EFFECTS OF THYROID-HORMONE ON LEFT-VENTRICULAR PERFORMANCE AND REGULATION OF CONTRACTILE AND CA2(-CYCLING PROTEINS IN THE BABOON - IMPLICATIONS FOR THE FORCE-FREQUENCY AND RELAXATION-FREQUENCY RELATIONSHIPS())

The transcriptional, posttranscriptional, and related functional effec ts of thyroid hormone on primate myocardium are poorly understood. The refore, we studied the effects of thyroid hormone on sarcoplasmic reti culum (SR) Ca2+-cycling proteins and myosin heavy chain (MHC) composit ion at the steady state mRNA and protein level and associated alterati ons of left ventricular (LV) performance in 8 chronically instrumented baboons. The force-frequency and relaxation-frequency relations were assessed as the response of LV isovolumic contraction (dP/dt(max)) and relaxation (Tau), respectively, to incremental atrial pacing. Both th e heart rate at which dP/dt(max) was maximal and Tau was minimal (crit ical heart rates) in response to pacing were increased significantly a fter thyroid hormone. Postmortem LV tissue from 5 thyroid-treated and 4 additional control baboons was assayed for steady state mRNA levels with cDNA probes to MHC isoforms and SR Ca2+-cycling proteins. Steady state SR Ca2+-ATPase and phospholamban mRNA increased in the hyperthyr oid state, and alpha-MHC mRNA appeared de novo, whereas beta-MHC mRNA decreased. Western analysis (4 thyroid-treated and 4 control baboons) showed directionally similar changes in MHC isoforms and a slight incr ease in SR Ca2+-ATPase. In contrast, there was a statistically nonsign ificant decrease in phospholamban protein, which resulted in a signifi cant 40% decrease in the ratio of phospholamban to SR Ca2+-ATPase. Thu s, thyroid hormone increases the transcription of Ca2+-cycling protein s and shifts MHC isoform expression in the primate LV. Our data sugges t that both transcriptional and posttranslational mechanisms determine the levels of these proteins in the hyperthyroid primate heart and me diate, in part, the observed enhanced basal and frequency-dependent LV performance.