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1.
Christian M. Hagen Frederik H. Aidt Paula L. Hedley Morten K. Jensen Ole Havndrup J?rgen K. Kanters Johanna C. Moolman-Smook Severin O. Larsen Henning Bundgaard Michael Christiansen 《PloS one》2013,8(8)
Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in genes coding for proteins involved in sarcomere function. The disease is associated with mitochondrial dysfunction. Evolutionarily developed variation in mitochondrial DNA (mtDNA), defining mtDNA haplogroups and haplogroup clusters, is associated with functional differences in mitochondrial function and susceptibility to various diseases, including ischemic cardiomyopathy. We hypothesized that mtDNA haplogroups, in particular H, J and K, might modify disease susceptibility to HCM. Mitochondrial DNA, isolated from blood, was sequenced and haplogroups identified in 91 probands with HCM. The association with HCM was ascertained using two Danish control populations. Haplogroup H was more prevalent in HCM patients, 60% versus 46% (p = 0.006) and 41% (p = 0.003), in the two control populations. Haplogroup J was less prevalent, 3% vs. 12.4% (p = 0.017) and 9.1%, (p = 0.06). Likewise, the UK haplogroup cluster was less prevalent in HCM, 11% vs. 22.1% (p = 0.02) and 22.8% (p = 0.04). These results indicate that haplogroup H constitutes a susceptibility factor and that haplogroup J and haplogroup cluster UK are protective factors in the development of HCM. Thus, constitutive differences in mitochondrial function may influence the occurrence and clinical presentation of HCM. This could explain some of the phenotypic variability in HCM. The fact that haplogroup H and J are also modifying factors in ischemic cardiomyopathy suggests that mtDNA haplotypes may be of significance in determining whether a physiological hypertrophy develops into myopathy. mtDNA haplotypes may have the potential of becoming significant biomarkers in cardiomyopathy. 相似文献
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目的:研究中国汉族肥厚型心肌病人群中α-Galactosidase A突变的患病率及其临床表现。方法:对439名肥厚型心肌病患者及156名健康对照GLA基因进行全外显子测序,及基因型及临床表型进行关联分析。结果:确定了2个致病性突变,包括1个错义突变E66Q和1个剪接位点的突变c.547+1GC。2个突变在156名健康人群未发现,在1000人基因组计划中未报道。确定中国汉族肥厚型心肌病人群中α-Galactosidase A突变0.45%的患病率。结论:Fabry病在中国汉族肥厚型心肌病人群中α-Galactosidase A突变的患病率较低。基因检测有助于Fabry病与肥厚型心肌病的鉴别诊断。 相似文献
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Tobias?B. Haack Robert Kopajtich Peter Freisinger Thomas Wieland Joanna Rorbach Thomas?J. Nicholls Enrico Baruffini Anett Walther Katharina Danhauser Franz?A. Zimmermann Ralf?A. Husain Jessica Schum Helen Mundy Ileana Ferrero Tim?M. Strom Thomas Meitinger Robert?W. Taylor Michal Minczuk Johannes?A. Mayr Holger Prokisch 《American journal of human genetics》2013,93(2):211-223
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Mitochondrial DNA (mtDNA) variants have been traditionally used as markers to trace ancient population migrations. Although experiments relying on model organisms and cytoplasmic hybrids, as well as disease association studies, have served to underline the functionality of certain mtDNA SNPs, only little is known of the regulatory impact of ancient mtDNA variants, especially in terms of gene expression. By analyzing RNA-seq data of 454 lymphoblast cell lines from the 1000 Genomes Project, we found that mtDNA variants defining the most common African genetic background, the L haplogroup, exhibit a distinct overall mtDNA gene expression pattern, which was independent of mtDNA copy numbers. Secondly, intra-population analysis revealed subtle, yet significant, expression differences in four tRNA genes. Strikingly, the more prominent African mtDNA gene expression pattern best correlated with the expression of nuclear DNA-encoded RNA-binding proteins, and with SNPs within the mitochondrial RNA-binding proteins PTCD1 and MRPS7. Our results thus support the concept of an ancient regulatory transition of mtDNA-encoded genes as humans left Africa to populate the rest of the world. 相似文献
