Beyond Adiposity

Q: What is the clinical evidence from this study?

Population: Heart failure with preserved ejection fraction (HFpEF). Intervention: Dapagliflozin vs. Hypomagnesemia diet alone. Primary outcome: Ratio between mitral peak early filling velocity E and longitudinal tissue velocity of the mitral anterior annulus e' (E/e') (p=0.019).

Harlan M. Krumholz; Silvio E. Inzucchi

doi:10.1016/j.jacc.2025.08.005

September 17, 2025Journal of the American College of Cardiology

Beyond Adiposity

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Why the study?

Does dapagliflozin prevent hypomagnesemia-induced cardiac diastolic dysfunction and inflammation in a preclinical HFpEF model?

Key Points

To determine whether dapagliflozin prevents hypomagnesemia-induced cardiac diastolic dysfunction and to identify the underlying molecular mechanisms.
Assessed cardiac function, oxidative stress, and inflammation in a low-magnesium mouse model treated with oral dapagliflozin for 3 weeks (N=7 to 25 per group).
Characterized macrophage phenotypes via flow cytometry and measured cardiac protein expression via Western blot.
Examined cellular magnesium handling, TRPM7 expression, and mitochondrial reactive oxygen species in cultured human RL-14 cardiomyocytes exposed to 5 μmol/L dapagliflozin.
Dapagliflozin prevented diastolic dysfunction, significantly reducing E/e' from 20.6 ± 4.2 in hypomagnesemic mice to 16.5 ± 2.4 (P = 0.019; control: 15.8 ± 2.0).
Dapagliflozin normalized serum magnesium levels (P < 0.001 vs hypomagnesemia) and reduced urine magnesium loss to 0.1 ± 0.0 mmol/L compared to 0.2 ± 0.1 mmol/L in untreated hypomagnesemic mice (P = 0.006).
Dapagliflozin restored TRPM7 expression (1.0 ± 0.2-fold of control, P = 0.015) and increased proresolving cardiac macrophages from 25.3% ± 7.3% to 49.8% ± 7.1% (P < 0.001).

Structured PICO

Does dapagliflozin prevent hypomagnesemia-induced cardiac diastolic dysfunction and inflammation in a preclinical HFpEF model?

P

Population

C57BL/6J mice with hypomagnesemia-induced cardiac diastolic dysfunction and human fetal RL-14 cardiomyocytes were studied to determine the mechanisms of dapagliflozin in HFpEF.

I

Intervention

Dapagliflozin 1.5 mg/kg daily via oral gavage for 3 weeks (in vivo); Dapagliflozin 5 μmol/L for 48 hours (in vitro).

C

Comparator

Untreated hypomagnesemia mice on low-Mg diet (15-30 mg/kg Mg2+) and control mice on normal chow (2 g/kg Mg2+).

O

Outcome

Cardiac diastolic function evaluated by E/e' ratio from echocardiography and ratio of S-glutathionylated cMyBPC to total cMyBPC.surrogate

Main Result

Absolute Event Rate: 16.5% vs 20.6%

p-value: p=0.019

Limitations

Only male HypoMg mice were studied because of excess mortality in the females exposed to HypoMg.
The HypoMg-induced DD model has a lower serum Mg2+ level than is common in humans with DM, so the dapagliflozin effects may be more pronounced.
The data cannot exclude a role of pH changes in the lusitropic effect of dapagliflozin.
Did not measure NHE1 activity directly as sodium-dependent pH changes after acid challenge

Implication

Dapagliflozin prevents hypomagnesemia-induced cardiac diastolic dysfunction, inflammation, and oxidative stress through modulation of NHE1 activity, independent of SGLT2.

Abstract

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Discussion

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Cite This Study

Krumholz et al. (2025) studied Heart failure with preserved ejection fraction (HFpEF). Dapagliflozin vs. Hypomagnesemia diet alone was evaluated on Ratio between mitral peak early filling velocity E and longitudinal tissue velocity of the mitral anterior annulus e' (E/e') (p=0.019).

synapsesocial.com/papers/6ad2b5134c9c4fbb13a7edc6 https://doi.org/10.1016/j.jacc.2025.08.005

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Beyond Adiposity

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Beyond Adiposity

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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