The effects of acute triiodothyronine therapy on myocardial gene expression in brain stem dead cardiac donors.
BACKGROUND
After brain stem death (BSD), a low T(3) state is common, and T(3) supplementation has been advocated to improve heart function and yield for transplantation.


OBJECTIVE
The aim of the study was to assess the effects of T(3) on expression of mRNAs encoding T(3)-responsive genes in the post-BSD human heart.


METHODS
Within a prospective double-blind trial, potential BSD cardiac donors undergoing hemodynamic optimization were randomized to T(3) (0.8 microg . kg(-1) bolus; infusion 0.113 microg . kg(-1) . h(-1)) or placebo (5% dextrose) for up to 6 h. Left ventricular biopsies were obtained at end-assessment from 30 donors (T(3); n=16). TaqMan real-time PCR was performed to investigate mRNA expression of the voltage-gated potassium channel Kv1.5, beta-1 adrenergic receptor (ADRB1), sarcoplasmic reticulum calcium ATPase type 2a (SERCA2a), and phospholamban (PLB).


RESULTS
Time between diagnosis of BSD and donor management was 13.2 h (range, 9.7-16.8 h). T(3) donors were managed for 7.6 (6.9-8.3) h. Median serum free T(3) (fT3) at baseline was 2.9 (2.3-3.8) pmol . liter(-1) (reference range, 3.3-7.5 pmol . liter(-1)). At baseline, 19 of 30 (56.7%) had low serum fT3, and T(3) treatment increased fT3 to supraphysiological levels (P < 0.001). Expression of mRNAs encoding Kv1.5 and SERCA2a was increased 1.99-fold and 1.51-fold (P = 0.015 and 0.043). There was no significant change in the expression of mRNAs encoding ADRB1 and PLB. Treatment with T(3) did not improve hemodynamic function compared with placebo.


CONCLUSIONS
Acute administration of T(3) in the BSD cardiac donor reverses the low T(3) state and increases expression of the mRNAs encoding Kv1.5 and SERCA2a, but not ADRB1 or PLB and is not associated with any improvement in hemodynamic performance.
James
Sally R
SR
Department of Cardiothoracic Surgery, University Hospitals Birmingham, National Health Service Foundation Trust, Edgbaston, Birmingham B15 2TH, United Kingdom.
Ranasinghe
Aaron M
AM
Venkateswaran
Rajamiyer
R
McCabe
Christopher J
CJ
Franklyn
Jayne A
JA
Bonser
Robert S
RS
D000704:Analysis of Variance; D001926:Brain Death / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016009:Chi-Square Distribution; D004311:Double-Blind Method; D015870:Gene Expression; D020869:Gene Expression Profiling; D006321:Heart / Q000187:drug effects*; D006801:Humans; D009206:Myocardium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism; D011446:Prospective Studies; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D018709:Statistics, Nonparametric; D014019:Tissue Donors; D020858:Tissue and Organ Harvesting; D014284:Triiodothyronine / Q000097:blood / Q000494:pharmacology*; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D014284:Triiodothyronine; D000099211:Phospholamban