Prediction of Serious Adverse Events of Patients with Hypertrophic Cardiomyopathy by Magnetic Resonance.

Although it is well known that patients with hypertrophic cardiomyopathy (HCM) have serious adverse events, such as life-threatening arrhythmia and heart failure, the prediction of such evens is still difficult. Recently, it has been reported that one of the causes of these serious adverse events is microvascular dysfunction, which can be noninvasively evaluated by employing cardiac magnetic resonance (CMR) imaging.We analyzed 32 consecutive HCM patients via CMR imaging and myocardial scintigraphy and divided them into two groups: ventricular tachycardia (VT) group and non-VT group. Myocardial perfusion studies were conducted quantitatively using the QMass® software, and each slice image was divided into six segments. The time-intensity curve derived from the perfusion image by CMR imaging was evaluated, and the time to 50% of the peak intensity (time 50% max) was automatically calculated for each segment.Although no difference was observed in various parameters of myocardial scintigraphy between the two groups, the VT group exhibited a higher mean of time 50% max and wider standard deviation (SD) of time 50% max in each segment than the non-VT group. The cutoff values were obtained by the receiver operating characteristic curves derived from the mean of time 50% max and SD of time 50% max. The two groups divided by the cutoff values exhibited significant differences in the occurrence of serious adverse events.CMR imaging may be useful for predicting serious adverse events of patients with HCM.

Effect of Obesity on the Prognostic Impact of Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Although obesity is associated with left ventricular hypertrophy, diastolic dysfunction, and occurrence of atrial fibrillation (AF), obese heart failure (HF) patients have a more favorable clinical outcome (obesity paradox). The clinical impact of AF on obese or lean HF patients has not been fully elucidated.Methods and Results:We analyzed 1,681 patients who were enrolled in the West Tokyo Heart Failure Registry (WET-HF Registry), a multicenter, prospective cohort registry from 2005 through 2014. We assigned them to 3 categories based on body mass index (BMI): low, BMI <18.5; medium, BMI ≥18.5 and <25; and high, BMI ≥25 (n=182/915/400). The clinical endpoint was all-cause death or readmission for acute decompensated HF. During 406 days of follow-up (IQR, 116-739 days), AF was associated with a higher risk of the endpoint in the HF with preserved ejection fraction (HFpEF) group (P<0.001, log-rank test), but not in the HF with reduced EF (HFrEF) group. AF was associated with a higher risk of the endpoint in low and medium BMI patients with HFpEF (P=0.016 and 0.009, respectively). On Multivariate Cox proportional hazards analysis, AF was an independent predictor of the endpoint in patients with BMI <25 from the HFpEF group (hazard ratio, 1.74; 95% CI: 1.21-2.54, P=0.003), but not in the other subgroups. CONCLUSIONS: AF had a negative impact on clinical outcome in non-obese patients with HFpEF.

A preliminary feasibility study of simultaneous dual-isotope imaging with a solid-state dedicated cardiac camera for evaluating myocardial perfusion and fatty acid metabolism.

