Human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties

Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in 11 genes encoding sarcomeric proteins. Most families present mutations in MYBPC3 and MYH7 encoding cardiac myosin-binding protein C and beta-myosin heavy chain. The consequences of MYH7 mutations have been extensively studied at the molecular level, but controversial results have been obtained with either reduced or augmented myosin motor function depending on the type or homogeneity of myosin studied. In the present study, we took advantage of the accessibility to an explanted heart to analyze for the first time the properties of human homozygous mutant myosin. The patient exhibited eccentric hypertrophy with severely impaired ejection fraction leading to heart transplantation, and carries a homozygous mutation in MYH7 (R403W) and a heterozygous variant in MYBPC3 (V896M). In situ analysis of the left ventricular tissue showed myocyte disarray and hypertrophy plus interstitial fibrosis. In vitro motility assays showed a small, but significant increase in sliding velocity of fluorescent-labeled actin filaments over human mutant cardiac myosin-coated surface compared to control (+18%; P<0.001). Mutant myosin exhibited a large increase in maximal actin-activated ATPase activity (+114%; P<0.05) and Km for actin (+87%; P<0.05) when compared to control. These data show disproportionate enhancement of mechanical and enzymatic properties of human mutant myosin. This suggests inefficient ATP utilization and reduced mechanical efficiency in the myocardial tissue of the patient, which could play an important role in the development of FHC phenotype.     

Myocardial involvement in acromegaly

We recently encountered a case of an acromegalic patient with congestive heart failure and secondary cardiomyopathy. Cardiac biopsies were available in addition to autopsy material. This enabled us to perform electron microscopical studies which have hitherto not been reported. This may help to clarify the relationship between these two conditions and reveal specific characteristics.     

Outcome in Dilated Cardiomyopathy Related to the Extent,Location, and Pattern of Late Gadolinium Enhancement

ObjectivesThis study sought to investigate the association between the extent, location, and pattern of late gadolinium enhancement (LGE) and outcome in a large dilated cardiomyopathy (DCM) cohort.BackgroundThe relationship between LGE and prognosis in DCM is incompletely understood.MethodsThe authors examined the association between LGE and all-cause mortality and a sudden cardiac death (SCD) composite based on the extent, location, and pattern of LGE in DCM.ResultsOf 874 patients (588 men, median age 52 years) followed for a median of 4.9 years, 300 (34.3%) had nonischemic LGE. Estimated adjusted hazard ratios for patients with an LGE extent of 0 to 2.55%, 2.55% to 5.10%, and >5.10%, respectively, were 1.59 (95% confidence interval [CI]: 0.99 to 2.55), 1.56 (95% CI: 0.96 to 2.54), and 2.31 (95% CI: 1.50 to 3.55) for all-cause mortality, and 2.79 (95% CI: 1.42 to 5.49), 3.86 (95% CI: 2.09 to 7.13), and 4.87 (95% CI: 2.78 to 8.53) for the SCD endpoint. There was a marked nonlinear relationship between LGE extent and outcome such that even small amounts of LGE predicted a substantial increase in risk. The presence of septal LGE was associated with increased mortality, but SCD was most associated with the combined presence of septal and free-wall LGE. Predictive models using LGE presence and location were superior to models based on LGE extent or pattern.ConclusionsIn DCM, the presence of septal LGE is associated with a large increase in the risk of death and SCD events, even when the extent is small. SCD risk is greatest with concomitant septal and free-wall LGE. The incremental value of LGE extent beyond small amounts and LGE pattern is limited.     

抗疟药物的心脏毒性

虽然长期应用抗疟药物诱发心脏毒性者罕见,但后果严重。临床主要表现为心脏传导阻滞、充血性心力衰竭、心律失常及心肌病。确诊需行心肌心内膜活检。光学显微镜下组织病理学改变为心肌细胞内大量空泡形成,电子显微镜下见髓样体及特征性的曲线体。抗疟药物被溶酶体选择性摄取后使溶酶体pH值升高,从而干扰溶酶体中酶类活性,导致糖原及磷脂积聚。     

Effect of nicorandil on left ventricular end-diastolic pressure during exercise in patients with hypertrophic cardiomyopathy.

