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November 9, 2021Journal of Clinical InvestigationOpen Access

Gasdermin D inhibition confers antineutrophil-mediated cardioprotection in acute myocardial infarction

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Key result

Genetic deletion or pharmacological inhibition of Gasdermin D attenuated myocardial injury, reduced infarct size, and significantly improved post-AMI survival (78.7% vs 50%) in mice.

Why the study?

Acute myocardial infarction induces blood leukocytosis correlating inversely with survival, but the molecular mechanisms driving leukocytosis in the infarcted heart remain poorly understood.

Does GSDMD inhibition reduce infarct size and improve cardiac function and survival in acute myocardial infarction?

Population

Mouse model of acute myocardial infarction

Comparison

GSDMD knockout or pharmacological inhibition vs controls

Design

Preclinical animal and mechanistic study

Discussion

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Overview

GSDMD targeting shows preclinical promise in AMI; leaves open whether inhibition improves human survival or ejection fraction.

Structured PICO

Does GSDMD inhibition reduce infarct size and improve cardiac function and survival in acute myocardial infarction?

P
Population
234 adult patients with first-time ST-segment elevation myocardial infarction and a single LAD branch blockage from a multicenter registry in east China, analyzed alongside murine AMI models.
I
Intervention
Genetic deletion of GSDMD (Gsdmd-/-), bone marrow-specific GSDMD knockout, pharmacological inhibition of GSDMD (NSA treatment), and neutrophil depletion (anti-Ly6G).
C
Comparator
Wild-type (WT) littermate controls and sham surgery.
O
Outcome
Infarct size, cardiac function (ejection fraction and fractional shortening), and post-AMI survival.surrogate

Main Result

Absolute Event Rate: 78.7% vs 50%

p-value: p=0.0108

Inhibition of GSDMD reduces early neutrophil mobilization and infarct size, presenting a potential novel therapeutic target for preventing post-AMI heart failure.

Limitations

  • The permanent coronary artery ligation infarct model differs substantially from the process of atherothrombosis in humans.
  • Further clinical proof-of-concept studies targeting GSDMD and neutrophil generation for management of AMI heart failure are needed.

Cite This Study

A 2021 study studied Acute myocardial infarction (n=234). Gasdermin D (GSDMD) inhibition (genetic deletion or necrosulfonamide) vs. Wild-type or vehicle control was evaluated on Post-AMI survival (murine model) (p=0.0108). Genetic deletion or pharmacological inhibition of Gasdermin D attenuated myocardial injury, reduced infarct size, and significantly improved post-AMI survival (78.7% vs 50%) in mice.

synapsesocial.com/papers/6a98804e87f32fbd37357eedhttps://doi.org/10.1172/jci151268
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