Simultaneous dual-isotope SPECT imaging with 201Tl and (123)I-ß-methyl-p-iodophenylpentadecanoic acid (BMIPP) is used to study the perfusion-metabolism mismatch. It predicts post-ischemic functional recovery by detecting stunned myocardium. On the other hand, (99m)Tc-MIBI is another radioisotope widely used in myocardial perfusion imaging because of its better image quality and lower radiation exposure than 201Tl. However, since the photopeak energies of (99m)Tc and (123)I are very similar, crosstalk hampers the simultaneous use of these two radioisotopes. To overcome this problem, we conducted simultaneous dual-isotope imaging study using the D-SPECT scanner (Spectrum-Dynamics, Israel) which has a novel detector design and excellent energy resolution. We first conducted a basic experiment using cardiac phantom to simulate the condition of normal perfusion and impaired fatty acid metabolism. Subsequently, we prospectively recruited 30 consecutive patients who underwent successful percutaneous coronary intervention for acute myocardial infarction, and performed (99m)Tc-MIBI/(123)I-BMIPP dual-isotope imaging within 5 days after reperfusion. Images were interpreted by two experienced cardiovascular radiologists to identify the infarcted and stunned areas based on the coronary artery territories. As a result, cardiac phantom experiment revealed no significant crosstalk between (99m)Tc and (123)I. In the subsequent clinical study, (99m)Tc-MIBI/(123)I-BMIPP dual-isotope imaging in all participant yielded excellent image quality and detected infarcted and stunned areas correctly when compared with coronary angiographic findings. Furthermore, we were able to reduce radiation exposure to significantly approximately one-eighth. In conclusion, we successfully demonstrated the practical application of simultaneous assessment of myocardial perfusion and fatty acid metabolism by (99m)Tc-MIBI and (123)I-BMIPP using a D-SPECT cardiac scanner. Compared with conventional (201)TlCl/(123)I-BMIPP dual-isotope imaging, the use of (99m)Tc-MIBI instead of (201)TlCl improves image quality as well as lowers radiation exposure.

Immunoadsorption therapy for dilated cardiomyopathy using tryptophan column-A prospective, multicenter, randomized, within-patient and parallel-group comparative study to evaluate efficacy and safety.

Over the past few decades, several cardiac autoantibodies have been reported in sera from patients with dilated cardiomyopathy (DCM). Immunoadsorption (IA) therapy is one of the therapeutic tools to remove such autoantibodies. The objective of this study was to investigate functional effects of IA therapy using a tryptophan column in severe DCM patients. Of 49 patients enrolled, 44 were randomized from 10 sites in Japan. IA therapy was conducted in 40 patients with DCM (refractory to standard therapy for heart failure, New York Heart Association [NYHA] class III/IV, left ventricular ejection fraction [LVEF] <30%). Mean echocardiographic LVEF was significantly improved (23.8 ± 1.3% to 25.9 ± 1.3%, P = 0.0015). However, mean radionuclide LVEF over 3 months of IA therapy was not significantly improved (20.8 ± 1.1% to 21.9 ± 1%, P = 0.0605). The cardiothoracic ratio was also significantly decreased (P = 0.0010). NYHA functional class (P < 0.0001), subjective symptoms assessed by a quality of life questionnaire (P = 0.0022), maximum oxygen consumption (P = 0.0074), and 6-minute walk distance (P = 0.0050) were improved after IA therapy. Subgroup analysis revealed improvement of echocardiographic LVEF in patients with higher baseline autoantibody scores but not in those with lower scores. IA therapy improved subjective symptoms and exercise capacity in patients with refractory heart failure resulting from DCM. Favorable effect on cardiac function was noted in patients with higher autoantibody scores. J. Clin. Apheresis 31:535-544, 2016. © 2015 Wiley Periodicals, Inc.

Aircraft transfer of pediatric patients with intractable cardiac or airway problems ­ single-institutional experience of a specialty hospital.

BACKGROUND: There is currently a well-established network for the allocation of donor organs for transplantation in Japan, and emergency patients are often transported by the "Doctor Helicopter". However, interhospital transfer of patients, which can require aircraft with specialized equipment, depends on arrangement by each responsible hospital. METHODS AND RESULTS: Since 2009 there were 41 interhospital aviation transfers of pediatric patients with intractable cardiac or airway diseases seeking surgical treatment at Sakakibara Heart Institute. Of these, 22 were newborns, 21 were on continuous drip infusion and 14 on mechanical ventilator support. In 15 cases (36.6%), a commercial airliner was used, with the remaining using chartered emergency aircraft (eg, local fire department helicopter, Self-Defense-Forces of Japan and the Doctor Helicopter). The median transfer time was 239 min for commercial airliners, 51 min for chartered aircraft departing directly from the referring hospital and 120.5 min for chartered aircraft departing from a nearby location. The efficiency of the transfer exemplified by the percentage of the time on board the aircraft was significantly lower for commercial airliners compared with chartered emergency aircraft. CONCLUSIONS: Further efforts and cooperation with government are required to obtain geographically uniform availability of carriers with optimal medical equipment to improve pediatric patient outcomes.

