Patients with chronic kidney disease (CKD) are at an increased risk not only for end-stage kidney disease (ESKD) but also for cardiovascular disease (CVD). In this review article, we summarize the current evidence of CKD as a high-risk condition for CVD based on reports from Japan and other countries to draw attention to the close clinical association between CKD and CVD. Several epidemiologic studies have shown that the presence of CKD and reduced renal function are independent predictors of CVD also in Japan. According to a post-hoc analysis of CASE-J, the power of CKD as a predictor of CVD is as strong as diabetes mellitus and a previous history of ischemic heart disease. CKD worsens classical risk factors including hypertension and dyslipidemia, and dyslipidemia is associated with increased thickness and stiffness of large arteries independent of major confounders. A post-hoc analysis of MEGA indicates that lipid-lowering therapy with statins reduces the risk of CVD, and that it appears to be more efficacious in patients with than without CKD. These reports from Japan and other countries suggest that CKD should be regarded as a high-risk condition comparable to diabetes mellitus, and that strict control of dyslipidemia would be beneficial in preventing CVD, at least early stages of CKD.
Aim: Cigarette-smoking induced oxidative DNA damage to endothelial cells has been reported to play an etiological role in atherosclerosis development. Individual vulnerability to oxidative stress through smoking exposure and the ability to repair DNA damage, which plays a critical role in modifying the risk susceptibility of large artery atherosclerotic (LAA) stroke, is hypothesized. Thus, we examined the effect of genetic polymorphisms of DNA repair pathway genes and cigarette smoking in relation to risk susceptibility of LAA stroke. Methods: We enrolled 116 LAA stroke patients and 315 healthy controls from the Armed Forces Taoyuan General Hospital, Taoyuan, Taiwan. Genotyping of polymorphisms of the OGG1 (Ser326Cys), XRCC1 (Arg399Gln), ERCC2 (Lys751Gln), and ERCC5 (Asp1104His) genes was performed and used to evaluate LAA stroke susceptibility. Results: Of those non-synonymous polymorphisms, the ERCC2Lys751Gln variant was found to be associated with LAA stroke risk (OR: 1.69, 95%CI: 1.02-2.86), and this association was more pronounced in smokers, manifesting a 2.73-fold increased risk of LAA stroke (p=0.027). A joint effect on risk elevation of LAA stroke was seen in those patients with OGG1 and ERCC2 polymorphisms (OR: 2.75, 95%CI: 1.26-6.00). Moreover, among smokers carrying the OGG1Ser326Cys polymorphism, there was a tendency toward an increased risk of LAA stroke in those patients who had a greater number of high-risk genotypes of XRCC1, ERCC2, and ERCC5 polymorphisms (ptrend=0.010). Conclusion: The susceptible polymorphisms of DNA repair pathway genes may have a modifying effect on the elevated risk of LAA stroke in smokers among ethnic Chinese in Taiwan.
Aim: Rho-kinase plays a critical role in various cellular functions. p38 mitogen-activated protein kinase (p38 MAPK) plays a central role in the inflammatory cytokine response to immune challenge. We evaluated the effects of a combination of fasudil, a Rho-kinase inhibitor, and FR167653, a p38 MAPK inhibitor, on cardiovascular remodeling, inflammation, and oxidative stress in Dahl salt-sensitive hypertensive (DS) rats. Methods: DS and Dahl salt-resistant (DR) rats were fed a high-salt diet at 6 weeks of age. Vehicle, fasudil (100 mg/kg per day), FR167653 (2 mg/kg per day), and a combination of fasudil and FR167653 were administered to 6-week-old DS rats for 5 weeks. Results: At the age of 11 weeks, in the left ventricle, DS rats were characterized by increased myocardial fibrosis, phosphorylation of p38 MAPK, and myosin phosphatase targeting subunit (MYPT-1), and NAD(P)H oxidase p22phox, p47phox, gp91phox, tumor necrosis factor-α and interleukin-1β expression compared with DR rats. Fasudil improved cardiovascular remodeling, inflammation, NAD(P)H oxidase subunits, and phosphorylation of p38 MAPK and MYPT-1. FR167653 also similarly ameliorated these indices but not MYPT-1 phosphorylation. Compared with either agent alone, a combination of fasudil and FR167653 was more effective for the improvement of myocardial damage, inflammation and oxidative stress. Conclusion: These findings suggest that the Rho-kinase and p38 MAPK pathways may play a pivotal role in ventricular hypertrophy; thus, we obtained the first evidence that a combination of Rho-kinase inhibitor and p38 MAPK inhibitor may provide a potential therapeutic target in hypertension with cardiovascular remodeling.
