Myocardial oxidative stress correlates with left ventricular dysfunction on strain echocardiography in a rodent model of sepsis

Abstract

Background: Recognition of cardiomyopathy in sepsis can be challenging due to the limitations of conventional measures such as ejection fraction (EF) and fractional shortening (FS) in the context of variable preload and afterload conditions. This study correlates myocardial function using strain echocardiography (SE) with cardiomyocyte oxidative stress in a murine model of sepsis.

Methods: C57BL/6J mice were randomized into control (n = 10), sham (n = 25), and a cecal ligation and puncture (CLP) (n = 33) model of sepsis. Echocardiography was performed pre-, 12, 24, and 48 h post-injury. Cardiac pro-inflammatory cytokines and mitochondrial redox scavenger expression were evaluated in a subset of each arm. To evaluate the influence of redox scavenger upregulation on oxidative injury and cardiac function, CLP was performed on mitochondrial catalase-upregulated C57BL/6J MCAT^+/+ mice (n = 12) and wild-type (WT) animals for comparison.

Results: Septic C57BL/6J mice exhibited depressed longitudinal strain (LS) when compared to sham and control at 24 h (p < 0.01) and 48 h (p = 0.04) post-CLP despite having a preserved EF. Furthermore, there was a significant association between increased odds of mortality and depressed LS (OR = 1.23, p = 0.04). Septic C57BL/6J mice concomitantly demonstrated increased expression of cardiomyocyte pro-inflammatory cytokines and decreased expression of redox scavengers at 24 and 48 h. When comparing C57Bl/6 MCAT ^+/+ mice and C57BL/6J WT mice, a significant decrease in LS was identified in the WT mice at 24 h (MCAT = -23 ± 5% vs. WT = -15 ± 4% p < 0.01) and 48 h (MCAT = -23 ± 7% vs. WT = -15 ± 4.3% p = 0.04) post-CLP which correlated with significant increase in the level of cardiac oxidative stress following CLP.

Conclusions: In this sepsis model, SE identified cardiomyopathy despite normal EF. SE depression temporally coincides with upregulation of inflammatory cytokines and decreases expression of key mitochondrial ROS scavengers. Upregulation of redox scavenger (CAT) abrogates oxidative stress and cardiac dysfunction in this sepsis model.

Keywords: Sepsis; Sepsis-induced myocardial dysfunction; Shock; Ultrasound.

Fig. 1

Strain analysis by echocardiogram post-processing software (VevoStrain, FUJIFILM VisualSonics Inc.). The parasternal long access view (a) was used to calculate the longitudinal strain (LS, %) (b) and the longitudinal strain rate (LSR, 1/sec). The parasternal short axis view (c) was used to calculate the circumferential strain (CS, %) (d) and circumferential strain rate (CSR, 1/sec)

Fig. 2

The temporal progression of heart rate, ejection fraction (EF), circumferential (CS), and longitudinal strain (LS) in C57BL/6J mice randomized to sham, control, and cecal ligation and puncture (CLP) groups. a Demonstrates an overall increase in heart rate overtime with no significant difference between the three groups. b and c Demonstrate notable depression in longitudinal strain (LS) in the CLP group at 24 and 48 h without change in the EF

Fig. 3

Quantitative real-time PCR of pro-inflammatory cytokines (TNF-α, IL-1, and Il-6) and mitochondrial free radical scavengers (SOD-2, GPX-2, Catalase) at 24 and 48 h following CLP. Significant increase in TNF-α, IL-1, and Il-6 is seen at 24 and 48 h in the CLP group when compared to sham and control (a–c). Significant decrease in mitochondrial ROS scavengers is seen at 24 and 48 h post-surgery in the CLP group when compared to sham and control (d–f)

Fig. 4

Photomicrographs of heart sections stained with dihydroethidium (DHE) in red and DAPI in blue (merged images) from septic MCAT ^+/+ (a, b, c) and WT mice (d, e, f). Significant increase in level of oxidative stress (signified by increased uptake of DHE) in the WT mice at 24 (e) and 48 h (f) following CLP. Minimal signs of oxidative stress are seen the MCAT ^+/+ mice following CLP