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Neurons
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
Because they increase the resting membrane conductance, HCN channels decrease the cell’s input resistance, membrane time constant, and space constant. Ih in dendrites plays an important role in the modulation of synaptic voltages (Section 6.3.2). Ih can also contribute to the afterdepolarization (ADP) and to the rebound depolarization mentioned later in connection with the ADP.
Usefulness of insertable cardiac monitors for risk stratification: current indications and clinical evidence
Published in Expert Review of Medical Devices, 2023
Amira Assaf, Dominic AMJ Theuns, Michelle Michels, Jolien Roos-Hesselink, Tamas Szili-Torok, Sing-Chien Yap
Congenital long QT syndrome (LQTS) is an inherited disease characterized by a prolonged heart-rate corrected QT interval and is associated with an increased risk of malignant ventricular arrhythmias triggered by early afterdepolarizations [47]. The diagnosis is based on a high Schwartz score (≥3.5) and/or the presence of a pathogenic mutation. Pathogenic mutations are found in up to 75% of patients and mainly comprise loss-of-function variants in KCNQ1 and KCNH2, or gain-of-function variants in SCN5A [48,49]. The cornerstone of treatment are beta blockers, preferably non-selective agents (i.e. nadolol and propranolol), and lifestyle measures (i.e. avoidance of QT prolonging drugs, correction of electrolyte abnormalities, avoidance of genotype-specific triggers) [18]. The antiarrhythmic effect of beta blockers is due to the prevention of early afterdepolarizations. In addition, LQT3 patients may benefit from blockers of the late sodium inward current (mexiletine, flecainide or ranolazine) [50]. In patients in whom beta blockers are not effective, not tolerated, not accepted, or contraindicated, left cardiac sympathetic denervation is recommended [17,18].
The Visible Heart® project and methodologies: novel use for studying cardiac monophasic action potentials and evaluating their underlying mechanisms
Published in Expert Review of Medical Devices, 2018
Megan M. Schmidt, Paul A. Iaizzo
As previously mentioned, due to their ability to represent the underlying TAPs, MAP recordings in novel groups of patients may provide unique insights relative to abnormal myocyte repolarizations (also known as repolarization syndromes). While other mapping technologies, such as optical mapping, may be able to record repolarization patterns from more points at any given time, the undetected morphology focal waveforms can be altered due to the use of paralytic drugs (thus the underutilization of stretch-activated channels) required for such techniques [42–45]. For example, Blana et al. conducted studies with mice genetically modified to express long QT syndrome type 3; they concluded that this model for long QT demonstrated both structural and electrophysiologic changes in atrial substrates [46]. Similarly, Shimizu et al. conducted some early studies on long QT syndrome and, through the study of afterdepolarizations, concluded that both verapamil and propranolol could help improve these abnormalities [47]. Interestingly, verapamil and propranolol have also been studied by other researchers, focusing on the ability to recreate a Brugada-like action potential [48–51]. Recently, using Visible Heart methodologies, we have initiated similar studies to generate Brugada-like action potentials in the right ventricular outflow tract of reanimated large mammalian hearts. This model allows us to monitor the focal and global applications of a variety of current and novel therapies for the treatment of early repolarization diseases.
Predicting the cardiac toxicity of drugs using a novel multiscale exposure–response simulator
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2018
Francisco Sahli Costabal, Jiang Yao, Ellen Kuhl
For a dofetilide concentration of 5.7x in Figure 7, our simulation predicts a spontaneous transitions from a sharp but smoothly propagating excitation pattern into rapid, irregular, asynchronous activation patterns of torsades de pointes type. Our model inherently captures the regional specificity of the ventricular myocardium and probes the dynamic interplay of its endocardial, midwall, epicardial, and Purkinje cells. A closer look at our activation sequences can help us identify the onset of torsadogenesis both in space and time: our activation profiles in Figure 7 suggest that the mechanisms that triggers torsades de pointes are early afterdepolarizations (Antzelevitch and Sicouri 1994) and not prolonged action potential duration. It is well known that a variety of drugs that block sodium and potassium channels can induce early afterdepolarizations, which may ultimately result in torsades de pointes; yet, the genesis and maintainance of early afterdepolarization-induced arrhythmias remain unclear (Pugsley et al. 2015). At a dofetilide concentration of 5.7x, according to the input to our model in Figure 4, only midwall cells experience early afterdepolarizations (Antzelevitch and Sicouri 1994), while endocardial, epicardial and Purkinje cells display a regular, yet prolonged, action potential profile. In the thin layer of midwall cells in the ventricular wall, endocardial and epicardial cells can overwrite this early afterdepolarization, as evidenced by the global excitation pattern of large re-entrant waves, highlighted by the orange and blue colors. In the region near the great vessels, which we have represented by midwall cells, early afterdepolarizations freezes the transmembrane potential close to the neutral state, highlighted by the green color. This region overwrites the activation of the Purkije fiber network and excites the heart in chaotic twisting patterns, a classical hallmark of torsades de pointes (Dessertenne 1966).