HLA Gene analysis in a Japanese family with hypertrophic cardiomyopathy by restriction fragment length polymorphism

Summary A large Japanese family with hypertrophic cardiomyopathy (HCM) was examined (n = 61). Ten of 14 affected family members who showed HCM on the basis of electrocardiography and two-dimensional echocardiography were subjected to human leukocyte antigen (HLA)-A,B,C typing by the lymphocyte cytotoxicity test and D, DR typing by restriction fragment length polymorphism (RFLP). As control, the HLA genotype of 14 non-affected family members was analyzed. HLA typing of the affected subjects with HCM revealed a very close association (67%) of HLA-DR (4w8) among A,B,C,D and DR. However, the LOD scores of HLA-DR4 and -DR w8 were 0.693 ( = 0.35) and 0.642 ( = 0.30) respectively. These data suggest that HLA-loci, analyzed on the basis of RFLP, may not be related with familial HCM with or without obstruction.     

静脉注射艾司洛尔对肥厚型心肌病心脏功能的影响

目的探讨β受体阻滞剂艾司洛尔对肥厚型心肌病患者血流动力学及左室收缩和舒张功能的影响。方法采用超声心动图-心导管同步血流动力学技术,测定13例肥厚型心肌病(HCM)患者(9例非梗阻性,4例梗阻性)静脉注射艾司洛尔前后的左室收缩和舒张功能。结果静脉注射艾司洛尔后HCM患者心率、收缩压、左室收缩压和左室射血分数明显减低(P<0.05,P<0.001),舒张压、左室压力最大上升速率无明显变化;左室流出道压差有减低趋势,其中4例梗阻性HCM患者用药后左室流出道压差明显减低〔(57.00±9.2)mmHg vs(23.27±12.96)mmHg,P<0.05〕;左室松弛时间常数、心腔僵硬度常数和左室压力最大下降速率无明显变化;左室舒张末压明显减低〔(19.62±10.55)mmHg vs(11.18±7.5)mmHg,P<0.05〕。结论艾司洛尔通过减低心肌收缩力、降低心脏后负荷和减慢心率而改善心肌顺应性,特别适用于梗阻性HCM患者。     

Prognostic value of heart rate variability in patients with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) have been reported to display impaired heart rate variability, although little is known regarding its prognostic value. By using fast Fourier transformation of 24-hour Holter recordings in 73 HCM patients at a stable clinical condition, we computed 4 spectral components: very low frequency, low frequency, high frequency, and total power. During 28 months, 7 HCM patients experienced death or acquired hospitalization for heart failure. Sudden death did not occurred. High frequency component was lower in HCM patients with cardiac events than that in patients without cardiac events (3.78 +/- 0.66 vs. 4.43 +/- 0.92 In(ms(2)), P =.045). There were no significant differences in other heart rate variability variables between HCM patients with and without cardiac events. In multivariate analysis, high frequency component remained to be an independent predictor of cardiac events (relative risk=0.10, 95% CI 0.01-0.73, P =.023). Heart rate variability analysis is predictive of heart failure in our cohort of HCM patients, whereas its predictive value of sudden death remains unclear.     

Prognostic significance of late gadolinium enhancement on cardiac magnetic resonance in patients with hypertrophic cardiomyopathy

Background

Late gadolinium enhancement (LGE) on cardiac MRI indicates the myocardial fibrosis in hypertrophic cardiomyopathy (HCM), and the prognostic value of LGE in HCM has been described in several studies, but controversy exists given the limited power of these studies to predict future adverse cardiac events. The objective of this study was to perform a meta-analysis to systematically evaluate the predictive value of LGE on cardiac magnetic resonance (CMR) for future adverse cardiac events.

Genetic susceptibility to autoimmune thyroid diseases in a Chinese Han population: Role of vitamin D receptor gene polymorphisms

Purpose

Previous studies have found that some immune-related genes were associated with autoimmune thyroid diseases (AITDs). A couple of studies have explored the association between vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR) gene polymorphisms and susceptibility to AITDs in different populations and found conflicting results. This case-control study was designed to evaluate the role of polymorphisms of VDR gene in the predisposition of AITDs in a Chinese Han population.

Methods

A total of 417 patients with Graves’ disease (GD), 250 patients with Hashimoto's thyroiditis (HT) and 301 healthy subjects were enrolled. The Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometer (MALDI-TOF-MS) Platform was applied to detect four SNPs (rs1544410, rs2228570, rs731236 and rs7975232) in the VDR gene.

