Fabry病在中国汉族肥厚型心肌病人群的患病率(英文)

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。     

Hypertrophic Cardiomyopathy. An Electrophysiological Study

Recordings of the transmembrane action potential of the cardiac myofibril from a patient with hypertrophic obstructive cardiomyopathy showed that the repolarization time was appreciably prolonged and that the maximum rate of follow was grossly reduced. This electrical abnormality is compatible with the late and irregular activation of the ventricular muscle in the disease. Propranolol was found to produce a similar “quinidine-like” effect on the transmembrane actionpotential in both cardiomyopathic and control tissue.     

肥厚梗阻性心肌病的外科治疗

目的：总结肥厚室间隔切除术治疗肥厚梗阻性心肌病的手术效果,探讨外科治疗策略。方法：2002年3月至2010年10月,外科手术治疗33例肥厚梗阻性心肌病病人。其中男16例,女17例;年龄13～59岁,平均（42.7±13.6）岁;左室流出道压差（LVOTGP）70～120 mmHg（1 mmHg=0.133Kpa）,平均（95.0±22.6）mmHg。其中合并二尖瓣关闭不全24例,主动脉瓣关闭不全7例,升主动脉增宽3例,冠心病2例。手术在全麻低温体外循环下完成,按常规经主动脉切口行室间隔心肌切除术,同期完成二尖瓣置换术（MVR）7例,二尖瓣成形术（MVP）7例,二尖瓣、主动脉瓣成形术（MVP＋AVP）5例,二尖瓣、升主动脉成形术3例,二尖瓣、主动脉瓣成形、冠状动脉旁路移植术（MVP＋AVP＋CABG）2例。分析比较病人术前超声心动图（UCG）,术中经食管心脏超声（TEE）,以及术后1周、3月、6月、1年超声心动图结果。结果：手术死亡1例（3.0%,1/33例）,主要死因为严重低心排综合症以及多脏器功能衰竭。二次开胸止血1例（3.0%,1/33例）。术中经食管心脏超声示所有病人二尖瓣前叶收缩期前向运动现象（SAM征）消失。存活病人手术效果良好,解剖狭窄解除,峰值压差降低,SAM现象基本消失。远期随访生存病人症状消失,生活质量明显改善,心功能I～II级,无远期死亡、并发症或再次手术。结论：外科治疗肥厚梗阻型心肌病具有良好的手术效果。了解病生理过程、术中仔细探察、手术切除彻底是手术成功的关键。     

肥厚梗阻性心肌病的外科治疗

目的:总结肥厚室间隔切除术治疗肥厚梗阻性心肌病的手术效果,探讨外科治疗策略。方法:2002年3月至2010年10月,外科手术治疗33例肥厚梗阻性心肌病病人。其中男16例,女17例;年龄13～59岁,平均(42.7±13.6)岁;左室流出道压差(LVOTGP)70～120 mmHg(1 mmHg=0.133Kpa),平均(95.0±22.6)mmHg。其中合并二尖瓣关闭不全24例,主动脉瓣关闭不全7例,升主动脉增宽3例,冠心病2例。手术在全麻低温体外循环下完成,按常规经主动脉切口行室间隔心肌切除术,同期完成二尖瓣置换术(MVR)7例,二尖瓣成形术(MVP)7例,二尖瓣、主动脉瓣成形术(MVP+AVP)5例,二尖瓣、升主动脉成形术3例,二尖瓣、主动脉瓣成形、冠状动脉旁路移植术(MVP+AVP+CABG)2例。分析比较病人术前超声心动图(UCG),术中经食管心脏超声(TEE),以及术后1周、3月、6月、1年超声心动图结果。结果:手术死亡1例(3.0%,1/33例),主要死因为严重低心排综合症以及多脏器功能衰竭。二次开胸止血1例(3.0%,1/33例)。术中经食管心脏超声示所有病人二尖瓣前叶收缩期前向运动现象(SAM征)消失。存活病人手术效果良好,解剖狭窄解除,峰值压差降低,SAM现象基本消失。远期随访生存病人症状消失,生活质量明显改善,心功能I～II级,无远期死亡、并发症或再次手术。结论:外科治疗肥厚梗阻型心肌病具有良好的手术效果。了解病生理过程、术中仔细探察、手术切除彻底是手术成功的关键。     

