Deciphering the Potential Effects of Collagenase that are Released Upon Systemic Inflammation on Cardiac Function

Introduction: Sepsis may cause systolic and diastolic cardiac dysfunction that is associated with high mortality. The underlying mechanisms are not well-understood. We have hypothesized that inflammation-induced release of neutrophil collagenases disrupts the cardiac extracellular matrix and can cause diastolic dysfunction.

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 the right and left ventricles. The preload was linearly swept back and forth between 1 and 29 mmHg within 1 minute. After stabilization and baseline recording, the perfusion solution was switched to Krebs-Henseleit perfusion with collagenase. The ventricle pressures and short-axis ultrasound cines (15MHz, 20 fps) of both ventricles were continuously recorded.

Results and discussion: The heart exhibited fast systolic and diastolic deteriorations upon the addition of collagenase. Counterintuitive to the expected cardiac dilatation, there were no changes in the epicardial diameters of both ventricles. The max(dP/dt) and min(dP/dt) progressively declined and were followed by a slower decline in the peak systolic pressures. Interestingly, there were overt progressive declines in the end-diastolic volumes of both ventricles and progressive slowing in the volume dynamics. The decrease in the end-diastolic ventricular volumes is explained by gradual myocardial wall thickening. The concurrent measurements of the end-diastolic volumes and pressures revealed that collagenase perfusion increased the diastolic stiffness of both ventricles. The systolic dysfunction can be partially attributed to the decrease in the end-diastolic volume.

Conclusions: The immediate effects of collagenase cleavage of the extracellular matrix are: decrease in the fast diastolic myocardial recoil, an increase in the diastolic stiffness and swelling of the myocardium due to edema. The study highlights the essential role of the matrix in the fast myocardial diastolic elastic recoil and the underlying mechanisms whereby inflammation may impair cardiac function.