Neurohumoral activation in congestive heart failure: A double-edged sword?

The search for the basic mechanism(s) responsible for the progressive and frequently irreversible deterioration of left ventricular pump function in congestive heart failure has been quite extensive; nonetheless, no single explanation has been forthcoming. Indeed, given the complexity of this disease process, it is becoming increasingly unlikely that a single pathogenetic mechanism will ever be uncovered for congestive heart failure. This review will examine recent experimental and clinical evidence which suggests that excessive adrenergic stimulation of the heart is double-edged. That is, while increased adrenergic input to the heart may initially enable the failing myocardium to function adequately for a period of months to years, continued excessive adrenergic stimulation of the heart through both local neural and circulating catecholamines may lead to frank myopathic effects on the heart, with resultant worsening of left ventricular function and the development of intractable congestive heart failure. While we do not mean to suggest that excessive sympathetic stimulation of the heart is the only, or even the major mechanism responsible for the development of irreversible congestive heart failure, the data reviewed herein do suggest that adrenergic stimulation may play a primary role in the pathogenesis of congestive heart failure.     

Diabetes mellitus carrying a mutation in the mitochondrial tRNALeu(UUR) gene

Summary We screened 214 Japanese NIDDM (non-insulin-dependent) diabetic patients with a family history of diabetes for mutations in the mitochondrial tRNA^Leu(UUR) gene using polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Six patients were identified as having an A to G transition at position 3243 (3243 mutation), but no patients were detected with a T to C transition at position 3271, in the mitochondrial tRNA^Leu(UUR) gene. These two mutations were not present in 85 healthy control subjects. It was disclosed that the patients' mothers were also affected by diabetes mellitus in five of the six cases. In these six affected patients, the 3243 mutation shows variable phenotypes, such as the degree of multiple organ involvement, intrafamilial and interfamilial differences in disease characteristics, and the degree of the involvement of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) phenotype. Endocrinological examinations revealed that those diabetic patients with the 3243 mutation show not only beta-cell dysfunction, but also a defect in alpha-cell function, which is considered characteristic of diabetes with the 3243 mutation. When compared with 50 selected diabetic control subjects without the 3243 mutation, whose mothers, but not fathers, were found to have diabetes, it was established statistically that those with the 3243 mutation possess the following clinical characteristics; 1) the age of diabetes onset is lower, 2) they have lean body constitutions, and 3) they are more likely to be treated with insulin than control subjects. We suggest that diabetes with the 3243 mutation possesses phenotypes distinct from those in common forms of diabetes.Abbreviations NIDDM non-insulin-dependent diabetes mellitus - IDDM insulin-dependent diabetes mellitus - MELAS mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes - PCR polymerase chain reaction - RFLP restriction fragment length polymorphism - BMI body mass index - ICA islet cell antibody - ICSA islet cell surface antibody - GAD glutamic acid decarboxylase     

Anesthetic considerations in myofibrillar myopathy

Myofibrillar myopathy (MFM) is a relatively newly recognized genetic disease that leads to progressive muscle deterioration. MFM has a varied phenotypic presentation and impacts cardiac, skeletal, and smooth muscles. Affected individuals are at increased risk of respiratory failure, significant cardiac conduction abnormalities, cardiomyopathy, and sudden cardiac death. In addition, significant skeletal muscle involvement is common, which may lead to contractures, respiratory insufficiency, and airway compromise as the disease progresses. This study is the first report of anesthetic management of a patient with MFM. We report multiple anesthetic encounters of a child with genetically confirmed BAG3‐myopathy, a subtype of MFM with severe childhood disease onset. A review of the anesthetic implications of the disease is provided, with specific exploration of possible susceptibility to malignant hyperthermia, rhabdomyolysis, and sensitivity to other anesthetic agents.     

氟美松对正常大鼠膈肌的影响

利用氟美松制备的大鼠类固醇肌病模型，研究了氟美松对大鼠膈肌的重量、收缩特性、肌纤维的横断面积、氧化酶活性、糖原和超微结构的影响。结果发现：（１）氟美松的使用可使大鼠膈肌明显萎缩，以Ⅱａ、Ⅱｂ型纤维萎缩为著；（２）在１００Ｈｚ电刺激下，膈肌的张力明显下降，膈肌耐疲劳的能力（１／２ＲＴ）显著提高；（３）膈肌中Ⅰ型、Ⅱｂ型纤维中ＡＴＰ酶、琥珀酸脱氢酶（ＳＤＨ）的活性均下降，膈肌中糖原含量增加。电镜观察发现氟美松可以导致膈肌线粒体增生、空泡样变性及部分肌丝局灶性破坏。氟美松导致的上述各种改变，可能直接或间接地影响膈肌物质能量代谢而导致其收缩性能的改变。     

D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2-hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D-2HG, we generated transgenic mice with conditionally activated IDH2^R140Q and IDH2^R172K alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span, recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant up-regulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2^R140Q-expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2^R140Q in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition.     

Gain‐of‐Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole‐exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca²⁺ sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca²⁺ levels and store‐operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single‐gene defect, which is consistent with Mendelian‐dominant inheritance.     

A novel MYH7 mutation with prominent paraspinal and proximal muscle involvement

Laing distal myopathy (LDM) is caused by mutations in the MYH7 gene, and known to have muscle weakness of distal limbs and neck flexors. Through whole exome sequencing, we identified a novel p.Ala1439Pro MYH7 mutation in a Korean LDM family. This missense mutation is located in more N-terminal than any reported rod domain LDM mutations. In the early stage of disease, the present patients showed similar clinical patterns to the previously described patients of LDM. However, in the later stage, fatty replacement and atrophy of paraspinal or proximal leg muscles was more severely marked than lower leg muscles, and asymmetric atrophies were observed in trapezius, subscapularis and adductor magnus muscles. Distal myopathy like LDM showed marked and predominant fatty infiltrations in paraspinal or proximal leg muscles with marked asymmetry. These observations expand the clinical spectrum of LDM with the MYH7 mutation.