ABSTRACT
BACKGROUND: The slow and rapid (I(Kr)) components of I(K) are major determinants of ventricular repolarization. Unlike I(Kr), which is homogeneously expressed across the transmural wall, I(Ks) expression is reduced in midmyocardial cells and presumably contributes significantly to transmural dispersion of repolarization. Increased dispersion of repolarization during pharmacologic blockade of I(Kr) is proarrhythmic, primarily due to relatively selective prolongation of midmyocardial cell action potential duration (APD). The mechanisms underlying proarrhythmia in heart disease associated with impaired repolarization, such as heart failure, are unknown. We hypothesize that, in contrast to I(Kr) blockade, I(Ks) blockade will have little effect on midmyocardial cells and hence decrease dispersion of repolarization in heart failure. OBJECTIVES: The purpose of this study was to determine the effect of blockade of the slow component of the delayed rectifier current (I(Ks)) on arrhythmogenic dispersion of repolarization and proarrhythmia in heart failure. METHODS: Optical action potentials were simultaneously recorded from 256 sites spanning the transmural wall of the arterially perfused canine wedge preparation. Hearts from dogs with heart failure induced by rapid pacing (n = 6) were compared with normals (n = 6). RESULTS: Baseline dispersion of repolarization, as measured from the range of transmural APD during stimulation at a cycle length of 2,000 ms, was significantly higher in heart failure (75 +/- 24 ms) compared with controls (39 +/- 21 ms, P < .04). I(Ks) blockade with 30 microM chromanol decreased dispersion of repolarization by 40% (P < .02) in heart failure, reducing it to values found in normals. Decreased dispersion of repolarization was due to a larger, relatively selective, drug-induced APD prolongation of epicardial (23%) compared with midmyocardial cells (9%, P < .02). VT could not be induced in failing hearts under conditions of I(Ks) blockade, and no proarrhythmia was observed. CONCLUSION: I(Ks) blockade significantly reduced heart failure-induced dispersion of repolarization to values seen in nonfailing hearts. By prolonging repolarization without increasing dispersion of repolarization, I(Ks) blockade may have antiarrhythmic effects without creating proarrhythmia.
Subject(s)
Action Potentials/drug effects , Chromans/pharmacology , Heart Failure/physiopathology , Heart Ventricles/drug effects , Potassium Channel Blockers/pharmacology , Potassium Channels, Calcium-Activated/antagonists & inhibitors , Sulfonamides/pharmacology , Action Potentials/physiology , Animals , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/physiopathology , Disease Models, Animal , Dogs , Heart Failure/complications , Heart Ventricles/physiopathology , Intermediate-Conductance Calcium-Activated Potassium Channels , MaleABSTRACT
The relationship between dialyzer fiber bundle volume (FBV), dialyzer life span, and small-solute clearance has yet to be clearly defined in continuous venovenous hemodialysis (CVVHD). This study sought to define this relationship using novel ultrasound dilution technology. We studied 55 sessions in 31 intensive care unit patients on CVVHD therapy. A session was defined as the life span of a single dialyzer. The following variables were assessed every 6 hours throughout each session, starting within 1 hour of initiation of that session: FBV, access recirculation, extracorporeal blood flow rate, effluent (EUN) to blood urea nitrogen (BUN) concentration ratio, effluent creatinine to blood creatinine concentration ratio, and urea nitrogen and creatinine clearances. Data were analyzed using random-effects linear models to estimate trends. Several dialysis-related and solute-removal parameters were analyzed for association with each other. Systemic or dialysis circuit heparin was administered in 28 of 55 sessions. One hundred seventy sets of FBV, 101 sets of urea clearance, and 102 sets of creatinine clearance measurements were performed. There was a declining trend for FBV (0.8 mL/h), heart rate (0.25 beats/min/h), and measured blood flow (0.33 mL/min/h; P < 0.05). Apart from dialysate inflow rate (P = 0.044), there was no significant correlation with EUN-BUN ratio. Session duration was associated with dialysis access site; the femoral access provided longer dialysis sessions than subclavian and internal jugular accesses (P = 0.029). We conclude that small-solute removal remains stable over the course of our CVVHD system life spans despite significant loss of hemodialyzer FBV.
