Letter by Metzler et al Regarding Article, “Intracoronary KAI-9803 as an Adjunct to Primary Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction”
To the Editor:
The Direct Inhibition of δ-Protein Kinase C Enzyme to Limit Total Infarct Size in Acute Myocardial Infarction (DELTA MI) Investigators1 report that the intracoronary application of KAI-9803, a δ-protein kinase C inhibitor, during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction, was safe and led both to a nonsignificant reduction of infarction as measured by creatine kinase MB and 99mtechnetium sestamibi.
We have previously demonstrated in an in vivo mouse model of myocardial infarction, that PKCδ deficiency (PKCδ−/−) is associated with a reduction of infarct size.2 Consistent with the findings described in the DELTA MI trial, this difference failed to reach statistical significance. However, we also observed that ischemic preconditioning before index ischemia resulted in exaggerated myocardial injury in PKCδ−/− hearts as shown by biomarker measurements (creatine kinase MB, troponin T, and lactate dehydrogenase isoenzyme 1) and triphenyltetrazolium chloride delineation of infarction. This increase in infarction in the preconditioned PKCδ−/− mice was in striking contrast to the preconditioning-induced cardioprotection in wild-type controls. On the basis of proteomic and metabolomic analyses, we demonstrated that PKCδ deficiency alters cardiac metabolism, that reactive oxygen species generated during early ischemic preconditioning oxidize key mitochondrial enzymes and that this metabolic adaptation to preconditioning is impaired in PKCδ−/− hearts.2,3
Evidence for PKCδ-mediated cardioprotection2,4 advises caution and further investigation of the therapeutic window of PKCδ inhibition in patients. The high dose of KAI-9803 administered to cohort 4 has already been associated with an increase, rather than a decrease, in infarct size.1 Notably, preinfarction angina, also called prodromal angina, is estimated to occur in ≈30% of all patients with myocardial infarction and reduces infarction size similar to ischemic preconditioning.5 Thus, we would like to draw attention to the potential deleterious effects of complete PKCδ inhibition in the myocardium, especially in patients with prodromal angina.
The Direct Inhibition of ƒ-Protein Kinase C Enzyme to Limit Total Infarct Size in Acute Myocardial Infarction (DELTA MI) Investigators. Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Circulation. 2008; 117: 886–896.
Mayr M, Metzler B, Mair J, McGregor E, Lercher A, Mayr U, Hu Y, Baier G, Leitges M, Pachinger O, Dunn M, Xu Q. Ischemic preconditioning exaggerates cardiac damage in PKC-δ null mice. Am J Physiol. 2004; 287: H946–H956.
Mayr M, Chung Y, Mayr U, McGregor E, Troy H, Baier G, Leitges M, Dunn MJ, Griffiths JR, Xu Q. Loss of PKC-δ alters cardiac metabolism. Am J Physiol. 2004; 286: H937–H945.
Fryer RM, Wang Y, Hsu AK, Gross GJ. Essential activation of PKC-delta in opioid-initiated cardioprotection. Am J Physiol. 2001; 280: H1346–H1353.
Ottani F, Galvani M, Ferrini D, Sorbello F, Limonetti P, Pantoli D, Rusticali F. Prodromal angina limits infarct size: a role of ischemic preconditioning. Circulation. 1995; 91: 291–297.