Capsaicin-induced cardioprotection. Is hypothermia or the salvage kinase pathway involved?

PURPOSE: Topical capsaicin application was shown to reduce infarct size in experimental animal models. We hypothesized that cardioprotective properties of topical capsaicin application could be related to its hypothermic effect. METHODS: In the first arm of the study, anesthetized rats received capsaicin cream (Caps group) or vehicle (Control group, Ctrl) applied either 15 or 30 min prior to a 30-min coronary artery occlusion followed by 2-h reperfusion. Core body temperature was allowed to run its course, and was monitored via rectal probe. At the end of the protocol, hearts were excised and risk zone and infarct size were measured. In an additional set of animals, hearts were excised immediately after a 15-min application of capsaicin/vehicle, and were used to measure phosphorylated Akt and Erk1/2 with western blots. In the second arm of the study Ctrl (n = 6) and Caps-treated (n = 5) animals were subjected to the same protocol as rats in the first arm, but core body temperature was maintained at 36 °C. RESULTS: In the first arm of the study, capsaicin produced a rapid decrease in rectal temperature ranging from 0.22 to 1.78 °C at pre-occlusion, with a median level of 0.97 °C. A capsaicin-induced temperature decrease of >0.97 °C was associated with a 31.2 % smaller infarct compared to the control group. Capsaicin treatment induced an increase in the levels of phosphorylated Akt and Erk1/2 at the end of capsaicin cream application. No increase in the phosphorylation of downstream p70S6 was observed. Levels of phosphorylated Akt- and Erk1/2 did not correlate with temperature changes after treatment. In the second arm of the study, in which body core temperature was maintained at 36 °C, no change in the infarct size was observed in the capsaicin vs. control group. CONCLUSION: In the current study we for the first time demonstrated that the capsaicin induced cardioprotective effect might be related to mild hypothermia, caused by capsaicin topical application. The salvage kinase pathway appears not to be critical for capsaicin-induced cardioprotection.

Plasmon-enhanced four-wave mixing for superresolution applications.

We introduce a nonlinear optical approach to transform spatial information stored in evanescent waves into propagating ones: we study analytically the use of partially degenerate four-wave mixing in thin metallic film to map a band of evanescent waves at a given frequency into a propagating-wave band at a different one. The relatively low efficiency of this process is compensated by setting the pump beam, mediating this transformation, to be a surface plasmon polariton, whose field enhancement increases the nonlinear interaction strength. This setting can be utilized for nonresonant plasmon-assisted superresolution applications that support transverse-electric polarization, in contrast to linear plasmonic imaging (such as superlens) that can only transfer transverse-magnetic waves.

Remote ischemic preconditioning for coronary artery bypass graft operations.

Ischemia-reperfusion injury occurs during coronary artery bypass graft operations. Strategies are needed to lower the extent of damage. Attempts to find these strategies have been occurring for more than 40 years, with remote ischemic preconditioning being one method. This review provides a look at potential mechanisms involved in remote ischemic preconditioning, experimental evidence supporting it, clinical studies that support and negate it, and potential reasons for differences between clinical studies. With remote ischemic preconditioning having the potential to better clinical outcomes in patients undergoing coronary artery bypass graft operations, a large clinical trial needs to be undertaken to better assess its practical clinical application.

Role of protein kinase C in ischemic "conditioning": from first evidence to current perspectives.

Since the discovery of ischemic preconditioning (IPC) 26 years ago, numerous studies attempted to determine the mechanism of this powerful form of cardioprotection. One of the first proposed pathways of IPC suggested that the preconditioning stimulus activated phospholipase C via G-protein, and diacylglycerol released from phospholipid moieties activated protein kinase C (PKC) by translocating it from the cytosol to the sarcolemmal membranes. The major protective isoform of PKC was found to be the PKC-∈. Despite some contradictions and controversies, today even the most skeptical opponents acknowledge that PKC plays a significant role in the mechanism of IPC. During recent years, both the role and the place of PKC-∈ in the mechanism of IPC have been revised. The current review presents the evolution of the "PKC theory" and summarizes the most recent data regarding the role of PKC in IPC. In addition to classical IPC, PKC appears to play a role in the mechanisms of newer conditioning protocols, that is, remote IPC and ischemic postconditioning.

