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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.

Myocardial contractility depends on temperature. We investigated the influence of mild hypothermia (37-31 degrees C) on isometric twitch force, sarcoplasmic reticulum (SR) Ca2+-content and intracellular Ca2+-transients in ventricular muscle strips from human and porcine myocardium, and on in vivo hemodynamic parameters in pigs. In vitro experiments: muscle strips from 5 nonfailing human and 8 pig hearts. Electrical stimulation (1 Hz), simultaneous recording of isometric force and rapid cooling contractures (RCCs) as an indicator of SR Ca2+-content, or intracellular Ca2+-transients (aequorin method). In vivo experiments: 8 pigs were monitored with Millar-Tip (left ventricle) and Swan-Ganz catheter (pulmonary artery). Hemodynamic parameters were assessed at baseline conditions (37 degrees C), and after stepwise cooling on cardiopulmonary bypass to 35, 33 and 31 degrees C. Hypothermia increased isometric twitch force significantly by 91 +/- 16 % in human and by 50 +/- 9 % in pig myocardium (31 vs. 37 degrees C; p < 0.05, respectively). RCCs or aequorin light emission did not change significantly. In anesthetized pigs, mild hypothermia resulted in an increase in hemodynamic parameters of myocardial contractility. While heart rate decreased from 111 +/- 3 to 73 +/- 1 min(-1), cardiac output increased from 2.4 +/- 0.1 to 3.1 +/- 0.31/min, and stroke volume increased from 21 +/- 1 to 41 +/- 3 ml. +dP/dtmax increased by 25 +/- 8% (37 vs. 31 degrees C; p < 0.05 for all values). Systemic and pulmonary vascular resistance did not change significantly during cooling. Mild hypothermia exerts significant positive inotropic effects in human and porcine myocardium without increasing intracellular Ca2+-transients or SR Ca2+-content. These effects translate into improved hemodynamic parameters of left ventricular function.

Physiologically, human atrial and ventricular myocardium are coupled by an identical beating rate and rhythm. However, contractile behavior in atrial myocardium may be different from that in ventricular myocardium, and little is known about intracellular Ca(2+) handling in human atrium under physiological conditions. We used rapid cooling contractures (RCCs) to assess sarcoplasmic reticulum (SR) Ca(2+) content and the photoprotein aequorin to assess intracellular Ca(2+) transients in atrial and ventricular muscle strips isolated from nonfailing human hearts. In atrial myocardium (n = 19), isometric twitch force frequency dependently (0. 25-3 Hz) increased by 78 +/- 25% (at 3 Hz; P < 0.05). In parallel, aequorin light signals increased by 111 +/- 57% (P < 0.05) and RCC amplitudes by 49 +/- 13% (P < 0.05). Similar results were obtained in ventricular myocardium (n = 13). SR Ca(2+) uptake (relative to Na(+)/Ca(2+) exchange) frequency dependently increased in atrial and ventricular myocardium (P < 0.05). With increasing rest intervals (1-240 s), atrial myocardium (n = 7) exhibited a parallel decrease in postrest twitch force (at 240 s by 68 +/- 5%, P < 0.05) and RCCs (by 49 +/- 10%, P < 0.05). In contrast, postrest twitch force and RCCs significantly increased in ventricular myocardium (n = 6). We conclude that in human atrial and ventricular myocardium the positive force-frequency relation results from increased SR Ca(2+) turnover. In contrast, rest intervals in atrial myocardium are associated with depressed contractility and intracellular Ca(2+) handling, which may be due to rest-dependent SR Ca(2+) loss (Ca(2+) leak) and subsequent Ca(2+) extrusion via Na(+)/Ca(2+) exchange. Therefore, the influence of rate and rhythm on mechanical performance is not uniform in atrial and ventricular myocardium.

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