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Genetically Determined Ventricular Arrhythmias
Published in Andrea Natale, Oussama M. Wazni, Kalyanam Shivkumar, Francis E. Marchlinski, Handbook of Cardiac Electrophysiology, 2020
Houman Khakpour, Jason S. Bradfield
Two variants of CPVT have been described based on their genetic mutation and mode of transmission. CPVT1 has a mutation in the ryanodine 2 receptor gene (RyR2) which leads to delayed afterdepolarization (DAD)-induced extrasystolic activity from defective calcium handling. The resulting transmural dispersion of repolarization provides the substrate for the development of re-entrant tachyarrhythmias.13,76 The RyR2 gene shows autosomal dominant inheritance. CPVT2 is defined by a mutation in the calsequestrin (CASQ2) gene and has an autosomal recessive inheritance. Other unidentified genes are also believed to result in CPVT. The ryanodine receptor is located on the sarcoplasmic reticulum and allows the release of calcium into the cell, thus facilitating excitation contraction coupling in the myocardium. Calsequestrin gene mutations interfere with sarcoplasmic calcium storage.13
Upper limb
Published in Aida Lai, Essential Concepts in Anatomy and Pathology for Undergraduate Revision, 2018
Malignant hyperpyrexia Due to defect in muscle ryanodine receptorsCauses: – general anaesthesia (most common)– neurolepticsSigns: – high temperature– widespread rigidity of skeletal muscleManagement: – dantrolene
Emergency drugs
Published in Daniel Cottle, Shondipon Laha, Peter Nightingale, Anaesthetics for Junior Doctors and Allied Professionals, 2018
Dantrolene is a drug used for malignant hyperthermia. It acts on the sarcoplasmic reticulum (inhibiting the ryanodine receptor) in skeletal muscle to reduce calcium ion release and thus decrease the damaging global muscle contractions. Vials contain dantrolene 20 mg plus mannitol 3 g and sodium hydroxide: it needs to be made up with 60 mL of sterile water.For malignant hyperthermia an initial dose of 1 mg/kg intravenously (approximately four vials) is given followed by repeated doses up to 10 mg/kg (average requirement is 2–3 mg/kg).This is difficult to dissolve and will require a large volume of sterile water and so is best made up in a large sterile theatre dish. It has a pH of 9.5 and causes tissue necrosis with extravasation.
Solanaceae glycoalkaloids: α-solanine and α-chaconine modify the cardioinhibitory activity of verapamil
Published in Pharmaceutical Biology, 2022
Szymon Chowański, Magdalena Winkiel, Monika Szymczak-Cendlak, Paweł Marciniak, Dominika Mańczak, Karolina Walkowiak-Nowicka, Marta Spochacz, Sabino A. Bufo, Laura Scrano, Zbigniew Adamski
Calcium ions play a crucial role in muscle contractions, and therefore, L-type calcium channels that move Ca2+ ions inward and trigger calcium release from the sarcoplasmic reticulum by activating the ryanodine receptor 2 (Striessnig et al. 2014) are just as important. Dysregulation of L-type Ca2+ channels is the basis of numerous cardiac disorders; therefore, they are also a common target in various therapies for cardiovascular diseases. L-type Ca2+ channel blockers, such as verapamil, are commonly used to treat hypertension, myocardial ischaemia, and arrhythmias (Limpitikul et al. 2018). The so-called α1 subunit forms the core of voltage-sensitive L-type Ca2+ channels. It associates with other subunits (β, α2δ, γ) to form heterooligomeric complexes. The β and α2/δ subunits are tightly but not covalently bound to the α1 subunit and modulate the biophysical properties and trafficking of the α1 subunit to the membrane (Bodi et al. 2005). The presence of L-type Ca2+ channels were also confirmed in the myocardium of Drosophila melanogaster (Limpitikul et al. 2018) and Musca domestica (Grabner et al. 1994). This tissue builds the dorsal vessel of the insect, traditionally called the heart. Even if not anatomically, the insect heart functionally and developmentally resembles the embryonic vertebrate heart. Thus, it offers an attractive alternative for studies conducted on mammals. Furthermore, many analyses can be performed in vivo without the need to sacrifice the test animal (Limpitikul et al. 2018).
Improving genetic diagnostics of skeletal muscle channelopathies
Published in Expert Review of Molecular Diagnostics, 2020
Vinojini Vivekanandam, Roope Männikkö, Emma Matthews, Michael G. Hanna
Mutations in RYR1, ATP1A2, MT-ATP6, and MT-ATP8 have been recently identified in cases of periodic paralysis. Skeletal muscle ryanodine receptor (RYR1) codes for the main sarcoplasmic reticulum-located calcium release channel in muscle and is critical for excitation contraction coupling. RYR1 mutations are known to cause several muscle phenotypes including congenital myopathies, rhabdomyolysis, myalgia, and malignant hyperthermia [77]. A periodic paralysis phenotype caused by RYR1 mutations has been reported in four cases to date [44,78]. Two patients had childhood onset with congenital myopathy and later episodes of periodic paralysis. The other two did not have myopathy but demonstrated later-onset periodic paralysis. Cramps and myalgia were experienced by all patients and typical periodic paralysis triggers such as cold and exercise were described in some.
Precision medicine in cardiac electrophysiology: where we are and where we need to go
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ashish Correa, Syed Waqas Haider, Wilbert S. Aronow
Linkage analyses and various studies led to identification of mutations in the cardiac ryanodine receptor gene RYR2 on chromosome 1q43 as the cause an autosomal dominant form of CPVT (referred to as CPVT1) [62–65]. Lahat et al. performed a genome-wide linkage analysis in 7 unrelated Israeli Bedouin families with an autosomal recessive form of CPVT (referred to as CPVT2), and mapped the disease locus to the calsequestrin-2 gene CASQ2 on chromosome 1q13 [66]. Both of these genes regulate calcium storage in the sarcoplasmic reticula of myocytes, and mutations in these genes result in calcium release in diastole (Figure 3). The resultant calcium overload can result in triggered activity by delayed after depolarizations that result in polymorphic VTs. Still, mutations at these 2 genetic loci account for only 50–70% of CPVT cases, and up to 200 variants across multiple genes may be associated with this disease [59,60,67].