Long-term levosimendan treatment improves systolic function and myocardial relaxation in mice with cardiomyocyte-specific disruption of the Serca2 gene.
In human heart failure (HF), reduced cardiac function has, at least partly, been ascribed to altered calcium homeostasis in cardiomyocytes. The effects of the calcium sensitizer levosimendan on diastolic dysfunction caused by reduced removal of calcium from cytosol in early diastole are not well known. In this study, we investigated the effect of long-term levosimendan treatment in a murine model of HF where the sarco(endo)plasmatic reticulum ATPase (Serca) gene is specifically disrupted in the cardiomyocytes, leading to reduced removal of cytosolic calcium. After induction of Serca2 gene disruption, these mice develop marked diastolic dysfunction as well as impaired contractility. SERCA2 knockout (SERCA2KO) mice were treated with levosimendan or vehicle from the time of KO induction. At the 7-wk end point, cardiac function was assessed by echocardiography and pressure measurements. Vehicle-treated SERCA2KO mice showed significantly diminished left-ventricular (LV) contractility, as shown by decreased ejection fraction, stroke volume, and cardiac output. LV pressure measurements revealed a marked increase in the time constant (τ) of isovolumetric pressure decay, showing impaired relaxation. Levosimendan treatment significantly improved all three systolic parameters. Moreover, a significant reduction in τ toward normalization indicated improved relaxation. Gene-expression analysis, however, revealed an increase in genes related to production of the ECM in animals treated with levosimendan. In conclusion, long-term levosimendan treatment improves both contractility and relaxation in a heart-failure model with marked diastolic dysfunction due to reduced calcium transients. However, altered gene expression related to fibrosis was observed.
Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway;
Vigdis
V
Hillestad
Frank
F
Kramer
Stefan
S
Golz
Andreas
A
Knorr
Kristin B
KB
Andersson
Geir
G
Christensen
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003971:Diastole / Q000187:drug effects*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D006835:Hydrazones / Q000494:pharmacology*; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D011724:Pyridazines / Q000494:pharmacology*; D020127:Recovery of Function; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000077464:Simendan; D013318:Stroke Volume / Q000187:drug effects; D013599:Systole / Q000187:drug effects*; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D002316:Cardiotonic Agents; D016326:Extracellular Matrix Proteins; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse
SERCA2; calcium transients; fibrosis; heart failure; levosimendan; relaxation