Early detection of myocardial dysfunctions in a model of myocardial inflammation

Introduction: Severe systemic inflammation may leads to myocardial dysfunction and death. Early detection of myocardial dysfunction in severe inflammations, as sepsis and COVID-19, is of great clinical merit. We hypothesized that myocardial involvement is associated with extracellular matrix (ECM) degradation due to discharge of metalloproteinases (MMPs) from activated macrophages and leukocytes. Moreover, it can explain development of both diastolic and systolic dysfunctions.

Methods: Isolated rat hearts were perfused with modified Krebs-Henseleit solution in a unique vertical Langendorff setup, with computer-controlled preload and afterload of both right and left ventricles. After baseline recording, the solution was switched to Krebs-Henseleit perfusion with collagenase (MMP8). The pressures and short-axis ultrasound cines (15MHz) of both ventricles were continuously recorded.

Results: Mark decreases in the LV EDV and systolic pressure developed with the initiation of ECM dismantling, along with increased diastolic stiffness and a shift of the end-diastolic pressure-volume relationship to lower volumes. The average diastolic stiffness to EDV ratio (S2V) increased from 0.30±0.31 mmHg/µL2 at baseline to 0.81±0.67 mmHg/µL2 after the collagenase perfusion yielded a 20% drop in systolic pressure (n=7, p=0.02). Concurrently, the RV S2V presented a similar trend, an increase from 0.13±0.17 mmHg/µL2 at baseline to 0.61±0.61 mmHg/µL2 with collagenase perfusion (n=5, P = 0.08). The decrease in the EDV was associated with myocardial wall thickening. An intact ECM is essential for the diastolic recoil. Dismantling the ECM diminishes the diastolic recoil, leads to development of edema, [AL1] and both increase diastolic stiffness. Normal decrease in EDV is associated with a decrease in the diastolic stiffness, with mild changes in S2V. Thus, significant increase in the S2V can be used for early detection of diastolic dysfunction.

Conclusion: Novel indices for early detection of myocardial dysfunction were developed. The study highlights the strong effects of inflation induced ECM degradation on cardiac dysfunctions.