Background: In patients with chronic heart failure (HF), acute HF decompensation strongly predicts adverse outcomes. Novel therapies are needed to prevent disease progression after acute decompensation. Rodent models that reflect the development of HF and the occurrence of decompensations may allow the testing of novel therapies. However, few such rodent models that reflect acute deterioration of pre-existing HF are available.

Objective: The current work aimed to establish a novel HF rat model, which combines two established protocols to achieve both the development of cardiac dysfunction and the ability to add a second stimulus to induce cardiac decompensation.

Methods: To induce HF, 10-week-old male Sprague-Dawley (SD) rats were challenged with a chronic volume overload by medium-sized infrarenal aortocaval fistula (ACF). After three weeks, rats received subcutaneous deoxycorticosterone acetate (DOCA) pellets (100mg) and 1% NaCl in the drinking water to further impair cardiac performance. The cessation of DOCA-release after 21 days allowed for the subsequent investigation of a two-week recovery phase, after which the study was terminated. Weight-matched and sham-operated SD rats without DOCA/salt served as controls. Longitudinal examinations were performed prior to ACF surgery, before/after DOCA/salt, and after recovery, each comprising blood collection and echocardiography. Further analyses included histological and gene expression analyses of harvested tissue.

Results: ACF surgery resulted in increased left ventricular (LV) mass, LV wall thickness and LV diameter as well as elevated levels of serum brain natriuretic peptide (BNP) with preserved systolic and diastolic function. DOCA/salt stimulus induced cardiac decompensation, indicated by reduced ejection fraction and fractional shortening, increased E/e’ as well as markedly increased LV mass, LV wall thickness, LV diameter and serum BNP. After cessation of the DOCA/salt effect, several echocardiographic parameters partially recovered. Histological analysis revealed biventricular enlargement and cardiac hypertrophy in ACF+DOCA/salt rats which was accompanied by decreased mRNA expression of α-MHC, suggesting pathological hypertrophy. Moreover, ACF+DOCA/salt induced significant cardiac interstitial fibrosis as well as an increase in pro-fibrotic mRNA expression of collagen I, CTGF and fibronectin. Increased lung, liver and spleen weight also pointed to significant organ congestion in ACF+DOCA/salt rats.

Conclusion: The present study longitudinally monitors cardiac structure and function in ACF-induced HF and subsequent DOCA/salt-induced decompensation. We observed partial recovery of cardiac performance after cessation of the DOCA/salt effect. Therefore, the combination of ACF and DOCA/salt may provide a promising model to study the pathophysiology of hypertension-induced acute on chronic HF and to test the efficacy of novel treatment strategies.