[Show abstract][Hide abstract] ABSTRACT: Resistant hypertension (HTN) occurs in 15-20% of treated hypertensive patients, and 70-80% of resistant hypertensive patients have obstructive sleep apnea (OSA). The characteristics of resistant HTN that predispose patients to OSA have not been reported. Therefore, we aimed to determine the clinical, laboratory, and polysomnographic features of resistant HTN that are significantly associated with OSA.
Hypertensive patients (n=475) who underwent portable polysomnography were enrolled. The patients were categorized into controlled (n=410) and resistant HTN (n=65) groups. The risk factors for the occurrence of OSA in controlled and resistant hypertensive patients were compared, and independent risk factors that are associated with OSA were analyzed.
Out of 475 patients, 359 (75.6%) were diagnosed with OSA. The prevalence of OSA in resistant HTN was 87.7%, which was significantly higher than that in controlled HTN (73.7%). Age, body mass index, neck circumference, waist circumference, and hip circumference were significantly higher in OSA. However, stepwise multivariate analyses revealed that resistant HTN was not an independent risk factor of OSA.
The higher prevalence and severity of OSA in resistant HTN may be due to the association of risk factors that are common to both conditions.
Yonsei medical journal 09/2015; 56(5):1258-65. DOI:10.3349/ymj.2015.56.5.1258 · 1.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Insulin inhibits ischemia/reperfusion-induced myocardial apoptosis through the PI3K/Akt/mTOR pathway. Survivin is a key regulator of anti-apoptosis against doxorubicin-induced cardiotoxicity. Insulin increases survivin expression in cardiac myocytes to mediate cytoprotection. However, the mechanism by which survivin mediates the protective effect of insulin against doxorubicin-associated injury remains to be determined. In this study, we demonstrated that pretreatment of H9c2 cardiac myocytes with insulin resulted in a significant decrease in doxorubicin-induced apoptotic cell death by reducing cytochrome c release and caspase-3 activation. Doxorubicin-induced reduction of survivin mRNA and protein levels was also significantly perturbed by insulin pretreatment. Reducing survivin expression with survivin siRNA abrogated insulin-mediated inhibition of caspase-3 activation, suggesting that insulin signals to survivin inhibited caspase-3 activation. Interestingly, pretreatment of H9c2 cells with insulin or MG132, a proteasome inhibitor, inhibited doxorubicin-induced degradation of the transcription factor Sp1. ChIP assay showed that pretreatment with insulin inhibited doxorubicin-stimulated Sp1 dissociation from the survivin promoter. Finally using pharmacological inhibitors of the PI3K pathway, we showed that insulin-mediated activation of the PI3K/Akt/mTORC1 pathway prevented doxorubicin-induced proteasome-mediated degradation of Sp1. Taken together, insulin pretreatment confers a protective effect against doxorubicin-induced cardiotoxicity by promoting Sp1-mediated transactivation of survivin to inhibit apoptosis. Our study is the first to define a role for survivin in cellular protection by insulin against doxorubicin-associated injury and show that Sp1 is a critical factor in the transcriptional regulation of survivin.
PLoS ONE 08/2015; 10(8):e0135438. DOI:10.1371/journal.pone.0135438 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Age-related changes in the immune system, commonly termed "immunosenescence," contribute to deterioration of the immune response and fundamentally impact the health and survival of elderly individuals. Immunosenescence affects both the innate and adaptive immune systems; however, the most notable changes are in T cell immunity and include thymic involution, the collapse of T cell receptor (TCR) diversity, an imbalance in T cell populations, and the clonal expansion of senescent T cells. Senescent T cells have the ability to produce large quantities of proinflammatory cytokines and cytotoxic mediators; thus, they have been implicated in the pathogenesis of many chronic inflammatory diseases. Recently, an increasing body of evidence has suggested that senescent T cells also have pathogenic potential in cardiovascular diseases, such as hypertension, atherosclerosis, and myocardial infarction, underscoring the detrimental roles of these cells in various chronic inflammatory responses. Given that cardiovascular disease is the number one cause of death worldwide, there is great interest in understanding the contribution of age-related immunological changes to its pathogenesis. In this review, we discuss general features of age-related alterations in T cell immunity and the possible roles of senescent T cells in the pathogenesis of cardiovascular disease.
Clinical and Experimental Medicine 07/2015; DOI:10.1007/s10238-015-0376-z · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Arterial stiffness is an independent predictor of cardiovascular disease risk. However, whether genetic risk variants are associated with arterial stiffness measures, such as pulse-wave velocity (PWV), is largely unknown. Therefore, we performed a genome-wide association study (GWAS) to identify single-nucleotide polymorphisms (SNPs) associated with PWV in a Korea population.
