Beneficial Effect of Calcium Treatment for Hyperkalemia Is Not Due to "Membrane Stabilization"

Abstract

Objectives: Hyperkalemia is a common life-threatening condition causing severe electrophysiologic derangements and arrhythmias. The beneficial effects of calcium (Ca 2+ ) treatment for hyperkalemia have been attributed to "membrane stabilization," by restoration of resting membrane potential (RMP). However, the underlying mechanisms remain poorly understood. Our objective was to investigate the mechanisms underlying adverse electrophysiologic effects of hyperkalemia and the therapeutic effects of Ca 2+ treatment.

Design: Controlled experimental trial.

Setting: Laboratory investigation.

Subjects: Canine myocytes and tissue preparations.

Interventions and measurements: Optical action potentials and volume averaged electrocardiograms were recorded from the transmural wall of ventricular wedge preparations ( n = 7) at baseline (4 mM potassium), hyperkalemia (8-12 mM), and hyperkalemia + Ca 2+ (3.6 mM). Isolated myocytes were studied during hyperkalemia (8 mM) and after Ca 2+ treatment (6 mM) to determine cellular RMP.

Main results: Hyperkalemia markedly slowed conduction velocity (CV, by 67% ± 7%; p < 0.001) and homogeneously shortened action potential duration (APD, by 20% ± 10%; p < 0.002). In all preparations, this resulted in QRS widening and the "sine wave" pattern observed in severe hyperkalemia. Ca 2+ treatment restored CV (increase by 44% ± 18%; p < 0.02), resulting in narrowing of the QRS and normalization of the electrocardiogram, but did not restore APD. RMP was significantly elevated by hyperkalemia; however, it was not restored with Ca 2+ treatment suggesting a mechanism unrelated to "membrane stabilization." In addition, the effect of Ca 2+ was attenuated during L-type Ca 2+ channel blockade, suggesting a mechanism related to Ca 2+ -dependent (rather than normally sodium-dependent) conduction.

Conclusions: These data suggest that Ca 2+ treatment for hyperkalemia restores conduction through Ca 2+ -dependent propagation, rather than restoration of membrane potential or "membrane stabilization." Our findings provide a mechanistic rationale for Ca 2+ treatment when hyperkalemia produces abnormalities of conduction (i.e., QRS prolongation).

Figure 1.. Hyperkalemia slows conduction, which is rescued by calcium treatment.

Top row. The effect of hyperkalemia and Ca2+ treatment on the ECG is shown. During hyperkalemia, a wide QRS showing a sine wave pattern is observed, which is normalized by Ca2+ treatment. Middle rows show endocardial (ENDO) and epicardial (EPI) action potentials at baseline, during hyperkalemia, and Ca2+ treatment. At baseline, transmural conduction time (difference between activation time of early activated ENDO and late activated EPI APs is relatively short (red hatched lines). Difference in repolarization times (a marker of DOR) is also shown (orange hatched lines). During hyperkalemia, marked conduction slowing occurs, with small prolongations in DOR. During Ca2+ treatment, conduction time normalizes. Representative isochronal contour maps of conduction time (lower row) are also shown under the 3 conditions. Earliest conduction is in white, while later conduction or repolarization is shown by darker colors. Note that with 12 mM [K+], there is marked conduction slowing, as indicated by crowding of isochrones and conduction block occurs in the subepicardium (dark line). With Ca2+ treatment, conduction velocity normalizes, and conduction block is prevented. Summary data for mean APD under each condition is also shown at bottom.

Figure 2.. Summary data of CV over all experiments is shown.

The greatest CV slowing from baseline (4mM) was observed between 8mM and 12mM [K+]. Ca2+ improved conduction which is expected to be antiarrhythmic. (n=7 preparations under all conditions except 8mM, n=5, *=p<0.02, **=p<.001).

Figure 3.. Effect of hyperkalemia and experimental conditions on the action potential.

Panel A. Shown are tracings of cellular action potentials recorded at baseline (black), hyperkalemia (8mM), gray), and after Ca2+ treatment (stippled) from isolated cardiomyocytes. Marked AP shortening occurs with hyperkalemia which is improved with Ca2+ treatment (*=p<0.05,**=p<0.01, n=7). Panel B. Summary data for APD under the 3 conditions is shown. Panel C. Summary data for High K + Ca condition, with and without verapamil, are shown.

Figure 4.. Effect of hyperkalemia and Ca+ on transmural APD and DOR.

Summary data of action potential duration as determined in the canine wedge preparation is shown. Compared to baseline (4mM [K+]) at high potassium, APD is shortened, but DOR is not significantly affected (difference between epicardial and endocardial APD) even in presence of calcium treatment (*=p<0.05).

Figure 5.. Effect of hyperkalemia and Ca+ Resting Membrane Potential.

Panel A. Shown are RMP and Phase 0 depolarization of representative action potentials in control (black), hyperkalemia (8mM potassium, black stippled) and hyperkalemia with Ca2+ treatment (grey). Note that although RMP rises during hyperkalemia, it is not affected by Ca2+ treatment. Panel B. Summary data for RMP is shown (*=p<.01, n=7). Panel C. Summary data for RMP during hyperkalemia and Ca2+ treatment, with and without verapamil, is shown.

Figure 6.. Effect of Verapamil and Ca2+ on transmural conduction.

Panel A. Upper row shows (in order left to right) transmural conduction maps at baseline, hyperkalemia, hyperkalemia + Ca2+ treatment, and hyperkalemia + Ca2+ treatment in the presence of L-type Ca2+ channel blockade with verapamil. Conduction slows during hyperkalemia and subsequent subepicardial conduction block is observed. Ca2+ treatment improves conduction and ameliorates conduction block. The addition of verapamil again slows conduction and conduction block returns. Panel B. Summary data for CV during hyperkalemia and Ca2+ treatment, with and without verapamil, is shown (*=p=0.02, **p<.001, n=3).