Myocyte Damage and Mass Loss Drives Increasing Water Content, Compliance, and Survival in Septic Cardiomyopathy
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Introduction/Purpose
During the septic cardiomyopathy, the mechanism and relationship to outcome of changes in left ventricular (LV) end diastolic volume (EDV) and ejection fraction (EF) remains obscure. We compared serial changes in LVEF and LVEDV to successive alterations in LV wall ultrastructure, water content, and total mass to investigate whether these measures can explain their basis.
Methods
We performed cardiac magnetic resonance imaging at 0,6,18,30,42,54, and 92h post-bacterial challenge in a large-animal model (n=57) that mimics human septic cardiomyopathy. LV tissue was obtained for electron microscopy (EM) upon death and 66h in sacrificed survivors.
Results
Between 0-6h post-challenge, LV compliance and EDV reached its greatest decline. Non-survivors (n=18) exhibited significantly greater reductions in LVEDV, along with more myocyte edema, mitochondrial swelling and myofilament fragmentation on EM. This increased tissue damage may explain why non-survivors developed worse LV compliance and a greater decline in LVEDV, which persisted until death. From 6-30h, LVEDV significantly improved to baseline in non-survivors, while survivors experienced ∼20% increases (n=39). Concurrently, there was significant LV mass loss and increases in percent water content that were significantly associated with increases in LVEDV. This is consistent with a passive mechanism for rapidly improving LV compliance and EDV. Full recovery of EF required additional days. We hypothesize the prolonged significant mass loss over 5d reflects an active process for remodeling fragmented myofilaments, eliminating myocyte edema, and mitochondrial swelling, ultimately restoring contractile function.
Conclusion
The septic cardiomyopathy constitutes a diffuse ultrastructural injury to myocytes with three phases. Initially, there is a decrease in LVEDV, and EF due to myocyte damage within 6h of bacterial challenge; next, the patient sees a passive LVEDV recovery from 6-30h, where LV mass loss increases relative wall percent water content, which facilitates wall compliance and LVEDV; and lastly, the patient sees mass loss beyond 30h consistent with an active repair mechanism of myocytes, returning systolic function to normal. Therefore, EDV changes are a pathophysiological biomarker for sepsis outcomes. A lower LVEDV indicates persistent unrepairable ultrastructure damage with worsening wall compliance and poorer outcomes. LVEDV dilation is a sign of near-full recovery of ultrastructure injury, augmenting wall compliance and improving outcomes.
Clinical Implications
We explain herein why septic cardiomyopathy findings don’t have clinical implications like heart failure. Septic patients who exhibit signs of heart failure, low LVEF with high EDVs, are doing well – reflecting mild myocyte injury, effective damaged tissues clearance, increased relative LV wall water content, and compliance. This augments the LVEDV, lowering the LVEF. Septic patients who deteriorate rapidly, contrary to heart failure patients, show high/normal LVEF and low/normal LVEDV. Here, the myocyte damage is severe, leading to insufficient wall repair, and this decreased wall compliance persists, preventing the LV from dilating and making LVEDV low which ultimately raises the LVEF.