Aim: In this study, we investigated the effect of (−)-epigallocatechin-3-gallate (EGCG) on cyclic nucleotide production and vasodilator-stimulated phosphoprotein (VASP) phosphorylation in collagen (10 µg/mL)-stimulated platelet aggregation. Methods: Washed platelets (108/mL) from Sprague-Dawley rats (6-7 weeks old, male) were preincubated for 3 min at 37°C in the presence of 2 mM exogenous CaCl2 with or without EGCG or other materials, stimulated with collagen (10 µg/mL) for 5 min, and then used for the determination of intracellular cytosolic Ca2+ ([Ca2+]i), thromboxane A2 (TXA2), adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP), and VASP phosphorylation. Results: EGCG dose-dependently inhibited collagen-induced platelet aggregation by inhibiting both [Ca2+]i mobilization and TXA2 production. Of two aggregation-inhibiting molecules, cAMP and cGMP, EGCG significantly increased intracellular levels of cAMP, but not cGMP. EGCG-elevated cAMP level was decreased by SQ22536, an adenylate cyclase inhibitor, but not by etazolate, a cAMPspecific phosphodiesterase inhibitor. In addition, EGCG elevated the phosphorylation of VASP-Ser157, a cAMP-dependent protein kinase (A-kinase) substrate, but not the phosphorylation of VASP-Ser239, a cGMP-dependent protein kinase substrate, in intact platelets and collagen-induced platelets, and VASP-Ser157 phosphorylation by EGCG was inhibited by both an adenylate cyclase inhibitor SQ22536 and an A-kinase inhibitor Rp-8-Br-cAMPS. We have demonstrated that EGCG increases cAMP via adenylate cyclase activation and subsequently phosphorylates VASP-Ser157 through A-kinase activation to inhibit [Ca2+]i mobilization and TXA2 production on collagen-induced platelet aggregation. Conclusions: These results strongly indicate that EGCG is a beneficial compound elevating cAMP level in collagen-platelet interaction, which may result in the prevention of platelet aggregation-mediated thrombotic diseases.
Aim: We evaluated the validity of circumferential carotid artery strain as a marker for subclinical atherosclerosis and its benefit in addition to carotid intima-media thickness (IMT) to detect high-risk groups. Methods: The study was a cross-sectional study. From April 2007 to July 2008, 1057 patients who had undergone both echocardiography and carotid ultrasonography were consecutively enrolled. Circumferential carotid strain was obtained from the ratio of change in circular length during the cardiac cycle. Results: As the number of risk factors for atherosclerosis increased from 0 to ≥4, circumferential strain decreased accordingly (5.1±2.1, 4.4±1.8, 3.8±1.6, 3.3±1.3, 3.1±1.3%, p < 0.001), whereas carotid IMT and β-stiffness increased (p < 0.001 for both IMT and β-stiffness). Patients with a high Framingham risk score (FRS) also showed lower circumferential strain (5.01±2.19, 3.46±1.34, 3.08±1.38, p < 0.001 for FRS < 5%, 5-15% and > 15%). Compared to patients with documented atherosclerotic disease, patients without known atherosclerotic disease showed significantly higher circumferential strain (3.25±1.30 vs. 4.18±1.89%, p < 0.001 for patients with vs. without documented atherosclerotic disease). The addition of circumferential carotid strain to IMT significantly improved the ability to detect patients at high risk for coronary heart disease, as assessed by the Framingham risk score (χ2 =61.0 from 42.4, p < 0.001), whereas β-stiffness did not have additive power (p = 0.439). Conclusion: Circumferential strain can be used as a screening tool for subclinical atherosclerosis and may help detect subjects at increased risk for atherosclerotic disease.