肥厚型心肌病的临床特征及治疗分析

目的:探讨肥厚型心肌病(hypertrophic cardiomyopathy,HCM)的临床特征及治疗方法.方法:回顾性分析我院2008年6月至2012年3月收治的85例经心脏超声或左室造影证实为肥厚型心肌病患者的临床特征及治疗方法和预后.结果:85例肥厚型心肌病患者的临床症状主要表现为胸闷、气短50例(58.8％);心前区疼痛21例(24.7％);心前区不适7例(8.2％);乏力2例(2.4％);心悸2例(2.4％);剑突下疼痛1例(1.2％);发现心电图异常前来就诊2例(2.4％).其中心尖肥厚型心肌病(apical hypertrophic cardiomyopathy)30例(35.3％);合并冠心病4例(血管狭窄小于70％)(4.8％)、心肌桥(myocardial bridge,MB)11例(12.9％)、冠状动脉粥样硬化症4例(4.8％)、冠状动脉粥样硬化症合并MB4例(4.8％)、冠心病合并MB3例(3.5％).67例患者服用β-受体阻滞剂(78.8％),4例患者同时服用β-受体阻滞剂及钙离子拮抗剂(4.8％),4例患者服用钙离子拮抗剂(4.8％),1例患者服用可达龙(1.2％),1例患者同时服用β-受体阻滞剂及可达龙(1.2％),8例患者因心率慢,未服用药物(9.6％).临床随访1～30(平均15.2±4.5)个月,临床症状均明显缓解.结论:HCM症状不典型,β-受体阻滞剂和钙离子拮抗剂在治疗肥厚型心肌病方面疗效肯定.     

Decreasing Tropomyosin Phosphorylation Rescues Tropomyosin-induced Familial Hypertrophic Cardiomyopathy

Studies indicate that tropomyosin (Tm) phosphorylation status varies in different mouse models of cardiac disease. Investigation of basal and acute cardiac function utilizing a mouse model expressing an α-Tm protein that cannot be phosphorylated (S283A) shows a compensated hypertrophic phenotype with significant increases in SERCA2a expression and phosphorylation of phospholamban Ser-16 (Schulz, E. M., Correll, R. N., Sheikh, H. N., Lofrano-Alves, M. S., Engel, P. L., Newman, G., Schultz Jel, J., Molkentin, J. D., Wolska, B. M., Solaro, R. J., and Wieczorek, D. F. (2012) J. Biol. Chem. 287, 44478–44489). With these results, we hypothesized that decreasing α-Tm phosphorylation may be beneficial in the context of a chronic, intrinsic stressor. To test this hypothesis, we utilized the familial hypertrophic cardiomyopathy (FHC) α-Tm E180G model (Prabhakar, R., Boivin, G. P., Grupp, I. L., Hoit, B., Arteaga, G., Solaro, R. J., and Wieczorek, D. F. (2001) J. Mol. Cell. Cardiol. 33, 1815–1828). These FHC hearts are characterized by increased heart:body weight ratios, fibrosis, increased myofilament Ca²⁺ sensitivity, and contractile defects. The FHC mice die by 6–8 months of age. We generated mice expressing both the E180G and S283A mutations and found that the hypertrophic phenotype was rescued in the α-Tm E180G/S283A double mutant transgenic animals; these mice exhibited no signs of cardiac hypertrophy and displayed improved cardiac function. These double mutant transgenic hearts showed increased phosphorylation of phospholamban Ser-16 and Thr-17 compared with the α-Tm E180G mice. This is the first study to demonstrate that decreasing phosphorylation of tropomyosin can rescue a hypertrophic cardiomyopathic phenotype.     

心尖肥厚型心肌病的临床特征及治疗

目的:总结心尖肥厚型心肌病的临床特征及治疗方法.方法:回顾性分析我院2008年6月至2012年2月期间经心脏超声或左室造影证实的33例心尖肥厚型心肌病患者的临床特征及治疗情况.结果:患者的临床症状表现为以胸闷、气短为主者20例;心前区不适4例;心前区疼痛5例;乏力2例;心悸l例;发现心电图异常前来就诊l例.32例患者行左室造影诊断为心尖肥厚型心肌病.l例因肾功能不全,未行左室造影,但经心脏超声诊断为心尖肥厚型心肌病.27例患者服用β-受体阻滞剂,2例患者服用钙离子拮抗剂,4例患者因心率慢,未服用药物,临床随访1～36(平均16.7± 4.1)个月,临床症状均明显缓解.结论:β-受体阻滞剂和钙离子拮抗剂均适用于治疗心尖肥厚型心肌病.     

