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1.
P. A. van der Zwaag I. A. W. van Rijsingen R. de Ruiter E. A. Nannenberg J. A. Groeneweg J. G. Post R. N. W. Hauer I. C. van Gelder M. P. van den Berg P. van der Harst A. A. M. Wilde J. P. van Tintelen 《Netherlands heart journal》2013,21(6):286-293
Background
Recently, we showed that the c.40_42delAGA (p.Arg14del) mutation in the phospholamban (PLN) gene can be identified in 10–15 % of Dutch patients with dilated cardiomyopathy or arrhythmogenic cardiomyopathy. The arrhythmogenic burden of the p.Arg14del mutation was illustrated by the high rate of appropriate ICD discharges and a positive family history for sudden cardiac death.Methods
Our goal was to evaluate the geographical distribution and the origin of this specific mutation in the Netherlands and to get an estimation of the prevalence in a Dutch population cohort. Therefore, we investigated the postal codes of the places of residence of PLN p.Arg14del mutation carriers and places of birth of their ancestors. In addition, a large population-based cohort (PREVEND) was screened for the presence of this mutation.Results
By April 2012, we had identified 101 probands carrying the PLN p.Arg14del mutation. A total of 358 family members were also found to carry this mutation, resulting in a total of 459 mutation carriers. The majority of mutation carriers live in the northern part of the Netherlands and analysing their grandparents’ places of birth indicated that the mutation likely originated in the eastern part of the province of Friesland. In the PREVEND cohort we identified six heterozygous PLN p.Arg14del mutation carriers out of 8,267 subjects (0.07 %).Conclusion
The p.Arg14del mutation in the PLN gene is the most frequently identified mutation in Dutch cardiomyopathy patients. The mutation that arose 575–825 years ago is likely to have originated from the eastern part of the province of Friesland and is highly prevalent in the general population in the northern part of the Netherlands. 相似文献2.
Small-angle X-ray scattering experiments were carried out to investigate the structural changes of cardiac thin filaments induced by the cardiomyopathy-causing E244D mutation in troponin T (TnT). We examined native thin filaments (NTF) from a bovine heart, reconstituted thin filaments containing human cardiac wild-type Tn (WTF), and filaments containing the E244D mutant of Tn (DTF), in the absence and presence of Ca2+. Analysis by model calculation showed that upon Ca2+-activation, tropomyosin (Tm) and Tn in the WTF and NTF moved together in a direction to expose myosin-binding sites on actin. On the other hand, Tm and Tn of the DTF moved in the opposite directions to each other upon Ca2+-activation. These movements caused Tm to expose more myosin-binding sites on actin than the WTF, suggesting that the affinity of myosin for actin is higher for the DTF. Thus, the mutation-induced structural changes in thin filaments would increase the number of myosin molecules bound to actin compared with the WTF, resulting in the force enhancement observed for the E244D mutation. 相似文献
3.
Ca2+ -dependent interaction of S100A1 with the sarcoplasmic reticulum Ca2+ -ATPase2a and phospholamban in the human heart 总被引:4,自引:0,他引:4
Kiewitz R Acklin C Schäfer BW Maco B Uhrík B Wuytack F Erne P Heizmann CW 《Biochemical and biophysical research communications》2003,306(2):550-557
The Ca(2+)-binding S100A1 protein displays a specific and high expression level in the human myocardium and is considered to be an important regulator of heart contractility. Diminished protein levels detected in dilated cardiomyopathy possibly contribute to impaired Ca(2+) handling and contractility in heart failure. To elucidate the S100A1 signaling pathway in the human heart, we searched for S100A1 target proteins by applying S100A1-specific affinity chromatography and immunoprecipitation techniques. We detected the formation of a Ca(2+)-dependent complex of S100A1 with SERCA2a and PLB in the human myocardium. Using confocal laser scanning microscopy, we showed that all three proteins co-localize at the level of the SR in primary mouse cardiomyocytes and confirmed these results by immunoelectron microscopy in human biopsies. Our results support a regulatory role of S100A1 in the contraction-relaxation cycle in the human heart. 相似文献
4.
5.
Antoine Muchir Wei Wu Fusako Sera Shunichi Homma Howard J. Worman 《Biochemical and biophysical research communications》2014
Background
Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of LmnaH222P/H222P mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in LmnaH222P/H222P mice and assessed if adding a MEK1/2 inhibitor would provide added benefit.Methods
Male LmnaH222P/H222P mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated.Results
Treatment of LmnaH222P/H222P mice with either benazepril or selumetinib started at 8 weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16 weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16 weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left ventricular fractional shortening at 20 weeks of age.Conclusions
Both ACE inhibition and MEK1/2 inhibition have beneficial effects on left ventricular function in LmnaH222P/H222P mice and both drugs together have a synergistic benefit when initiated after the onset of left ventricular dysfunction. These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor in addition to standard of care in patients with dilated cardiomyopathy caused by LMNA mutations. 相似文献6.
