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Mitochondrial Dysfunction and Heart Diseases
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Cardiac voltage-gated sodium channels (Nav) consist of heteromeric assembly of a pore-forming α subunit and auxiliary β subunits. Nav 1.5 (SCN5A) is the major Nav α subunit expressed in myocardium.101 Nav channels play a critical role by generating the rapid upstroke (phase 0) of the action potential to excite cardiomyocytes. Nav channels also regulate the conduction of electrical impulse within the myocardium, together with cardiac gap junctions. Abnormal cardiac Nav channels has been described in several hereditary cardiac diseases, in myocardial ischemia102 and heart failure.103 Gain of function (GOF) mutation of Nav 1.5 can cause long QT syndrome type III and rare familial atrial fibrillation,104 while loss of function (LOF) mutation have been reported to cause Brugada syndrome,105 progressive cardiac conduction defect, sinus node dysfunction, atrial arrhythmias, and poor pacemaker capture.106 Mutation of SCN5A has also been reported in multifocal ectopic premature Purkinje-related complexes (GOF mutations), isolated cardiac conduction defect (LOF mutations), sick sinus syndrome (LOF mutations), atrial fibrillation (LOF or GOF mutations) [see review107]. In addition, both loss- and gain-of-function mutations may cause dilated cardiomyopathy, which increase the risk of arrhythmia.
Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
ACM results from mutations in at least 13 desmosomal genes. Desmosomes are highly specialized cell adhesion junctions which confer resistance to mechanical stress and preserve cellular integrity in cardiac tissue and epidermis. Without normal desmosomes, myocytes detach from one another and die, particularly when the heart muscle is placed under stress (such as during vigorous exercise). Inheritance is usually autosomal dominant but the recessive form called Naxos disease shows severe cardiac disease from an early age. This provided the first genetic evidence for the cause of this disease in the desmosome and fascia adherens. Proteins from three separate families assemble to form desmosomal cadherins (desmoglein and desmocollin), armadillo proteins (plakoglobin and plakophilin) and plakins (desmoplakin). A plakoglobin deletion was first found in Naxos disease, followed by mutations in desmoplakin, plakophilin-2, desmoglein-2, desmocollin-2 and plakoglobin in the dominant forms. Thus, ACM is mainly a disease of the cardiomyocyte junction, and plakophilin-2 (PKP2) mutations are the most common. Convincing evidence is emerging that, particularly for DSG2 and DSC2, many carriers have a second variant. Variants in genes associated with other cardiomyopathies and arrhythmia syndromes have been reported in ACM patients, including in the sarcomere genes, DES (desmin), TTN (titin), LMNA (lamin A/C), PLN (phospholamban), SCN5A (Nav1.5) and FLNC (filamin C). Other non-desmosomal genes implicated in ACM include the cardiac ryanodine-2 receptor, the transforming growth factor β3 and the TMEM43 genes. These findings highlight the genetic heterogeneity and complexity of cardiomyopathies and arrhythmia syndromes. Genotype only occasionally informs management of affected patients. Individuals with multiple pathogenic variants do have earlier-onset disease and a higher risk for malignant ventricular arrhythmias and sudden death. Another genotype/phenotype association that may guide management is a very high risk of sudden death among male carriers of the founder TMEM43 variant p. (Ser358Leu). The likelihood of left ventricular involvement varies among carriers of different mutations with biventricular disease common among patients with PLN or DSP variants. The clinical utility of genetic sequencing for ACM is primarily to inform cascade screening for at-risk family members. Up to 20% have no known mutation so other factors are involved in the ACM phenotype.
Antinociceptive activity of doliroside B
Published in Pharmaceutical Biology, 2023
Xishan Bai, Yanhong Li, Yuxiao Li, Min Li, Ming Luo, Kai Tian, Mengyuan Jiang, Yong Xiong, Ya Lu, Yukui Li, Haibo Yu, Xiangzhong Huang
Similar to GABA channel, FMP assay was used for the functional test of sodium channels. As shown in Figure 8, DBDS has weaker effect on peripheral sodium channel Nav1.7 (IC50 = 32.62 ± 4.90 µM), central nervous system (CNS) subtype Nav1.2 (IC50 = 140.67 µM), and stronger inhibition on skeletal muscle subtype Nav1.4 (IC50 = 3.29 ± 2.12 µM). Fortunately, DBDS has no effect on Nav1.5 subtype of cardiac sodium channel (Figure 8(C)), a potential target of cardiac safety. Tetrodotoxin (TTX) was used as the positive control, and the half inhibitory concentrations are 0.016 ± 0.015 µM for Nav1.2, 0.005 ± 0.001 µM for Nav1.4, 3.4 ± 0.24 µM for Nav1.5, and 0.02 ± 0.003 µM for Nav1.7channels. In the meanwhile, we also tested the effect of DBDS on another pain target – TRPV1 channel. As shown in Figure 9, TRPV1 activator capsaicin induced a significant activation of TRPV1 channel, but DBDS (10 µM) did not alter the activity of TRPV1. In addition, we also tested the direct effect of DBDS and found that DBDS alone could not induce any change of TRPV1 activity. For TRPV1 channel, capsazepine was used as an inhibitor control (IC50 = 7.3 ± 0.06 µM).
Indications for mexiletine in the new ESC guidelines and beyond
Published in Expert Opinion on Pharmacotherapy, 2023
Mate Vamos, Elod-Janos Zsigmond, Stefan H. Hohnloser
The most frequently diagnosed types of inherited long QT syndromes (LQT) are LQT type 1, 2, and 3. In LQT type 1 and 2 prolonged repolarization is the result of reduced outward potassium current due to loss-of-function mutations in KCNQ1 and KCNH2 genes [11]. In contrast, LQT3 is caused by an increased inward sodium current as the result of gain-of-function mutations in the SCN5A gene, coding for the alpha-subunit of the sodium channel NaV1.5. The capability of mexiletine to shorten the QT interval in LQT3 is well described [12]. Mazzanti et al., in their retrospective cohort study of 34 genotyped LQT3 patients, demonstrated for the first time that besides shortening the QTc interval (on average by 63 ± 6 ms), long-term treatment with mexiletine also reduced the occurrence of life-threatening arrhythmic events. Both, the mean number of arrhythmic events per patient and the annual rate of arrhythmic events were significantly reduced [13]. Hence, the use of mexiletine in LQT3 nicely exemplifies a genotype-specific drug treatment strategy. Accordingly, AHA/ACC/HRS Guidelines mention mexiletine as an additional medication in LQT3 patients [2], while the new ESC Guidelines go even further, recommending it as a first-line therapy, class I indication, level of evidence C (Table 2) [3].
Bridging the gap: Super-resolution microscopy of epithelial cell junctions
Published in Tissue Barriers, 2018
Emily I. Bartle, Tejeshwar C. Rao, Tara M. Urner, Alexa L. Mattheyses
Super-resolution studies of the intercalated disc in murine cardiomyocytes are also of interest when considering desmosome structure. AC associated defects in desmosomal proteins, including Pkp2, can result in disruption of the intercalated disc. dSTORM revealed a nanoscale retraction of the microtubule plus end from N-cadherin in Pkp2 deficient mice, suggesting a mechanism for AC that relies on Pkp2 integrity.104 Related work found that, like disruption of Pkp2, truncation of Cx43 dissociated the microtubule plus end from the junction site and resulted in mislocalization of NaV1.5, the sodium channel protein integral to cardiac function.105 The use of dSTORM in these studies linked electrical coupling, cell adhesion, and excitability in the heart through a common mechanism of microtubule attachment.