Nationwide distribution of cardiovascular practice in Japan - results of Japanese circulation society 2010 annual survey.

BACKGROUND: The geographic distribution of cardiovascular (CV) health-care services has not been assessed systematically. METHODS AND RESULTS: Data of the Japanese Circulation Society (JCS) annual survey were provided to the JCS working group with the permission of the JCS Scientific Committee. The status of CV practice in 2010 was then assessed in 47 prefectures retrospectively, along with national census and gross domestic product (GDP) data. The surveyed indices included resources (hospitals, beds and cardiologists), burden (number of inpatients), and outcome (CV mortality and autopsy) in each prefecture, which correlated well with respective populations or GDP. Inequality of geographic distribution was evident for pediatrics among the 47 prefectures, according to Lorenz curve, Gini coefficient or the maximum/minimum ratio for each index. According to the Gini coefficients, only the number of inpatients (medical or acute myocardial infarction) and beds for the total number of general hospitals or the hospitals surveyed in the present JCS study were lower than expected with regard to GDP. CONCLUSIONS: Geographic disparity of CV resources or burden was larger in pediatrics than in CV medicine or surgery. Improvement of equality in CV practice with regard to appropriateness and quality are the coming challenges for the JCS.

Beat-to-beat alterations of acoustic intensity and frequency at the maximum power of heart sounds are associated with NT-proBNP levels.

Background: Auscultatory features of heart sounds (HS) in patients with heart failure (HF) have been studied intensively. Recent developments in digital and electrical devices for auscultation provided easy listening chances to recognize peculiar sounds related to diastolic HS such as S3 or S4. This study aimed to quantitatively assess HS by acoustic measures of intensity (dB) and audio frequency (Hz). Methods: Forty consecutive patients aged between 46 and 87 years (mean age, 74 years) with chronic cardiovascular disease (CVD) were enrolled in the present study after providing written informed consent during their visits to the Kitasato University Outpatient Clinic. HS were recorded at the fourth intercostal space along the left sternal border using a highly sensitive digital device. Two consecutive heartbeats were quantified on sound intensity (dB) and audio frequency (Hz) at the peak power of each spectrogram of S1-S4 using audio editing and recording application software. The participants were classified into three groups, namely, the absence of HF (n = 27), HF (n = 8), and high-risk HF (n = 5), based on the levels of NT-proBNP < 300, ≥300, and ≥900 pg/ml, respectively, and also the levels of ejection fraction (EF), such as preserved EF (n = 22), mildly reduced EF (n = 12), and reduced EF (n = 6). Results: The intensities of four components of HS (S1-S4) decreased linearly (p < 0.02-0.001) with levels of body mass index (BMI) (range, 16.2-33.0 kg/m2). Differences in S1 intensity (ΔS1) and its frequency (ΔfS1) between two consecutive beats were non-audible level and were larger in patients with HF than those in patients without HF (ΔS1, r = 0.356, p = 0.024; ΔfS1, r = 0.356, p = 0.024). The cutoff values of ΔS1 and ΔfS1 for discriminating the presence of high-risk HF were 4.0 dB and 5.0 Hz, respectively. Conclusions: Despite significant attenuations of all four components of HS by BMI, beat-to-beat alterations of both intensity and frequency of S1 were associated with the severity of HF. Acoustic quantification of HS enabled analyses of sounds below the audible level, suggesting that sound analysis might provide an early sign of HF.

Lamr1 functional retroposon causes right ventricular dysplasia in mice.