Results

In the rs7975232 allele A frequency showed a significant increase in GD patients (30.34% vs. 25.42% in controls; P = 0.041, OR = 1.278, 95%CI = 1.010–1.617). However, no relationship was found between clinical phenotypes and the four SNPs.

Conclusions

This result suggests that the VDR gene may be one susceptibility gene which contributes to the risk of GD.     

Relation of late gadolinium enhancement in cardiac magnetic resonance on the diastolic volume recovery of left ventricle with hypertrophic cardiomyopathy

Objective

The purpose of the study was to investigate the influence of late gadolinium enhancement (LGE) on the diastolic volume recovery of left ventricle in patients with hypertrophic cardiomyopathy (HCM).

Methods

Twenty-four HCM patients were studied through report-card 4.0. The presence or absence of late gadolinium enhancement was recorded according to a standardized methodology with a threshold value of six standard deviations above background. The LGE positive and negative groups were correlated to left ventricular end diastolic volume index (EDVI), left ventricular mass, left ventricular ejection fraction (EF), peak filling rate (PFR), peak ejecting rate (PER), normalized peak filling or ejecting rate (NPFR or NPER), time to peak filling or ejecting rate (TPFR or TPER), and diastolic volume recovery (DVR).

Results

PFR, NPFR, SV, SVI, EF, CO, CI, FS in LGE positive group were lower than LGE negative group, DVR_10-40, DVR₁₀₀, end systolic volume (ESV), end systolic volume index (ESVI), ESD were higher in LGE positive group, and the differences were statistically significant. The average LGE mass (ROI, region of interest) was 20.78 g, about 13.67% of left ventricle mass in LGE positive HCM group. Pearson correlation was noted between the LGE percent (ROI%) and ESV (0.692, P<0.05), ROI% and EF (–0.718, P<0.05), ROI% and PFR (–0.534, P<0.05), DVR_20-40 (0.547, 0.544, 0.906, P<0.05) etc. The correlation between ROI% and DVR₄₀ was best (0.906, P<0.05), and the correlation between ROI% and ESVI, ROI% and EF were both bigger than 0.7, showed the correlation was good.

Conclusions

In addition to common quotas used to assess the structure and function of left ventricle in HCM, volume-time curve parameters may have potential to evaluate cardiac function in HCM. The correlation between DVR generated from volume-time curve with LGE was good, and may be a marker of effect of enhancement/scar tissue on diastolic function.     

Prognostic value of intra-left ventricular electromechanical asynchrony in patients with hypertrophic cardiomyopathy.

AIMS: We sought to assess the indexes of myocardial activation delay, using Doppler myocardial imaging (DMI), as potential predictors of cardiac events in patients with hypertrophic cardiomyopathy (HCM). The distribution and magnitude of left ventricular (LV) hypertrophy are not uniform in patients with HCM, which results in heterogeneity of regional LV systolic function. METHODS AND RESULTS: The study population included 123 HCM patients (39.4+/-5.9 years) and 123 age- and sex-matched healthy subjects, followed up for 48.4+/-8.8 months. By use of pulsed DMI, the following regional parameters were evaluated in six different basal myocardial segments: myocardial peak velocities and systolic time-intervals; myocardial intraventricular (intra-V-Del) and interventricular (inter-V-Del) systolic delays. DMI analysis in HCM showed lower myocardial systolic and early-diastolic peak velocities of all the segments. As for time intervals, HCM showed significant inter- and intra-V delays (P<0.0001), whereas homogeneous systolic activation of the ventricular walls was assessed in controls. During the follow-up, 16 cardiac deaths (12 sudden deaths) were observed in HCM patients. InHCM, DMI intra-V-Del was the most powerful independent predictor of sudden cardiac death (P<0.0001). In particular, an intra-V-Del>45 ms is identified with high sensitivity and specificity in HCM patients at higher risk of ventricular tachycardia and sudden cardiac death (test accuracy: 88.8%). CONCLUSION: In HCM patients, DMI indexes of intra-V-Del may provide additional information for selecting subgroups of HCM patients at increased risk of ventricular arrhythmias and sudden cardiac death at follow-up. Accordingly, such patients may be more actively identified for early intensive treatment and survey.     

