Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that ventricular myocardium is composed of at least 3 electrophysiologically distinct cell types: epicardial, endocardial, and M cells. Action potentials recorded from epicardial and M cells, unlike those recorded from endocardium, display a spike-and-dome morphology, the result of a prominent transient outward current-mediated phase 1. M cells are distinguished from endocardial and epicardial cells by the ability of their action potential to prolong disproportionately in response to a slowing of rate and/or to agents with class III actions. This intrinsic electrical heterogeneity contributes to the inscription of the electrocardiogram as well as to the development of a variety of cardiac arrhythmias. The transmural dispersion of repolarization is in large part responsible for the inscription of the J wave and T wave of the electrocardiogram. Because full repolarization of epicardium defines the peak of the T wave and that of the M cells, the end of the T wave, the interval between the peak and the end of the T wave provides a valuable index of transmural dispersion of repolarization. Differences in the response of the 3 cell types to pharmacologic agents and/or pathophysiological states often results in amplification of intrinsic electrical heterogeneities, thus providing a substrate as well as a trigger for the development of reentrant arrhythmias, including torsade de pointes (TdP) commonly associated with the long QT syndrome (LQTS) and the polymorphic ventricular tachycardia/fibrillation encountered in patients with the Brugada syndrome. Early repolarization of the epicardial action potential results in abnormal abbreviation of action potential duration due to an all-or-none repolarization at the end of phase 1 of the epicardial action potential. The loss of the action potential dome in epicardium but not endocardium gives rise to a large dispersion of repolarization across the ventricular wall, resulting in a transmural voltage gradient that manifests in the electrocardiogram as an ST segment elevation (or idiopathic J wave). Under these conditions, heterogeneous repolarization of the epicardial action potential gives rise to phase 2 reentry, which provides an extrasystole capable of precipitating ventricular tachycardia/fibrillation (or rapid TdP). Experimental models displaying these phenomena show electrocardiographic characteristics similar to those of the Brugada syndrome as well as those encountered during acute ischemia. Transmural dispersion of repolarization is also greatly amplified in LQTS. Disproportionate prolongation of the M-cell action potential contributes to the development of long QT intervals, wide-based or notched T waves, and a large transmural dispersion of repolarization, which provides the substrate for the development of a polymorphic ventricular tachycardia closely resembling torsade de pointes. An early afterdepolarization-induced triggered beat is thought to provide the extrasystole that precipitates TdP. Pharmacologic models of the LQT1, LQT2 and LQT3 forms of LQTS mimic the distinctive electrocardiographic, electrophysiologic, and pharmacologic responses observed in patients with these 3 different genetic syndromes. In LQTS, as in the Brugada syndrome, a mutation in an ion channel gene (in some cases the same gene--SCN5A) is responsible for the development of a large transmural dispersion of repolarization, which serves to provide the arrhythmogenic substrate tha can lead to sudden death.
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PMID:Transmural dispersion of repolarization and arrhythmogenicity: the Brugada syndrome versus the long QT syndrome. 1068 20

Body surface electrocardiograms and electrograms recorded from the surfaces of the heart are the basis for diagnosis and treatment of cardiac electrophysiological disorders and arrhythmias. Given recent advances in understanding the molecular mechanisms of arrhythmia, it is important to relate these electrocardiographic waveforms to cellular electrophysiological processes. This modeling study establishes the following principles: (1) voltage gradients created by heterogeneities of the slow-delayed rectifier (I(Ks)) and transient outward (I(to)) potassium current inscribe the T wave and J wave, respectively; T-wave polarity and width are strongly influenced by the degree of intercellular coupling through gap-junctions. (2) Changes in [K+]o modulate the T wave through their effect on the rapid-delayed rectifier, I(Kr). (3) Alterations of I(Ks), I(Kr), and I(Na) (fast sodium current) in long-QT syndrome (LQT1, LQT2, and LQT3, respectively) are reflected in characteristic QT-interval and T-wave changes; LQT1 prolongs QT without widening the T wave. (4) Accelerated inactivation of I(Na) on the background of large epicardial I(to) results in ST elevation (Brugada phenotype) that reflects the degree of severity. (5) Activation of the ATP-sensitive potassium current, I(K(ATP)), is sufficient to cause ST elevation during acute ischemia. These principles provide a mechanistic cellular basis for interpretation of electrocardiographic waveforms.
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PMID:Ionic current basis of electrocardiographic waveforms: a model study. 1198 83