Study participants consisted of 402 patients in the Yonsei cardiovascular genome center cohort. Arterial stiffness was measured as brachial-ankle pulse-wave velocity (baPWV). Genotyping was performed in 402 subjects with the Axiom(™) Genome-Wide ASI 1 Array Plate containing more than 600,000 SNP markers. The findings were tested for replication in independent subjects from a community-based cohort of 1206 individuals, using a Taqman assay to include two candidate SNPs. Associations with PWV were evaluated using an additive genetic model that included age, gender, systolic blood pressure and diastolic blood pressure as covariates. GWAS and replication analyses were conducted using the measured genotype method implemented in PLINK and SAS.
We observed two candidate SNPs associated with baPWV in GWAS: rs7271920 (p = 7.15 × 10(-9)) and rs10125157 (p = 8.25 × 10(-7)). However, neither of these was significant in the replication cohort.
In summary, we did not identify any common genetic variants associated with baPWV in cardiovascular patients.
[Show abstract][Hide abstract] ABSTRACT: Familial hypercholesterolemia (FH) is a genetic disorder with an increased risk of early-onset coronary artery disease. Although some clinically diagnosed FH cases are caused by mutations in LDLR, APOB, or PCSK9, mutation detection rates and profiles can vary across ethnic groups. In this study, we aimed to provide insight into the spectrum of FH-causing mutations in Koreans. Among 136 patients referred for FH, 69 who met Simon Broome criteria with definite family history were enrolled. By whole-exome sequencing (WES) analysis, we confirmed that the 3 known FH-related genes accounted for genetic causes in 23 patients (33.3%). A substantial portion of the mutations (19 of 23 patients, 82.6%) resulted from 17 mutations and 2 copy number deletions in LDLR gene. Two mutations each in the APOB and PCSK9 genes were verified. Of these anomalies, two frameshift deletions in LDLR and one mutation in PCSK9 were identified as novel causative mutations. In particular, one novel mutation and copy number deletion were validated by co-segregation in their relatives. This study confirmed the utility of genetic diagnosis of FH through WES.
PLoS ONE 05/2015; 10(5):e0126706. DOI:10.1371/journal.pone.0126706 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to determine the value of additional multiple biomarkers in the prediction of premature coronary artery disease (CAD).
Data from 503 CAD patients and 503 healthy control patients with matching age and sex were collected. The patient group consisted of male (25 to 55 years) and female (30 to 60 years) patients with documented angiographic multi-vessel CAD. Baseline characteristics of conventional risk factors and biomarkers were collected. We compared the conventional risk factors model with the model with six additional biomarkers (hs-CRP, IL-6, RAGE, Lp-LPA2, adiponectin, and RANTES), which have shown significant association with premature CAD. We also evaluated the effects of adding each of the six biomarkers to the conventional laboratory data. The additional biomarkers model resulted in improvements in the C-statistic (0.953 vs. 0.937, P=0.0003) in comparison with the conventional risk factors model. Among the 6 biomarkers added to the patient group, hs-CRP and IL-6 had a significant discriminative power to predict the risk of premature CAD (hs-CRP; P = 0.0005, IL-6; P= 0.003).
Although conventional risk factors were more strongly associated with premature CAD than were biomarkers, adding the 6 biomarkers (hs-CRP, IL-6, RAGE, Lp-LPA2, adiponectin, and RANTES) improved the prediction of premature CAD moderately. We found that hs-CRP and IL-6 had shown a significant contribution in the prediction of premature CAD.
[Show abstract][Hide abstract] ABSTRACT: The effectiveness of remote patient monitoring and physician care for the treatment of hypertension has not been demonstrated in a randomized clinical trial. The objective of this study was to evaluate the effectiveness of remote patient monitoring with or without remote physician care in reducing office blood pressure in patients with hypertension. A total of 374 hypertensive patients over 20 years of age were randomized into the following three groups: group (1) control, the patients received usual clinical care with home BP monitoring; group (2) the patients were remotely monitored and received office follow-up; and group (3) the patients received remote monitoring without physician office care using the remote monitoring device. For each group, in-office follow-up care was scheduled every 8 weeks for 24 weeks. The primary end point was the difference in sitting SBP at the 24-week follow-up. No difference between the three groups was observed in the primary end point (adjusted mean sitting SBP was as follows: group 1: -8.9±15.5 mm Hg, group 2: -11.3±15.9 mm Hg, group 3: -11.6±19.8 mm Hg, (NS). Significant differences in achieving the target BP at the 24th week of follow-up were observed between groups 1 and 2. The subjects over 55-years old had a significant decrease in the adjusted mean sitting SBP in groups 2 and 3 compared with that of the control group. Remote monitoring alone or remote monitoring coupled with remote physician care was as efficacious as the usual office care for reducing blood pressure with comparable safety and efficacy in hypertensive patients.Hypertension Research advance online publication, 19 March 2015; doi:10.1038/hr.2015.32.