Management of Pregnancy Complicated by Hypertrophic Obstructive Cardiomyopathy

We report our experiences with nine women suffering from hypertrophic obstructive cardiomyopathy who between them had 13 pregnancies, 10 of which were directly managed by us. Though at first we felt that the theoretical hazards of vaginal delivery indicated elective caesarean section, experience has convinced us that in the absence of an obstetrical contraindication these patients may be delivered vaginally provided a betaadrenergic blocking drug is administered during pregnancy and especially during labour, ergometrine is given at the end of the second stage, adequate supplies of cross-matched blood are available, and prophylaxis against infective endocarditis is administered. We have found no evidence of any adverse effects of either propranolol or pronethalol on the foetus.     

Abnormal T2-STIR Magnetic Resonance in Hypertrophic Cardiomyopathy: A Marker of Advanced Disease and Electrical Myocardial Instability

Background

Myocardial hyperintensity on T2-weighted short-tau inversion recovery (STIR) (HyT2) cardiac magnetic resonance (CMR) images has been demonstrated in patients with hypertrophic cardiomyopathy (HCM) and is considered a sign of acute damage. The aim of the current study was to evaluate the relationship between HyT2 and both a) markers of ventricular electrical instability and b) clinical and CMR parameters.

Methods

Sixty-five patients underwent a thorough clinical examination, consisting of 24-h ECG recording and CMR examination including functional evaluation, T2-STIR images and late gadolinium enhancement (LGE).

Results

HyT2 was detected in 27 patients (42%), and subjects with HyT2 showed a greater left ventricle (LV) mass index (p<0.001), lower LV ejection fraction (p = 0.05) and greater extent of LGE (p<0.001) compared to those without HyT2. Twenty-two subjects (34%) presented non-sustained ventricular tachycardia (NSVT) on the 24-h ECG recording, 21 (95%) of whom exhibited HyT2. Based on the logistic regression analysis, HyT2 (odds ratio [OR]: 165, 95% CI 11–2455, p<0.001) and LGE extent (1.1, 1.0–1.3, p<0.001) served as independent predictors of NSVT, while the presence of LGE was not associated with NSVT occurrence (p = 0.49). The presence of HyT2 was associated with lower heart rate variability (p = 0.006) and a higher number of arrhythmic risk factors (p<0.001).

Conclusions

In HCM patients, HyT2 upon CMR examination is associated with more advanced disease and increased arrhythmic burden.     

A Murine Hypertrophic Cardiomyopathy Model: The DBA/2J Strain

Familial hypertrophic cardiomyopathy (HCM) is attributed to mutations in genes that encode for the sarcomere proteins, especially Mybpc3 and Myh7. Genotype-phenotype correlation studies show significant variability in HCM phenotypes among affected individuals with identical causal mutations. Morphological changes and clinical expression of HCM are the result of interactions with modifier genes. With the exceptions of angiotensin converting enzyme, these modifiers have not been identified. Although mouse models have been used to investigate the genetics of many complex diseases, natural murine models for HCM are still lacking. In this study we show that the DBA/2J (D2) strain of mouse has sequence variants in Mybpc3 and Myh7, relative to widely used C57BL/6J (B6) reference strain and the key features of human HCM. Four-month-old of male D2 mice exhibit hallmarks of HCM including increased heart weight and cardiomyocyte size relative to B6 mice, as well as elevated markers for cardiac hypertrophy including β-myosin heavy chain (MHC), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and skeletal muscle alpha actin (α1-actin). Furthermore, cardiac interstitial fibrosis, another feature of HCM, is also evident in the D2 strain, and is accompanied by up-regulation of type I collagen and α-smooth muscle actin (SMA)-markers of fibrosis. Of great interest, blood pressure and cardiac function are within the normal range in the D2 strain, demonstrating that cardiac hypertrophy and fibrosis are not secondary to hypertension, myocardial infarction, or heart failure. Because D2 and B6 strains have been used to generate a large family of recombinant inbred strains, the BXD cohort, the D2 model can be effectively exploited for in-depth genetic analysis of HCM susceptibility and modifier screens.     

