Genome-Wide Association Study Meta-Analysis Reveals Transethnic Replication of Mean Arterial and Pulse Pressure Loci

Kelly, Tanika N.,Takeuchi, Fumihiko,Tabara, Yasuharu,Edwards, Todd L.,Kim, Young Jin,Chen, Peng,Li, Huaixing,Wu, Ying,Yang, Chi-Fan,Zhang, Yonghong,Gu, Dongfeng,Katsuya, Tomohiro,Ohkubo, Takayoshi,Gao American Heart Association, Inc. 2013 Hypertension Vol.62 No.5

<P>We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26 600 East Asian participants (stage 1) followed by replication study of up to 28 783 participants (stage 2). For novel loci, statistical significance was determined by a <I>P</I><5.0×10<SUP>–8</SUP> in joint analysis of stage 1 and stage 2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of transethnic replication was determined by consistency in effect direction and a Bonferroni-corrected <I>P</I><1.4×10<SUP>–3</SUP>. No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for transethnic replication including rs17249754 at <I>ATP2B1</I> (<I>P</I>=7.5×10<SUP>–15</SUP>), rs2681492 at <I>ATP2B1</I> (<I>P</I>=3.4×10<SUP>–7</SUP>), rs11191593 at <I>NT5C2</I> (1.1×10<SUP>–6</SUP>), rs3824755 at <I>CYP17A1</I> (<I>P</I>=1.2×10<SUP>–6</SUP>), and rs13149993 at <I>FGF5</I> (<I>P</I>=2.4×10<SUP>–4</SUP>). Two additional variants showed suggestive evidence of transethnic replication (consistency in effect direction and <I>P</I><0.05), including rs319690 at <I>MAP4</I> (<I>P</I>=0.014) and rs1173771 at <I>NPR3</I> (<I>P</I>=0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at <I>ATP2B1</I> (<I>P</I>=1.2×10<SUP>–5</SUP>) and rs11191593 at <I>NT5C2</I> (<I>P</I>=1.1×10<SUP>–3</SUP>), with suggestive evidence of replication among an additional 2 variants including rs3824755 at <I>CYP17A1</I> (<I>P</I>=6.1×10<SUP>–3</SUP>) and rs2681492 at <I>ATP2B1</I> (<I>P</I>=9.0×10<SUP>–3</SUP>). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mm Hg for mean arterial pressure and from 0.03 to 0.21 mm Hg for pulse pressure. In conclusion, we present the first evidence of transethnic replication of several mean arterial and pulse pressure loci in an East Asian population.</P>

Previous Statin Use and High-Resolution Magnetic Resonance Imaging Characteristics of Intracranial Atherosclerotic Plaque : The Intensive Statin Treatment in Acute Ischemic Stroke Patients With Intracranial Atherosclerosis Study

Chung, Jong-Won,Hwang, Jaechun,Lee, Mi Ji,Cha, Jihoon,Bang, Oh Young American Heart Association, Inc. 2016 Stroke Vol.47 No.7

<P>Background and Purpose-Although statin use has been linked to the stabilization of systemic atherosclerosis, its effect on symptomatic intracranial atherosclerotic plaques has yet to be explored. We hypothesized that premorbid statin use is associated with plaque instability in intracranial arteries and may lead to differential patterns (size and distribution) of ischemic lesions in patients with acute intracranial atherosclerotic stroke. Methods-One hundred and thirty-six patients with acute infarcts caused by intracranial atherosclerotic stroke underwent high-resolution magnetic resonance imaging. Patients were categorized into 3 groups based on their premorbid statin use: nonuser, low-dose user, and high-dose user, according to the 2013 American College of Cardiology/American Heart Association guidelines on blood cholesterol. Symptomatic lesions in intracranial arteries were analyzed using high-resolution magnetic resonance imaging for vascular morphology (degree of stenosis, remodeling index, and wall index) and plaque activation (pattern and volume of enhancement). The cortical distribution and volume of ischemic brain lesions were measured using diffusion-weighted imaging. Results-Among the enrolled patients, 38 (27.94%) were taking statins before the index stroke (22 low-dose statins and 16 high-dose statins). The degree of stenosis, remodeling index, and wall index did not differ between the 3 groups. However, the volume of plaque enhancement was significantly lower in statin users (nonuser, 33.26 +/- 40.72; low-dose user, 13.15 +/- 17.53; high-dose user, 3.13 +/- 5.26; P=0.002). Premorbid statin use was associated with a higher prevalence of nonembolic stroke and a decrease in large cortical infarcts (P=0.012). Conclusions-Premorbid statin usage is independently associated with reduced plaque enhancement and a decrease in large cortical lesions in patients with intracranial atherosclerotic stroke.</P>