Arrhythmogenic right ventricular dysplasia (ARVD) is a hereditary cardiomyopathy that causes sudden death in the young. We found a line of mice with inherited right ventricular dysplasia (RVD) caused by a mutation of the gene laminin receptor 1 (Lamr1). This locus contained an intron-processed retroposon that was transcribed in the mice with RVD. Introduction of a mutated Lamr1 gene into normal mice by breeding or by direct injection caused susceptibility to RVD, which was similar to that seen in the RVD mice. An in vitro study of cardiomyocytes expressing the product of mutated Lamr1 showed early cell death accompanied by alteration of the chromatin architecture. We found that heterochromatin protein 1 (HP1) bound specifically to mutant LAMR1. HP1 is a dynamic regulator of heterochromatin sites, suggesting that mutant LAMR1 impairs a crucial process of transcriptional regulation. Indeed, mutant LAMR1 caused specific changes to gene expression in cardiomyocytes, as detected by gene chip analysis. Thus, we concluded that products of the Lamr1 retroposon interact with HP1 to cause degeneration of cardiomyocytes. This mechanism may also contribute to the etiology of human ARVD.

Polyvascular Disease and the Incidence of Cancer in Patients with Coronary Artery Disease.

Introduction: Based on the possible relation of atherosclerotic cardiovascular disease to the development of cancer, we examined whether polyvascular disease, as a surrogate marker of the severity of atherosclerosis, is associated with the incidence of cancer in patients with coronary artery disease (CAD). Methods: A total of 8,856 patients with CAD between January 2009 and July 2014 were eligible for this observational study. Two cohorts were established based on the presence or absence of polyvascular disease (i.e., polyvascular disease and CAD only) and tracked for the incidence of cancer and all causes of death. Polyvascular disease was defined when accompanied by diagnosed aortic and/or peripheral arterial disease or other arterial diseases at enrollment. Results: With a median follow-up of 1,095 d, the incidence of cancer was markedly higher in the cohort of 716 patients with polyvascular disease than in the cohort of 8,140 patients with CAD only (8.8% vs. 4.9%, P = 0.0001). A large difference in the incidence of cancer was also found in accordance with a number of the coexisting vascular disease with CAD. With the adjustment of shared common risks, polyvascular disease was an independent contributor to the incidence of cancer (hazard ratio, 1.362; 95% confidence interval [CI], 1.029-1.774). In a total of 548 patients (6.2% of participants) died during follow-up, and all-cause, cardiovascular, and cancer mortalities were all higher in the cohort with polyvascular disease than in the cohort with CAD only. Conclusion: The presence of polyvascular disease may be associated with the incidence of cancer in patients with CAD, implying a pivotal role of the severity of atherosclerosis in cancer development (ClinicalTrials.gov. number: NCT04198896).

Different characteristics of peripartum cardiomyopathy between patients complicated with and without hypertensive disorders. -Results from the Japanese Nationwide survey of peripartum cardiomyopathy-.

BACKGROUND: There has been no nationwide survey concerning peripartum cardiomyopathy (PPCM) among the Asian population, and clinical profiles of PPCM complicated with hypertensive disorders complicating pregnancy (HD) as the major risk factor of PPCM have not been characterized. METHODS AND RESULTS: A retrospective, nationwide survey of PPCM in 2007 and 2008 all over Japan was performed and the clinical characteristics were compared between patients with and without HD. We obtained data for 102 patients. HD during pregnancy occurred in 42 patients (41%). Patients with HD were older than those without HD (33.8 vs. 31.9 years old, P<0.05) and babies were delivered more frequently by Caesarean section (81% vs. 52%, P<0.01). Although cardiac parameters at diagnosis were similar in patients with and without HD, patients with HD were hospitalized for a shorter period and had better cardiac function after 7 months. Multivariate regression analysis revealed that HD was independently associated with a shorter hospital stay and a higher left ventricular ejection fraction at last follow up. CONCLUSIONS: PPCM complicated with HD had different clinical characteristics from those without HD. This condition might be a unique subset of PPCM that is characterized by relatively swift recovery except in the cases of death. In order to prevent severe heart failure and maternal death, peripartum women should be treated with HD cautiously and must immediately undergo a cardiac examination as needed.

Spatial Feature Extraction of Vectorcardiography via Minimum Volume Ellipsoid Enclosure in Classifying Left Ventricular Hypertrophy.

