Arrhythmogenic cardiomyopathy and Brugada syndrome: Diseases of the connexome

This review summarizes data in support of the notion that the cardiac intercalated disc is the host of a protein interacting network, called “the connexome”, where molecules classically defined as belonging to one particular structure (e.g., desmosomes, gap junctions, sodium channel complex) actually interact with others, and together, control excitability, electrical coupling and intercellular adhesion in the heart. The concept of the connexome is then translated into the understanding of the mechanisms leading to two inherited arrhythmia diseases: arrhythmogenic cardiomyopathy, and Brugada syndrome. The cross-over points in these two diseases are addressed to then suggest that, though separate identifiable clinical entities, they represent “bookends” of a spectrum of manifestations that vary depending on the effect that a particular mutation has on the connexome as a whole.     

家族性扩张型心肌病的分子遗传研究进展

扩张型心肌病是一种以左心室和,或右心室扩大、心肌收缩功能受损为主要特征的心肌疾病,是除冠心病和高血压以外导致心力衰竭的主要病因之一。家族性扩张型心肌病约占扩张型心肌病的35％。目前为止,发现的和扩张型心肌病相关的基因突变主要是心肌蛋白基因突变和细胞骨架蛋白基因突变,此外还有线粒体DNA的突变和能量代谢相关的基因突变。本文对引起家族性扩张型心肌病的分子遗传进展进行了总结。     

Deletion of MLIP (Muscle-enriched A-type Lamin-interacting Protein) Leads to Cardiac Hyperactivation of Akt/Mammalian Target of Rapamycin (mTOR) and Impaired Cardiac Adaptation

Aging and diseases generally result from tissue inability to maintain homeostasis through adaptation. The adult heart is particularly vulnerable to disequilibrium in homeostasis because its regenerative abilities are limited. Here, we report that MLIP (muscle enriched A-type lamin-interacting protein), a unique protein of unknown function, is required for proper cardiac adaptation. Mlip^−/− mice exhibited normal cardiac function despite myocardial metabolic abnormalities and cardiac-specific overactivation of Akt/mTOR pathways. Cardiac-specific MLIP overexpression led to an inhibition of Akt/mTOR, providing evidence of a direct impact of MLIP on these key signaling pathways. Mlip^−/− hearts showed an impaired capacity to adapt to stress (isoproterenol-induced hypertrophy), likely because of deregulated Akt/mTOR activity. Genome-wide association studies showed a genetic association between Mlip and early response to cardiac stress, supporting the role of MLIP in cardiac adaptation. Together, these results revealed that MLIP is required for normal myocardial adaptation to stress through integrated regulation of the Akt/mTOR pathways.     

Cardiolipin fingerprinting of leukocytes by MALDI-TOF/MS as a screening tool for Barth syndrome

Barth syndrome (BTHS), an X-linked disease associated with cardioskeletal myopathy, neutropenia, and organic aciduria, is characterized by abnormalities of card­iolipin (CL) species in mitochondria. Diagnosis of the disease is often compromised by lack of rapid and widely available diagnostic laboratory tests. The present study describes a new method for BTHS screening based on MALDI-TOF/MS analysis of leukocyte lipids. This generates a “CL fingerprint” and allows quick and simple assay of the relative levels of CL and monolysocardiolipin species in leukocyte total lipid profiles. To validate the method, we used vector algebra to analyze the difference in lipid composition between controls (24 healthy donors) and patients (8 boys affected by BTHS) in the high-mass phospholipid range. The method of lipid analysis described represents an important additional tool for the diagnosis of BTHS and potentially enables therapeutic monitoring of drug targets, which have been shown to ameliorate abnormal CL profiles in cells.     

NEDD8 Ultimate Buster 1 Long (NUB1L) Protein Suppresses Atypical Neddylation and Promotes the Proteasomal Degradation of Misfolded Proteins

Neddylation is a posttranslational modification that controls diverse biological processes by covalently conjugating the ubiquitin-like protein NEDD8 to specific targets. Neddylation is commonly mediated by NEDD8-specific enzymes (typical neddylation) and, sometimes, by ubiquitin enzymes (atypical neddylation). Although typical neddylation is known to regulate protein function in many ways, the regulatory mechanisms and biological consequence of atypical neddylation remain largely unexplored. Here we report that NEDD8 conjugates were accumulated in the diseased hearts from mouse models and human patients. Proteotoxic stresses induced typical and atypical neddylation in cardiomyocytes. Loss of NUB1L exaggerated atypical neddylation, whereas NUB1L overexpression repressed atypical neddylation through promoting the degradation of NEDD8. Activation of atypical neddylation accumulated a surrogate misfolded protein, GFPu. In contrast, suppression of atypical neddylation by NUB1L overexpression enhanced GFPu degradation. Moreover, NUB1L depletion accumulated a cardiomyopathy-linked misfolded protein, CryAB^R120G, whereas NUB1L overexpression promoted its degradation through suppressing neddylation of ubiquitinated proteins in cardiomyocytes. Consequently, NUB1L protected cells from proteotoxic stress-induced cell injury. In summary, these data indicate that NUB1L suppresses atypical neddylation and promotes the degradation of misfolded proteins by the proteasome. Our findings also suggest that induction of NUB1L could potentially become a novel therapeutic strategy for diseases with increased proteotoxic stress.     

