Sacubitril/Valsartan attenuates progression of diabetic cardiomyopathy through immunomodulation properties: an opportunity to prevent progressive disease
Authors' conclusion
Immune cells are significantly involved in DbCM progression, impacting myocardial homeostasis and HF progression. Neprilysin inhibition by Sacubitril/Valsartan improved adverse cardiac remodelling in experimental DbCM through direct regulation of inflammation, highlighting immunomodulation as a novel mechanism underlying established its cardioprotective actions.
Study context
- Population
- Diabetic patients with pre-clinical HF with preserved ejection fraction (HFpEF) from the PARABLE trial, and diabetic cardiomyopathy (DbCM) (high-fat diet and streptozotocin) micePARABLE trial patients
- Participants
- 35 vs 25
- Comparison
- Sacubitril/Valsartan vs Valsartan
- Sac/Valn = 35
- Valn = 25reference
- Outcome
- Plasma neprilysin activity
- Follow-up
- 3 months after treatment
Methodological detailsexperimental DbCM mouse model (high-fat diet and streptozotocin), clinical samples from the PARABLE trial, snRNA-sequencing, in vitro macrophage study
- Experimental DbCM mouse model (high-fat diet and streptozotocin)
- Clinical samples from the PARABLE trial
- snRNA-sequencing
- In vitro macrophage study
Main finding
As reported in the abstract
- Sacubitril/Valsartan effectively reduced plasma neprilysin activity in diabetic patients with pre-clinical HFpEF (PARABLE trial) and in DbCM mice
- Baseline plasma neprilysin activity correlated with worsening cardiac performance (left atrial stiffness index) at 18 months in patients
- Diastolic dysfunction and pathological remodelling in DbCM mice improved by Sacubitril/Valsartan, but not Valsartan
- Increased pro-inflammatory monocyte (Ccr2+ Ly6chi) infiltration and reduced MHC-II macrophages in progressive experimental DbCM were prevented by Sacubitril/Valsartan
- IRF7 implicated as central mediator of Sacubitril/Valsartan-induced immunomodulation; LBQ657 and Valsartan suppressed glucose-induced IRF7 expression and paracrine activation of cardiac fibroblast differentiation in vitro
Original publication
Sacubitril/Valsartan attenuates progression of diabetic cardiomyopathy through immunomodulation properties: an opportunity to prevent progressive disease. Cardiovasc Diabetol. Published 14 May 2025. doi:10.
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