Myocyte apoptosis and reduced SR gene expression precede the transition from chronically stunned to hibernating myocardium

A systematic transition from chronic stunning to hibernation occurs as coro nary flow reserve decreases to a critical level. Hibernating myocardium exh ibits apoptosis-induced myocyte loss and a reduction in the expression of t he sarcoplasmic reticulum (SR) Ca2+ ATPase but whether similar cellular cha nges occur in chronic stunning is unknown. Pigs with a chronic left anterio r descending coronary artery (LAD) stenosis were studied one (n = 9) or two (n = 10) months after instrumentation. Anterior hypokinesis with normal le vels of resting perfusion developed at each time-point, consistent with chr onic stunning. After I month, subendocardial flow reserve was moderately re duced (adenosine/rest, LAD: 3.60 +/- 0.91 v Remote: 6.00 +/- 0.54, P <0.01) with no regional differences in SR protein expression, no increase in apop tosis (32 +/- 6 v 21 +/- 5 nuclei/10(6) myocyte nuclei, p-ns) and no region al myocyte loss (1976 +/- 44 v 1955 +/- 30 nuclei/mm(2), p-ns). After 2 mon ths, sub-endocardial flow reserve in chronically stunned myocardium was sev erely impaired (LAD: 1.41 +/- 0.21 v Remote: 5.59 +/- 0.96, P <0.01). There were small but significant reductions in LAD mRNA and protein levels for t he SRCa2+ ATPase and phospholamban whereas calsequestrin was unchanged. In addition, regional myocyte apoptosis increased (127 +/- 24 v 55 +/- 9 nucle i/106 myocyte nuclei, P<0.01), resulting in the onset of myocyte loss.(1293 <plus/minus> 50 v 1394 +/- 32 nuclei/mm(2), P<0.01). Apoptosis-induced myo cyte loss and reductions in SR protein expression are not invariably presen t in viable chronically dysfunctional myocardium. They are induced as the p ropensity of a region to develop reversible ischemia increases (as reflecte d by coronary flow reserve). The temporal progression indicates that altera tions in SR protein expression and myocyte apoptosis precede the transition from chronically stunned to hibernating myocardium, <(c)> 2001 Academic Pr ess.