Characterization of Sepsis Cardiomyopathy in a Nonhuman Primate Model of Sepsis

Sunday, February 23, 2025

9:45am – 10:45am Eastern Time

Location: Connections Central Theater 1

Tomohiro Abe, MD, PhD (he/him/his)

Oklahoma Medical Research Foundation

Disclosure(s): No relevant financial relationship(s) to disclose.
RS

Robert Silasi, PhD

Research Assistant Professor
Oklahoma Medical Research Foundation

Disclosure information not submitted.
RK

Ravi Keshari, PhD

Associate Staff Scientist
Oklahoma Medical Research Foundation

Disclosure information not submitted.
GR

Girija Regmi, PhD

Postdoctoral Associate AD
College of Veterinary Medicine, University of Georgia

Disclosure information not submitted.
CL

Cristina Lupu, PhD

Staff Scientist
Oklahoma Medical Research Foundation

Disclosure information not submitted.
NP

Narcis Popescu, PhD

Research Associate Professor
Oklahoma Medical Research Foundation

Disclosure information not submitted.
MC

Mark Coggeshall, PhD

Affiliate
Oklahoma Medical Research Foundation

Disclosure information not submitted.
SM

Satoshi Matsuzaki, PhD

Associate Staff Scientist
Oklahoma Medical Research Foundation

Disclosure information not submitted.
KH

Kenneth Humphries, PhD

Associate Professor
Oklahoma Medical Research Foundation

Disclosure information not submitted.
FL

Florea Lupu, PhD

Professor
Oklahoma Medical Research Foundation

Disclosure information not submitted.

Disclosure(s):

Tomohiro Abe, MD, PhD: No relevant financial relationship(s) to disclose.

Introduction: Sepsis-induced cardiomyopathy is increasingly recognized in the clinical setting. Elucidating its pathogenesis is challenging due to difficulty in obtaining patient tissue and variable responses in rodent models. This study investigates cardiac changes in septic shock using a non-human primate sepsis model.

Methods: Papio anubis baboons (BW 7.4–10.3kg, n=6) were infused with a 37.5 mg/kg (LD50 dose) of Bacillus anthracis peptidoglycan (PGN). The experiment's endpoint was survival at 7 days. Vital signs and echocardiographic assessments were conducted at 1, 2, 3, 4, 6, and 8 hours post-challenge. Animals were euthanized upon developing irreversible organ damage or at the endpoint. Heart tissue was collected immediately post-euthanasia for histopathological analysis, single-nucleus RNA sequencing (snRNA-Seq), and mitochondrial functional analysis. Tissues from healthy animals in a biobank served as controls (n=3).

Results: Post-challenge, baboons exhibited a hyperdynamic response with increased heart rate and decreased mean arterial pressure. Echocardiographic data showed reductions in intravascular volume, stroke volume, longitudinal contraction, and cardiac index, more pronounced in non-survivors. Histopathological analysis revealed interstitial edema, cardiomyocyte swelling, myofibrillar degeneration, and inflammatory cell infiltration. SnRNA-Seq of 13,425 nuclei characterized key cell populations, including three distinct cardiomyocyte groups (5,141 in total). Pathway analysis using Qiagen IPA indicated significant changes in genes related to mitochondrial function and energetic metabolism (electron transport, oxidative phosphorylation, ATP synthesis), cell death, inflammation, fibrosis, and cardiomyopathy signaling. Top upstream regulators were PAMPs and inflammatory cytokines, such as TNF and IL1b. Mitochondrial functional analysis indicated decreased electron transport chain activity and disrupted metabolism, particularly in non-survivors.

Conclusions: PGN-induced sepsis cardiomyopathy likely results from reduced intravascular volume and structural and functional changes in cardiomyocytes, contributing to the impaired contractility seen in sepsis-induced cardiomyopathy.