SARCOPLASMIC-RETICULUM CA-RELEASE CHANNEL AND ATP-SYNTHESIS ACTIVITIES ARE EARLY MYOCARDIAL MARKERS OF HEART-FAILURE PRODUCED BY RAPID VENTRICULAR PACING IN DOGS

The contraction-relaxation cycle of the heart is dependent on a cycle of ATP production and utilization and a cycle of Ca uptake and Ca rele ase by the sarcoplasmic reticulum (SR). Heart failure (HF) is associat ed with abnormalities of myocardial Ca and ATP cycling, but the time c ourse of their development is unknown. This study tested the hypothesi s that, compared with ATP-utilizing and Ca-uptake activities, decrease s in ATP-synthesis and Ca-release activities occurred earlier in the d evelopment of HF and persisted longer during recovery from HF. HF was induced by right ventricular pacing of dogs at 250 beats/min. Dogs wer e studied after 1 week of pacing (n = 8, early HF), at HF (n = 11, sev ere HF), and 4 weeks after cessation of pacing (n = 9) and were compar ed with dogs not subjected to pacing. At early HF, there were decrease d activities (p < 0.05) of the SR Ca-release channel (rate constant fr om 199 +/- 36 x 10(-4) to 90 +/- 16 x 10(-4) s(-1)), mitochondrial ATP synthesis (from 11.2 +/- 2.4 to 7.0 +/- 2.2 international units (IU)/ g), and creatine kinase (CK) from 2028 +/- 266 to 1811 +/- 79 IU/g). T he decreased Ca-channel activity was due to a 32% decrease in maximal activity (rate constant from 249 +/- 50 x 10(-4) to 170 +/- 29 X 10(-4 ) s(-1)) and to a 2-fold increase (from 19.1 +/- 12.4 to 42.0 +/- 14.2 %) in inhibition of maximal channel activity (p < 0.05). At severe HF, Ca-uptake (rate constant from 407 +/- 41 x 10(-4) to 296 +/- 77 x 10( -4) s(-1)) and ATP-utilization activities also became depressed (from 27.2 +/- 3.3 to 20.3 +/- 1.9 IU/g), and CK further decreased to 1321 /- 241 IU/g (p < 0.05). Four weeks after cessation of pacing, only tot al Ca-cycling (sum of Ca uptake and Ca release), Ca-uptake, and CK act ivities were significantly recovered (p < 0.05). Left ventricular ejec tion fraction was significantly correlated with total Ca cycling (n = 12, r = 0.68, p < 0.02), Ca-channel inhibition (n = 12, r = -0.60, p < 0.04), and basal ATPase (n = 11, r = 0.69, p < 0.02). We conclude tha t biochemical measurements of ATP- and Ca-cycling activities correlate with myocardial performance, and that compared with ATP-utilization a nd Ca-uptake activities, inhibition of ATP synthesis and Ca release oc curs earlier in the development of HF and persists longer during recov ery from HF.