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Orthostatic Blood Pressure Test for Risk Stratification in Patients with Hypertrophic Cardiomyopathy
Julia Münch Ali Aydin Anna Suling Christian Voigt Stefan Blankenberg Monica Patten 《PloS one》2015,10(6)
Background
Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in young adults, mainly ascribed to ventricular tachycardia (VT). Assuming that VT is the major cause of (pre-) syncope in HCM patients, its occurrence is essential for SCD risk stratification and primarily preventive ICD-implantation. However, evidence of VT during syncope is often missing. As the differentiation of potential lethal causes for syncope such as VT from more harmless reasons is crucial, HCM patients were screened for orthostatic dysregulation by using a simple orthostatic blood pressure test.Methods
Over 15 months (IQR [9;20]) 100 HCM patients (55.8±16.2 yrs, 61% male) were evaluated for (pre-)syncope and VT (24h-ECGs, device-memories) within the last five years. Eighty patients underwent an orthostatic blood pressure test. Logistic regression models were used for statistical analysis.Results
In older patients (>40 yrs) a positive orthostatic test result increased the chance of (pre-) syncope by a factor of 63 (95%-CI [8.8; 447.9], p<0.001; 93% sensitivity, 95%-CI [76; 99]; 74% specificity, 95%-CI [58; 86]). No correlation with VT was shown. A prolonged QTc interval also increased the chance of (pre-) syncope by a factor of 6.6 (95%-CI [2.0; 21.7]; p=0.002).Conclusions
The orthostatic blood pressure test is highly valuable for evaluation of syncope and presyncope especially in older HCM patients, suggesting that orthostatic syncope might be more relevant than previously assumed. Considering the high complication rates due to ICD therapies, this test may provide useful information for the evaluation of syncope in individual risk stratification and may help to prevent unnecessary device implantations, especially in older HCM patients. 相似文献6.
Yilu Wang Jizheng Wang Yubao Zou Jingru Bao Kai Sun Ling Zhu Tao Tian Hu Shen Xianliang Zhou Ferhaan Ahmad Rutai Hui Lei Song 《PloS one》2014,9(7)
Background
Sex plays an important role in the clinical expression and prognosis of various cardiovascular diseases. This study was designed to observe the effects of sex on hypertrophic cardiomyopathy (HCM).Methods and Results
A total of 621 unrelated patients with HCM without heart failure (460 males) were enrolled from 1999 to 2011. Compared to male patients, at baseline female patients were older at diagnosis (49.6±17.2 years vs. 46.7±14.4 years, P = 0.033), and had greater frequency of left ventricular outflow tract obstruction (72/161, 44.7% vs. 149/460, 32.4%, P = 0.005). During the average four year follow-up period (range 2–7 years), survival analysis showed that the incidences of mortality from all causes, cardiovascular death and progression to chronic heart failure were greater in women than in men (P = 0.031, 0.040 and 0.012, respectively). After adjustment for multiple factors that may confound survival and cardiac function, female sex remained an independent risk factor for all-cause mortality, cardiovascular death, and chronic heart failure [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.21–3.95, P = 0.010; HR 2.19, 95% CI 1.17–4.09, P = 0.014; HR 1.73, 95% CI 1.12–2.69, P = 0.014, respectively] in HCM patients. Subgroup analysis revealed that female sex as a risk factor was identified only in patients younger than 50 years old (P = 0.011, 0.011 and 0.009, respectively), but not for those 50 years or older.Conclusion
Our results suggest that female sex is associated with worse survival and heart failure in HCM patients. Further studies are required to determine whether female hormones modify the clinical expression and prognosis of HCM. 相似文献7.
