Myocardial Regeneration Therapy for Ischemic Cardiomyopathy with Cyclin A2
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Objective: Heart failure therapies ranging from revascularization to remodeling to replacement are variably effective. Theoretically, endogenous repair via myocardial regeneration would be an ideal therapy. This study examined the ability to initiate regeneration by adenoviral-mediated expression of the cell cycle regulator cyclin A2. Our prior studies have demonstrated robust cyclin A2 transgene expression and marked anti-phosphorylated histone H3 activity with this strategy, indicating the induction of cardiomyocyte mitosis.
Methods: Adult male, Lewis rats (n=24) underwent LAD ligation followed by borderzone intramyocardial delivery of either cyclin A2 adenoviral vector (n=12) or empty adenonull vector as a control (n=12). Six weeks later, when animals are typically in heart failure, in vivo myocardial function was analyzed by pressure catheter and cardiac output monitor. Hearts were explanted for immunofluorescence staining to detect Ki-67 expression and BrdU uptake. Ventricular geometry was then analyzed.
Results: Ki-67 expression colocalized to alpha-sarcomeric actin stained cells was significantly upregulated in Cyclin A2 animals compared to Null controls, suggesting borderzone cardiomyocyte cell cycle activation. Preliminary BrdU uptake studies were confirmatory. Cyclin A2 hearts demonstrated increased borderzone wall thickness. Pmax, Max dP/dt and cardiac output were greater in Cyclin A2 animals compared to controls (Table).
Conclusions: In failing hearts, directed cyclin A2 expression induced cardiomyocyte mitotic activity, increased borderzone wall thickness, and improved ventricular function and may serve as an ideal myocardial regenerative therapy.
Table 1 | Null Control | Cyclin A2 | p-value |
| Ki-67 (Per 1000 cells) | 20.4 ± 6.0 | 46.3±7.2 | <0.0001 |
| BrdU (% positive cells) | 0.8 ± 0.9 | 5.5 ± 0.2 | <0.01 |
| Wall Thickness (mm) | 1.4 ± 0.0 | 1.5 ± 0.0 | <0.01 |
| Pmax (mmHg) | 58 ± 1 | 62 ± 1 | <0.0001 |
| Max dP/dt (mmHg/msec) | 2.42 ± 0.03 | 2.64 ± 0.03 | <0.001 |
| Cardiac Output (ml/min) | 23.2 ± 0.6 | 27.1 ± 0.7 | <0.001 |
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