Combined empagliflozin and sacubitril/valsartan therapy achieved greater improvement in contractile performance and broader cardioprotective effects than either monotherapy in a rat model of HF.
Does combined empagliflozin and sacubitril/valsartan therapy improve ex vivo cardiac function and molecular markers in a rat model of heart failure?
Dual therapy with empagliflozin and sacubitril/valsartan provides greater cardioprotective effects than either monotherapy in a rat model of heart failure.
Background/Objectives: This study aimed to clarify the cardioprotective effects of combined empagliflozin and sacubitril/valsartan therapy in an experimental rat model of heart failure (HF). The main research question was whether dual treatment provides greater functional and molecular benefit than either monotherapy, with particular emphasis on oxidative stress, inflammation, apoptosis, and JAK2/STAT3 signaling. Methods: HF was induced in rats by 7-day isoproterenol administration and confirmed four weeks later by echocardiographic evidence of reduced ejection fraction (<55%). The animals were then assigned to healthy control, untreated HF, empagliflozin, sacubitril/valsartan, and combined empagliflozin/sacubitril/valsartan groups. Following four weeks of treatment, ex vivo cardiac function was evaluated using the Langendorff technique. Serum cardiospecific markers and natriuretic peptides were measured by ELISA. Oxidative stress parameters were determined in coronary venous effluent, while myocardial gene expression of selected (anti)oxidative, (anti)inflammatory, (anti)apoptotic, and signaling markers was assessed by RT-PCR. Myocardial collagen content was evaluated using Picrosirius red staining. Results: HF rats exhibited impaired ex vivo myocardial function, elevated cardiac injury markers, increased oxidative stress, upregulation of pro-inflammatory and pro-apoptotic genes, activation of JAK2/STAT3 signaling, and increased myocardial collagen content. Both monotherapies produced partial benefit. In contrast, combined treatment achieved the most pronounced improvement in contractile performance, attenuated oxidative stress more consistently, reduced expression of TNF-α, IL-1β, IL-6, IL-17, Bax, CASP-3, and CASP-9, favorably modulated JAK2, STAT3, mTOR, and PPARγ expression, and decreased myocardial collagen content. Conclusions: Dual empagliflozin and sacubitril/valsartan therapy exerted broader cardioprotective effects than either monotherapy, likely through coordinated antioxidant, anti-inflammatory, anti-apoptotic, and signaling-related mechanisms.
Murić et al. (2026) studied Heart failure (experimental rat model). Combined empagliflozin and sacubitril/valsartan vs. Healthy control, untreated HF, empagliflozin monotherapy, sacubitril/valsartan monotherapy was evaluated on Ex vivo cardiac function, oxidative stress, inflammation, apoptosis, and JAK2/STAT3 signaling. Combined empagliflozin and sacubitril/valsartan therapy achieved greater improvement in contractile performance and broader cardioprotective effects than either monotherapy in a rat model of HF.