Department of Anesthesiology

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Chronic unloading by left ventricular assist device reverses contractile dysfunction and alters gene expression in end-stage heart failure.

TitleChronic unloading by left ventricular assist device reverses contractile dysfunction and alters gene expression in end-stage heart failure.
Publication TypeJournal Article
Year of Publication2000
AuthorsHeerdt PM, Holmes JW, Cai B, Barbone A, Madigan JD, Reiken S, Lee DL, Oz MC, Marks AR, Burkhoff D
JournalCirculation
Volume102
Issue22
Pagination2713-9
Date Published2000 Nov 28
ISSN1524-4539
KeywordsAdult, Aged, Blotting, Northern, Blotting, Western, Calcium-Transporting ATPases, Female, Gene Expression Regulation, Heart Failure, Heart Ventricles, Heart-Assist Devices, Humans, Male, Middle Aged, Myocardial Contraction, RNA, Messenger, Ryanodine Receptor Calcium Release Channel, Sarcolemma, Sodium-Hydrogen Antiporter
Abstract

BACKGROUND: Left ventricular (LV) assist devices (LVADs) can improve contractile strength and normalize characteristics of the Ca(2+) transient in myocytes isolated from failing human hearts. The purpose of the present study was to determine whether LVAD support also improves contractile strength at different frequencies of contraction (the force-frequency relationship [FFR]) of intact myocardium and alters the expression of genes encoding for proteins involved in Ca(2+) handling.

METHODS AND RESULTS: The isometric FFRs of LV trabeculae isolated from 15 patients with end-stage heart failure were compared with those of 7 LVAD-supported patients and demonstrated improved contractile force at 1-Hz stimulation, with reversal of a negative FFR after LVAD implantation. In 20 failing hearts, Northern blot analysis for sarcoplasmic endoreticular Ca(2+)-ATPase subtype 2a (SERCA2a), the ryanodine receptor, and the sarcolemmal Na(+)-Ca(2+) exchanger was performed on LV tissue obtained before and after LVAD implantation. These paired data demonstrated an upregulation of all 3 genes after LVAD support. In tissue obtained from subsets of these patients, Western blot analysis was performed, and oxalate-supported Ca(2+) uptake by isolated sarcoplasmic reticular membranes was determined. Despite higher mRNA for all genes after LVAD support, only SERCA2a protein was increased. Functional significance of increased SERCA2a was confirmed by augmented Ca(2+) uptake by sarcoplasmic reticular membranes isolated from LVAD-supported hearts.

CONCLUSIONS: LVAD support can improve contractile strength of intact myocardium and reverse the negative FFR associated with end-stage heart failure. The expression of genes encoding for proteins involved in Ca(2+) cycling is upregulated (reverse molecular remodeling), but only the protein content of SERCA2a is increased.

Alternate JournalCirculation
PubMed ID11094037