Cardiovascular Pathophysiology and Genomics Research Unit, Faculty of Health Sciences, School of Physiology, University of the Witwatersrand Medical School, 7 York Road, Parktown, Johannesburg, 2193, South Africa.
Basic Res Cardiol. 2012 Jan;107(1):238. doi: 10.1007/s00395-011-0238-0. Epub 2011 Dec 22.
As adrenergic-induced cardiac dilatation is associated with cardiomyocyte cell death, whether cessation of excessive adrenergic effects can achieve complete reverse chamber remodelling in established cardiac dilatation and pump dysfunction has been questioned. We assessed whether following the development of cardiac dilatation and pump dysfunction subsequent to 6 months of daily β-adrenergic receptor agonist administration (isoproterenol [ISO] at 0.01 mg/kg daily) to rats, withdrawal of ISO administration for a further 4 months (ISO + recovery) reverses the adverse effects on the heart. Chronic ISO administration and the withdrawal of ISO administration were associated with changes in cardiomyocyte apoptosis, but not myocardial necrosis (pathological score). After 6 months of ISO administration, left ventricular (LV) end diastolic and systolic diameters, and the volume intercept of the LV diastolic pressure-volume relationship (LV V (0)), were markedly increased and LV endocardial fractional shortening (FS(end)), LV end systolic chamber (slope of the systolic pressure-volume relationship-Ees) and myocardial (slope of the systolic stress-strain relationship-En) contractility were substantially decreased. Chronic ISO administration produced a 2.5 times increase in LV V (0) (ISO = 0.40 ± 0.04 vs. saline = 0.16 ± 0.01, P < 0.001). Following a 6-month period of ISO administration and a subsequent withdrawal period for a further 4 months, LV chamber diameters, LV V (0) (ISO + recovery = 0.21 ± 0.02 vs. saline = 0.23 ± 0.02, P < 0.001), FS(end), LV Ees and LV En were all noted to be similar to control rats. The proportion of ISO + recovery rats with LV chamber diameters, LV V (0), FS(end), LV Ees and LV En values above or below the 95% confidence interval for the saline + recovery rats was similar to the proportion of saline + recovery rats above or below their own 95% confidence intervals. In conclusion, even in the presence of adrenergic-induced cardiomyocyte apoptosis, marked cardiac dilatation and pump dysfunction produced by chronic β-adrenergic receptor activation can be completely reversed by withdrawal of the excessive adrenergic stimulus.
由于肾上腺素能诱导的心脏扩张与心肌细胞死亡有关，因此，在已建立的心脏扩张和泵功能障碍中，停止过度的肾上腺素能作用是否能完全逆转心室重构一直受到质疑。我们评估了在大鼠接受 6 个月的每日β-肾上腺素能受体激动剂（异丙肾上腺素[ISO]，每日 0.01mg/kg）治疗后出现心脏扩张和泵功能障碍，随后再停止 ISO 治疗 4 个月（ISO+恢复期）是否可以逆转心脏的不良影响。慢性 ISO 治疗和 ISO 停药与心肌细胞凋亡的变化有关，但与心肌坏死（病理评分）无关。在 ISO 治疗 6 个月后，左心室（LV）舒张末期和收缩末期直径以及 LV 舒张压力-容积关系的容积截距（LV V（0））明显增加，而 LV 心内膜节段缩短分数（LV FS(end)）、LV 收缩末期室腔（收缩压力-容积关系斜率-Ees）和心肌（收缩应力度-应变关系斜率-En）收缩性明显降低。慢性 ISO 治疗使 LV V（0）增加了 2.5 倍（ISO=0.40±0.04 比盐水=0.16±0.01，P<0.001）。在 ISO 治疗 6 个月后，再停药 4 个月，LV 腔室直径、LV V（0）（ISO+恢复期=0.21±0.02 比盐水=0.23±0.02，P<0.001）、LV FS(end)、LV Ees 和 LV En 均与对照组大鼠相似。LV 腔室直径、LV V（0）、LV FS(end)、LV Ees 和 LV En 值大于或小于盐水+恢复期大鼠 95%置信区间的 ISO+恢复期大鼠的比例与大于或小于自身 95%置信区间的盐水+恢复期大鼠的比例相似。总之，即使存在肾上腺素能诱导的心肌细胞凋亡，慢性β-肾上腺素能受体激活引起的明显心脏扩张和泵功能障碍也可以通过停止过度的肾上腺素能刺激而完全逆转。
