Myocardial regeneration therapy for ischemic cardiomyopathy with cyclin A2.
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 antiphosphorylated histone H3 activity with this strategy, indicating the induction of cardiomyocyte mitosis.


METHODS
Adult male, Lewis rats underwent left anterior descending coronary artery ligation followed by intramyocardial delivery of either cyclin A2 adenoviral vector (n = 8) or empty adeno-null vector as a control (n = 8) into the peri-infarct border zone. In vivo myocardial function was analyzed by echocardiography and invasive left ventricular pressure catheter at 6 weeks, when the animals are traditionally in heart failure. Hearts were explanted for immunoblotting and left ventricular geometric analysis. Cellular proliferation was assessed by proliferating cellular nuclear antigen expression.


RESULTS
Cyclin A2 hearts exhibited improved left ventricular function as compared with controls including enhanced cardiac output (32 +/- 3.3 vs 26 +/- 5.0 mL/min, P < .05), stroke volume (0.16 +/- 0.04 vs 0.11 +/- 0.04 mL, P < .05), ejection fraction (72% +/- 7.4% vs 46.% +/- 8.5%, P < .05), fractional shortening (35% +/- 5.4% vs 19% +/- 4.3%, P < .002), maximum pressure (72 +/- 9.3 vs 61 +/- 2.9 mm Hg, P < .05), and end-systolic pressure (67 +/- 7.0 vs 55 +/- 7.0 mm Hg, P < .05). Enhanced myocardial preservation was demonstrated by enhanced left ventricular border zone wall thickness. Increased myocardial proliferation was evidenced by increased expression of proliferating cell nuclear antigen expression in cyclin A2-treated hearts.


CONCLUSIONS
In failing hearts, targeted delivery of cyclin A2 improves hemodynamic function, as measured by echocardiography and pressure catheter analysis, preserves ventricular wall thickness, and may serve as an ideal myocardial regenerative therapy.
Woo
Y Joseph
YJ
Division of Cardiothoracic Surgery, Division of Cardiology, Department of Medicine, Columbia University School of Medicine, New York, New York, USA. wooy@uphs.upenn.edu
Panlilio
Corinna M
CM
Cheng
Richard K
RK
Liao
George P
GP
Suarez
Erik E
EE
Atluri
Pavan
P
Chaudhry
Hina W
HW
D000256:Adenoviridae; D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology; D018797:Cell Cycle Proteins / Q000008:administration & dosage*; D019925:Cyclin A / Q000008:administration & dosage*; D056751:Cyclin A2; D004195:Disease Models, Animal; D005822:Genetic Vectors; D015552:Injections, Intralesional; D008297:Male; D009203:Myocardial Infarction / Q000150:complications; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000209:etiology; D032383:Myocytes, Cardiac / Q000502:physiology*; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D012038:Regeneration / Q000187:drug effects*; D016277:Ventricular Function, Left / Q000187:drug effects
C503722:Ccna2 protein, rat; D018797:Cell Cycle Proteins; D019925:Cyclin A; D056751:Cyclin A2; D018809:Proliferating Cell Nuclear Antigen