Hypertrophic Cardiomyopathy in Owl Monkeys (Aotus spp.)

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.     

Private Mitochondrial DNA Variants in Danish Patients with Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease primarily caused by mutations in genes coding for sarcomeric proteins. A molecular-genetic etiology can be established in ~60% of cases. Evolutionarily conserved mitochondrial DNA (mtDNA) haplogroups are susceptibility factors for HCM. Several polymorphic mtDNA variants are associated with a variety of late-onset degenerative diseases and affect mitochondrial function. We examined the role of private, non-haplogroup associated, mitochondrial variants in the etiology of HCM. In 87 Danish HCM patients, full mtDNA sequencing revealed 446 variants. After elimination of 312 (69.9%) non-coding and synonymous variants, a further 109 (24.4%) with a global prevalence > 0.1%, three (0.7%) haplogroup associated and 19 (2.0%) variants with a low predicted in silico likelihood of pathogenicity, three variants: MT-TC: m.5772G>A, MT-TF: m.644A>G, and MT-CYB: m.15024G>A, p.C93Y remained. A detailed analysis of these variants indicated that none of them are likely to cause HCM. In conclusion, private mtDNA mutations are frequent, but they are rarely, if ever, associated with HCM.     

Gender-Specific Clinical Characteristics of Deep Q Waves in Hypertrophic Cardiomyopathy

Background: Despite male predominance in the prevalence of hypertrophic cardiomyopathy (HCM), repeated diagnosis at our institute indicates a possible higher prevalence of deep Q waves with HCM in women.Objective: The current study examined gender similarities and differences in the prevalence of deep Q waves in HCM and in the morphologic and electrocardiographic features of HCM with deep Q waves.Methods: Patients with HCM underwent cardiac magnetic resonance (CMR) imaging to identify the prevalence of deep Q waves in electrocardiographic limb leads, and to analyze the relationship between distribution patterns of deep Q waves and those of the localization of maximum amplitude of left ventricular (LV) hypertrophy. Contiguous LV short-axis images were obtained from the base toward the apex.Results: Of the 200 consecutive patients (172 males, aged 20–78 years; 28 females, aged 16–79 years) with HCM who underwent CMR imaging, 10 male and 8 female patients had deep Q waves. Deep Q waves were more prevalent in females with HCM than in their male counterparts (28.6% vs 5.8%, respectively; P < 0.001). Of the 18 patients with deep Q waves, maximum wall thickness was localized at either the basal anterior wall or the midventricular septum in 9 (90%) of the 10 male patients and 6 (75%) of the 8 female patients. In both sexes, the Q wave distribution pattern of I and aVL and of II and aVF indicated localization of maximum hypertrophy at the midventricular septum in 6 (75%) of the 8 patients with the former pattern, and at the basal anterior wall in 9 (90%) of the 10 patients with the latter pattern.Conclusions: Diagnostic deep Q waves were detected more frequently in female patients with HCM than in their male counterparts. In HCM with deep Q waves in limb leads, morphologic and electrocardiographic analysis showed similar features in both sexes. (Gend Med.Keywords: deep Q wave, hypertrophic cardiomyopathy, gender, cardiac magnetic resonance.     

肥厚型心肌病患者心肌mtDNA大片段缺失的探讨

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.     

Genetic diagnostics and genetic counselling in Hypertrophic Cardiomyopathy (HCM)

Dutch professional groups involved in drawing up this guideline: cardiologists, paediatric cardiologists, clinical geneticists, clinical molecular geneticists, genetic counsellors, psychosocial workers, associated with or cooperating with the university hospitals’ outpatient clinics for cardiogenetics. Approved by the NVVC, VKGN and NVK (paediatric cardiology section). NVVC - Nederlandse Vereniging voor Cardiologie – Dutch Society for Cardiology; VKGN - Vereniging Klinische Genetica Nederland – the Netherlands Society for Clinical Genetics; NVK - Nederlandse Vereniging Kindergeneeskunde – Dutch Society for Paediatrics. First published in Dutch in June 2009.