Hyoung-gon Lee Qun Chen Julie A. Wolfram Sandy L. Richardson Anna Liner Sandra L. Siedlak Xiongwei Zhu Nicholas P. Ziats Hisashi Fujioka Dean W. Felsher Rudy J. Castellani Maria L. Valencik John A. McDonald Brian D. Hoit Edward J. Lesnefsky Mark A. Smith 《PloS one》2009,4(9)
While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a “fetal re-expression” pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart. 相似文献
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肥厚型心肌病患者心肌mtDNA大片段缺失的探讨 总被引:1,自引:0,他引:1
应用Long PCR及Primer Shift Long PCR 技术对3例肥厚型心肌病(HCM)患者和10例正常引产胎儿的13份心肌标本予以线粒体 DNA缺失检测,结果在1例HCM患者心肌线粒体DNA中发现约5.0kb缺失,而在正常引产胎儿的标本未见该缺失,提示HCM的发生可能与mtDNA缺失相关。
Astract Using long PCR and primer shift long PCR techniques, we analyzed the mitochondrial DNA (mtDNA) isolated from the heart muscles of 3 hypertrophic cardiomyopathy (HCM) patients and 10 normal abortive fetuses. Almost 5.0kb deletion was found in the heart mtDNA of one HCM patient, while no deletion was detected in that of 10 fetuses. It is concluded that HCM may correlate with mtDNA deletion. 相似文献
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目的:探讨肥厚型心肌病患者静息脉压和运动诱导的血压异常之间的关系。方法:根据Bruce方案,对70例2007年1月至2012年1月在我院治疗的肥厚型心肌病患者进行症状限制运动试验,监测患者的血液动力学指标,即分别在患者仰卧休息和运动结束后测量血压。结果:肥厚型心肌病患者中,运动后血压反应异常者与正常者相比,前者的静息脉压显著高于后者。表现出运动性非正常血压反应的肥厚型心肌病患者,静息脉压明显高于无运动性非正常血压反应患者(P=0.007)。根据二分类Logistic回归分析,控制年龄、性别、左室后壁厚度、室间隔厚度、左室流出道梗阻等混杂因素后,静息脉压可以有效预测肥厚型心肌病患者的运动性非正常血压反应(P=0.016)。结论:与传统的收缩压、舒张压以及平均动脉压相比,静息脉压可作为一个有效的辅助检测指标预防肥厚型心肌病患者心脏猝死的发生。 相似文献
14.
Gael Cagnone Te-Sha Tsai Kanokwan Srirattana Fernando Rossello David R. Powell Gary Rohrer Lynsey Cree Ian A. Trounce Justin C. St. John 《Genetics》2016,202(3):931-944
The maternally inherited mitochondrial genome (mtDNA) is present in multimeric form within cells and harbors sequence variants (heteroplasmy). While a single mtDNA variant at high load can cause disease, naturally occurring variants likely persist at low levels across generations of healthy populations. To determine how naturally occurring variants are segregated and transmitted, we generated a mini-pig model, which originates from the same maternal ancestor. Following next-generation sequencing, we identified a series of low-level mtDNA variants in blood samples from the female founder and her daughters. Four variants, ranging from 3% to 20%, were selected for validation by high-resolution melting analysis in 12 tissues from 31 animals across three generations. All four variants were maintained in the offspring, but variant load fluctuated significantly across the generations in several tissues, with sex-specific differences in heart and liver. Moreover, variant load was persistently reduced in high-respiratory organs (heart, brain, diaphragm, and muscle), which correlated significantly with higher mtDNA copy number. However, oocytes showed increased heterogeneity in variant load, which correlated with increased mtDNA copy number during in vitro maturation. Altogether, these outcomes show that naturally occurring mtDNA variants segregate and are maintained in a tissue-specific manner across generations. This segregation likely involves the maintenance of selective mtDNA variants during organogenesis, which can be differentially regulated in oocytes and preimplantation embryos during maturation. 相似文献
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P. Lestienne I. Nelson P. Riederer H. Reichmann K. Jellinger 《Journal of neurochemistry》1991,56(5):1819-1819
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神经肌肉性疾病患者线粒体DNA突变的分析 总被引:1,自引:0,他引:1
为了探讨神经肌肉性疾病的发病与线粒体DNA突变的关系,采用PCR技术检测了20例患有不同神经肌肉性疾病儿童的外周血和骨骼肌细胞中的线粒体DNA(mtDNA),发现其中6例患儿有mtDNA缺失,其中1例至少有2968bp片段的缺失,另5例至少有2000bp片段的缺失,此缺失区位于线粒体呼吸链复合物1、4、5、编码区,表明该突变对神经肌肉性疾病的发生有一定作用。 相似文献
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为了探讨神经肌肉性疾病的发病与线粒体DNA突变的关系,采用PCR技术检测了 20例患有不同神经肌肉性疾病儿童的外周血和骨骼肌细胞中的线粒体DNA(mtDNA),发现其中6例患儿有mtDNA缺失,其中1例至少有2968bp片段的缺失, 另5例至少有2000bp片段的缺失,此缺失区位于线粒体呼吸链复合物1、 4、5、编码区,表明该突变对神经肌肉性疾病的发生有一定作用。