The voltage criteria used to diagnose left ventricular hypertrophy (LVH) in the chest and limb leads are by no means absolute. In addition to QRS voltages, QRS axis and duration, and P wave characteristics, repolarization (STT) changes have been focused attention due to their representing left ventricular overload. Vectorcardiography (VCG) has been studied specifically on its repolarization abnormality. The present study aims to devise spatial feature extraction of VCG and assess it in the LVH classification task. A minimum volume ellipsoid enclosure was applied to six segments obtained from upstroke and downstroke of each P, QRS, and T loops of a single-beat VCG. For the evaluation, VCG and 12 lead ECG dataset along with LVH labels of 61 subjects were derived from public open data, PTB-XL. These classification performances were compared with the LVH diagnosis criteria in the standard 12 lead ECG. As a result, the Random Forest classifier trained by the proposed spatial VCG feature resulted in accuracy of 0.904 (95% confidence interval: 0.861-0.947) when the classbalanced dataset was evaluated, which slightly exceeded the feature of 12 lead ECG. The feature importance analysis provided the quantitative ranking of the spatial feature of VCG, which were practically similar to those of ECG in the LVH classification task. Since the VCG are spatially comparable with three-dimensional data of CT, MRI, or Echocardiography, VCG will shed light on the spatial behavior of electrical depolarization and repolarization abnormalities in cardiac diseases.

Unsupervised Heart Sound Decomposition and State Estimation with Generative Oscillation Models.

This paper proposes a new generative probabilistic model for phonocardiograms (PCGs) that can simultaneously capture oscillatory factors and state transitions in cardiac cycles. Conventionally, PCGs have been modeled in two main aspects. One is a state space model that represents recurrent and frequently appearing state transitions. Another is a factor model that expresses the PCG as a non-stationary signal consisting of multiple oscillations. To model these perspectives in a unified framework, we combine an oscillation decomposition with a state space model. The proposed model can decompose the PCG into cardiac state dependent oscillations by reflecting the mechanism of cardiac sounds generation in an unsupervised manner. In the experiments, our model achieved better accuracy in the state estimation task compared to the empirical mode decomposition method. In addition, our model detected S2 onsets more accurately than the supervised segmentation method when distributions among PCG signals were different.

Tonometric Condition of Cellular Polypropylene Film Sensors in Measuring Arterial Pressure Waveform.

Tonometric continuous measurement of arterial pressure becomes feasible using a cellular polypropylene (Cellular PP) film sensor. A pulsatile arterial vascular phantom model was used to find the range of optimal tonometric conditions and the responsiveness to dynamic pressure changes. The optimal tonometric condition was assessed by the correlation coefficient between the hydraulic pressure and the Cellular PP output using two different types of tubes (the latex tube and the hydrogel tube) to simulate arteries. With a setting of the normal blood pressure range, the output of Cellular PP correlated strongly with the level of hydraulic pressure, 0.998 and 0.989 in the latex tube and the hydrogel tube, respectively. For maintaining the optimal tonometric condition, the depressed depths of the latex and the hydrogel tube were less than 1.2 and 0.6 mm, respectively. The phantom model also demonstrated that the Cellular PP sensor followed changes in a hydraulic pressure dynamically under the optimal tonometric conditions. The present results demonstrated the Cellular PP film sensor is applicable to the arterial tonometry in measuring the instantaneous blood pressure while the sensor is adjusted to maintain the minimal flatness of the underlying arterial wall.Clinical Relevance- To understand the physiological characteristics of blood pressure and arterial system, the instantaneous measurement of blood pressure is necessary. The present study suggests that Cellular PP films are applicable to peripheral arteries tonometrically to obtain simultaneously the respective blood pressure waveforms.

High-density association study and nomination of susceptibility genes for hypertension in the Japanese National Project.

