What is the clinical evidence from this study?

Study design: Other. Population: Diabetic cardiomyopathy (n=96). Intervention: Sacubitril/valsartan vs. Vehicle or Valsartan (30 mg/kg/day). Primary outcome: Left ventricular stiffness constant (p=<0.01).

October 23, 2024Scientific Reports12 citationsOpen Access

Sacubitril/valsartan improves diastolic left ventricular stiffness with increased titin phosphorylation via cGMP-PKG activation in diabetic mice

Q: What are the key findings of this study?

Sacubitril/valsartan significantly reduced diastolic left ventricular stiffness in diabetic mice compared to vehicle, associated with increased titin phosphorylation via cGMP-PKG activation.

NFNozomi Furukawa HMHiroki Matsui HSHiroaki Sunaga

Key Result

Sacubitril/valsartan significantly reduced diastolic left ventricular stiffness in diabetic mice compared to vehicle, associated with increased titin phosphorylation via cGMP-PKG activation.

Structured PICO

Does sacubitril/valsartan improve diastolic left ventricular stiffness in a diabetic mouse model?

Population

10-12-week-old male C57BL/6Ncr mice with streptozotocin (STZ)-induced type 1 diabetes and diastolic dysfunction (n=96 total across groups).

Intervention

Sacubitril/valsartan (Sac/Val) administered orally by gavage once daily for 1 month, starting 4 months after STZ injection.

Comparator

Valsartan (Val) or solvent vehicle (Veh) administered orally by gavage once daily for 1 month. Non-diabetic mice were also used as controls.

Outcome

Diastolic left ventricular stiffness (stiffness constant calculated from left ventricular EDPVR) and titin phosphorylation levels.surrogate

Sacubitril/valsartan improves diastolic left ventricular stiffness in diabetic mice by increasing titin phosphorylation via cGMP-PKG activation, providing a potential molecular mechanism for its benefits in HFpEF.

Main Result

Absolute Event Rate: 0.01% vs 0.12%

p-value: p=<0.01

Limitations

Unable to identify specific amino acids in titin phosphorylated by Sac/Val.
Did not evaluate other post-translational modifications of titin like oxidation or S-glutathionylation.
Discrepancy in cardiac output between preliminary and drug administration experiments.
Catheter data obtained via open chest examination may affect LVEDP measurements.

Abstract

Titin, a giant sarcomeric protein, regulates diastolic left ventricular (LV) passive stiffness as a molecular spring and could be a therapeutic target for diastolic dysfunction. Sacubitril/valsartan (Sac/Val), an angiotensin receptor neprilysin inhibitor, has been shown to benefit patients with heart failure with preserved ejection fraction. The effect of Sac/Val is thought to be due to the enhancement of the cGMP/PKG pathway via natriuretic peptide. In this study, the effects of Sac/Val on LV diastolic dysfunction are demonstrated in a mouse diabetic cardiomyopathy model focusing on titin phosphorylation. Sac/Val-treated diabetic mice showed a greater increase in myocardial levels of cGMP-PKG than Val-treated and control mice. Conductance catheter analysis showed a significant reduction in LV stiffness in diabetic mice, but not in non-diabetic mice. Notably, diastolic LV stiffness was significantly reduced in Sac/Val-treated diabetic hearts compared with Val-treated or vehicle-treated diabetic mice. The phosphorylation level of titin (N2B), which determines passive stiffness and modulates active contraction, was higher in Sac/Val-treated hearts compared with Val-treated hearts in diabetic mice. Given that alteration of titin phosphorylation through PKG contributes to myocardial stiffness, the beneficial effects of Sac/Val in heart failure might be partly attributed to the induction of titin phosphorylation.

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