Impaired myocardial perfusion in patients with hypertrophic cardiomyopathy: Assessment with digital subtraction coronary arteriography

Summary To study the clinical significance of abnormal myocardial perfusion in patients with hypertrophic cardiomyopathy (HCM), we performed a computerized washout analysis of digital subtraction coronary arteriograms in 28 patients with HCM and 16 control subjects. The contrast disappearance half-life (T 1/2) was calculated from a time-density curve generated in the four sectors of the myocardium perfused by the left anterior descending coronary artery and the mean T 1/2 was calculated by averaging T 1/2 values for these four sectors. Patients with HCM demonstrated longer T 1/2 in the ventricular septal region than control subjects. Thirteen (46%) of the patients with HCM presented abnormally longer mean T 1/2 values, suggesting impaired myocardial perfusion. Family histories of HCM were more frequent in patients with abnormal mean T 1/2 values (92% vs 47%;p<0.05). On the exercise stress test, patients with abnormal T 1/2 values presented significantly lower exercise tolerance with more frequent exercise-induced ST segment depression (62% vs 13%;p<0.05). However, there were no significant differences between the two groups with regard to ventricular wall thickness, left ventricular end-diastolic pressure, or the severity of systolic narrowing of the coronary arteries.These findings suggest that 13 (46%) of the patients with HCM have impaired myocardial perfusion, which may be a manifestation of intramural coronary artery disease in addition to left ventricular hypertrophy, elevated left ventricular end-diastolic pressure, or systolic narrowing of the coronary arteries. Additionally, significant association of the prolonged T 1/2 with a familial occurrence of HCM and depressed exercise tolerance with ST segment depression imply that impaired myocardial perfusion could be an important inherent pathophysiological state leading to myocardial ischemia during exercise.This study was supported in part by a Research Grant for Intractable Diseases from the Ministry of Health and Welfare of Japan.     

Prognostic value of systemic blood pressure response during exercise in a community-based patient population with hypertrophic cardiomyopathy

OBJECTIVES

The present study was designed to prospectively evaluate the prognostic relevance of abnormal blood pressure response to exercise (ABPR), defined as hypotension or failed blood pressure increase (<20 mm Hg) with exercise, in a community-based hypertrophic cardiomyopathy (HCM) population representative of the overall disease spectrum.

BACKGROUND

Abnormal blood pressure response to exercise has been proposed as a marker for hemodynamic instability and increased risk for disease-related mortality in highly selected patient populations with HCM.

METHODS

The study population comprised 126 patients (aged 42 ± 14 years) who underwent maximal symptom-limited cycloergometer exercise testing as part of the standard evaluation at our institution, and who were followed systematically for 4.7 ± 3.7 years after testing.

RESULTS

Of the 126 study patients, 98 (78%) had a normal blood pressure response during exercise, whereas the other 28 (22%) had ABPR, including nine with hypotension and 19 with failed blood pressure rise. During the follow-up period, nine patients (7%) died of HCM-related causes (three suddenly and six heart failure–related), of whom four had ABPR. In those patients aged ≤50 years, survival analysis after exercise testing showed a significantly increased risk for cardiovascular mortality associated with ABPR compared with a normal exercise response (p = 0.04), with an odds ratio of 4.5 (95% confidence interval: 1.1, 20.1). However, ABPR showed low positive predictive accuracy for cardiovascular mortality (i.e., 14%), whereas negative predictive accuracy was high (i.e., 95%).

CONCLUSIONS

A hypotensive blood pressure response during exercise occurred in over 20% of a community-based patient cohort with HCM, and was associated with adverse long-term prognosis in patients <50 years old. However, the positive predictive accuracy of this blood pressure response is too low to justify modifications of clinical management or to allow identification of the high-risk patient based solely on an abnormal test result. By virtue of its high negative predictive accuracy for HCM-related mortality, the blood pressure response to exercise appears to be most valuable (in conjunction with the absence of other well recognized risk factors) as a screening test for the identification of low-risk subsets of patients.     

5-羟色胺受体4基因多态性与汉族人群慢性阻塞性肺疾病的关联性研究

目的 研究5-羟色胺受体4（HTR4）基因多态性与汉族人群慢性阻塞性肺疾病（COPD）及肺功能指标的相关性.方法 采用病例对照的研究方法,用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法对126例COPD患者及110例健康对照者的单核苷酸多态性（SNP）位点rs3995090进行基因分型,并分析该SNP位点与COPD、第1秒用力呼气容积（FEV1）及FEV1/用力肺活量（FVC）相关性.结果 SNP位点rs3995090基因型频率均符合Hardy-Weinberg平衡定律（P＞0.05）.rs3995090在COPD患者中最小等位基因频率A为34％,在健康人群中为25％,组间比较差异有统计学意义（P＜0.05）.在COPD患者及健康对照者中,rs3995090基因型与FEV1值之间均存在相关性（P均＜0.05）.结论 HTR4基因多态性可能与汉族人群COPD的发病及肺功能指标FEV1值之间存在关联性.     