Essential hypertension is one of the most common, complex diseases, of which considerable efforts have been made to unravel the pathophysiological mechanisms. Over the last decade, multiple genome-wide linkage analyses have been conducted using 300-900 microsatellite markers but no single study has yielded definitive evidence for 'principal' hypertension susceptibility gene(s). Here, we performed a three-tiered, high-density association study of hypertension, which has been recently made possible. For tier 1, we genotyped 80 795 SNPs distributed throughout the genome in 188 male hypertensive subjects and two general population control groups (752 subjects per group). For tier 2 (752 hypertensive and 752 normotensive subjects), we genotyped a panel of 2676 SNPs selected (odds ratio >or= 1.4 and P

A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart.

Marked sarcomere disorganization is a well-documented characteristic of cardiomyocytes in the failing human myocardium. Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC2v), which is involved in the development of human cardiomyopathy, is an important structural protein that affects physiologic cardiac sarcomere formation and heart development. Integrated cDNA expression analysis of failing human myocardia uncovered a novel protein kinase, cardiac-specific myosin light chain kinase (cardiac-MLCK), which acts on MLC2v. Expression levels of cardiac-MLCK were well correlated with the pulmonary arterial pressure of patients with heart failure. In cultured cardiomyocytes, knockdown of cardiac-MLCK by specific siRNAs decreased MLC2v phosphorylation and impaired epinephrine-induced activation of sarcomere reassembly. To further clarify the physiologic roles of cardiac-MLCK in vivo, we cloned the zebrafish ortholog z-cardiac-MLCK. Knockdown of z-cardiac-MLCK expression using morpholino antisense oligonucleotides resulted in dilated cardiac ventricles and immature sarcomere structures. These results suggest a significant role for cardiac-MLCK in cardiogenesis.

Association of four genetic loci with uric acid levels and reduced renal function: the J-SHIPP Suita study.

BACKGROUND: Recent genome-wide association studies have identified several genetic variants as susceptibility loci for serum uric acid (UA) levels. We also identified a common nonsense mutation, W258X, responsible for renal hypouricemia. Here, we investigated clinical implications of these genetic variants by cross-sectional and longitudinal genetic epidemiological analysis. METHODS: The study enrolled 5,165 Japanese subjects aged 64 ± 12 years from the general population. Clinical parameters were obtained from the personal health records, evaluated at medical checkups. RESULTS: Serum UA levels were significantly different between the SLC22A12 rs11231825 (CC/CT/TT: 4.5 ± 1.6, 5.0 ± 1.4, 5.3 ± 1.4 mg/dl; p = 7.6 × 10(-20)), SLC2A9 rs1014290 (TT/TG/GG: 4.9 ± 1.4, 5.1 ± 1.4, 5.3 ± 1.4 mg/dl; p = 3.1 × 10(-11)) and ABCG2 rs2231142 (TT/TG/GG: 5.3 ± 1.5, 5.2 ± 1.4, 5.1 ± 1.4 mg/dl; p = 2.0 × 10(-5)) genotypes. During 9.4 years of follow-up, 87 new cases of hyperuricemia were diagnosed. Multiple logistic regression analysis identified the accumulation of risk alleles as a significant determinant of future development of hyperuricemia (OR = 7.94; 95% CI: 1.97-53.6). In contrast, subjects with nonsense mutation predominantly showed lower UA levels (XX/XW/WW: 1.3 ± 1.7, 3.6 ± 1.0, 5.2 ± 1.4 mg/dl; p = 9.3 × 10(-82)). However, these subjects showed significantly reduced renal function (ß = -0.111; p < 0.001) independently of possible covariates. CONCLUSION: Accumulation of risk genotypes was an independent risk factor for future development of hyperuricemia. Genetically developed hypouricemia was an independent risk factor for decreased renal function.

The first clinical pilot study of intravenous adrenomedullin administration in patients with acute myocardial infarction.

