The conventional isoproterenol-induced heart failure model does not consistently mimic the diaphragmatic dysfunction observed in patients.

Ignacio Cabrera-Aguilera,Joaquim Gea,Alicia Calvo-Fernández,Esther Barreiro,Isaac Almendros,Ramon Farré,Bryan Falcones,Begoña Benito,Núria Farré

doi:10.1371/journal.pone.0236923

Abstract

Heart failure (HF) impairs diaphragm function. Animal models realistically mimicking HF should feature both the cardiac alterations and the diaphragmatic dysfunction characterizing this disease. The isoproterenol-induced HF model is widely used, but whether it presents diaphragmatic dysfunction is unknown. However, indirect data from research in other fields suggest that isoproterenol could increase diaphragm function. The aim of this study was to test the hypothesis that the widespread rodent model of isoproterenol-induced HF results in increased diaphragmatic contractility. Forty C57BL/6J male mice were randomized into 2 groups: HF and healthy controls. After 30 days of isoproterenol infusion to establish HF, in vivo diaphragmatic excursion and ex vivo isolated diaphragm contractibility were measured. As compared with healthy controls, mice with isoproterenol-induced HF showed the expected changes in structural and functional echocardiographic parameters and lung edema. isoproterenol-induced HF increased in vivo diaphragm excursion (by ≈30%, p<0.01) and increased by ≈50% both ex vivo peak specific force (p<0.05) and tetanic force (p<0.05) at almost all 10–100 Hz frequencies (p<0.05), with reduced fatigue resistance (p<0.01) when compared with healthy controls. Expression of myosin genes encoding the main muscle fiber types revealed that Myh4 was higher in isoproterenol-induced HF than in healthy controls (p<0.05), suggesting greater distribution of type IIb fibers. These results show that the conventional isoproterenol-induced HF model increases diaphragm contraction, a finding contrary to what is observed in patients with HF. Therefore, this specific model seems limited for translational an integrative HF research, especially when cardio-respiratory interactions are investigated.

Highlights

Heart failure (HF) is a very prevalent disease and a major public health problem with considerably associated mortality and health system expenditure
At end-point mice in the HF group showed a significant increase in structural parameters (LVEDD and LVESD) and a significant decrease in functional parameters (LVEF and fraction shortening (FS)) as compared with healthy controls, confirming heart hypertrophy and decay in cardiac function (Table 1)
The results of this study reveal that the conventional HF rodent model based on continuous infusion of isoproterenol for 30 days is associated with considerable enhancement of diaphragm contractility

Summary

Introduction

Heart failure (HF) is a very prevalent disease and a major public health problem with considerably associated mortality and health system expenditure. Contrary to requiring major surgeries as when HF is induced by myocardial infarction or aortic ligation, HF is induced almost non-invasively by placing a subcutaneous pump to continuously infuse isoproterenol. It is noteworthy, that there are no data describing whether this widely used HF model results in diaphragm dysfunction. In isolated muscle testing of rats with septic peritonitis, isoproterenol added to organ bath increased diaphragmatic contractility [13], as reported when imposing cardiac pressure overload by transverse aorta constriction in a rodent model [14]

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