Development of Profound Diastolic Dysfunction Early in Septic Shock is Associated with Mortality in a Large Animal Model and in Humans

Authors

August A. Culbert BA1,2*, Verity J. Ford MD3*, Steven Solomon PhD3, Junfeng Sun PhD3, Harvey Klein MD4, Jing Feng MS BS3, Willard Applefeld MD3,5, Michael A. Solomon MD3, Robert L. Danner MD3, Marcus Chen MD6, and Charles Natanson MD3,6

1 Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH
2 Medical Research Scholars Program, National Institutes of Health, Bethesda, MD
3 Critical Care Medicine Department, National Institutes of Health, Bethesda, MD
4 Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD
5 Division of Cardiology, Duke University Medical Center, Durham, NC
6 National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD
* co-contribution

Introduction

Sepsis is a leading cause of mortality in hospitalized patients worldwide. Survivors of septic shock develop a transient marked decrease in left ventricular ejection fraction (LVEF) associated with increased end-diastolic volume (EDV), which resolves to near normal in 7-10 days. In contrast, non-survivors exhibit two distinct patterns: most show no increase in EDV with a reduced LVEF, while a minority retain a normal LVEF. The explanation for this paradox remains unknown. Here, we assess the role of systolic and diastolic function in the pathophysiology of sepsis-induced cardiomyopathy in humans and in a large animal model that simulates the cardiac changes of human septic shock.

Methods

Forty-eight purpose-bread beagles (10-12kg; 1-2 years old) received an intrapulmonary challenge of Staphylococcus aureus (1.2 x 109 CFU/kg) and then were managed with standard intensive care unit interventions including sedation and mechanical ventilation, antibiotics, fluid resuscitation, and observed with invasive hemodynamic monitoring until death or up to 96 hours (survivors). No vasopressors were administered to avoid altering cardiac function. Serial cardiac magnetic resonance (CMR) imaging, invasive hemodynamics, and laboratory measurements were obtained at baseline and at 6, 18, 30, 42, 54, and 96 hours post-bacterial challenge. In addition, a systemic literature review was conducted in PubMed to identify clinical studies of septic shock patients with echocardiographic imaging measures of LVEF, EDV, and outcomes (1).

Results

Thirty-two septic animals survived to 96 hours (“survivors”), while 18 died between 9 and 82 hours after bacterial challenge (“non-survivors”). Non-survivors demonstrated significantly lower mean EDV at each timepoint from 6 to 54 hours (p=0.005), with EDV first dropping below baseline at 6 hours (p=0.0005). Changes in LV preload or afterload did not explain the observed LV volumetric changes. Survivors developed an elevated mean EDV from baseline from 30-96 hours (all, p=0.001), suggesting a diastolic compensation mechanism during sepsis, whereas non-survivors' failed to increase their EDVs above baseline. Both survivors and non-survivors had similar reductions in systolic function (LVEF and stroke volume), except at 6 hours when non-survivors displayed a higher mean LVEF (p=0.03). Following a systematic literature review, a total of 12 clinical septic cardiac echocardiographic studies met inclusion criteria from 1983-2022. The human data are consistent, with non-survivors showing significantly smaller EDV than survivors (standard mean difference 0.36 [0.21;0.52], p<0.0001) with no significant differences in LVEF (p=0.40).

Conclusion

Our results highlight that early diastolic dysfunction, characterized by impaired cardiac relaxation (reduced EDV), is a critical marker of mortality in septic shock in both a large animal model and human subjects (2–5). In non-survivors, reduced EDV with preserved stroke volume resulted in elevated LVEF during early sepsis, masking an underlying systolic dysfunction compared with survivors of septic shock. These findings underscore the role of diastolic dysfunction in septic cardiomyopathy and highlight the need for future studies to explore cardiac dysfunction as a therapeutic target for the treatment of septic shock.

References

  1. Ford VJ, Applefeld WN, Wang J, et al. Cardiac magnetic resonance studies in a large animal model that simulates the cardiac abnormalities of human septic shock. J Am Heart Assoc. 2024;13:e034026. [PMID: 39101510] doi:10.1161/JAHA.123.034026
  2. Hollenberg SM, Singer M. Pathophysiology of sepsis-induced cardiomyopathy. Nat Rev Cardiol. 2021;18:424-434. [PMID: 33473203] doi:10.1038/s41569-020-00492-2
  3. Wang J, Applefeld WN, Sun J, et al. Mechanistic insights into cell-free hemoglobin-induced injury during septic shock. Am J Physiol Heart Circ Physiol. 2021;320:H2385-H2400. [PMID: 33989079] doi:10.1152/ajpheart.00092.2021
  4. Hasegawa D, Ishisaka Y, Maeda T, et al. Prevalence and prognosis of sepsis-induced cardiomyopathy: a systematic review and meta-analysis. J Intensive Care Med. 2023;38:797-808. [PMID: 37272081] doi:10.1177/08850666231180526
  5. Ford VJ, Applefeld WN, Wang J, et al. In a canine model of septic shock, cardiomyopathy occurs independent of catecholamine surges and cardiac microvascular ischemia. J Am Heart Assoc. 2024;13:e034027. [PMID: 39101496] doi:10.1161/JAHA.123.034027

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