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Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
PRKAG2 deficiency is a rare autosomal dominant disease with increased glycogen storage due to increased cellular uptake of glucose as opposed to a defect in glycogen degradation. Patients present at a young age with marked cardiac hypertrophy, skeletal myopathy, and arrhythmias often related to Wolff-Parkinson-White syndrome. Poor LV systolic dysfunction and high-grade AV block necessitating pacemaker implantation may occur over time.
The cardiovascular system
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Mary N Sheppard, C. Simon Herrington
Hypertrophic cardiomyopathy (HCM) is inherited in an autosomal dominant pattern, associated with mutations in 11 or more genes encoding proteins of thick and thin myofilament contractile components of the cardiac sarcomere or Z disk, with beta-myosin heavy chain and myosin-binding protein C genes most commonly involved. Genetic testing panels show vast heterogeneity and diverse molecular pathways, with more than 2000 sarcomere mutations identified. Some of the mutations are considered to be pathogenic, but in others pathogenicity is uncertain, and many are confined to single families. Genetic testing is useful in cascade screening of family members thereby eliminating 50% from further screening once shown to be negative. However, genotype−phenotype correlations have been inconsistent, and single (or multiple) sarcomere variants are unreliable in predicting prognosis, with no specific role in risk stratification. Genetic testing will also identify affected family members without left ventricular hypertrophy. Such gene carriers characteristically have no cardiac events or symptoms, and many carriers will never have HCM but can nevertheless transmit disease-causing mutations to subsequent generations. Genetic testing can also identify metabolic and storage phenocopies (e.g. lysosome-associated membrane protein 2 [LAMP2] cardiomyopathy, Fabry's disease, PRKAG2 syndrome, and amyloidosis that mimic HCM).
Myricetin derivative-rich fraction from Syzygium malaccense prevents high-fat diet-induced obesity, glucose intolerance and oxidative stress in C57BL/6J mice
Published in Archives of Physiology and Biochemistry, 2023
Devi Nallappan, Kien Chai Ong, Uma Devi Palanisamy, Kek Heng Chua, Umah Rani Kuppusamy
Hyperglycaemia is associated with high blood glucose level and insulin resistance. A clear indication of hyperinsulinemia upon prolonged high-fat diet consumption was observed in the present study as reported previously (Martins et al. 2018). Meanwhile, the oral administration of MD exhibited the preventative efficacy of hyperinsulinemia. In this study, the antihyperglycemic efficacy of MD could be possibly attributed to improved glucose intake and high insulin sensitivity in insulin-responsive cells. Our previous in vitro studies using 3T3-L1 cells showed that myricetin derivatives from S. malaccense exhibited insulin-like property by facilitating high glucose uptake with upregulation of adiponectin, solute carrier family 2 facilitated glucose transporter (Slc2a4/GLUT4), protein kinase B (Akt1), peroxisome proliferator-activated receptor-gamma (PPARγ), and protein kinase, AMP-activated (PRKAG2). Therefore, it is pertinent to suggest that MD was able to prevent hyperglycaemia by reducing insulin resistance in the mice fed HFD through a similar mechanism (Arumugam et al. 2016).
Gene therapy to terminate tachyarrhythmias
Published in Expert Review of Cardiovascular Therapy, 2022
Kohei Kawajiri, Kensuke Ihara, Tetsuo Sasano
In the cardiac field, one of the diseases that has been studied earlier for treatment using CRISPR/Cas9 is Duchenne muscular dystrophy. Refaey et al. reported genome editing for dystrophic cardiac muscles in mice genetically engineered to develop Duchenne muscular dystrophy [112]. In this study, efficient truncation of mutant exon 23 of the Dmd gene restored dystrophin protein expression, cardiac fiber structure, and contraction of the papillary muscles. In the field of arrhythmia, as mentioned in the chapter on CPVT, genome editing by CRISPR/Cas9 has also been applied to knock-in mice with RyR2 mutant [100]. A study by Xie et al utilized CRISPR/Cas9 gene editing in mouse models of PRKAG2 cardiac syndrome, which is a hereditary disease caused by a mutation in the PRKAG2 gene and characterized by ventricular arrhythmia and progressive heart failure. The study demonstrated the therapeutic potential of CRISPR/Cas9 packaged into an AAV9 vector, which disabled the dominant mutant allele of the PRKAG2 gene [113]. In vivo editing for PRKAG2 transgenic and knock-in mice, left ventricular wall thickness was significantly reduced and ECG abnormalities were normalized. Dave et al. reported that genome editing reverses arrhythmia susceptibility in mice expressing the mutation in the phospholamban (PLN) gene associated with malignant arrhythmia and ventricular dilation [114]. This study showed that disruption of human PLN-deletion of Arg14 (R14del) allele by AAV9-CRISPR/Cas9 improves cardiac function and reduces VT susceptibility in humanized PLN-R14del mice.
An update on diagnosis and therapy of metabolic myopathies
Published in Expert Review of Neurotherapeutics, 2018
Multisystem involvement may occur in all types of metabolic myopathy, but particularly in mitochondrial disorders. In mitochondrial disorders all organs/tissues other than the muscle can be affected, particularly the brain, eyes, ears, endocrine organs, the heart, and the gastrointestinal tract. More rarely affected are the kidneys, the hematological system, the skin, lungs, bones, the cartilage, or the cellular immune system. Organs other than the muscle affected in GSDs are the heart (GSD-II, GSD-III (Forbes-Cori disease), GSD-IV (Andersen’s disease), polyglucosan storage myopathy (PGBM1)), the peripheral nerves (GSD-II, GSD-III, GSD-IV), the liver in form of hepatomegaly or hepatopathy (GSD-III), the hematological system (GSD-VII, GSD-IX), or the skin (GSD-XI). Organs/tissues other than the muscle affected in FAODs include the peripheral nerves (MTPD) and the skin (NLSD-I) [5]. In patients with adenosine monophosphate-kinase deficiency (AMPK) deficiency due to mutations in the PRKAG2 gene, hypertrophic cardiomyopathy may be part of the phenotype [14].