Risk Factors Associated With the Presence of Unruptured Intracranial Aneurysms

Kang, Hyun Goo,Kim, Bum Joon,Lee, Jisung,Kim, Mi-Jung,Kang, Dong-Wha,Kim, Jong S.,Kwon, Sun U. American Heart Association, Inc. 2015 Stroke Vol.46 No.11

<P><B>Background and Purpose—</B></P><P>With the increased investigation of cerebral arteries using magnetic resonance angiography in the general population, the detection of unruptured intracranial aneurysms (UIAs) has increased. Understanding the distribution and factors associated with UIAs might be helpful for understanding the pathomechanism.</P><P><B>Methods—</B></P><P>Subjects who underwent magnetic resonance angiography with a health examination at the Health Screening and Promotion Center were enrolled. The incidence and risk factors of UIAs (age, sex, hypertension, diabetes mellitus, smoking, alcohol, and coronary artery disease) were investigated by comparing patients with and without UIAs. These risk factors were also investigated by the UIA location, distal internal carotid artery, anterior cerebral artery and middle cerebral artery (MCA), MCA bifurcation, anterior and posterior communicating artery, and posterior circulation.</P><P><B>Results—</B></P><P>Among 187 166 subjects who received health examination, 18 954 underwent magnetic resonance angiography. Of them, 367 (1.93%) had UIAs. Age (odds ratio [OR], 1.02; <I>P</I>=0.003), women (OR, 2.00; <I>P</I><0.001), hypertension (OR, 2.21; <I>P</I><0.001), smoking (OR, 1.66; <I>P</I>=0.001), and coronary artery disease (OR, 0.23; <I>P</I><0.001) were independently associated with the presence of UIAs. Hypertension was associated with most UIAs, except for those located at sidewalls (anterior cerebral artery and MCA). MCA aneurysms were associated with old age and smoking. Distal internal carotid artery, posterior communicating artery, and MCA-bifurcation aneurysms were associated with female sex. Anterior communicating artery aneurysms were associated with smoking and alcohol. Posterior circulation UIAs were only associated with hypertension. Coronary artery disease was negatively associated with anterior circulation aneurysms.</P><P><B>Conclusions—</B></P><P>The risk factors for UIAs differ by their location, compared with the control. Interestingly, the presence of coronary artery disease was protective against the presence of UIAs.</P>

25-Hydroxyvitamin D Status Is Associated With Chronic Cerebral Small Vessel Disease

Chung, Pil-Wook,Park, Kwang-Yeol,Kim, Jeong-Min,Shin, Dong-Woo,Park, Moo-Seok,Chung, Yun Jae,Ha, Sam-Yeol,Ahn, Suk-Won,Shin, Hae-Won,Kim, Yong Bum,Moon, Heui-Soo American Heart Association, Inc. 2015 Stroke Vol.46 No.1