Delayed AICD therapy and cardiac arrest resulting from undersensing of ventricular fibrillation in a subject with hypertrophic cardiomyopathy–A case report

Defibrillation testing is no longer routinely performed after automatic implantable cardioverter-defibrillator (AICD) implantation. However, certain subjects undergoing AICD implantation may be at higher risk of undersensing of ventricular arrhythmias resulting in potentially fatal outcomes. We present the case of a 30-year-old woman with hypertrophic cardiomyopathy (HCM; ‘asymmetric septal hypertophy’ morphologic variant) and prophylactic AICD who experienced an out of hospital cardiac arrest. AICD interrogation revealed undersensing as a result of intermittent high amplitude electrograms during an episode of ventricular fibrillation (VF). The subject underwent replacement and repositioning of the AICD lead along with pulse generator replacement (that utilized a different VF sensing algorithm) with appropriate sensing of VF and successful defibrillation testing. The presence of intermittent high amplitude electrograms during episodes of VF in AICDs using the AGC function should be recognized as a situation that may necessitate interventions to prevent undersensing and consequent delay in therapy.     

Heart Failure in Chronic Myocarditis: A Role for microRNAs?

Myocarditis is an inflammatory disease of the heart, which can persist over a long time. During this time, known as the chronic phase of myocarditis, ongoing inflammation damages the cardiomyocytes. The loss of cardiac cells culminates in the development of dilated cardiomyopathy, often followed by non-ischemic heart failure due to diminished cardiac function. During the course of the disease, expression levels of non-coding small RNAs, called microRNAs (miRNAs), change. Although mainly studied in the acute setting, some of these changes in expression level appear to persist in the chronic phase. In addition to being a much-needed diagnostic tool, these miRNA could provide new treatment options. miRNA-based intervention strategies already showed promising results in the treatment of ischemic cardiovascular diseases in preclinical animal models. By implementing more knowledge on the role of miRNAs in the progression towards heart failure, this can potentially be used in the development of miRNA-based therapeutic interventions in the treatment of myocarditis and thereby preventing the progression towards heart failure. The first part of this review will focus on the natural course of myocarditis and the progression towards heart failure. Secondly, we will discuss the current knowledge on alterations of miRNA expression patterns, and suggest some possible future interventions.     

心脏特异表达Calponin 1转基因小鼠的心脏功能分析

目的建立心脏特异表达Calponin 1转基因小鼠,研究Calponin 1对心脏发育及心肌病的调节作用。方法利用心脏特异启动子α-MHC构建转基因表达载体,显微注射法建立Calponin 1转基因小鼠,PCR法鉴定转基因小鼠的基因型,Western Blot检测Calponin 1在心脏组织中的表达,心脏超声检测转基因小鼠的心脏结构和功能,HE染色和Masson染色检测转基因小鼠心脏的病理改变。结果 Calponin 1在野生型小鼠心脏中有表达,在扩张型心肌病小鼠的心脏组织表达降低。通过显微注射法,建立了2个心脏组织Calponin 1基因高表达的转基因小鼠系。与野生型小鼠相比,Calponin 1转基因小鼠收缩期左室内径（LVID,systolic）增加28%（P〈0.01,n=12）,舒张期左室内径（LVID,diastolic）增加16.2%（P〈0.01,n=12）,收缩期左室后壁厚度（LVPW,systolic）减小15.7%（P〈0.01,n=12）,舒张期左室后壁厚度（LVPW,diastolic）减小21%（P〈0.01,n=12）,射血分数（ejection fraction,EF）降低11.5%（P〈0.01,n=12）,短轴内径缩短率（fraction shortening,FS）降低14.6%（P〈0.05,n=12）。转基因小鼠心脏组织病理H＆E染色和Masson染色显示,转基因小鼠心室扩张,心肌细胞不均匀肥大,细胞间隙变大,心肌间质纤维增多。结论 Calponin 1在心脏特异过表达引起转基因小鼠心脏左室内径增加,收缩期容积和舒张期容积显著增大,心室壁变薄,射血分数及短轴缩短率降低等扩张性心肌病表型,推测Calponin 1是参与心肌病病理发生的基因之一。     

Acute left ventricular failure in a patient with hydroxychloroquine-induced cardiomyopathy

We present the case of a 75-year-old woman with a medical history of rheumatoid arthritis treated with hydroxychloroquine, who was admitted with acute left-sided heart failure due to a hydroxychloroquine-induced cardiomyopathy as supported by endomyocardial biopsy.