Heart rate changes and myocardial sodium

Abstract

Historic studies with sodium ion (Na⁺ ) micropipettes and first-generation fluorescent probes suggested that an increase in heart rate results in higher intracellular Na⁺ -levels. Using a dual fluorescence indicator approach, we simultaneously assessed the dynamic changes in intracellular Na⁺ and calcium (Ca²⁺ ) with measures of force development in isolated excitable myocardial strip preparations from rat and human left ventricular myocardium at different stimulation rates and modeled the Na⁺ -effects on the sodium-calcium exchanger (NCX). To gain further insight into the effects of heart rate on intracellular Na⁺ -regulation and sodium/potassium ATPase (NKA) function, Na⁺ , and potassium ion (K⁺ ) levels were assessed in the coronary effluent (CE) of paced human subjects. Increasing the stimulation rate from 60/min to 180/min led to a transient Na⁺ -peak followed by a lower Na⁺ -level, whereas the return to 60/min had the opposite effect leading to a transient Na⁺ -trough followed by a higher Na⁺ -level. The presence of the Na⁺ -peak and trough suggests a delayed regulation of NKA activity in response to changes in heart rate. This was clinically confirmed in the pacing study where CE-K⁺ levels were raised above steady-state levels with rapid pacing and reduced after pacing cessation. Despite an initial Na⁺ peak that is due to a delayed increase in NKA activity, an increase in heart rate was associated with lower, and not higher, Na⁺ -levels in the myocardium. The dynamic changes in Na⁺ unveil the adaptive role of NKA to maintain Na⁺ and K⁺ -gradients that preserve membrane potential and cellular Ca²⁺ -hemostasis.

Keywords: calcium; heart rate; potassium; sodium.

FIGURE 1

Dynamic changes in intracellular sodium with rate changes. Simultaneous Ca²⁺ (Fura‐2), Na⁺ (ANG‐2), and force tracings in rat myocardium exposed to stimulation rate changes from 60/min to 180/min and back to 60/min. The circular inlay presents a single force (black) and Ca²⁺ transient (gray)

FIGURE 2

Sodium Peak and Trough Comparison. Schematic presentation of the Na⁺‐peak (top) and the Na⁺‐trough (bottom) with box and whisker plots of the measured magnitude of peak (trough), time to peak, and peak (trough) duration. The data are presented as box and whisker plots that visualize the full range of the data

FIGURE 3

Force, Ca, and Na Time to Peak Comparison. Box and whisker plots of time to peak for Na⁺, Ca²⁺, and systolic force after an increase in the stimulation rate from 60/min to 180/min demonstrating the sequential temporal coupling. When the times to the Na⁺‐peak and the force peak were compared the time to the force peak was significantly delayed

FIGURE 4

Additional Increase in Stimulation Rate and Stimulation Cessation. Panel (a) demonstrates a Na⁺ and Ca²⁺ and force tracing in response to a stepwise increase in stimulation frequency from 60/min, 180/min, and 360/min demonstrating a second sodium peak and corresponding changes in Ca²⁺ and force. Panel (b) demonstrates the restoration of higher Na⁺‐levels after stimulation cessation to baseline levels followed by pacing at 60/min

FIGURE 5

Human Example. Simultaneous Na⁺ (ANG‐2), Ca²⁺ (Fura‐2), and force tracings in human myocardium obtained from patients with coronary artery disease and hypertension with rate changes from 60/min to 180/min and back to 60/min showing a similar but less pronounced pattern compared to rat myocardium

FIGURE 6

Coronary Effluent. Coronary sinus Na⁺‐ and K⁺‐levels with sinus rhythm and with pacing at 125/min. The samples were drawn at a steady state and 15 to 60 s after changing the heart rate. p‐values from paired t‐tests are provided. Error bars are +/− SEM

FIGURE 7

NCX dependence on intracellular Na⁺ and stimulation rate. Effects of changes in intracellular Na⁺ on NCX activity denoted as E_Na/Ca–E_m. (a) At 60/min, NCX activities in both diastole and systole are reduced with increasing [Na⁺]i due to the reduction in E_Na and the resulting reduction in E_Na/Ca. At concentrations higher than 10 mM, NCX activity is reversed during systole because of E_Na/Ca < E_m. (b) At 180/min, NCX activity is again reduced with increasing [Na⁺]_i. However, due to systole now making up a higher fraction of the cardiac cycle, net NCX exchange over a full cycle is more sensitive to the effects of [Na⁺]_i compared to 60 bpm. Considering that Ca²⁺ influx is three times higher at 180/min compared to 60/min, the effective (eff) NCX activity is nearly zero at 12.5 mM and negatively valued at 15 mM