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Use of the isolated perfused heart for evaluation of cardiac toxicity
P G Anderson1, S B Digerness, J L Sklar
1Department of Pathology, University of Alabama, Birmingham 35294.
Abstract:
The isolated perfused rat heart model can be used to evaluate cardiotoxicity, and is especially useful in distinguishing direct vs indirect cardiac injury. Various perfusion systems can be used to characterize the pathophysiologic as well as morphologic changes induced by drugs or chemicals of interest. The isolated perfused heart was used in the studies described herein to characterize the mechanism of allylamine cardiotoxicity. Rat hearts were perfused with Krebs-Henseleit buffer containing 10 mM allylamine and a latex balloon was inserted into the left ventricle to monitor pressure. Coronary flow in hearts perfused with 10 mM allylamine was similar to control hearts at 5, 10, and 30 min, but was reduced by 1 hr (11.5 +/- 0.6 ml/min/g wet heart weight vs 16.0 +/- 0.7, p less than 0.01). Peak left ventricular systolic pressure increased in hearts perfused with allylamine for 5 min (156 +/- 8 mm Hg vs 103 +/- 9, p less than 0.01), but by 2 hr was decreased compared to controls (89 +/- 6 vs 105 +/- 5, p less than 0.05). End diastolic pressure was markedly increased at 2 hr (58 +/- 3 vs 4 +/- 0.8, p less than 0.01). Morphologically, allylamine perfused hearts exhibited significant contraction band changes as well as numerous cells with marked swelling of the sarcoplasmic reticulum. The findings in this study suggest that allylamine produces direct myocardial damage that appears to be independent of coronary flow. These studies demonstrate that the isolated perfused rat heart model can be used to evaluate mechanisms of acute cardiotoxicity.
Insights
The isolated perfused rat heart model effectively identifies direct cardiac injury from allylamine. This method demonstrates allylamine causes myocardial damage independent of coronary flow changes.
Area of Science:
- Cardiovascular Research
- Toxicology
- Pharmacology
Background:
- Cardiotoxicity assessment is crucial for drug safety.
- Distinguishing direct versus indirect cardiac injury requires specific models.
- The isolated perfused heart model offers a controlled environment for mechanistic studies.
Purpose of the Study:
- To investigate the mechanism of allylamine-induced cardiotoxicity.
- To evaluate the utility of the isolated perfused rat heart model in assessing direct myocardial injury.
- To characterize the pathophysiological and morphological changes induced by allylamine.
Main Methods:
- Isolated perfused rat heart model utilizing Krebs-Henseleit buffer.
- Perfusion with 10 mM allylamine and monitoring of left ventricular pressure and coronary flow.
- Morphological assessment of cardiac tissue for cellular changes.
Main Results:
- Allylamine perfusion led to reduced coronary flow by 1 hour and altered left ventricular pressures.
- Significant increases in end-diastolic pressure were observed after 2 hours.
- Morphological analysis revealed contraction band changes and sarcoplasmic reticulum swelling, indicating direct myocardial damage.
Conclusions:
- Allylamine induces direct myocardial damage that is independent of alterations in coronary flow.
- The isolated perfused rat heart model is a valuable tool for evaluating acute cardiotoxicity mechanisms.
- This model can effectively differentiate direct from indirect cardiac injury.