Prognostic value of global longitudinal strain in hypertrophic cardiomyopathy: A systematic review and meta‐analysis

BackgroundAs previously reported, impairment of left ventricular global longitudinal strain (LVGLS) is associated with myocardial fibrosis, arrhythmias, and heart failure in hypertrophic cardiomyopathy (HCM) patients.HypothesisThis study aimed to estimate the association between LVGLS measured by echocardiography and major adverse cardiovascular events (MACE) in patients with HCM.MethodsPubmed, Embase, Scopus, and Cochrane Library databases were systematically searched for evaluating the difference of LVGLS between MACE and non‐MACE and the relevance of LVGLS and MACE in HCM patients, mean difference (MD), and pooled hazard ratios (HR) with 95% confidence interval (CI) were calculated. Publication bias was detected by funnel plots and Egger''s test, and trim‐and‐fill analysis was employed when publication bias existed.ResultsA total of 13 studies reporting 2441 HCM patients were included in this meta‐analysis. Absolute value of LVGLS was lower in the group of HCM with MACE (MD = 2.74, 95% CI: 2.50–2.99, p < .001; I ² = 0, p = .48). In the pooled unadjusted model, LVGLS was related to MACE (HR = 1.14, 95% CI: 1.06–1.22, p < .05, I ² = 58.4%, p < .01) and there is a mild heterogeneity, and sensitivity analysis showed stable results. In the pooled adjusted model, LVGLS was related to MACE (HR = 1.12, 95% CI: 1.08–1.16, p < .05; I ² = 0%, p = .442). Egger''s tests showed publication bias, and trim‐and‐fill analysis was applied, with final results similar to the previous and still statistically significant.ConclusionThe meta‐analysis suggested that impaired LVGLS was associated with poor prognosis in HCM patients.     

溶质载体家族22A4和5基因多态性与中国汉族人群克罗恩病的关联分析

目的 探讨中国汉族人群中溶质载体家族22A4(SLC22A4)和SLC22A5基因单核苷酸多态性(SNP)与克罗恩病(CD)的相关性.方法 采用直接测序方法测定80例汉族CD患者和80名健康对照者的SLC22A4和SLC22A5基因所有外显子区序列,检测其SNP位点,并进行统计学分析.结果 ①C1672T位点和G-207C位点在汉族人群中不存在多态性.发现SLC22A4和SLC22A5基因全编码区分别有2个和3个SNP.②病例一对照关联分析显示,SLC22A4和SLC22A5基因的SNP在基因型和等位基因型频率方面,CD患者和对照者间差异无统计学意义(P>0.05).结论 在中国汉族人群中,SLC22A4和SLC22A5基因多态性和CD易感性无相关性.     

Prognostic value of electrocardiographic time intervals and QT rate dependence in hypertrophic cardiomyopathy

Introduction

Preventing sudden cardiac death (SCD) is one of the main goals in hypertrophic cardiomyopathy (HCM). Many variables have been proposed, however the European and American guidelines do not incorporate any ECG or Holter monitoring derived variables other than the presence of ventricular arrhythmia in their risk stratification models. In the present study we evaluated electrocardiographic parameters in risk stratification of HCM.

Single nucleotide polymorphisms of the factor IX gene for linkage analysis in the southern Chinese population

Carrier detection and prenatal testing for haemophilia B in Oriental populations have been hampered by the lack of informative markers within the factor IX (FIX) gene. We detected a T/C nucleotide variation at nucleotide 32770 in the poly-A region of the FIX gene in the mother of a haemophilia B child. Analysis of 139 unrelated alleles revealed a heterozygosity rate of 0.193, thus offering an additional marker for linkage analysis. Together with two other polymorphic sites (5' MseI and 3' HhaI) found in Chinese and Thai populations, these polymorphisms were useful in 66% of the families studied.     

