Acute Catecholamine Exposure Causes Reversible Myocyte Injury Without Cardiac Regeneration

Abstract

Rationale Catecholamines increase cardiac contractility, but exposure to high concentrations or prolonged exposures can cause cardiac injury. A recent study demonstrated that a single subcutaneous injection of isoproterenol (ISO; 200 mg/kg) in mice causes acute myocyte death (8-10%) with complete cardiac repair within a month. Cardiac regeneration was via endogenous cKit+ cardiac stem cell (CSC)-mediated new myocyte formation. Objective Our goal was to validate this simple injury/regeneration system and use it to study the biology of newly forming adult cardiac myocytes. Methods and Results C57BL/6 mice (n=173) were treated with single injections of vehicle, 200mg/kg or 300mg/kg ISO, or with two daily doses of 200mg/kg ISO for 6 days. Echocardiography revealed transiently increased systolic function and unaltered diastolic function 1 day after single ISO injection. Single ISO injections also caused membrane injury in about 10% of myocytes but few of these myocytes appeared to be necrotic. Circulating troponin I levels after ISO were elevated, further documenting myocyte damage. However, myocyte apoptosis was not increased after ISO injury. Heart weight to body weight ratio and fibrosis were also not altered 28 days after ISO injection. Single or multiple dose ISO injury was not associated with an increase in the percentage of 5-ethynyl-2’-deoxyuridine (EdU)-labeled myocytes. Furthermore, ISO injections did not increase new myocytes in cKit+/Cre × R-GFP transgenic mice. Conclusions A single dose of ISO causes injury in about 10% of the cardiomyocytes. However, most of these myocytes appear to recover and do not elicit cKit+ cardiac stem cell (CSC)-derived myocyte regeneration.

Is Stimulation of Cardiomyocyte Renewal a Facette of Reversible Catecholamine Toxicity?

“…16 Genetic fate mapping experiments in mice, currently considered the most stringent method to study this question in animals, indicated that c-kit + progenitor cells indeed form cardiomyocytes in normal heart development, but at a low rate (<0.008% in adult mice 17 ). This rate was confirmed in the Wallner et al study 8 and not affected by isoprenaline injections. In contrast, the study by Ellison et al, 7 using a different lentivirus-based genetic labeling approach, reported baseline values of c-kit-derived cardiomyocytes of 0.06% raising to 4% 28 days after the isoprenaline injection.…”

“…9 However, as outlined above, the C57Bl/6J mice used in the study by Wallner et al 8 did show signs of toxicity, and it seems unlikely that a different degree of β-adrenergic desensitization can account for major differences in acute (single dose) effects. Yet, different mouse strains may well differ in their acute response to isoprenaline and the reversibility of toxicity, leaving open the possibility that a single high dose of isoprenaline induces a Takotsubo-like cardiomyopathy 24 hours after injection in some, but not the C57Bl/6J strain.…”

“…Ablation of c-kit + cells ablated the regenerative response and replenishment with the progeny of 1 c-kit + cell restored it. 7 In a study published in this issue of Circulation Research, Wallner et al 8 set out to validate the data and study at more detail the mechanisms of cardiomyocyte renewal in this simple model. Unexpectedly, none of the key findings could be confirmed (Table).…”

“…Moreover, even sustained application of isoprenaline (6×2 doses of 200 mg/kg), which was associated with hypertrophy and fibrosis, did not induce cardiomyocyte regeneration. 8 If it is not the type of injury stimulus, it could be the wrong subject, that is, an isoprenaline-subsensitive mouse strain. In fact, differences between mouse strains in terms of isoprenaline sensitivity have been described and…”

PEG-coated gold nanoparticles attenuate &beta;-adrenergic receptor-mediated cardiac hypertrophy

“…18 The acute cardiac hypertrophy model reflects cardiac remodeling following acute cardiac injuries. 19 The safety of AuNPs in ISO-induced chronic cardiac hypertrophy model has been demonstrated in our previous study. 20 Thus, in the present study, the safety of AuNPs in ISO-induced acute cardiac hypertrophy model was investigated.…”