E. Otten R. H. Lekanne dit Deprez M. M. Weiss M. van Slegtenhorst M. Joosten J. J. van der Smagt N. de Jonge W. S. Kerstjens-Frederikse M. T. R. Roofthooft A. H. M. M. Balk M. P. van den Berg J. S. Ruiter J. P. van Tintelen 《Netherlands heart journal》2010,18(10):478-485
Background. About 30% of dilated cardiomyopathy (DCM) cases are familial. Mutations are mostly found in the genes encoding lamin A/C, beta-myosin heavy chain and the sarcomeric protein cardiac troponin-T (TNNT2). Mutations in TNNT2 are reported in approximately 3% of DCM patients. The overall phenotype caused by TNNT2 mutations is thought to be a fully penetrant, severe disease. This also seems to be true for a recurrent deletion in the TNNT2 gene; p.K217del (also known as p.K210del). Methods. We compared the phenotype of all Dutch patients identified as carrying the TNNT2 p.K217del mutation with those described in the literature. All index patients underwent cardiological evaluation. Family screening was done in all described families. Results. Six DCM patients carrying the TNNT2 p.K217del mutation were identified from four Dutch families. Mean age of disease manifestation was 33 years. Heart transplantation was required in three of them at ages 12, 18 and 19 years. These outcomes are comparable with those described in the literature. Conclusion. Carriers of the TNNT2 p.K217del mutation in our Dutch families, as well as in families described in the literature before, generally show a severe, early-onset form of DCM. (Neth Heart J 2010;18:478-85.) 相似文献
7.
目的:探讨交感神经阻滞对有糖尿病、心腔扩张的顽固心衰患者心脏收缩功能和心腔大小的影响。方法:经胸3~胸4棘突间隙穿刺至硬膜外腔,留置硬膜外导管,0.5%利多卡因3~5ml每2h推注一次,持续4w,适当辅以常规治疗。测定并比较TEB治疗前及后4w射血分数(EF)、左室内径(LVED)和左房内径(LAED)等指标的变化。结果:治疗后左室射血分数(EF)由治疗前的(31.53±9.29)%升为(44.75±8.32)%(P0.05);左室内径(LVED)由治疗前的(70.59±6.25)mm缩减到(63.59±7.05)mm(P0.05);左房内径(LAED)由治疗前的(46.16±7.19)mm缩减到(39.05±7.23)mm(P0.05)。结论:心区交感神经阻滞结合常规用药对有糖尿病、心腔扩张的顽固心衰患者的心脏功能有明显改善作用,并使其扩大的心脏明显缩小。 相似文献
8.
Inhibition of nitric oxide synthase enhances contractile response of ventricular myocytes from streptozotocin-diabetic rats 总被引:1,自引:0,他引:1
The contractile hyporesponsiveness of the streptozotocin diabetic rat heart in vitro to β-adrenergic agonists is eliminated
when the heart is perfused with NG-nitro-l-arginine methyl ester (l-NAME), a non-selective inhibitor of nitric oxide synthase (NOS). The following study evaluated the hypothesis that an increased
production of NO/cGMP within the diabetic myocyte inhibits the β-adrenergic-stimulated increase in calcium current and contractile
response. Male Sprague-Dawley rats were given an intravenous injection of streptozotocin (60 mg/kg). After 8 weeks, L-type
calcium currents were recorded in ventricular myocytes using the whole cell voltage-clamp method. Shortening of isolated myocytes
was determined using a video edge detection system. cAMP and cGMP were measured using radioimmunoassay. Nitric oxide production
was determined using the Griess assay kit. Basal cGMP levels and nitric oxide production were elevated in diabetic myocytes.
Shortening of the diabetic myocytes in response to isoproterenol (1 μM) was markedly diminished. However, there was no detectable
difference in the isoproterenol-stimulated L-type calcium current or cAMP levels between control and diabetic myocytes. Acute
superfusion of the diabetic myocyte with l-NAME (1 mM) decreased basal cGMP and markedly enhanced the shortening response to isoproterenol but did not alter isoproterenol-stimulated
calcium current. These data suggest that increased production of NO/cGMP within the diabetic myocyte suppressed β-adrenergic
stimulated shortening of the myocyte. However, NO/cGMP apparently does not suppress shortening of the myocyte by inhibition
of the β-stimulated calcium current. 相似文献
9.
Rosman J Dhillon S Mayer A Hanon S Paul S 《Indian pacing and electrophysiology journal》2007,7(4):215-217
Background
Cardiac Resynchronization Therapy (CRT) is indicated for the treatment of advanced heart failure with severe systolic dysfunction and intraventricular conduction delay. Patient selection for this technology is vital, though it remains unclear which patients benefit most from CRT. We tested the hypothesis that patients with non-ischemic cardiomyopathy have a superior mortality benefit from CRT than ischemic cardiomyopathy patients.Methods
We evaluated 95 CRT patients to determine which factors predict mortality.Results
Patients with non-ischemic cardiomyopathy had a significantly better prognosis than patients with ischemic cardiomyopathy.Conclusion
Larger prospective studies can substantiate this finding and better delineate which patients benefit most from CRT. 相似文献10.
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。 相似文献