Abstract:To understand the relation to mechanism of neuromuscular disease and mtDNA mutation,using PCR technique,we investigated blood and /or skeletal muscle of 20 patients with neuromuscular diseases.A deletion in the length of 2000~2968bp was found in blood mitochondrial DNA of 6 patients with neuromuscular disease.The deletion region partially lies in the coding region of resoiratony chain complex 1,4,5.It is suggested that this mutation ois related with neuromuscular diseases. 相似文献
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Pacemaker syndrome represents the clinical consequences of the haemodynamic adverse effects of atrioventricular asynchrony during pacing. Patients suffering from hypertrophic cardiomyopathy may be particularly sensitive to these effects because of the importance of atrial systolic contribution to left ventricular diastolic filling. In this case report, we describe the symptoms and cause of pacemaker syndrome in a patient with hypertrophic obstructive cardiomyopathy. 相似文献
20.
Grant G Knowlen Richard E Weller Ruby L Perry Janet F Baer Alfonso S Gozalo 《Comparative medicine》2013,63(3):279-287
Cardiac hypertrophy is a common postmortem finding in owl monkeys. In most cases the animals do not exhibit clinical signs until the disease is advanced, making antemortem diagnosis of subclinical disease difficult and treatment unrewarding. We obtained echocardiograms, electrocardiograms, and thoracic radiographs from members of a colony of owl monkeys that previously was identified as showing a 40% incidence of gross myocardial hypertrophy at necropsy, to assess the usefulness of these modalities for antemortem diagnosis. No single modality was sufficiently sensitive and specific to detect all monkeys with cardiac hypertrophy. Electrocardiography was the least sensitive method for detecting owl monkeys with hypertrophic cardiomyopathy. Thoracic radiographs were more sensitive than was electrocardiography in this context but cannot detect animals with concentric hypertrophy without an enlarged cardiac silhouette. Echocardiography was the most sensitive method for identifying cardiac hypertrophy in owl monkeys. The most useful parameters suggestive of left ventricular hypertrophy in our owl monkeys were an increased average left ventricular wall thickness to chamber radius ratio and an increased calculated left ventricular myocardial mass. Parameters suggestive of dilative cardiomyopathy were an increased average left ventricular myocardial mass and a decreased average ratio of left ventricular free wall thickness to left ventricular chamber radius. When all 4 noninvasive diagnostic modalities (physical examination, echocardiography, electrocardiography, and thoracic radiography) were used concurrently, the probability of detecting hypertrophic cardiomyopathy in owl monkeys was increased greatly.Abbreviations: LVFWTd, left ventricular free wall thickness at end-diastole; STd, interventricular septal thickness at end-diastole; EDD, left ventricular chamber diameter at end-diastole; ESD, left ventricular chamber diameter at end-systole; VHS, vertebral heart scaleOwl monkeys (Aotus spp.) are maintained and used primarily as a nonhuman primate model for the study of malaria.17,38,45 These neotropical monkeys have also been shown to be useful for the study of visceral leishmaniasis,5 various viruses,1,20-22,27 streptotrichosis,19 campylobacteriosis,16 and toxoplasmosis.34 Owl monkeys are naturally susceptible to a variety of internal parasites,37,39 hemolytic anemia, and glomerulonephritis.8,13,40Approximately 40% of Aotus monkeys dying from all causes in a colony maintained for dispersement to investigators for the study of malaria have gross evidence of myocardial hypertrophy at necropsy.40 This incidence is similar to the 41% mortality ascribed to cardiovascular disease in captive adult lowland gorillas,25 and the report that, in humans, cardiovascular disease represents 42% of all deaths in the United States.9 The hypertrophy in owl monkeys almost obliterates the left ventricular chamber and causes marked thickening