Adrenomedullin (AM) is a 52-amino-acid vasodilator peptide that was originally isolated from human pheochromocytoma. In the previous experimental study with rat ischemia/reperfusion model, AM reduced infarct size and inhibited myocyte apoptosis. AM also suppressed the production of oxygen-free radicals. The present study was designed to evaluate the feasibility of intravenous administration of AM in patients with acute myocardial infarction. We studied 10 patients with first acute myocardial infarction [male to female ratio: 9 to 1, age: 65 ± 9 (mean ± SD) years, peak creatine phosphokinase level: 4215 ± 1933 (SD) U/L], who were hospitalized within 12 hours of symptom onset. Proceeding reperfusion therapy, AM infusion was initiated and continued at concentration of 0.0125-0.025 µg·kg·min for 12 hours. Follow-up coronary angiography and left ventriculography were performed at 3 months. Cardiac magnetic resonance was examined at 1 month and 3 months after AM therapy. During infusion of AM, hemodynamics kept stable except 2 patients. Wall motion index in the infarct area at 3 months was significantly improved compared with that at baseline, and infarct size evaluated by cardiac magnetic resonance was significantly decreased at 3 months. In conclusion, intravenous administration of AM, which possesses a variety of potential cardiovascular protective actions, can be adjunctive to percutaneous coronary intervention.

A genome-wide association study of hypertension-related phenotypes in a Japanese population.

BACKGROUND: Large-scale genome-wide association studies (GWAS) have been successful in identifying genes that contribute to common diseases and phenotypes. A GWAS of hypertension-related phenotypes in a Japanese population was conducted in the current study. METHODS AND RESULTS: A total of 936 participants were recruited from the Suita Study and a GWAS with 538,732 single nucleotide polymorphisms (SNP) was performed. The phenotypes included were systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI), waist-to-hip ratio (WHR), plasma renin activity (PRA), plasma aldosterone concentration (PAC), plasma brain natriuretic peptide (BNP) concentration and alcohol consumption (AC). The SNP exceeding the genome-wide significance level were subjected to subsequent association studies using samples available from the Suita Study and Nomura Study. There is no master gene in the Japanese population that profoundly affects SBP, DBP, BMI, WHR, PRA and PAC. AC was influenced by the functional polymorphism in ALDH2, which affected BP levels in men. The BNP concentration was influenced by a polymorphism in the 3' region of the gene encoding for BNP. However, this polymorphism did not influence blood pressure (BP). Six SNP were identified to be associated with hypertension in both the Suita and Nomura studies. CONCLUSIONS: Although several candidate SNP relevant to hypertension and those influencing AC and BNP were identified, our middle-sized GWAS indicated that there is no master gene in Japanese people that profoundly affects BP-related phenotypes.

Association of the functional variant in the 3-hydroxy-3-methylglutaryl-coenzyme a reductase gene with low-density lipoprotein-cholesterol in Japanese.

BACKGROUND: The association between single nucleotide polymorphisms (SNPs) at 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and low-density lipoprotein-cholesterol (LDL-C) levels has been well replicated in genome-wide association studies (GWAS) of white populations. Recently, the common intronic SNP of HMGCR (rs3846662) has been reported to be a functional variant, influencing the alternative splicing of exon 13. The aim of this study was to examine the association between rs3846662 of HMGCR and the level of LDL-C in Japanese. METHODS AND RESULTS: Significant differences in LDL-C levels were observed among the genotypes of rs3846662 (P=0.0002 (n=2,686) and P=0.004 (n=2,110)) for the Suita and Ehime samples, respectively. The G allele of rs3846662 was associated with higher LDL-C levels (beta, 3.56; P=4.91x10(-5)). Consistent with this observation, the risk G allele at rs3846662 was more prevalent in subjects with myocardial infarction (MI) (n=701) than in subjects without MI (n=3,118); 0.559 and 0.511 in MI cases and controls, respectively (nominal P=0.0038). The odds ratio adjusted for age, sex, diabetes, hypertension, and drinking and smoking habits was 1.15 (95% confidence interval 1.04-1.28; P=0.0075). CONCLUSIONS: The previously reported association of rs3846662 with LDL-C levels was replicated in the present Suita and Ehime samples. The LDL-associated SNP, rs3846662, appears to confer susceptibility to MI in Japanese.