Rate Dependence of [Na ⁺ ] _i and Contractility in Nonfailing and Failing Human Myocardium

Abstract

Background — In the failing human heart, altered Ca 2+ homeostasis causes contractile dysfunction. Because Ca 2+ and Na + homeostasis are intimately linked through the Na + /Ca 2+ exchanger, we compared the regulation of [Na + ] i in nonfailing (NF) and failing human myocardium. Methods and Results — [Na + ] i was measured in SBFI-loaded muscle strips. At slow pacing rates (0.25 Hz, 37°C), isometric force was similar in NF (n=6) and failing (n=12) myocardium (6.4±1.2 versus 7.2±1.9 mN/mm 2 ), but [Na + ] i and diastolic force were greater in failing (22.1±2.6 mmol/L and 15.6±3.2 mN/mm 2 ) than in NF (15.9±3.1 mmol/L and 3.50±0.55 mN/mm 2 ; P <0.05) myocardium. In NF hearts, increasing stimulation rates resulted in a parallel increase in force and [Na + ] i without changes in diastolic tension. At 2.0 Hz, force increased to 136±17% of the basal value ( P <0.05), and [Na + ] i to 20.5±4.2 mmol/L ( P <0.05). In contrast, in failing myocardium, force declined to 45±3%, whereas [Na + ] i increased to 27.4±3.2 mmol/L (both P <0.05), in association with significant elevations in diastolic tension. [Na + ] i was higher in failing than in NF myocardium at every stimulation rate. [Na + ] i predicted in myocytes from Na + pipette -contraction relations was 8.0 mmol/L in NF (n=9) and 12.1 mmol/L in failing (n=57; P <0.05) myocardium at 0.25 Hz. Reverse-mode Na + /Ca 2+ exchange induced significant Ca 2+ influx in failing but not NF myocytes, compatible with higher [Na + ] i in failing myocytes. Conclusions — Na + i homeostasis is altered in failing human myocardium. At slow heart rates, the higher [Na + ] i in failing myocardium appears to enhance Ca 2+ influx through Na + /Ca 2+ exchange and maintain sarcoplasmic reticulum Ca 2+ load and force development. At faster rates, failing myocytes with high [Na + ] i cannot further increase sarcoplasmic reticulum Ca 2+ load and are prone to diastolic Ca 2+ overload.

Excitation-contraction coupling and mitochondrial energetics

“…[Na + ] i rises by ∼3-5 mM in response to an increase of stimulation frequency [58,154,155]. In humans, [Na + ] i is 8 mM in normal resting myocytes and elevated to 12 mM in cells from patients with heart failure [155]. Similar absolute increases of [Na + ] i were observed in various animal models of cardiac failure [5,58,154] and hypertrophy [154,156].…”

“…However, data on the effects of mNCEinhibition on cardiac energetics in vivo are presently not available. Furthermore, considering that the physiological increase of [Na + ] i during an increase of heart rate [58,154,155] could potentially prevent mitochondrial Ca 2+ overload (as discussed in the previous chapter), it remains unclear whether mNCE-inhibition may have adverse effects on energetics under physiological conditions. Clearly, more in vitro and in vivo research is needed to further evaluate the mNCE as a therapeutic target.…”

“…The physiological range of [Na + ] i in resting cardiac myocytes is ∼5-15 mM and is species-dependent: While in small animals (i.e., mice and rats), [Na + ] i is between 10 and 15 mM, larger animals and humans have [Na + ] i between 5 and 10 mM [154]. [Na + ] i rises by ∼3-5 mM in response to an increase of stimulation frequency [58,154,155]. In humans, [Na + ] i is 8 mM in normal resting myocytes and elevated to 12 mM in cells from patients with heart failure [155].…”

“…Physiologically, [Na + ] i is elevated in species with higher heart rates (e. g., mice or rats [154]). Furthermore, [Na + ] i generally increases at an increase of heart rate in many different species [58,154,155]. In this context, the elevation of [Na + ] i could potentially represent a physiological, protective mechanism by inhibiting mitochondrial Ca 2+ -overload and fatal opening of the PTP [29].…”

The role of Na dysregulation in cardiac disease and how it impacts electrophysiology

“…Thus, there is the danger that diastolic function may be impaired as the stimulation frequency increases. This has been demonstrated in human failing cardiac muscle [40].…”