Department of Biomedical Sciences, The Panum Institute, Blegdamsvej, Copenhagen N, Denmark.
Exp Physiol. 2011 Jul;96(7):647-63. doi: 10.1113/expphysiol.2011.058503. Epub 2011 May 13.
Widely used murine models of adrenergic-induced cardiomyopathy offer little insight into electrical derangements seen in human heart failure owing to profound differences in the characteristics of ventricular repolarization in mice and rats compared with humans. We therefore sought to determine whether sustained adrenergic activation may produce a clinically relevant heart failure phenotype in the guinea-pig, an animal species whose ventricular action potential shape and restitution properties resemble those determined in humans. Isoprenaline (ISO), a β-adrenoceptor agonist, was infused at variable dosage and duration using either subcutaneously implanted osmotic minipumps or daily injections, in an attempt to establish the relevant treatment protocol. We found that 3 months of daily ISO injections (final dose of 1 mg kg(-1), i.p.) promote heart failure evidenced by cardiac hypertrophy [increased cardiac weights, left ventricular (LV) posterior wall thickness, myocyte cross-sectional area and LV protein content], cardiac dilatation (increased LV internal diameters), basal systolic dysfunction (reduced LV fractional shortening determined by echocardiography and flattened LV systolic pressure-volume and stress-strain relationships assessed in isolated, perfused heart preparations), reduced contractile reserve in the presence of acute β-adrenoceptor stimulation, and pulmonary oedema (increased lung weights). These changes were associated with prolongation of LV epicardial action potential, effective refractory period and QT interval, an upward shift of the electrical restitution curve determined over a wide range of diastolic intervals, and reduced maximal restitution slope. The physiological right ventricular-to-LV difference in action potential duration was eliminated in ISO-treated hearts, thereby contributing to impaired activation-to-repolarization coupling and reversed right ventricular-to-LV difference in repolarization time. In summary, we establish the guinea-pig model of ISO-induced cardiomyopathy, which enables the correlation of detrimental structural and contractile changes with repolarization abnormalities typically seen in human heart failure.
广泛使用的肾上腺素诱导心肌病的鼠模型，由于小鼠和大鼠心室复极的特征与人类有很大的不同，因此对人类心力衰竭中所见的电紊乱几乎没有深入的了解。因此，我们试图确定持续的肾上腺素激活是否可能在豚鼠中产生一种与临床相关的心衰表型，豚鼠是一种心室动作电位形态和复极特性与人类相似的动物物种。异丙肾上腺素（ISO），一种β-肾上腺素能受体激动剂，通过皮下植入的渗透微型泵或每日注射，以不同的剂量和持续时间输注，试图建立相关的治疗方案。我们发现，3 个月的每日 ISO 注射（最终剂量为 1mg/kg，ip）促进心力衰竭，表现为心脏肥大[增加心脏重量、左心室（LV）后壁厚度、心肌细胞横截面积和 LV 蛋白含量]、心脏扩张（增加 LV 内径）、基础收缩功能障碍（通过超声心动图测定的 LV 分数缩短率降低和 LV 收缩压力-容积和应激-应变关系在分离的灌注心脏标本中评估）、急性β-肾上腺素能刺激下收缩储备减少以及肺水肿（肺重量增加）。这些变化与 LV 心外膜动作电位、有效不应期和 QT 间期延长、宽范围舒张间隔下确定的电复极曲线向上移位以及最大复极斜率降低有关。在 ISO 处理的心脏中，消除了生理右心室到 LV 动作电位时程的差异，从而导致激活到复极偶联受损，并导致复极时间的右心室到 LV 差异反转。总之，我们建立了 ISO 诱导的心肌病的豚鼠模型，该模型使有害的结构和收缩变化与人类心力衰竭中常见的复极异常相关联。
