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Updated: Jun 17, 2026
Acute Myocardial Infarction in Rats
Published on: February 16, 2011
Brief postinfarction calcineurin blockade affects left ventricular remodeling and Ca2+ handling in the rat
Urszula Mackiewicz1, Michał Maczewski, Emilia Klemenska
1Department of Clinical Physiology, Medical Centre of Postgraduate Education, Marymoncka 99/103, 01-813 Warszawa, Poland. urszulam@cmkp.edu.pl
Abstract:
The role of calcineurin (CN) pathway in the post-myocardial infarction (MI) heart remains unclear. We investigated effects of early and brief inhibition of CN pathway with cyclosporine A (CsA) after MI on both immediate and delayed changes in left ventricular (LV) morphology, haemodynamics, and cardiomyocyte performance. CsA/saline was administered for 4 days, starting 24 h after MI/sham surgery in the rat. MI resulted in CN overactivity, peaking on day 3, accompanied by significant intracellular Ca(2+) overload due to marked decrease of NCX function. On day 7 and in week 8, CN activity decreased and normalized, respectively. It was accompanied by normalization of Ca(2+) handling parameters (only SERCA function was moderately decreased). CsA abolished post-MI CN overactivity, protected against Ca(2+) overload on day 3 and slightly improved SERCA function on day 7. Moreover, CsA reduced hypertrophy on days 3 and 7 after MI, increased wall stress on day 7 and in week 8, and lowered ejection fraction, augmented LV dilation as well increased mortality in week 8. Our study demonstrates that blockade of brief post-MI CN overactivity with CsA has delayed detrimental effects: increased mortality and worse LV function. CsA prevented early cardiomyocyte hypertrophy, decreased wall thickness and thus increased the wall stress, the main stimulus for detrimental LV dilation. Furthermore, CsA treatment prevented early Ca(2+) overload related to decreased NCX function. Role of this early Ca(2+) overload is unclear; it might be an element of positive feedback loop amplifying CN activation in post-MI heart.
Insights
Early inhibition of the calcineurin (CN) pathway with cyclosporine A after heart attack (myocardial infarction) initially protected heart cells but led to worse heart function and increased mortality later on.
Area of Science:
- Cardiovascular Biology
- Pharmacology
- Molecular Medicine
Background:
- The calcineurin (CN) pathway's role after myocardial infarction (MI) is not fully understood.
- Post-MI, CN overactivity and intracellular calcium (Ca2+) overload, linked to reduced NCX function, are observed.
- CN activity and Ca2+ handling normalize over time, though SERCA function may remain impaired.
Purpose of the Study:
- To investigate the effects of early, brief calcineurin inhibition with cyclosporine A (CsA) on the post-MI heart.
- To assess immediate and delayed changes in left ventricular (LV) morphology, hemodynamics, and cardiomyocyte function following MI and CsA treatment.
Main Methods:
- Rats underwent MI or sham surgery, followed by 4 days of CsA or saline administration starting 24 hours post-surgery.
- Evaluated CN activity, intracellular Ca2+ handling (NCX, SERCA), LV morphology, hemodynamics, and mortality at various time points (day 3, day 7, week 8).
Main Results:
- MI induced CN overactivity and Ca2+ overload by day 3, with normalization by week 8.
- CsA abolished early CN overactivity, reduced cardiomyocyte hypertrophy, and prevented early Ca2+ overload.
- However, CsA treatment led to increased LV dilation, reduced ejection fraction, increased wall stress, and higher mortality by week 8.
Conclusions:
- Briefly blocking the post-MI CN overactivity with CsA has delayed detrimental effects on cardiac function and survival.
- While CsA prevents early hypertrophy and Ca2+ overload, it increases wall stress, promoting adverse LV remodeling and mortality.
- The role of early Ca2+ overload in amplifying CN activation post-MI warrants further investigation.
