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 release by the sarcoplasmic reticulum (SR). Heart failure (HF) is associated with abnormalities of myocardial Ca and ATP cycling, but the time course of their development is unknown. This study tested the hypothesis that, compared with ATP-utilizing and Ca-uptake activities, decreases in ATP-synthesis and Ca-release activities occurred earlier in the development of HF and persisted longer during recovery from HF. HF was induced by right ventricular pacing of dogs at 250 beats/min. Dogs were studied after 1 week of pacing (n = 8, early HF), at HF (n = 11, severe HF), and 4 weeks after cessation of pacing (n = 9) and were compared with dogs not subjected to pacing. At early HF, there were decreased activities (p < 0.05) of the SR Ca-release channel (rate constant from 199 ± 36 × 10−4 to 90 ± 16 × 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). The decreased Ca-channel activity was due to a 32% decrease in maximal activity (rate constant from 249 ± 50 × 10−4 to 170 ± 29 × 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 × 10−4 to 296 ± 77 × 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 total Ca-cycling (sum of Ca uptake and Ca release), Ca-uptake, and CK activities were significantly recovered (p < 0.05). Left ventricular ejection 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 that biochemical measurements of ATP- and Ca-cycling activities correlate with myocardial performance, and that compared with ATP-utilization and Ca-uptake activities, inhibition of ATP synthesis and Ca release occurs earlier in the development of HF and persists longer during recovery from HF.Key words: Ca-release channel, sarcoplasmic reticulum, rapid ventricular pacing, congestive heart failure, Ca ATPase pump, mitochondria.