Nelson O Lynne, Robbins Charles T, Wu Yiming, Granzier Henk
College of Veterinary Medicine, Washington State Univ., Pullman, WA 99164, USA.
Am J Physiol Heart Circ Physiol. 2008 Jul;295(1):H366-71. doi: 10.1152/ajpheart.00234.2008. Epub 2008 May 23.
The hibernation phenomenon captures biological as well as clinical interests to understand how organs adapt. Here we studied how hibernating grizzly bears (Ursus arctos horribilis) tolerate extremely low heart rates without developing cardiac chamber dilation. We evaluated cardiac filling function in unanesthetized grizzly bears by echocardiography during the active and hibernating period. Because both collagen and titin are involved in altering diastolic function, we investigated both in the myocardium of active and hibernating grizzly bears. Heart rates were reduced from 84 beats/min in active bears to 19 beats/min in hibernating bears. Diastolic volume, stroke volume, and left ventricular ejection fraction were not different. However, left ventricular muscle mass was significantly lower (300 +/- 12 compared with 402 +/- 14 g; P = 0.003) in the hibernating bears, and as a result the diastolic volume-to-left ventricular muscle mass ratio was significantly greater. Early ventricular filling deceleration times (106.4 +/- 14 compared with 143.2 +/- 20 ms; P = 0.002) were shorter during hibernation, suggesting increased ventricular stiffness. Restrictive pulmonary venous flow patterns supported this conclusion. Collagen type I and III comparisons did not reveal differences between the two groups of bears. In contrast, the expression of titin was altered by a significant upregulation of the stiffer N2B isoform at the expense of the more compliant N2BA isoform. The mean ratio of N2BA to N2B titin was 0.73 +/- 0.07 in the active bears and decreased to 0.42 +/- 0.03 (P = 0.006) in the hibernating bears. The upregulation of stiff N2B cardiac titin is a likely explanation for the increased ventricular stiffness that was revealed by echocardiography, and we propose that it plays a role in preventing chamber dilation in hibernating grizzly bears. Thus our work identified changes in the alternative splicing of cardiac titin as a major adaptive response in hibernating grizzly bears.
冬眠现象引发了生物学以及临床领域的兴趣，以了解器官是如何适应的。在此，我们研究了冬眠的灰熊（棕熊）如何耐受极低的心率而不发生心腔扩张。我们通过超声心动图评估了未麻醉的灰熊在活跃期和冬眠期的心脏充盈功能。由于胶原蛋白和肌联蛋白都参与改变舒张功能，我们对活跃期和冬眠期灰熊的心肌进行了研究。心率从活跃期灰熊的84次/分钟降至冬眠期灰熊的19次/分钟。舒张末期容积、每搏量和左心室射血分数没有差异。然而，冬眠期灰熊的左心室肌肉质量显著更低（分别为300±12克和402±14克；P = 0.003），因此舒张末期容积与左心室肌肉质量之比显著更高。冬眠期间早期心室充盈减速时间更短（分别为106.4±14毫秒和143.2±20毫秒；P = 0.002），提示心室僵硬度增加。限制性肺静脉血流模式支持了这一结论。I型和III型胶原蛋白的比较未显示两组灰熊之间存在差异。相反，肌联蛋白的表达发生了改变，更僵硬的N2B亚型显著上调，而更柔韧的N2BA亚型减少。活跃期灰熊中N2BA与N2B肌联蛋白的平均比值为0.73±0.07，在冬眠期灰熊中降至0.42±0.03（P = 0.006）。僵硬的N2B心脏肌联蛋白上调可能是超声心动图显示的心室僵硬度增加的原因，我们认为它在防止冬眠灰熊的心腔扩张中起作用。因此，我们的研究确定心脏肌联蛋白可变剪接的变化是冬眠灰熊的主要适应性反应。
