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Ion Channel Remodeling — A Potential Mechanism Linking Sleep Apnea and Sudden Cardiac Death

View Article: PubMed Central - PubMed

ABSTRACT

This study is the first to link potential mechanisms between OSA and prolonged QTc and SCD, suggesting an inverse association with mRNA expression of K+ channels with severity of OSA. CPAP therapy diminishing OSA is able to reverse this relationship in 4 weeks for moderate OSA. It remains to be determined whether this effect persists in the long term and what duration of therapy is required to restore circulating levels to those in subjects without OSA. Studies showing reproducibility and an association with measured QTc levels during sleep and wakefulness will strengthen this observation. Also requiring clarification is the nature of the interaction between K+ channel remodeling and hypoxemia and other acute effects of apnea, in the genesis of QT prolongation during apneas.

No MeSH data available.


Schematic representation of types of action potential (AP) throughout the heart. The major differences are between the nodal tissues (sinoatrial and atrioventricular nodes) and ventricular Purkinje/myocardium. (A) on the left hand side, the ventricular AP and associated Na+, K+, and Ca2+ channels are shown. Phase 0 corresponds with the QRS wave, phase 3 with the peak of the T wave, phase 4 with the isoelectric line of the surface ECG changes. (B) action potentials from different regions within the heart. ICa indicates inward calcium current L‐type; IKr, delayed inward rectifier K+; IKs, slowly activating K+ channel; INa, inward voltage‐dependent sodium channel; INCX, sodium‐calcium exchanger; Ito, transient outward; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Adapted from Dumotier, Heart12 by permission from BMJ Publishing Group Limited, and from Nattel et al, Physiological Reviews,13 with permission by the American Physiological Society.
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jah31723-fig-0001: Schematic representation of types of action potential (AP) throughout the heart. The major differences are between the nodal tissues (sinoatrial and atrioventricular nodes) and ventricular Purkinje/myocardium. (A) on the left hand side, the ventricular AP and associated Na+, K+, and Ca2+ channels are shown. Phase 0 corresponds with the QRS wave, phase 3 with the peak of the T wave, phase 4 with the isoelectric line of the surface ECG changes. (B) action potentials from different regions within the heart. ICa indicates inward calcium current L‐type; IKr, delayed inward rectifier K+; IKs, slowly activating K+ channel; INa, inward voltage‐dependent sodium channel; INCX, sodium‐calcium exchanger; Ito, transient outward; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Adapted from Dumotier, Heart12 by permission from BMJ Publishing Group Limited, and from Nattel et al, Physiological Reviews,13 with permission by the American Physiological Society.

Mentions: The negative cytosolic resting membrane potential (phase 4) of approximately −80 mV is maintained largely by the action of transmembrane cellular pumps (predominantly Na+/K+ ATPase and Na+/Ca2+ exchanger) and closed voltage‐gated ion channels (Figure 1).12, 13 The cardiac action potential (AP) is initiated in the sinoatrial node (SAN) by the slowly leaking inward “funny” current sodium channels (If), leading to the recruitment of Ca2+ channels and causing the positive depolarization current (phase 0). Gap junctions facilitate spread to adjacent cells in the atria, internodal tracts, atrioventricular node (AVN), His bundle, and both right and left bundles, the Purkinje cells, and finally, the ventricular myocardium. Phase 0 in all of the heart cells except for the SAN and AVN is caused by the opening of Na+ channels, flooding the cytoplasm with Na+ ions and causing the positive depolarization of the membrane. As the wave of depolarization spreads, sarcoplasmic Ca2+ release leads to muscular contraction (excitation‐contraction coupling). Immediately after phase 0, repolarization begins with phase 1 (largely due to Cl− ions), followed by phase 2, the plateau stage where the inner membrane potential remains relatively constant due to the influx of Ca2+. Phase 3 is the latter stage of repolarization and the relative refractory period, during which a new stimulus such as a ventricular extrasystole (VE) can trigger arrhythmia. AP duration is determined largely by activation of K+ channels. Thus, inactivation and/or down‐regulation of these K+ channels, which can be primary in genetic LQTS or secondary to other pathological states, can prolong the QTc on the surface ECG. Neurohumoral changes can modify the regionally specific AP further: increased sympathetic tone increases automaticity and conduction velocity and decreases the AP duration, leading to more rapid AP firing and recovery. Conversely, heightened parasympathetic tone decreases automaticity and prolongs the refractory periods.


