In cardiovascular research, several mouse strains with differing genetic backgrounds are used to investigate mechanisms leading to and sustaining ventricular arrhythmias. The genetic background has been shown to affect the studied phenotype in other research fields. Surprisingly little is known about potential strain-specific susceptibilities towards ventricular arrhythmias in vivo. Here, we hypothesized that inter-strain differences reported in the responsiveness of the β-adrenergic pathway, which is relevant for the development of arrhythmias, translate into a strain-specific vulnerability. To test this hypothesis, we characterized responses to β-adrenergic blockade (metoprolol) and β-adrenergic stimulation (isoproterenol) in 4 mouse strains commonly employed in cardiovascular research (Balb/c, BS, C57Bl/6 and FVB) using telemetric ECG recordings. We report pronounced differences in the electrical vulnerability following isoproterenol: Balb/c mice developed the highest number and the most complex arrhythmias while BS mice were protected. Balb/c mice, therefore, seem to be the background of choice for experiments requiring the occurrence of arrhythmias while BS mice may give insight into electrical stability. Arrhythmias did not correlate with the basal β-adrenergic tone, with the response to β-adrenergic stimulation or with the absolute heart rates during β-adrenergic stimulation. Thus, genetic factors dominate the susceptibility to ventricular arrhythmias in this model of β-adrenergic stimulation.
ObjectivesPrevious small animal models for simulation of mechanical unloading are solely performed in healthy or infarcted hearts, not representing the pathophysiology of hypertrophic and dilated hearts emerging in heart failure patients. In this article, we present a new and economic small animal model to investigate mechanical unloading in hypertrophic and failing hearts: the combination of transverse aortic constriction (TAC) and heterotopic heart transplantation (hHTx) in rats.MethodsTo induce cardiac hypertrophy and failure in rat hearts, three-week old rats underwent TAC procedure. Three and six weeks after TAC, hHTx with hypertrophic and failing hearts in Lewis rats was performed to induce mechanical unloading. After 14 days of mechanical unloading animals were euthanatized and grafts were explanted for further investigations.Results50 TAC procedures were performed with a survival of 92% (46/50). When compared to healthy rats left ventricular surface decreased to 5.8±1.0 mm² (vs. 9.6± 2.4 mm²) (p = 0.001) after three weeks with a fractional shortening (FS) of 23.7± 4.3% vs. 28.2± 1.5% (p = 0.01). Six weeks later, systolic function decreased to 17.1± 3.2% vs. 28.2± 1.5% (p = 0.0001) and left ventricular inner surface increased to 19.9±1.1 mm² (p = 0.0001). Intraoperative graft survival during hHTx was 80% with 46 performed procedures (37/46). All transplanted organs survived two weeks of mechanical unloading.DiscussionCombination of TAC and hHTx in rats offers an economic and reproducible small animal model enabling serial examination of mechanical unloading in a truly hypertrophic and failing heart, representing the typical pressure overloaded and dilated LV, occurring in patients with moderate to severe heart failure.
Background Unloading of failing hearts by left ventricular assist devices induces an extensive cardiac remodeling which may lead to a reversal of the initial phenotype–or to its deterioration. The mechanisms underlying these processes are unclear. Hypothesis Heterotopic heart transplantion (hHTX) is an accepted model for the study of mechanical unloading in rodents. The wide variety of genetically modified strains in mice provides an unique opportunity to examine remodeling pathways. However, the procedure is technically demanding and has not been extensively used in this area. To support investigators adopting this method, we present our experience establishing the abdominal hHTX in mice and describe refinements to the technique. Methods In this model, the transplanted heart is vascularised but implanted in series, and therefore does not contribute to systemic circulation and results in a complete mechanical unloading of the donor heart. Training followed a systematic program using a combination of literature, video tutorials, cadaveric training, direct observation and training in live animals. Results Successful transplantation was defined as a recipient surviving > 24 hours with a palpable, beating apex in the transplanted heart and was achieved after 20 transplants in live animals. A success rate of 90% was reached after 60 transplants. Operative time was shown to decrease in correlation with increasing number of procedures from 200 minutes to 45 minutes after 60 operations. Cold/warm ischemia time improved from 45/100 to 10/20 minutes. Key factors for success and trouble shootings were identified. Conclusion Abdominal hHTX in the mouse may enable future examination of specific pathways in unloading induced myocardial remodeling. Establishment of the technique, however, is challenging. Structured training programs utilising a variety of training methods can help to expedite the process. Postoperative management, including daily scoring increases animal wellbeing and helps to predict survival.
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