Cardiac Magnetic Resonance Studies in a Large Animal Model that Simulates the Cardiac Abnormalities of Human Septic Shock

Abstract

BackgroundSeptic shock, in humans and in our well-established animal model, is associated with increases in biventricular end diastolic volume (EDV) and decreases in ejection fraction (EF). These abnormalities occur over 2 days and reverse within 10 days. Septic non-survivors do not develop an increase in EDV. The mechanism for this cardiac dysfunction and EDV differences is unknown. MethodsPurpose-bred beagles randomized to receive intrabronchial Staphylococcus aureus (n=27) or saline (n=6) were provided standard ICU care including sedation, mechanical ventilation, and fluid resuscitation to a pulmonary arterial occlusion pressure of over 10mmHg. No catecholamines were administered. Over 96h, cardiac magnetic resonance imaging, echocardiograms, and invasive hemodynamics were serially performed, and laboratory data was collected. Tissue was obtained at 66h from six septic animals. ResultsFrom 0-96h after bacterial challenge, septic animals vs. controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%) which was more pronounced at 48h in non-survivors than survivors. On histology, edema was located predominantly in myocytes, the interstitium, and endothelial cells. Edema was associated with significantly worse biventricular function (lower EFs), ventricular-arterial coupling, and circumferential strain. In septic animals, from 0-24h, the EDV decreased from baseline and, despite cardiac filling pressures being similar, decreased significantly more in non-survivors. From 24-48h, all septic animals had increases in biventricular chamber sizes. Survivors biventricular EDVs were significantly greater than baseline and in non-survivors, where biventricular EDVs were not different from baseline. Preload, afterload, or HR differences did not explain these differential serial changes in chamber size. ConclusionSystolic and diastolic cardiac dysfunction during sepsis is associated with ventricular wall edema. Rather than differences in preload, afterload, or heart rate, structural alterations to the ventricular wall best account for the volume changes associated with outcome during sepsis. In non-survivors, from 0-24h, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part explain, the EDV increases from 24-48h. However, these changes continued and even accelerated into the recovery phase consistent with a reparative process rather than ongoing injury. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIUtilizing multimodal imaging and hemodynamics, we demonstrate the cardiac changes of sepsis have injury and reparative phases. C_LIO_LIThe injury phase (0-24h) has EDV decreases more profound in non-survivors and is associated with worse ventricular compliance, myocardial edema, and diastolic dysfunction. C_LIO_LIThe recovery phase has left ventricular mass loss with wall thinning in survivors that explains the EDV increases (24-96h). These progressed into the EF recovery phase consistent with a reparative process removing damaged tissue. C_LIO_LIThis is the first controlled CMR sepsis study supporting ventricular wall edema is a fundamental aspect of sepsis pathophysiology and dry mass loss a reparative mechanism. C_LI What are the clinical implications?O_LIDespite optimizing filling pressures, the cardiac changes in ventricular wall structure and function associated with survival and non-survival in sepsis still occurred, thereby discounting fluid resuscitation as the major factor of therapeutic importance for cardiac function and survival. C_LIO_LIThe changes reported here have potential implications for sepsis treatment especially in the field of fluid resuscitation. These findings yield new understanding into the pathophysiology of sepsis cardiac dysfunction and allow for novel phenotyping and prognosticating of the syndrome with ventricular compliance and EDVs. This also offers potentially high yielding targets for research for new therapeutic approaches for sepsis and heart failure. C_LI