AIMS: Impaired coronary microcirculation is thought to contribute to myocardial ischaemia, causing an abnormal increase in left ventricular end-diastolic pressure during exercise in individuals with hypertrophic cardiomyopathy. The effects of nicorandil on left ventricular end-diastolic pressure during exercise were examined in patients with this condition. METHODS AND RESULTS: Left ventricular pressures and dimensions were measured simultaneously during supine bicycle exercise in 23 patients with nonobstructive hypertrophic cardiomyopathy, before and after intravenous injection of either nicorandil (0.1 mg/kg) or propranolol (0.15 mg/kg). Exercise thallium-201 scintigraphy was also performed. Patients were grouped according to the changes in left ventricular end-diastolic pressure during exercise before treatment. Group I comprised 13 patients in whom left ventricular end-diastolic pressure increased progressively to abnormal values during exercise; group II comprised 10 patients in whom left ventricular end-diastolic pressure changed biphasically. The extents of both left ventricular hypertrophy and ischemic burden during exercise were greater in group I than in group II. Of the eight group I patients who received nicorandil, four individuals exhibited biphasic changes in left ventricular end-diastolic pressure during exercise after its administration whereas four subjects showed no such effect of the drug. Left ventricular end-diastolic pressure increased progressively during exercise after propranolol treatment in all 6 group II patients given this drug. CONCLUSION: Nicorandil has a salutary effect on the changes in left ventricular end-diastolic pressure during exercise in patients with hypertrophic cardiomyopathy.     

扩张性心肌病患儿心率变异性的预后意义

目的探讨扩张性心肌病(DCM)患儿心率变异性(HRV)变化的预后意义。方法收集42例扩张性心肌病患儿,分成A组心功能Ⅰ～Ⅱ级(NYHA分级,n=20)和B组心功能Ⅲ～Ⅳ级(n=22),以及健康儿童对照组(n=20);采用Mars3000动态心电图仪常规记录24h动态心电图,分析HRV时域参数(SDNN、SDANN、PNN50和rMSSD)和频域参数(TF、VLF、LF、HF、LF/HF)。结果(1)DCM患儿(A组与B组)与对照组比较,各参数差异均有统计学意义(P<0.01);(2)DCM患儿共死亡16例,存活26例,死亡组与存活组各参数比较,t检验有统计学意义。结论HRV可作为评估DCM患儿病情程度的指标,并可作为预后的预测因子。     

Cardiac stem cells and myocardial disease

Recent data indicate that the heart is a self-renewing organ and contains a pool of progenitor cells (PCs). According to the new paradigm, this resident population of multipotent undifferentiated cells gives rise to myocytes, endothelial cells, smooth muscle cells and fibroblasts. Understanding the function of cardiac PCs is critical for the implementation of these cells in the treatment of the diseased human heart. However, cardiac repair is an extremely complex phenomenon. Efficient myocardial regeneration requires restoration of segmental and focal areas of myocardial scarring, replacement of damaged coronary arteries, arterioles and capillaries, and substitution of hypertrophied poorly contracting myocytes with smaller better functioning parenchymal cells. To achieve these goals, the acquisition of a more profound knowledge of the biology of cardiac PCs cells and their fate following pathologic insults represents an essential need.     

细胞因子和糖尿病心肌病

Diabetic cardiomyopathy (DCM), as an independent diabetic cardiac complication, has been paid more attention to. In clinical study, DCM was characterized by left ventricular diastolic dysfunction at the early stage. The pathogenesis of DCM is characterized by myocyte hypertrophy and cardiac fibrosis,ex-tracellular matrix accumulation and deposition. The development of DCM is multifactorial, the mechanism is still unclear. Several mechanisms are involved in the pathogenesis of DCM including myocardial fibrosis,in-terstitial inflammation and endothelial dysfunction. Cytokines can involve in multiple pathophysiological processes. In this review, the relationships between transforming growth factor-β1, connective tissue growth factor, tumor necrosis factor-α, insulin-like growth factor-1 ,adiponectin ,thrombospondin-1 and DCM are sum-marized. It may be the basis of therapeutic approaches for ameliorating DCM.