Oral levosimendan prevents postinfarct heart failure and cardiac remodeling in diabetic Goto-Kakizaki rats.
BACKGROUND
Diabetes increases the risk for fatal myocardial infarction and development of heart failure. Levosimendan, an inodilator acting both via calcium sensitization and opening of ATP-dependent potassium channels, is used intravenously for acute decompensated heart failure. The long-term effects of oral levosimendan on postinfarct heart failure are largely unknown.


OBJECTIVE
To examine whether oral treatment with levosimendan could improve cardiac functions and prevent cardiac remodeling after myocardial infarction in a rodent model of type 2 diabetes, the Goto-Kakizaki rat.


METHODS
Myocardial infarction (MI) was induced to diabetic Goto-Kakizaki and nondiabetic Wistar rats by coronary ligation. Twenty-four hours after surgery, Goto-Kakizaki and Wistar rats were randomized into four groups: MI group without treatment, MI group with levosimendan for 12 weeks (1 mg/kg per day), sham-operated group, sham-operated group with levosimendan. Blood pressure, cardiac functions as wells as markers of cardiac remodeling were determined.


RESULTS
In Goto-Kakizaki rats, MI induced systolic heart failure, pronounced cardiac hypertrophy in the remote area, and sustained cardiomyocyte apoptosis. Postinfarct cardiac remodeling was associated with increased atrial natriuretic peptide, interleukin-6 and connective tissue growth factor mRNA expressions, as well as three-fold increased cardiomyocyte senescence, measured as cardiac p16 mRNA expression. Levosimendan improved cardiac function and prevented postinfarct cardiomyocyte hypertrophy, cardiomyocyte apoptosis, and cellular senescence. Levosimendan also ameliorated MI-induced atrial natriuretic peptide, IL-6, and connective tissue growth factor overexpression as well as MI-induced disturbances in calcium-handling proteins (SERCA2, Na-Ca exchanger) without changes in diabetic status or systemic blood pressure. In nondiabetic Wistar rats, MI induced systolic heart failure; however, the postinfarct cardiac remodeling was associated with less pronounced cardiac hypertrophy, cardiomyocyte apoptosis, inflammatory reaction, and induction of cellular senescence. Levosimendan only partially prevented postinfarct heart failure and cardiac remodeling in Wistar rats.


CONCLUSIONS
Our findings suggest a therapeutic role for oral levosimendan in prevention of postinfarct heart failure and cardiac remodeling in type 2 diabetes and underscore the importance of sustained cardiomyocyte apoptosis and induction of cellular senescence in the pathogenesis.
Louhelainen
Marjut
M
Institute of Biomedicine, Pharmacology, University of Helsinki, FI-00014 Helsinki, Finland.
Vahtola
Erik
E
Forsten
Hanna
H
Merasto
Saara
S
Kytö
Ville
V
Finckenberg
Piet
P
Leskinen
Hanna
H
Kaheinen
Petri
P
Tikkanen
Ilkka
I
Levijoki
Jouko
J
Mervaala
Eero
E
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000494:pharmacology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D048909:Diabetes Complications / Q000473:pathology / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D004195:Disease Models, Animal; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D018398:Homeodomain Proteins / Q000378:metabolism; D006835:Hydrazones / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D011724:Pyridazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D050794:STAT1 Transcription Factor / Q000187:drug effects; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D000077464:Simendan; D020257:Ventricular Remodeling / Q000187:drug effects*
C506948:Atp2a2 protein, rat; D002316:Cardiotonic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; D006835:Hydrazones; D011724:Pyridazines; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D000077464:Simendan; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases