ACE angiotensin converting enzyme BAL bronchoalveolar lavage CRT cardiac resynchronization therapy CT computed tomography 18 F-FDG fluorine-18 fluorodeoxyglucose 67 Ga gallium-67 HRCT high resolution computed tomography ICD implantable cardioverter defibrillator MRI magnetic resonance imaging PET positron emission tomography sIL-2R soluble interleukin 2 recepter SPECT single photon emission computed tomography JCS GUIDELINES

t has been thought that lysosomes carry the non-selective bulk of protein degradation that occurs in cellular remodeling and the removal of abnormal cellular components. 1 In the process of lysosomal degradation, lysosomal membranes and lysosomal enzymes play important roles. Lysosome-associated membrane proteins are thought to be structural or functional components of the lysosomal membrane. 2 Cathepsins are hydrolytic enzymes in lysosomes that degrade damaged proteins. Lysosomal function is broadly categorized into autophagy and heterophagy. Autophagy is the process of sequestration of intracellular components and their subsequent degradation by the lysosomal vacuoles. In contrast, sequestered cell organelles derived exogenously from other cells are degraded in the lysosomes through a process called heterophagy. 3 It is reported that, under the conditions of sublethal injury such as ischemia, cardiomyocytes contain autophagic vacuoles ranging from those in which organelles are readily identified to those characteristic of residual bodies. 4,5 Morphological studies of cardiomyopathic hearts have revealed degenerative changes such as vacuolization and myofibrillar lysis. 6 In hearts from cases of dilated cardiomyopathy Japanese Circulation Journal Vol. 65, November 2001 (DCM), increased activity of lysosomal enzymes is found, 7-9 but the precise mechanism of lysosomal function in the pathogenesis of DCM remains poorly understood. It is speculated that autophagic function is associated with the irreversible degeneration preceding myocardial cell death. MethodsTwenty-seven patients with idiopathic DCM (20 men, 7 women; mean age, 47±14 years) who had undergone partial left ventriculectomy were included in the study. 10,11 Specimens of left ventricular myocardium, resected during surgery, were examined and for the control, 5 autopsied hearts from patients who had died of non-cardiac diseases were used. Light MicroscopyThe formalin-fixed tissues were embedded in paraffin. Sections were cut, deparafinized, stained with hematoxylineosin and observed under a light microscope. ImmunohistochemistryIn situ localization of cathepsin D, a lysosomal enzyme, and lysosome-associated membrane protein-1 (LAMP-1) were examined immunohistochemically, using an anticathepsin D antibody (Upstate biotechnology, NY, USA) and an anti-LAMP-1 antibody (Santa Cruz, CA, USA), respectively. The sections were incubated with the biotinylated secondary antibody and the avidin-biotin peroxidase complex method was carried out. Positive reactions were optically detected by 3,3'-diaminobenzidine. Sections were counterstained with hematoxylin and examined under a light microscope. Autophagic Degeneration as a Possible Mechanism of Myocardial Cell Death in Dilated CardiomyopathyHiroaki Shimomura, MD; Fumio Terasaki, MD; Tetsuya Hayashi, MD; Yasushi Kitaura, MD; Tadashi Isomura, MD*; Hisayoshi Suma, MD*In failing hearts, cardiomyocytes degenerate and interstitial fibrosis, which indicates cardiomyocyte loss, becomes more prominent in the myocardium...

Insulin resistance or diabetes is associated with limited exercise capacity, which can be caused by the abnormal energy metabolism in skeletal muscle. Oxidative stress is involved in mitochondrial dysfunction in diabetes. We hypothesized that increased oxidative stress could cause mitochondrial dysfunction in skeletal muscle and make contribution to exercise intolerance in diabetes. C57/BL6J mice were fed on normal diet or high fat diet (HFD) for 8 wk to induce obesity with insulin resistance and diabetes. Treadmill tests with expired gas analysis were performed to determine the exercise capacity and whole body oxygen uptake (Vo(2)). The work (vertical distance x body weight) to exhaustion was reduced in the HFD mice by 36%, accompanied by a 16% decrease of peak Vo(2). Mitochondrial ADP-stimulated respiration, electron transport chain complex I and III activities, and mitochondrial content in skeletal muscle were decreased in the HFD mice. Furthermore, superoxide production and NAD(P)H oxidase activity in skeletal muscle were significantly increased in the HFD mice. Intriguingly, the treatment of HFD-fed mice with apocynin [10 mmol/l; an inhibitor of NAD(P)H oxidase activation] improved exercise intolerance and mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism itself. The exercise capacity and mitochondrial function in skeletal muscle were impaired in type 2 diabetes, which might be due to enhanced oxidative stress. Therapies designed to regulate oxidative stress and maintain mitochondrial function could be beneficial to improve the exercise capacity in type 2 diabetes.

In recent years, advancements in diagnostic imaging modalities, such as cardiac magnetic resonance (CMR) and 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography (PET), as well as the accumulation of cases, have allowed a more accurate diagnosis of cardiac sarcoidosis (CS). In addition, emerging cases of "isolated CS" in which no obvious lesions are present in organs other than the heart have been reported, and the clinical importance of CS has become recognized. Many issues including etiology, pathology, diagnosis, and treatment of CS remain to be solved. Considering this situation, guidelines for the diagnosis and treatment of cardiac sarcoidosis were recently updated by the Japanese Circulation Society and were published in February 2017.

Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.