<P><B>Background and Purpose—</B></P><P>The aim of this study was to determine the association between 25-hydroxyvitamin D (25(OH)D) and neuroimaging correlates of cerebral small vessel disease.</P><P><B>Methods—</B></P><P>We identified 759 consecutive patients with acute ischemic stroke or transient ischemic attack. Lacunes, white matter hyperintensity, and cerebral microbleed (CMB) were assessed using MR images. Deep CMB was defined as the presence of CMB in basal ganglia, thalamus, or brain stem. The association between 25(OH)D and small vessel disease was tested using linear and logistic regression analyses.</P><P><B>Results—</B></P><P>Mean age was 68 (±13) years. Mean level of 25(OH)D was 34.1±17.8 nmol/L. On bivariate analysis, a 25-nmol/L decrease in 25(OH)D was associated with lacunes (regression coefficient, 0.23; 95% confidence interval [CI], 0.02–0.45), severe white matter hyperintensity (odds ratio, 2.05; 95% CI, 1.41–3.08), and deep CMB (odds ratio, 1.28; 95% CI, 1.01–1.63). Also, 25(OH)D deficiency (≤25 nmol/L) was associated with lacunes (regression coefficient, 0.5; 95% CI, 0.04–0.95), severe white matter hyperintensity (odds ratio, 2.74; 95% CI, 1.31–6.45), and deep CMB (odds ratio, 1.68; 95% CI, 1.03–2.78). The association remained significant even after multivariable adjustment and in the subgroup of previously healthy patients.</P><P><B>Conclusions—</B></P><P>25(OH)D is inversely associated with lacunes, white matter hyperintensity, and deep CMB. Our findings suggest that 25(OH)D is linked to small vessel disease, and in future trials it should be tested whether 25(OH)D supplementation can prevent small vessel disease.</P>

Clinical Implications and Determinants of Left Atrial Mechanical Dysfunction in Patients With Stroke

Kim, Darae,Shim, Chi Young,Hong, Geu-Ru,Kim, Mi-Hyun,Seo, Jiwon,Cho, In Jeong,Kim, Young Dae,Chang, Hyuk-Jae,Ha, Jong-Won,Heo, Ji Hoe,Chung, Namsik American Heart Association, Inc. 2016 Stroke Vol.47 No.6

<P>Background and Purpose-The evaluation of sources of cardioembolism with transesophageal echocardiography (TEE) in patients with stroke is crucial but semi-invasive. We hypothesized that the size and mechanical function of the left atrium (LA) assessed by transthoracic echocardiography (TTE) could provide useful information on high risk of cardioembolism on TEE in patients with stroke. Furthermore, we sought to define the determinants of LA mechanical dysfunction in these patients. Methods-A total of 248 patients with acute ischemic stroke (147 men; 64 +/- 13 years) who underwent 2-dimensional and speckle tracking TTE followed by TEE were analyzed. Results-LA appendage emptying velocity, prevalence of LA or LA appendage thrombus, prevalence of aortic plaques, and incidence of embolic stroke showed significant differences among the 4 groups classified according to the median values of the LA volume index and global LA longitudinal strain (LALS). Patients at high risk of cardioembolism evidenced by TEE revealed significantly larger LA volume index and lower global LALS than those without. Global LALS (cutoff, 11.5%; area under the curve, 0.947; sensitivity, 100%; specificity, 91%; P<0.001) revealed a significantly better diagnostic power (P=0.04) for LA or LA appendage thrombus than LA volume index (cutoff, 36.2 mL/m(2); area under the curve, 0.823; sensitivity, 88%; specificity, 75%; P=0.002). Age, left ventricular systolic function, LA volume index, and pulse wave velocity were independent determinants for global LALS. Conclusions-LA mechanical dysfunction is closely associated with high risks of cardioembolism. Global LALS assessed by speckle tracking TTE well discriminates the presence of LA or LA appendage thrombus on TEE in patients with acute ischemic stroke.</P>

Oxidative Stress–Mediated Thrombospondin-2 Upregulation Impairs Bone Marrow–Derived Angiogenic Cell Function in Diabetes Mellitus

Bae, Ok-Nam,Wang, Jie-Mei,Baek, Seung-Hoon,Wang, Qingde,Yuan, Hong,Chen, Alex F. American Heart Association, Inc. 2013 Arteriosclerosis, thrombosis, and vascular biology Vol.33 No.8

