Abstract Background Prompt restoration of blood flow after acute myocardial infarction is crucial to preserve cardiac function and limit myocardial damage. However, reperfusion itself can worsen injury and is frequently accompanied by microvascular injury. Preclinical studies suggest that systemic administration of C1-esterase inhibitor (C1-INH), by inhibiting the complement and contact activation systems, may protect the coronary microvasculature during ischaemia-reperfusion injury. Purpose To assess the cardioprotective potential of C1-INH in both ex vivo and in vivo rat models of AMI. Methods Hearts of male Wistar rats (n = 14) were perfused in a Langendorff system and subjected to global ischaemia, followed by 2 hours of reperfusion. C1-INH (6 IU/ml) or placebo was infused for 15 minutes before ischaemia and during the first 5 minutes of reperfusion. Global infarct size was quantified, and cardiac function was assessed through rate-pressure product recovery, vascular resistance, and end-diastolic pressure. In vivo, rats (n = 28) underwent 45 minutes of ischaemia via occlusion of the left anterior descending coronary artery, followed by 3 hours of reperfusion. C1-INH (100 IU/kg) or placebo was administered intravenously before ischaemia. Cardiac magnetic resonance imaging (CMR) was performed to assess myocardial function and infarct size, and Evans blue/TTC/Thioflavin-S staining was used to define the infarct area and no-reflow. Results C1-INH treatment did not significantly decrease overall infarct size in isolated perfused rat hearts (36.6 ± 5.7% vs 35.0 ± 8.0% of total heart area, p = 0.683) or improve cardiac function compared to placebo (Fig 1). Similarly, in the in vivo rat model of acute myocardial infarction, C1-INH failed to decrease LGE-CMR infarct size (20.4 ± 10.4% vs 21.7 ± 6.8% LV, p = 0.713) or improve myocardial function compared to placebo (Fig 2A-F). Evans blue/TTC/Thioflavin-S staining showed no reduction in infarct size (39.9 ± 14.1% vs 45.7 ± 4.8% of AAR, p = 0.231) or no-reflow (23.5 ± 12.0% vs 27.5 ± 2.0% of AAR, p = 0.313) with C1-INH compared to placebo (Fig 2G-J). ELISA confirmed high plasma C1-INH antigen (689.4 ± 256.6 µg/mL) and activity levels (495.9 ± 211.7 µg/mL) at the onset of ischaemia in C1-INH-treated rats whereas placebo samples remained below detection limits (Fig 2K-M). Conclusion C1-INH did not provide cardioprotection in both isolated and in vivo rat models of myocardial ischaemia-reperfusion injury, suggesting it is insufficient as a stand-alone therapy. This supports the need for multimodal strategies targeting the complex, multifaceted mechanisms driving reperfusion injury.For image description, please refer to the figure legend and surrounding text. For image description, please refer to the figure legend and surrounding text.
Reijmersdal et al. (Fri,) studied this question.