042). Our data show that ERI was related with LVM index, LV systolic function and cardiovascular events in patients with hemodialysis. By monitoring of ERI, early identification of the EPO resistance may be helpful to predict the cardiovascular risk in hemodialysis patients.

Age is an Independent Risk Factor for the Early Morning Blood Pressure Surge in Patients Never-Treated for Hypertension

Background and Objectives The early morning blood pressure surge (EMBPS) has been reported to be associated with cardiovascular events. The aim of this study was to investigate the relationship between 24-hour ambulatory BP monitoring (ABPM) parameters and conventional cardiovascular risk factors. Subjects and Methods Patients (n=346) never-treated for essential hypertension with no other cardiovascular risk factors, such as diabetes, dyslipidemia, and nephropathy were enrolled. The EMBPS was defined as the early morning systolic BP minus the lowest night systolic BP. We compared the 24-hour ABPM parameters in two groups divided by age (<60 and ≥60 years) and examined the association between the 24-hour ABPM parameters and cardiovascular risk factor. Results The EMBPS (18±14 vs. 24±14 mmHg, p=0.002), 24-hour mean blood pressure {MBP; 102±9 vs. 105±11 mmHg, p=0.044}, and 24-hour mean pulse pressure (PP; 52±10 vs. 58±11 mmHg, p<0.001) were significantly increased in the elderly subjects compared to the younger subjects. The degree of decrease was less in the elderly subjects (10±8 vs. 7±10%, p=0.002). Based on multivariate analysis, age was an independent risk factor for the highest quartile of EMBPS (>28 mmHg) after adjusting for gender differences, body mass index, and various 24-hour ABPM parameters (odds ratio, 1.051; 95% confidence interval, 1.028-1.075; p<0.001). Conclusion Age is an independent risk factor for EMBPS in patients with never-treated hypertension. BP control in the early morning period is more important in elderly patients so as to prevent cardiovascular events.

Effects of Sacubitril/Valsartan (LCZ696) on Natriuresis, Diuresis, Blood Pressures, and NT-proBNP in Salt-Sensitive Hypertension.

Salt-sensitive hypertension (SSH) is characterized by impaired sodium excretion and subnormal vasodilatory response to salt loading. Sacubitril/valsartan (LCZ696) was hypothesized to increase natriuresis and diuresis and result in superior blood pressure control compared with valsartan in Asian patients with SSH. In this randomized, double-blind, crossover study, 72 patients with SSH received sacubitril/valsartan 400 mg and valsartan 320 mg once daily for 4 weeks each. SSH was diagnosed if the mean arterial pressure increased by ≥10% when patients switched from low (50 mmol/d) to high (320 mmol/d) sodium diet. The primary outcome was cumulative 6- and 24-hour sodium excretion after first dose administration. Compared with valsartan, sacubitril/valsartan was associated with a significant increase in natriuresis (adjusted treatment difference: 24.5 mmol/6 hours, 50.3 mmol/24 hours, both P<0.001) and diuresis (adjusted treatment difference: 291.2 mL/6 hours, P<0.001; 356.4 mL/24 hours, P=0.002) on day 1, but not on day 28, and greater reductions in office and ambulatory blood pressure on day 28. Despite morning dosing of both drugs, ambulatory blood pressure reductions were more pronounced at nighttime than at daytime or the 24-hour average. Compared with valsartan, sacubitril/valsartan significantly reduced N-terminal pro B-type natriuretic peptide levels on day 28 (adjusted treatment difference: −20%; P=0.001). Sacubitril/valsartan and valsartan were safe and well tolerated with no significant changes in body weight or serum sodium and potassium levels with either treatments. In conclusion, sacubitril/valsartan compared with valsartan was associated with short-term increases in natriuresis and diuresis, superior office and ambulatory blood pressure control, and significantly reduced N-terminal pro B-type natriuretic peptide levels in Asian patients with SSH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01681576.