| Autor: |
Kim SY; Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea., Kim KH; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas., Schilling JM; Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California., Leem J; Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California., Dhanani M; Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California., Head BP; Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California., Roth DM; Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California., Zemljic-Harpf AE; Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California., Patel HH; Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California. |
| Abstrakt: |
Cirrhotic cardiomyopathy is a clinical syndrome in patients with liver cirrhosis characterized by blunted cardiac contractile responses to stress and/or heart rate-corrected QT (QTc) interval prolongation. Caveolin-3 (Cav-3) plays a critical role in cardiac protection and is an emerging therapeutic target for heart disease. We investigated the protective role of cardiac-specific overexpression (OE) of Cav-3 in cirrhotic cardiomyopathy. Biliary fibrosis was induced in male Cav-3 OE mice and transgene negative (TG neg ) littermates by feeding a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; 0.1%) for 3 wk. Liver pathology and blood chemistries were assessed, and stress echocardiography, telemetry, and isolated heart perfusion studies to assess adrenergic responsiveness were performed. Cav-3 OE mice showed a similar degree of hyperdynamic contractility, pulmonary hypertension, and QTc interval prolongation as TG neg mice after 3 wk of DDC diet. Blunted systolic responses were shown in both DDC-fed Cav-3 OE and TG neg hearts after in vivo isoproterenol challenge. However, QTc interval prolongation after in vivo isoproterenol challenge was significantly less in DDC-fed Cav-3 OE hearts compared with DDC-fed TG neg hearts. In ex vivo perfused hearts, where circulatory factors are absent, isoproterenol challenge showed hearts from DDC-fed Cav-3 OE mice had better cardiac contractility and relaxation compared with DDC-fed TG neg hearts. Although Cav-3 OE in the heart did not prevent cardiac alterations in DDC-induced biliary fibrosis, cardiac expression of Cav-3 reduced QTc interval prolongation after adrenergic stimulation in cirrhosis. NEW & NOTEWORTHY Prevalence of cirrhotic cardiomyopathy is up to 50% in cirrhotic patients, and liver transplantation is the only treatment. However, cirrhotic cardiomyopathy is associated with perioperative morbidity and mortality after liver transplantation; therefore, management of cirrhotic cardiomyopathy is crucial for successful liver transplantation. This study shows cardiac myocyte specific overexpression of caveolin-3 (Cav-3) provides better cardiac contractile responses and less corrected QT prolongation during adrenergic stress in a cirrhotic cardiomyopathy model, suggesting beneficial effects of Cav-3 expression in cirrhotic cardiomyopathy. |