Aim: Increasing evidence indicates that antimicrobial peptides, human neutrophil peptide-1, -2, and -3 (HNP1-3) and human antimicrobial peptide LL-37 are involved in the pathophysiology of atherosclerosis; however, little is known about their circulating protein levels in acute myocardial infarction (AMI). We therefore investigated whether their plasma levels are associated with stable coronary artery disease (CAD) and acute ST-segment elevation myocardial infarction (STEMI). Methods: Systemic or local (culprit artery) blood samples were obtained from 112 consecutive male subjects including no CAD (n = 31) controls, stable CAD (n = 44) and STEMI (n = 47). Plasma HNP1-3 and LL-37 levels were measured by the ready-to-use solid-phase enzyme-linked immunosorbent assay (ELISA) based on the sandwich principle. Results: Systemic HNP1-3 in STEMI was increased compared with no CAD (p = 0.000) and stable CAD (p = 0.008), and systemic HNP1-3 in stable CAD was higher than in no CAD (p = 0.004). Systemic LL-37 in STEMI was decreased compared with no CAD (p = 0.009) and stable CAD (p =0.001) and restored within 1 day following STEMI (p = 0.000). Local LL-37 levels in STEMI were higher than systemic levels (p = 0.013). The areas under the ROC curve of systemic HNP1-3 and LL-37 for STEMI were 0.717 (95% CI: 0.624, 0.811; p = 0.000) and 0.702 (95% CI: 0.609, 0.795; p = 0.000), respectively. In addition, ischemia time in the STEMI group correlated with systemic and local levels of HNP1-3 (rs = −0.360, p = 0.013; rs = 0.608, p = 0.000, respectively), and was also associated with systemic and local levels of hs-CRP (rs = 0.408, p = 0.004; rs = 0.425, p = 0.003, respectively), but not with those of LL-37 (all p > 0.05). Conclusion: STEMI was associated with transiently decreased LL-37, but persistently increased HNP1-3 in the systemic circulation and the diagnostic accuracy for STEMI were moderate. Future studies should pay more attention to their prognostic values for myocardial infarction.
Aim: Heterozygous patients with familial hypercholesterolemia (FH) are known to be associated with a high risk of coronary artery disease (CAD), which is a major determinant of their clinical outcome. The prognosis of heterozygous FH patients substantially varies, being dependent on the level of their CAD risk, and their therapeutic regimen should be individualized. We assessed critical levels of LDL-cholesterol (LDL-C) and Achilles tendon thickness (ATT) to identify heterozygous FH patients at “very high” risk for CAD. Methods: One hundred and nine heterozygous FH patients who had no history of CAD and had had their plasma lipid profile and ATT assessed before treatment were followed up until their first CAD event or 31 December 2010. Multivariable logistic regression models were used to analyze the correlation of LDL-C and/or ATT levels with the risk of developing CAD. Results: During the follow-up period, 21 of the 109 patients had a CAD event, diagnosed by coronary angiogram. Individuals in the highest tertile of LDL-C had a CAD risk 8.29-fold higher than those in the lowest tertile. Individuals in the highest tertile of the ATT group had a 7.82-fold higher CAD risk than those in the lowest tertile. Those who had either LDL-C ≥ 260 mg/dL or ATT ≥ 14.5 had a 23.94-fold higher CAD risk than those with LDL-C < 260 mg/dL and ATT <14.5 mm. Conclusions: In heterozygous FH patients, LDL-C 260 mg/dL or higher and/or ATT 14.5 mm or thicker are useful markers for extracting patients at “very high” risk for CAD.