Ion Channel Remodeling — A Potential Mechanism Linking Sleep Apnea and Sudden Cardiac Death
Schematic representation of types of action potential (AP) throughout the heart. The major differences are between the nodal tissues (sinoatrial and atrioventricular nodes) and ventricular Purkinje/myocardium. (A) on the left hand side, the ventricular AP and associated Na+, K+, and Ca2+ channels are shown. Phase 0 corresponds with the QRS wave, phase 3 with the peak of the T wave, phase 4 with the isoelectric line of the surface ECG changes. (B) action potentials from different regions within the heart. ICa indicates inward calcium current L‐type; IKr, delayed inward rectifier K+; IKs, slowly activating K+ channel; INa, inward voltage‐dependent sodium channel; INCX, sodium‐calcium exchanger; Ito, transient outward; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Adapted from Dumotier, Heart12 by permission from BMJ Publishing Group Limited, and from Nattel et al, Physiological Reviews,13 with permission by the American Physiological Society.
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jah31723-fig-0001: Schematic representation of types of action potential (AP) throughout the heart. The major differences are between the nodal tissues (sinoatrial and atrioventricular nodes) and ventricular Purkinje/myocardium. (A) on the left hand side, the ventricular AP and associated Na+, K+, and Ca2+ channels are shown. Phase 0 corresponds with the QRS wave, phase 3 with the peak of the T wave, phase 4 with the isoelectric line of the surface ECG changes. (B) action potentials from different regions within the heart. ICa indicates inward calcium current L‐type; IKr, delayed inward rectifier K+; IKs, slowly activating K+ channel; INa, inward voltage‐dependent sodium channel; INCX, sodium‐calcium exchanger; Ito, transient outward; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Adapted from Dumotier, Heart12 by permission from BMJ Publishing Group Limited, and from Nattel et al, Physiological Reviews,13 with permission by the American Physiological Society.
Mentions: The negative cytosolic resting membrane potential (phase 4) of approximately −80 mV is maintained largely by the action of transmembrane cellular pumps (predominantly Na+/K+ ATPase and Na+/Ca2+ exchanger) and closed voltage‐gated ion channels (Figure 1).12, 13 The cardiac action potential (AP) is initiated in the sinoatrial node (SAN) by the slowly leaking inward “funny” current sodium channels (If), leading to the recruitment of Ca2+ channels and causing the positive depolarization current (phase 0). Gap junctions facilitate spread to adjacent cells in the atria, internodal tracts, atrioventricular node (AVN), His bundle, and both right and left bundles, the Purkinje cells, and finally, the ventricular myocardium. Phase 0 in all of the heart cells except for the SAN and AVN is caused by the opening of Na+ channels, flooding the cytoplasm with Na+ ions and causing the positive depolarization of the membrane. As the wave of depolarization spreads, sarcoplasmic Ca2+ release leads to muscular contraction (excitation‐contraction coupling). Immediately after phase 0, repolarization begins with phase 1 (largely due to Cl− ions), followed by phase 2, the plateau stage where the inner membrane potential remains relatively constant due to the influx of Ca2+. Phase 3 is the latter stage of repolarization and the relative refractory period, during which a new stimulus such as a ventricular extrasystole (VE) can trigger arrhythmia. AP duration is determined largely by activation of K+ channels. Thus, inactivation and/or down‐regulation of these K+ channels, which can be primary in genetic LQTS or secondary to other pathological states, can prolong the QTc on the surface ECG. Neurohumoral changes can modify the regionally specific AP further: increased sympathetic tone increases automaticity and conduction velocity and decreases the AP duration, leading to more rapid AP firing and recovery. Conversely, heightened parasympathetic tone decreases automaticity and prolongs the refractory periods.

View Article: PubMed Central - PubMed

ABSTRACT

This study is the first to link potential mechanisms between OSA and prolonged QTc and SCD, suggesting an inverse association with mRNA expression of K+ channels with severity of OSA. CPAP therapy diminishing OSA is able to reverse this relationship in 4 weeks for moderate OSA. It remains to be determined whether this effect persists in the long term and what duration of therapy is required to restore circulating levels to those in subjects without OSA. Studies showing reproducibility and an association with measured QTc levels during sleep and wakefulness will strengthen this observation. Also requiring clarification is the nature of the interaction between K+ channel remodeling and hypoxemia and other acute effects of apnea, in the genesis of QT prolongation during apneas.

No MeSH data available.