Both Systolic and Diastolic Dysfunction Characterize Nonischemic Inhibition of Myocardial Energy Metabolism: An Experimental Strain Rate Echocardiographic Study Josef Korinek, MD, Peter C. Anagnostopoulos, MD, Cristina Pislaru, MD, Petras Dzeja, PhD, James B. Seward, MD, Andre Terzic, MD, PhD, and Marek Belohlavek, MD, PhD, Rochester, Minnesota Background: Ischemia is primarily a metabolic event. However, regional functional changes can be affected by structural alterations. We developed an experimental model of sole myocardial energy me- tabolism inhibition and characterized the resulting regional dysfunction. Methods: In 12 pigs, we regionally inhibited creat- ine kinase (CK) and, consequently, myocyte high- energy phosphate transfer by intracoronary admin- istration of iodoacetamide. Myocardial biopsies for CK activity and structural analyses and strain rate (SR) echocardiography scans were obtained at base- line and 60 minutes after iodoacetamide administra- tion. Plasma levels of the CK isoenzyme MB and troponin I were assessed to determine possible myo- cardial damage. Results: CK activity in the iodoacetamide-perfused myocardium decreased to 0.5% of the original value and was accompanied by a reduction in peak systolic SR (P < .0001), end-systolic strain (P < .0001), and peak SRs of myocardial early and late filling waves (P < .0001). Microscopy showed contracture without sarcomere disruption. Plasma levels of CK isoenzyme MB and troponin I did not change. Conclusions: Regional inhibition of myocyte ener- getics leads to both systolic and diastolic dysfunc- tion by SR echocardiography, but the presence of a residual phosphotransfer protects microstructural integrity. (J Am Soc Echocardiogr 2004;17:1239-44.) Myocardial contraction and relaxation result from cyclic interactions between actin and myosin that form a dynamic actomyosin complex. Energy for contrac- tion is provided by adenosine triphosphate (ATP). 1 ATP is also a source of energy for sarcoplasmic reticu- lum calcium pump ATPase, which catalyzes the up- take of calcium to the sarcoplasmic reticulum, thus, facilitating conditions for relaxation. 2 Moreover, ATP displaces adenosine diphosphate from binding to a contracted actomyosin complex and allows the actual relaxation. 3 ATP is produced by mitochondria and delivered to its use sites by a mechanism of phospho- transfer. Normally, phosphotransfer is 90% catalyzed by creatine kinase (CK). 4 Experimentally induced inhibition of phospho- transfer (CK) by iodoacetamide (IAA) should lead to cessation of actomyosin cycling associated with diastolic and systolic dysfunction but with preserved intracellular and extracellular structural integrity. 5-8 Although energy metabolism in isolated myocardial strips or cardiomyocytes has been characterized under various working conditions in vitro, 9 regional functional changes in the left ventricle (LV) associ- ated solely with inhibition of actomyosin cross- bridge cycling have never been described. Strain rate (SR) echocardiography has proven suitable for regional analysis of LV systolic and diastolic func- tion. 10-13 The phosphotransfer inhibition would sim- ulate an impairment of myocyte energy metabolism, as it is typical for myocardial ischemia, 14 but without the accompanying structural changes that could confound characterization of regional function by SR echocardiography. We hypothesized that regional nonischemic inhi- bition of myocardial energy metabolism by IAA From the Department of Internal Medicine, Division of Cardio- vascular Diseases and Department of Physiology and Biomedical Engineering (C.P.), Mayo Clinic. Supported by the HL 68555 grant (Dr Belohlavek) and Research Training Fellowship (Dr Anagnostopoulos) from the National Institutes of Health, and by a research grant (Dr Belohlavek) from GE Medical Ultrasound. Reprint requests: Marek Belohlavek, MD, PhD, Translational Ul- trasound Research, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (E-mail: belohlavek.marek@mayo.edu). 0894-7317/$30.00 Copyright 2004 by the American Society of Echocardiography. doi:10.1016/j.jecho.2004.08.015 1239