Hypertension Research 03/2015; 38(7). DOI:10.1038/hr.2015.32 · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: T-cell-mediated immune responses play important roles in the progression of atherosclerotic disease. Studies have linked various inflammatory biomarkers with the burden of coronary artery calcification, but the significance of T-cell-specific chemokines in coronary artery calcification has not been confirmed. We aimed to examine the association between serum levels of the monokine induced by gamma interferon (MIG) and the coronary artery calcium score (CACS).
We enrolled 456 individuals (285 men, 66.5±5.8 years) who were registered in the Mapo-gu public health center cohort. We selected 228 individuals with a CACS of more than 100 and 228 age-matched and sex-matched individuals with a CACS of less than 100. All participants underwent coronary computed tomography for CACS measuring. Clinical and laboratory variables including serum MIG levels were analyzed at the time of enrollment.
The serum level of MIG was significantly higher in participants with a CACS of more than 100 (152.1±119.1 vs. 130.3±112.9, P=0.046). Serum MIG levels correlated significantly with CACS (r=0.113, P=0.016), and higher levels of MIG were associated with severe plaque burden (CACS>400, P=0.025). Multiple linear regression analysis showed that serum MIG levels were associated independently with CACS after controlling for confounding factors and medications (β=0.114, P=0.026).
Serum MIG levels were associated independently with CACS after adjusting for traditional cardiovascular risk factors. These findings suggest that MIG may be used as a novel biomarker for T-cell inflammation and atherosclerotic plaque burden in humans.
[Show abstract][Hide abstract] ABSTRACT: Aim:
The immune system may play an important role in the pathogenesis of cardiovascular disease. T cell-driven inflammation in human hypertension and atherosclerosis has recently been revealed. In the present study, we evaluated the association between serum levels of the C-X-C chemokine receptor type 3 chemokines and the carotid intima media thickness (IMT) in humans.
One hundred sixty-four consecutive patients undergoing baseline and 2-year follow-up carotid IMT (110 men, 62.4±10.0 years) were enrolled. The maximum carotid IMT (max-IMT) and the mean carotid IMT (mean-IMT) were measured at baseline and after 24 months. Clinical and laboratory variables, including serum levels of the monokine induced by gamma interferon (MIG) and interferon gamma-induced protein 10 (IP-10), were analyzed at the time of initial enrollment.
The baseline max- and mean-IMT were 0.992±0.235 and 0.793±0.191 mm, respectively. The serum levels of MIG and IP-10 significantly correlated with the carotid IMT. However, there was no significant correlation between the serum levels of MIG or IP-10 and IMT changes. A multivariate regression analysis revealed the serum MIG to be independently associated with the carotid IMT (max-IMT: β=0.194, p=0.010; mean-IMT: β=0.184, p=0.016) when controlled for age, sex, diabetes mellitus history, smoking history, body mass index, blood pressure, total cholesterol, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and aspirin and statin medication.
Circulating MIG levels are independently associated with the carotid IMT, after adjusting for confounding factors and medications. These findings indicate the potential clinical implication of MIG with respect to early atherosclerosis in humans.
Journal of atherosclerosis and thrombosis 01/2015; 22(8). DOI:10.5551/jat.28886 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The activation of receptor for advanced glycation end products (RAGE) signaling is mainly associated with myocardial ischemia/reperfusion injury. Thus the blockade of RAGE-ligands axis can be considered as a potential therapeutic strategy to protect myocardial infarction after ischemia/reperfusion injury. Herein, we strengthened the cardioprotective effect with combinatorial treatment of soluble RAGE (sRAGE) and RAGE siRNA (siRAGE) causing more effective suppression of RAGE-mediated signaling transduction. For pharmacological blockade of RAGE, sRAGE, the extracellular ligand binding domain of RAGE, acts as a pharmacological ligand decoy and inhibits the interaction between RAGE and its ligands. For genetic deletion of RAGE, siRAGE suppresses the expression of RAGE by participating in RNA interference mechanism. Therefore, we combined these two RAGE blockade/deletion strategies and investigated the therapeutic effects on rat ischemic and reperfused myocardium. According to our results, based on RAGE expression level analysis and infarct size/fibrosis measurement, co-treatment of sRAGE and siRAGE exhibited synergic cardioprotective effects; thus the newly designed regimen can be considered as a promising candidate for the treatment of myocardial infarction.