Aim: Paraoxonase-1 (PON1) is an antioxidant enzyme located in high density lipoprotein (HDL). PON1 was defined as a protective factor against atherosclerosis. The aim of this study was to investigate the possible relationship between serum paraoxonase (PONase), homocysteine thiolactonase (HTase) activities and PON1 Q192R polymorphism, and the extent and severity of atherosclerosis. Methods: Blood specimens were collected from 142 individuals who had no coronary artery lesions angiographically (control group) and 128 individuals who had angiographically documented coronary artery disease of several degrees (patient group). The extent and severity of arterial lesions were evaluated by the Gensini scoring system. PONase and HTase activities were measured in serum using a spectrophotometric method. PON1 Q192R polymorphism was evaluated using PCR-RFLP after DNA isolation from blood. Results: Serum PONase and HTase activities were significantly lower in the patient group than in healthy controls (135.7±56.0U/mL vs 153.8±62.0U/mL, p< 0.05; 36.0±6.1 U/mL vs 43.0±4.04 U/mL, p< 0.01; respectively). In the patient group, there was a negative correlation between PONase, HTase activities and the Gensini score (r=−0.168, p= 0.039; r=−0.164, p= 0.006, respectively). In both groups, there was no significant difference in the distribution of PON1 Q192R polymorphism. In the patient group, the distribution of Gensini scores according to genotypes was not significant. Conclusion: It has been concluded that serum PONase and HTase activities might be a more relevant marker than PON1 genotype in evaluating the extent and severity of atherosclerosis.
Aim: The post-challenge glucose (PCG) level has been suggested to be superior to the fasting blood glucose (FG) level for predicting the risk of future cardiovascular disease (CVD); however, the extent of its superiority has not been consistently shown among previous cohort studies. Therefore, we conducted a meta-analysis to summarize the quantitative association of FG and PCG with CVD risk and compared the strengths of the two associations. Method: Electronic literature searches using MEDLINE and EMBASE with an additional manual search were conducted for prospective observational studies of the association of FG and PCG with CVD risk. Studies were included if they were prospective studies in which the relative risk (RR) of CVD per 1 standard deviation increase in both FG and PCG could be estimated. Pooled relative risks for the incremental increase were calculated as RRFG and RRPCG using a bivariate random-effects model. Result: Data were obtained from 14 eligible studies that included 70,889 participants and 2,927 cases. The pooled RRFG and RRPCG (95% confidence interval) were, respectively, 1.15 (1.06 to 1.26) and 1.24 (1.12 to 1.36); the difference was significant (P =0.001). The association of PCG with CVD risk was stronger in studies that targeted participants with a baseline mean FG < 100 mg/dl (P < 0.001) or mean age ≥ 55 years (P =0.004). Conclusions: Overall, the association of PCG with CVD risk was stronger than that of FG by approximately 50% on a log scale. Measuring PCG is especially important in populations with relatively low FG levels or in the elderly, although it is often burdensome in routine clinical practice.
Aim: The aim of this study was to find a region of low wall shear stress (WSS) in a basilar artery using 3-dimensional (3D) geometric analysis and blood flow simulation. Methods: A 61-year-old patient who underwent follow-up time-of-flight magnetic resonance angiography (TOF-MRA) of the brain was recruited as the subject of the present study. In the basilar artery, the angle of the directional vector was calculated for the region of low WSS. The subject's 3D arterial geometry and blood flow velocity from a transcranial Doppler examination were used for a blood flow simulation study. The regions of low WSS identified by both geometric analysis and blood flow simulation were compared, and these methods were repeated for the basilar arteries of various geometries from other patients. Results: Two distinct arterial angulations along the basilar artery were identified: lateral and anterior angulations on the anteroposterior and lateral TOF-MR views, respectively. A low WSS region was observed in the distal portion along the inner curvatures of both angulations in the basilar artery. The directional vectors of the region of low WSS calculated by geometric analysis and blood flow simulation were very similar (correlation coefficient= 0.996, p < 0.001). Follow-up MRA confirmed the progression of plaque in the region of low WSS. Conclusion: Detailed geometric analysis and blood flow simulation of the basilar artery identified lateral and anterior angulations which determined the low WSS region in the distal portion along the inner curvatures of the angulations.