<P><B>Objective—</B></P><P>Circulating angiogenic cells play an essential role in angiogenesis but are dysfunctional in diabetes mellitus characterized by excessive oxidative stress. We hypothesize that oxidative stress–mediated upregulation of thrombospondin-2 (TSP-2), a potent antiangiogenic protein, contributes to diabetic bone marrow–derived angiogenic cell (BMAC) dysfunction.</P><P><B>Approach and Results—</B></P><P>BMACs were isolated from adult male type 2 diabetic db/db mice and control db/+ (C57BLKS/J) mice. In Matrigel tube formation assay, angiogenic function was impaired in diabetic BMACs, accompanied by increased oxidative stress and nicotinamide adenine dinucleotide phosphate oxidase activity. BMAC angiogenic function was restored by overexpression of dominant negative Rac1 or by overexpression of manganese superoxide dismutase. TSP-2 mRNA and protein were both significantly upregulated in diabetic BMACs, mediated by increased oxidative stress as shown by a decrease in TSP-2 level after overexpression of dominant negative Rac1 or manganese superoxide dismutase. Silencing TSP-2 by its small interfering RNA in diabetic BMACs improved BMAC function in tube formation, adhesion, and migration assays. Notably, the upregulation of TSP-2 was also found in BMACs from streptozotocin-induced type 1 diabetic mice, and normal BMACs with high glucose treatment. let-7f, a microRNA which has been related to endothelial angiogenic function, is found to play key role in TSP-2 increase, but let-7f did not directly interact with TSP-2 mRNA.</P><P><B>Conclusions—</B></P><P>The upregulation of TSP-2 mediated by increased oxidative stress contributes to angiogenesis dysfunction in diabetic BMACs.</P>

Hypoxia Inhibits Cellular Senescence to Restore the Therapeutic Potential of Old Human Endothelial Progenitor Cells via the Hypoxia-Inducible Factor-1α–TWIST-p21 Axis

Lee, Sang Hun,Lee, Jun Hee,Yoo, So Young,Hur, Jin,Kim, Hyo-Soo,Kwon, Sang Mo American Heart Association, Inc. 2013 Arteriosclerosis, thrombosis, and vascular biology Vol.33 No.10

<P><B>Objective—</B></P><P>Endothelial progenitor cells (EPCs) can significantly improve tissue repair by providing regeneration potential within injured cardiovascular tissue; however, it is challenging to obtain a sufficient amount of functional EPCs from aged patients for autologous stem cell therapy. To overcome this issue, we aimed to establish adequate ex vivo expansion protocols and identify repair modulators of cellular senescence. The senescence repair circuit of hypoxia-preconditioned senescent EPCs (hyp-old EPCs) was examined in an effort to enhance their regenerative potential.</P><P><B>Approach and Results—</B></P><P>Long-term culturing of EPCs in normoxic conditions markedly induced the expression of p21, whereas siRNA targeting of p21 in old EPCs significantly enhanced the proliferation potential of cells. Hyp-old EPCs displayed increased hypoxia-inducible factor-1α and TWIST expression. siRNA inhibition of TWIST, a target molecule of the hypoxia-inducible factor-1α, markedly upregulated the expression of p21 in hyp-old EPCs by reprogramming cell-cycle regulatory proteins. In a hindlimb model of ischemia, the transplantation of hyp-old EPCs enhanced the blood flow ratio and capillary density, improved cellular proliferation and cell survival at ischemic sites, and augmented the secretion of pivotal tissue angiogenic cytokines. It has been previously demonstrated that the restoration of old EPCs from a senescent state by hypoxia preconditioning is tightly mediated by the downregulation of p21 via the hypoxia-inducible factor-1α–TWIST axis.</P><P><B>Conclusions—</B></P><P>This study introduces ex vivo expansion protocols involving hypoxic preconditioning that are suitable for efficiently expanding old EPCs without senescence through modulation of the hypoxia-induced hypoxia-inducible factor-1α–TWIST-p21 axis. In addition, the expanded cells are shown to be useful for therapeutic vasculogenesis.</P>

CD34 Hybrid Cells Promote Endothelial Colony-Forming Cell Bioactivity and Therapeutic Potential for Ischemic Diseases

Lee, Jun Hee,Lee, Sang Hun,Yoo, So Young,Asahara, Takayuki,Kwon, Sang Mo American Heart Association, Inc. 2013 Arteriosclerosis, thrombosis, and vascular biology Vol.33 No.7