SAA1 gene polymorphisms and the risk of AA amyloidosis in Japanese patients with rheumatoid arthritis

To investigate the precise modality of association between SAA1 gene polymorphisms and the development of AA amyloidosis in patients with rheumatoid arthritis (RA), Japanese patients with RA (n = 153), among whom 29 were histologically diagnosed as having amyloidosis, were genotyped for three single nucleotide polymorphisms (SNPs), C-13T, C2995T, and C3010T, in the SAA gene. Pairwise linkage disequilibrium coefficients between each pair of SNPs were calculated and estimated haplotype frequencies were compared between patients with and without amyloidosis. Possible associations between these SNPs and amyloidosis were analyzed by a case–control study and by the Kaplan–Meier method, in which the endpoint was defined as the time of diagnosis of AA amyloidosis. The -13T and 2995C alleles, which were in a tight linkage disequilibrium, were more frequent in the patients with amyloidosis, and the groups with the -13TT and 2995CC genotype had worse survival curves than patients without these genotypes, whereas C3010T was not associated with amyloidosis. Moreover, the haplotype containing −13C and 2995T was found to be protective. Both C-13T and C2995T were associated with the development of amyloidosis. Examining both polymorphisms may be more useful than examining only one of them for estimating the risk of the development of amyloidosis.     

SAA1 gene polymorphisms and the risk of AA amyloidosis in Japanese patients with rheumatoid arthritis

Abstract

To investigate the precise modality of association between SAA1 gene polymorphisms and the development of AA amyloidosis in patients with rheumatoid arthritis (RA), Japanese patients with RA (n = 153), among whom 29 were histologically diagnosed as having amyloidosis, were genotyped for three single nucleotide polymorphisms (SNPs), C-13T, C2995T, and C3010T, in the SAA gene. Pairwise linkage disequilibrium coefficients between each pair of SNPs were calculated and estimated haplotype frequencies were compared between patients with and without amyloidosis. Possible associations between these SNPs and amyloidosis were analyzed by a case–control study and by the Kaplan–Meier method, in which the endpoint was defined as the time of diagnosis of AA amyloidosis. The -13T and 2995C alleles, which were in a tight linkage disequilibrium, were more frequent in the patients with amyloidosis, and the groups with the -13TT and 2995CC genotype had worse survival curves than patients without these genotypes, whereas C3010T was not associated with amyloidosis. Moreover, the haplotype containing ?13C and 2995T was found to be protective. Both C-13T and C2995T were associated with the development of amyloidosis. Examining both polymorphisms may be more useful than examining only one of them for estimating the risk of the development of amyloidosis.     

华南地区汉族人群BCRP基因G34A和C421A多态性

目的 研究乳腺癌耐药蛋白(BCRP)单核苷酸多态(SNP) G34A和C421A在华南地区汉族人群中的分布,同时比较不同地区人群间BCRP基因型及等位基因频率分布的差异.方法 采用聚合酶链反应-单链构象多态性(PCR-SSCP)方法,检测华南地区无亲缘关系的汉族人群BCRP基因G34A和C421A多态性,结合文献比较不同人群间等位基因频率的差异.结果 华南地区人群BCRP基因G34A基因型分布频率为:GG基因型267例(39.03％)、GA基因型328例(47.95％)、AA基因型89例(13.02％).C421A基因型分布频率为:CC基因型288例(45.79％),CA基因型277例(44.04％),AA基因型64例(10.17％).其基因型频率在东亚、高加索以及非洲人群中的分布存在显著差异(P＜0.05).结论 BCRP基因在华南汉族人群中存在G34A和C421A多态性,其在不同人群中的分布频率存在显著差异.     

2个汉族肥厚型心肌病家系致病基因与TCAP基因的关系研究

目的:确定候选基因TCAP与两个汉族家系家族性肥厚型心肌病(HCM)之间的连锁关系.方法:在排除13个已知家族性HCM致病基因与这两个汉族家系家族性HCM的连锁关系基础上,选择TCAP基因作为这两个汉族HCM家系的候选致病基因,在其所在的染色体区域选取4个微卫星标记(Marker)进行单倍型连锁分析.结果:D17S1814、D17S838、D17Sac091178和D17S1818这4个微卫星标记在重组率θ=0时,家系1的LOD值在-2.689754～-0.645666范围内,家系2的LOD值在-1.396476～0.416726之间;在重组率θ=0.1时,两个家系中最大的LOD值仅为0.272605.结论:TCAP基因与这两个汉族家系的HCM无连锁关系,TCAP基因不是这两个家系的致病基因,提示这两个汉族家系的致病基因可能是全新的未知致病基因.