Left ventricular mechanics and myocardial calcium dynamics in short-term and long-term hyperthyroid mice
The thyroid hormone is involved in cardiac adaptation to physiological and pathological stimuli. Although short-term hyperthyroidism enhances cardiac performance, longstanding hyperthyroidism can cause impairment of the contractility by pathological Ca2+ handling. Because the thyroid hormone affects cardiovascular hemodynamics by decreasing systemic arterial resistance and increasing circulating blood volume, it is important to accurately analyze left ventricular (LV) mechanics by using an index that is independent of ventricular loading conditions. Therefore, we adopted the end-systolic elastance (Ees), which is obtained by the linear regression of the end-systolic pressure-volume relationships. This reflects sensitive changes in the contractile state in a manner independent of both preload and afterload, providing an index of LV contractility. To better understand the hypertrophy caused by hyperthyroidism, we normalized the Ees according to LV weight for different sized heart. Hyperthyroidism was induced by a daily intraperitoneal injection of triiodothyronine (T3) at a dose of 2,000 mg/kg body weight. Mice were divided into three groups: the synchronous control group, the T3 administration for one-week group (T3-short), and the T3 administration for eight-week group (T3-long). We investigated global LV mechanics, the expression of Na+/ Ca2+ exchanger (NCX), the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), and the Ca2+ handling of isolated cardiomyocytes in each group. Ees values in the control and T3- short were similar, and those in T3-long were significantly smaller than the control (256 ± 60, 249 ± 70 and 154 ± 57 mmHg･ml-1･gLV-1, respectively). The values of arterial elastance in both T3-short and T3-long, which represent afterload, were significantly smaller than the control. NCX expression was decreased in T3-short and declined in a time-dependent manner in T3-long. On the other hand, SERCA expression was rapidly elevated in T3-short and remained high in T3-long. These changes may be beneficial for cardiomyocytes in terms of O2 consumption for excitation-contraction coupling. In isolated cardiomyocyte experiments, cell shortening of T3-long mice was significantly lower than that of the control mice, but the average peak amplitude of Ca2+ transients in T3-long was 79% and not significantly different. In conclusion, we evaluated LV contractility by using an Ees index in hyperthyroid mice. Although T3 administration shifted the Ca2+ route in excitation-contraction coupling to the O2-saving energetics, LV contractility was diminished with long-term T3 administration, showed constancy in peak amplitude of the Ca2+ transients, and a decrease in NCX activity. doi：10.11482/KMJ-E41（2）41 (Accepted on October 6, 2015)