<P><B>Objective—</B></P><P>Although endothelial progenitor cells (EPCs) have been reported to promote neovessel formation during vascular injury, the function of supporting cells of EPCs and their interaction with EPCs during EPC isolation remain unclear.</P><P><B>Approach and Results—</B></P><P>We investigated the functional properties of 2 types of EPCs, also known as endothelial colony-forming cells (ECFCs), CD34<SUP>−</SUP>/CD34<SUP>+</SUP> cell–derived ECFCs (hybrid-dECFCs) and CD34<SUP>+</SUP> cell–derived ECFCs (stem-dECFCs), isolated using different methods, to elucidate the role of CD34<SUP>−</SUP> cell populations as cell-supporting niches. Using EPC colony-forming and insert coculture assays, we found that CD34<SUP>−</SUP> accessory cells dynamically modulate hematopoietic stem cell–derived endothelial cell progenitor commitment via angiogenic cytokines secreted by CD34<SUP>−</SUP>/CD11b<SUP>+</SUP> macrophages. On the basis of these findings, we isolated 2 types of ECFCs and investigated their bioactivities. We found that stem-dECFCs showed remarkably retarded cell growth, enhanced senescence, and decreased characteristics of ECFCs, whereas hybrid-dECFCs showed greater proliferative properties but delayed senescence. In a murine hind-limb ischemia model, hybrid-dECFCs showed significantly enhanced blood perfusion, capillary density, transplanted cell survival and proliferation, and angiogenic cytokine secretion compared with stem-dECFCs. In particular, the migratory capacity of hybrid-dECFCs was significantly enhanced, in part mediated via an augmented phosphorylation cascade of focal adhesion kinase and Src, resulting in a highly increased incorporation capacity of hybrid-dECFCs compared with stem-dECFCs. CD34<SUP>−</SUP> accessory cells of hybrid-dECFCs might be niche-supporting cells that facilitate cell survival, increase the secretion of angiogenic cytokines, and increase incorporation.</P><P><B>Conclusions—</B></P><P>This study provided important insight into blood vessel formation and repair in ischemic diseases for ECFC-based cell therapy.</P>

Quantitative Assessment of Aortic Elasticity With Aging Using Velocity-Vector Imaging and Its Histologic Correlation

Kim, Sung-Ai,Lee, Kyung Hye,Won, Ho-Yeon,Park, Sungha,Chung, Ji Hyung,Jang, Yangsoo,Ha, Jong-Won American Heart Association, Inc. 2013 Arteriosclerosis, thrombosis, and vascular biology Vol.33 No.6

<P><B>Objective—</B></P><P>Velocity-vector imaging (VVI) represents a valuable new method for noninvasive quantification of vascular properties associated with aging. The purpose of this study was to assess the correlations between VVI parameters and histological changes with aging.</P><P><B>Approach and Results—</B></P><P>Fourteen mongrel dogs were classified as either young (n=7; age, 1–2 years; female; weighing 22–29 kg) or senescent (n=7; age, 8–12 years; female; weighing 36–45 kg). The short-axis image of the descending thoracic aorta was obtained for VVI analysis with transesophageal echocardiography. The location of the image was identified using fluoroscopic guidance, and the aortic tissue was extracted. After dividing the aortic wall into 6 segments, both regional and segmental tissue collagen and elastin contents were quantified and correlated with the aortic elastic properties. In the regional analysis, the M-mode–derived aortic dimensions and elastic moduli except for intima-media thickness were not significantly different between the groups, whereas the VVI-derived aortic area and fractional area changes showed more dilated and stiffer aorta in senescent dogs. Also, fractional area change was significantly correlated with the tissue collagen content unlike the M-mode–derived elastic moduli. In the segmental analysis, the radial velocity, circumferential strain, and strain rates of VVI were more reduced in senescent dogs than young dogs, and the radial velocity and circumferential strain showed independent associations with the collagen content of the corresponding aortic wall.</P><P><B>Conclusions—</B></P><P>VVI was a feasible method for direct quantification of aortic elastic properties with a significant histological correlation.</P>

Demonstration of Prosthetic Aortic Valve Dehiscence in a Patient With Noninfectious Aortitis by Multimodality Imaging : Findings of Echocardiography and Computed Tomography

Koo, Hyun Jung,Yang, Dong Hyun,Kang, Joon-Won,Han, Kichang,Chung, Cheol Hyun,Song, Jae-Kwan,Lee, Inchul,Lim, Tae-Hwan American Heart Association, Inc. 2013 CIRCULATION - Vol.128 No.7