of the left ventricular free wall and interventricular septum. A similar incidence of myocardial hypertrophy has previously been reported in other owl monkey colonies.13,31,32Most of the deaths in the owl monkey colony at our institution can be attributed to various identifiable causes typical for this species.40 However, several monkeys in this colony had gross evidence of myocardial hypertrophy at death but had shown no clinical signs of disease and displayed no gross or microscopic etiology for death. A prominent feature of the spontaneous deaths within this particular colony of Aotus monkeys was ‘sudden death,’ particularly during periods of high physical and psychologic stress.40 Ventricular arrhythmias have been hypothesized as possible cause of sudden death in chimpanzees with cardiomyopathy,10 and a similar mechanism might be responsible for sudden death in captive owl monkeys.Gross hypertrophy of the left ventricle has many causes in humans and animals. In the absence of gross evidence of resistive lesions (that is, coarctation of the aorta, aortic stenosis) or shunting lesions (that is, ventricular septal defect, patent ductus arteriosus, atrial septal defect), hypertrophic cardiomyopathy and hypertension are the 2 most likely causes of or stimulus for the left ventricular hypertrophy observed in our colony.4,18 Because no gross lesions that contribute to myocardial hypertrophy have been found at necropsy, we presumed that the hypertrophic changes in our monkeys are due to hypertrophic cardiomyopathy or to increased afterload secondary to hypertension. Spontaneous hypertension has been reported as causing dilated cardiomyopathy in wooly monkeys,11 and vitamin E deficiency is a cause of cardiomyopathy (primarily dilative) in gelada baboons as well as other primates.23,24 Cardiac changes secondary to experimental trypanosomiasis have occurred in vervet28 and squirrel monkeys29 and after group A streptococcal infection in rhesus monkeys.26 However, only a few reports detail spontaneous myocardial hypertrophic changes in nonhuman primates.3,10,13,32 Because of the high incidence of cardiac hypertrophy in clinically normal owl monkeys, it is difficult to establish ‘normal’ reference values for the species. One group of authors31 was reluctant to suggest reference intervals for normal echocardiographic variables in owl monkeys due to inability to confirm that monkeys classified as normal were free of cardiac disease.The left ventricular hypertrophy in the owl monkey colony we present has been speculated to be the result of renal-induced hypertension. Many of these monkeys have evidence of glomerular lesions at necropsy. Spontaneous primary systemic hypertension has been suggested as the etiology of the cardiomyopathy and renal disease in owl monkeys,13 however, no relationship between antemortem blood pressure and the presence or absence of renal lesions and myocardial hypertrophy in these monkeys had been established until recently. A recent study35 using chronically implanted pressure transducers in A. nancymae found that 30% of the monkeys had resting mean arterial pressures in the hypertensive range (>110 mm Hg), and all animals had exaggerated pressor responses in response to routine husbandry procedures (mean arterial pressure, 125 to 196 mm Hg). These same authors concluded that the hypertension observed was consistent with a neural-based essential hypertension that possibly was engendered by the frequent hyperreactive responses of the sympathetic nervous system of these animals to environmental events.35This study was undertaken to identify individual owl monkeys with left ventricular hypertrophy by using noninvasive diagnostic techniques antemortem. Physical examination, echocardiography, electrocardiography, and thoracic radiography were selected as potential diagnostic modalities with the greatest probability of yielding sensitive and specific information regarding left ventricular hypertrophy in individual monkeys prior to postmortem examination. 相似文献