The positive-charged S4 segments undergo outward movement upon membrane depolarization, opening the central pore to allow Na + entry ( 39, 40). The NaV1.5 α-subunit, encoded by SCN5A ( 38), has four domains (I to IV), each of which contain six transmembrane segments (S1 to S6). Each Na + channel is formed by a pore-forming α-subunit, a modulatory β-subunit and additional regulatory proteins. Na + channels are found in high numbers in the periphery of the SAN, where they are thought to play a role in exit conduction of APs to the atrium ( 36, 37). Pacemaker activity: from the maximum diastolic potential (MDP), spontaneous phase 4 depolarization brings the membrane to the threshold potential (TP), thereby initiating an action potential. Together, the complex interplay of ion channels and pumps gives rise to the pacemaker action potential (AP), which is uniquely character-ized by spontaneous depolarization during phase 4 ( Fig. By contrast, the Ca 2+-mediated mechanism involves rhythmic release of Ca 2+ from the sarcoplasmic reticulum (SR), subsequent reuptake by the SR Ca 2+-ATPase and extrusion via the Na +-Ca 2+ exchanger ( 35).
HCN4 is the predominant subtype found in the SAN ( 33, 34). There are four recognized HCN channel isoforms (1 to 4) ( 32). I f has several unusual properties for a transmembrane current, including activation by a hyperpolarized voltage, permeability to both Na + and K + ions, regulation by intracellular cAMP, and small single channel conductance ( 31). The voltage-dependent mechanism involves the funny current ( I f) mediated by HCN channels located at the plasma membrane ( 30). To understand the molecular basis of how ion channel dysfunction leads to bradycardia or tachycardia, and the causal relationship between bradycardia and tachycardia, the mechanisms responsible for automaticity in the sinoatrial node (SAN) and mediating action potential conduction need to be considered.Īutomaticity of SAN is dependent on two closely coupled clocks, voltage- and calcium-dependent mechanisms ( Fig. These studies have identified the roles of different ion channels, such as hyperpolarization-activated, cyclic nucleotide-gated (HCN), Na + and transient receptor potential (TRP) channels, ryanodine receptors (RyR) and gap junctions ( 26– 28), as well as tissue-level mechanisms, in the pathogenesis of TBS. Our understanding of cardiac electrophysiology has significantly advanced with the use of pre-clinical animal models, which are amenable to pharmacological, physical or genetic manipulation for studying the consequences of ion channel abnormalities ( 16– 19), and have provided insight for translational application ( 14, 20– 25). A related condition, Bayes syndrome, involves inter-atrial block associated with AF ( 5– 15). Tachycardia complicates approximately 50% of SSS cases ( 2– 4). The association between sick sinus syndrome (SSS) and atrial fibrillation (AF) has been recognized for more than 5 decades since 1968 ( 1) with the first description of tachycardia-bradycardia syndrome (TBS) reported 5 years later ( 2). The aim of this article is to review the different ion channels involved in TBS, examine the three-way relationship between ion channel dysfunction, tachycardia and bradycardia in TBS and to consider its current and future therapies. Alternatives to electronic pacemakers are gene-based bio-artificial sinoatrial node and cell-based bio-artificial pacemakers, which are promising techniques whose long-term safety and efficacy need to be established.
The mainstay treatment option for SSS is pacemaker implantation, an effective approach, but has disadvantages such as infection, limited battery life, dislodgement of leads and catheters to be permanently implanted in situ.
Dysfunction of ion channels responsible for initiation or conduction of cardiac action potentials may underlie both bradycardia and tachycardia bradycardia can also increase the risk of tachycardia, and vice versa. Techniques such as genetic screening and molecular diagnostics together with the use of pre-clinical models have elucidated the electrophysiological mechanisms of this condition. Tachycardia-bradycardia syndrome (TBS) is a complication of SSS characterized by alternating tachycardia and bradycardia.
Sick sinus syndrome (SSS) encompasses a group of disorders whereby the heart is unable to perform its pacemaker function, due to genetic and acquired causes.
0 kommentar(er)
