Dispersion of Ventricular Repolarization in Left Ventricular Hypertrophy: Influence of Afterload and Dofetilide

Gillis, Anne M.; Mathison, Heather J.; Kulisz, Elzbieta; Lester, Wanda M.

doi:10.1111/j.1540-8167.1998.tb00140.x

Cited by 25 publications

(27 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…15 In another study by Bauer et al, 7 a limited section of the LV was investigated by tridimensional recordings. In the study by Gillis et al, 8 only epicardial MAP recordings were analyzed. The present study leaves little doubt that significant spatial DR can develop between contiguous ventricular sites in the in vivo canine heart and can provide the primary substrate for functional conduction block and reentrant tachyarrhythmias.…”

Section: Discussionmentioning

confidence: 99%

“…4 Several studies have questioned whether marked spatial dispersion of ventricular repolarization is detectable in vivo [5][6][7] and whether class III antiarrhythmic agents result in an increased DR in the hypertrophied heart. 8 The present study was conducted to investigate if the hypertrophied heart is associated with increased spatial DR in vivo and an increased susceptibility to proarrhythmic effects of class III antiarrhythmic agents. For this purpose, we investigated a known model of ventricular hypertrophy 9 in which dogs with chronic atrioventricular (AV) block develop ventricular hypertrophy secondary to chronic volume overload.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Electrophysiological Mechanism of Enhanced Susceptibility of Hypertrophied Heart to Acquired Torsade de Pointes Arrhythmias

et al. 2002

View full text Add to dashboard Cite

Background-Cardiac hypertrophy is associated with increased incidence of sudden death and susceptibility to proarrhythmic effects of antiarrhythmic agents. However, the in vivo electrophysiologic mechanism of the arrhythmias has not been investigated in detail. Methods and Results-Dose-dependent susceptibility to Torsade de Pointes (TdP) by class III drug dofetilide, 3, 10, and 30 g/kg, was compared in 6 control dogs (C) and in 5 dogs 6 to 8 weeks after induction of complete atrioventricular block (AVB) that resulted in ventricular hypertrophy (H). Tridimensional ventricular activation and repolarization (R) patterns were simultaneously analyzed from unipolar extracellular electrograms, and local R was measured from activation recovery intervals. Both R and transmural dispersion of R (TDR) were significantly greater in dogs with H compared with C. Dofetilide resulted in cycle length-dependent and dose-dependent prolongation of R, which was more marked in left ventricular endocardium/midmyocardium compared with epicardium, resulting in significant increase of TDR. These changes were more accentuated in dogs with H compared with C. All 5 dogs with H developed TdP at a dose of 3 to 10 g/kg, whereas only 1 of 6 C dogs developed TdP at 30 g/kg. TdP was initiated by subendocardial focal activity that infringed on TDR, resulting in functional conduction block and reentrant excitation. Conclusions-Enhanced susceptibility of hypertrophied heart to class III drugs is attributable to baseline increased TDR and greater dose-related accentuation of TDR compared with nonhypertrophied heart. This provides the electrophysiologic substrate for drug-induced TdP.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Electrophysiological Mechanism of Enhanced Susceptibility of Hypertrophied Heart to Acquired Torsade de Pointes Arrhythmias

et al. 2002

View full text Add to dashboard Cite

show abstract

“…13 Dofetilide reduced dispersion of repolarization in normal animals 38 but had no effect on dispersion of repolarization in a canine myocardial infarction model 39 or in a rabbit model of left ventricular hypertrophy. 40 In patients with stable angina or ventricular tachycardia, dispersion of repolarization was not affected by dofetilide. 16,17 Pharmacokinetics Dofetilide is well absorbed after oral administration, with an absolute bioavailability of Ͼ90%.…”