Archives of Pharmacal Research 01/2015; 38(7). DOI:10.1007/s12272-014-0527-x · 2.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The impact of exaggerated blood pressure response (EBPR) to exercise on left ventricular function and the mechanism of its association are poorly understood. This study investigated the impact of arterial stiffening on left ventricular function in individuals with an EBPR to exercise. We hypothesized that individuals with low pulse pressure (PP) amplification during exercise would have worse left ventricular function than those with high PP amplification in individuals with an EBPR to exercise.
Fifty-nine individuals with an EBPR to exercise (18 men, age 57 ± 12 years) and 59 age and sex-matched controls were studied. Radial artery tonometry was performed at rest and immediately after exercise during supine bicycle exercise echocardiography.
There were no differences in left ventricular structure or function between individuals with an EBPR to exercise and controls. When individuals with an EBPR to exercise were divided into two groups on the basis of PP amplification after exercise [Group 1 (n = 30), high PP amplification after exercise; Group 2 (n = 29), low PP amplification after exercise], group 2 showed larger left atrial volume and lower early diastolic (e') and systolic (S') mitral annular velocities. Left ventricular apical rotation was also exaggerated in group 2. In multiple regression, PP amplification after exercise was an independent determinant of e' (β = 0.16, P = 0.019) and S' (β = 0.25, P = 0.009) in individuals with an EBPR to exercise.
In individuals with an EBPR to exercise, the degree of left ventricular dysfunction is variable. EBPR to exercise in the presence of arterial stiffening contributes to the deterioration of left ventricular function.
Journal of Hypertension 12/2014; 33(3). DOI:10.1097/HJH.0000000000000431 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We aimed to assess the therapeutic efficacy of differentially modified soluble receptor for advanced glycation end products (sRAGE) in vivo using vessel ultrasound sonography and to compare the sonography data with those from postmortem histomorphologic analyses to have a practical reference for future clinical applications.Methods
Vessel ultrasound sonography was performed in a sRAGE-treated rat carotid artery balloon injury model at different time points after the surgery, and therapeutic efficacy of different doses of sRAGE produced in Chinese hamster ovary cells and with different N-glycoform modifications were assessed.ResultsVessel ultrasound sonography found that sRAGE produced in Chinese hamster ovary cells with complex N-glycoform modifications is highly effective, and is consistent with our recent findings in the same model assessed with histology. We also found that sonography is less sensitive than histology when a higher dose of sRAGE is administered.Conclusions
Sonograph results are consistent with those obtained from histology; that is, sRAGE produced in Chinese hamster ovary cells has significantly higher efficacy than insect cell-originated sRAGE cells.
Current Therapeutic Research 11/2014; 76. DOI:10.1016/j.curtheres.2014.08.001 · 0.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim:
In this study, we investigated the genetic determinants of lesion characteristics and the severity of coronary artery disease (CAD) using a genome-wide association study (GWAS) and replication genotyping.
The discovery set for GWAS consisted of 667 patients exhibiting angiographically diagnosed CAD with symptoms. For replication genotyping, 837 age- and sex-matched CAD patients were selected. Genetic determinants of lesion characteristics (diffuse vs. non-diffuse lesions), the number of diseased vessels (multi-vessel vs. single vessel disease) and the modified Duke score (high vs. low), which indicates the severity of CAD, were analyzed after adjusting for confounding factors.
Single nucleotide polymorphisms (SNPs) rs12917449, rs10152898 and rs231150 were associated with diffuse lesions, while rs1225006 and rs6745588 were associated with multi-vessel disease. However, on replication genotyping, no significant associations were found between any of these five SNPs and the lesion characteristics or CAD severity. In contrast, in the combined population of both the discovery and replication sets, genotypes rs125006 of CPNE4 and rs231150 of TRPS1 were found to be significantly associated with the modified Duke score. The addition of rs1225006 to conventional risk factors had significant incremental value in the model of the score.
The associations between five SNPs identified using GWAS and angiographic characteristics were not significant in the current replication study. However, two variants, particularly rs1225006, were found to be associated with the severity of CAD in the combined set. These results indicate the potential clinical implication of these variants with respect to the risk of CAD.
Journal of atherosclerosis and thrombosis 10/2014; 22(4). DOI:10.5551/jat.26047 · 2.73 Impact Factor