ENDOMYOCARDIAL GENE-EXPRESSION DURING DEVELOPMENT OF PACING TACHYCARDIA-INDUCED HEART-FAILURE IN THE DOG

Selective and specific changes in gene expression characterize the end -stage failing heart. However, the pattern and relation of these chang es to evolving systolic and diastolic dysfunction during development o f heart failure remains undefined. In the present study, we assessed s teady-state levels of mRNAs encoding a group of cardiac proteins durin g the early development of left ventricular dysfunction in dogs with p acing-induced cardiomyopathy. Corresponding hemodynamic assessments we re made in the conscious state in the same animals and at the same tim e points at baseline, after 1 week of ventricular pacing, and at the o nset of clinical heart failure. Systolic dysfunction dominated after 1 week of pacing, whereas diastolic dysfunction was far more pronounced with the onset of heart failure. Atrial natriuretic factor mRNA was u ndetectable in 7 of 12 hearts at baseline but was expressed in all hea rts at 1 week (P<.01 by chi(2) test), and it increased markedly with p rogression to failure (P=.05). Creatine kinase-B mRNA also rose marked ly with heart failure (P<.01). Levels of mRNA encoding beta-myosin hea vy chain, mitochondrial creatine kinase, phospholamban, and sarcoplasm ic reticulum Ca2+-ATPase did not significantly change from baseline, d espite development of heart failure. Additional analysis to determine if these mRNA changes were related to the severity of diastolic or sys tolic dysfunction revealed that phospholamban mRNA decreased in hearts with larger net increases in end-diastolic pressure (+19.2+/-1.9 mmHg );compared with those hearts in which it did not change (+4.0+/-4.9, P <.02). These results suggest that selective alterations in gene expres sion occurring during early and later development of heart failure in the tachycardia-paced dog may be related to specific hemodynamic abnor malities.