Section: Effects Of Dofetilide On Arrhythmias In Animal Modelsmentioning

confidence: 99%

Dofetilide

2000

View full text Add to dashboard Cite

Dofetilide is a new antiarrhythmic drug that recently was recommended for approval by an advisory committee to the Food and Drug Administration (FDA) for treatment of patients with persistent atrial fibrillation. Dofetilide is a specific blocker of the rapid component of the outward delayed rectifier potassium current I Kr and will represent the first drug with relatively pure class III antiarrhythmic properties to be widely released. Basic ElectrophysiologyCardiac depolarization results principally from the flow of inward Na ϩ and Ca 2ϩ ions as the rapid and slow inward currents. Repolarization results from a balance between inactivation of the slow inward current and activation of repolarizing predominantly K ϩ currents. Early repolarization results from a transient outward current, I TO , which is activated rapidly by membrane depolarization. Terminal repolarization is mediated by outward delayed rectifier K ϩ currents, I K , which are activated slowly (over a period of 200 to 300 ms) on membrane depolarization and turn off, or deactivate, relatively slowly on membrane repolarization.I K can be separated pharmacologically into 2 components: a rapidly activating component, I Kr , and a slower component, I Ks , each carried by a separate ion channel molecule. 1,2 HERG channels are responsible for I Kr , whereas I Ks flows through KvLQT1 channels. Specific blockers of I Kr are therefore classified as pure class III antiarrhythmic agents because they produce only prolongation of action potential duration (and hence of QT interval). These actions may result in arrhythmia termination or suppression but can also lead to excess QT prolongation and polymorphic ventricular tachycardia. Examples of specific I Kr blockers include the methanesulfonanilide agents dofetilide, E4031, almokalant, and D-sotalol. Effects of Dofetilide on I krDofetilide blocks I Kr in all myocardial tissues with high potency (50% effective concentration [EC 50 ] in the nanomolar range). Block is voltage dependent and most prominent at depolarized potentials. 1,3,4 It does not occur in resting muscle but rather develops on depolarization. 1,5 Recovery from block is also potential dependent and is very slow at hyperpolarized potentials close to the resting potential. 1 Steady-state block at any dose is constant and does not change with increasing heart rate 1,3 because the recovery time is much greater than the diastolic interval. 1 Dofetilide block of I Kr increases as extracellular potassium concentration ([K]o) is reduced. 6 This sensitivity of dofetilide block to [K]o is of obvious clinical importance. Even moderate hypokalemia would be expected to disproportionately increase action potential prolongation induced by dofetilide, and correction of hypokalemia is of crucial importance in treating QT prolongation and torsade de pointes caused by I Kr blockade. Conversely, hyperkalemia blunts the effect of dofetilide, 7 suggesting the possibility of reduced efficacy after acute coronary occlusion or during rapid heart rates, when local cardiac tis...

show abstract

“…It has been shown that long-term administration of IGF-I regulates the expression of the K ϩ channel in cultured neonatal rat ventricular myocytes (18). Most studies regarding the electrophysiological alterations associated with cardiac hypertrophy were performed on the pressure-overload model, which has been associated with reduction in I to (6,15,16,53) and no change (6,57) or a decrease in I K (13,14,29,30) and I K1 (5,15,37). Interestingly, Brooksby et al (5) have shown that the electrical remodeling related to cardiac hypertrophy was restricted to a decrease in I K1 current density with no difference in the resting potential level of cardiomyocytes from control and spontaneously hypertensive rats.…”

mentioning

confidence: 99%

Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy

Teos¹,

Zhao²,

Alvin³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

The potassium channels IK and IK1, responsible for the action potential repolarization and resting potential respectively, are altered during cardiac hypertrophy. The activation of insulin-like growth factor-I (IGF-I) during hypertrophy may affect channel activity. The aim was to examine the modulatory effects of IGF-I on IK and IK1 through mitogenactivated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways during hypertrophy. With the use of specific inhibitors for ERK1/2 (PD98059), p38 MAPK (SB203580) and PI3K/Akt (LY294002), Western blot and whole cell patch-clamp were conducted on sham and aorto-caval shunt-induced hypertrophy adult rat myocytes. Basal activation levels of MAPKs and Akt were increased during hypertrophy. Acute IGF-I (10 Ϫ8 M) enhanced basal activation levels of these kinases in normal hearts but only those of Akt in hypertrophied ones. IK and IK1 activities were lowered by IGF-I. Inhibition of ERK1/2, p38 MAPK, or Akt reduced basal IK activity by 70, 32, or 50%, respectively, in normal cardiomyocytes vs. 53, 34, or 52% in hypertrophied ones. However, basal activity of IK1 was reduced by 45, 48, or 45% in the former vs. 63, 43, or 24% in the latter. The inhibition of either MAPKs or Akt alleviated IGF-I effects on IK and IK1. We conclude that basal IK and IK1 are positively maintained by steady-state Akt and ERK activities.

show abstract

Dispersion of Ventricular Repolarization in Left Ventricular Hypertrophy: Influence of Afterload and Dofetilide

Cited by 25 publications

References 44 publications

Electrophysiological Mechanism of Enhanced Susceptibility of Hypertrophied Heart to Acquired Torsade de Pointes Arrhythmias

Electrophysiological Mechanism of Enhanced Susceptibility of Hypertrophied Heart to Acquired Torsade de Pointes Arrhythmias

Dofetilide

Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy

Contact Info

Product

Resources

About