Is Stimulation of Cardiomyocyte Renewal a Facette of Reversible Catecholamine Toxicity?
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- adrenergic agonists
- green fluorescent protein
The cardiotoxicity of high doses of catecholamines has been described more than half a century ago as an infarct-like injury.1 Sustained application of isoprenaline in rats reproducibly and dose-dependently induces cardiomegaly, myocardial necrosis, cardiomyocyte hypertrophy, fibrosis, and cardiac dysfunction,2 associated with the full molecular signature of chronic heart failure.3 The simplicity and robustness of the model and the fact that catecholamine toxicity is a likely pathogenic factor in systolic heart failure and the treatment of acute decompensated heart failure in patients made isoprenaline infusion one of the most frequently used experimental models in cardiovascular research. Isoprenaline cardiotoxicity is associated with lowering of mean arterial blood pressure and, as noted early,2 seems to be largely reversible. Because necrotic, that is, dying cardiomyocytes are unlikely to recover, the interesting possibility exists that the loss of myocytes in catecholamine cardiotoxicity is compensated for by an injury-induced stimulation of cardiomyocyte renewal.
Article, see p 865
In fact, recent publications provided evidence in favor of this hypothesis. An article on cats showed that a 10-day infusion of high doses of isoprenaline (1.1 mg/kg×h) induced myocyte death (increase in troponin plasma levels), hypertrophy, fibrosis, and cardiac dysfunction. Although the increase in cardiac collagen content was irreversible, cardiac dysfunction and hypertrophy showed partial recovery in 4 weeks after the end of injury phase.4 Recovery at this time point was associated with a robust increase in the number of left atrial myocytes that had incorporated 5-bromodeoxyuridine (BrdU) given during the isoprenaline infusion (≈2% versus 0.018 in control). Because the increase in BrdU incorporation during the 10-day isoprenaline infusion was restricted to nonmyocytes (18.6% versus 2.5% in control), the data suggested the new myocytes observed after 28 days to be derived from stimulated nonmyocytes, potentially c-kit+ cardiac progenitor cells. The data would be …