The effect of acute versus delayed remote ischemic preconditioning on reperfusion induced ventricular arrhythmias.

INTRODUCTION: The effect of remote ischemic preconditioning (RIPC) on arrhythmias in in vivo models is unknown. Our purpose was to determine effects of both acute and delayed RIPC on arrhythmias. METHODS AND RESULTS: In the acute protocol anesthetized open chest rats were exposed to 5 minutes of proximal left coronary artery occlusion (CAO) and 10 minutes of reperfusion. Rats were either untreated (ischemia/reperfusion, IR group, n = 17) or received RIPC (n = 14) with 5 minutes bilateral femoral occlusions followed by 5 minutes of reperfusion times 3, started 30 minutes before CAO. At reperfusion, onset of ventricular tachycardia (VT) was delayed in RIPC group (25.7 seconds) versus IR (8.8 seconds; P = 0.04). Number of episodes of VT was 17.0 in IR versus 3.0 in the RIPC group (P = 0.01) and duration of VT was 54.1 seconds in IR versus 4.9 seconds in RIPC (P = 0.019). Number of ventricular premature complexes (VPC) was 26.0 in IR and 10.0 in RIPC rats (P = 0.04). Levels of reperfusion injury salvage kinases (RISK), that is, phospho-Akt and phospho-p70S6 in the risk area of IR and RIPC hearts were similarly higher compared to the nonischemic areas both at 1 and 10 minutes into reperfusion. Delayed RIPC was induced on day 1 and on day 2, myocardial IR was induced. Delayed RIPC did not affect VT or VPC. CONCLUSION: Acute RIPC of the lower limbs induced a powerful delay in/and reduction in IR induced ventricular arrhythmias, but without evoking the RISK pathway; a late protective phase of RIPC on arrhythmias did not occur.

Ranolazine as a cardioplegia additive improves recovery of diastolic function in isolated rat hearts.

BACKGROUND: Ranolazine (Ran), an antianginal agent, inhibits late Na(+) current. The purpose of this study was to determine whether there was an added benefit of adding Ran to cardioplegia (CP) in a model of global ischemia/reperfusion. METHODS AND RESULTS: Isolated rat hearts were Langendorff-perfused and exposed to 40-minute normothermic, cardioplegic global ischemia and 30 minutes of reperfusion. Before ischemia and during reperfusion, hearts were treated with no drug (control) or with the late Na(+) current inhibitors Ran (5 micromol/L) or tetrodotoxin (1 micromol/L). Ischemic cardioplegic arrest led to an increase of left ventricular end-diastolic pressure (LVEDP) by > or =20 mm Hg (ie, cardiac contracture). Ten out of 11 hearts treated with CP alone developed contracture, whereas 6 out of 11 hearts treated with CP plus Ran developed contracture. Ran added to CP reduced LVEDP at the end of ischemia from 41+/-5 mm Hg in CP alone to 26+/-3 mm Hg in CP plus Ran (P=0.024). Area under the curve for LVEDP during the entire ischemic period was also smaller in CP plus Ran versus CP alone. The percent increase (from baseline) of LVEDP measured at the end of 30-minute reperfusion was smaller for CP plus Ran (66+/-18%) versus CP alone (287+/-90%; P=0.035). The area under the curve for LVEDP during reperfusion was smaller in CP plus Ran versus CP alone. Tetrodotoxin (1 micromol/L) also reduced cardiac contracture during ischemia/reperfusion, compared to CP alone. CONCLUSIONS: Our results suggest that Ran may have therapeutic potential as an adjunct to CP and further support a protective role of Na(+) current inhibition during ischemia/reperfusion.

Particulate air pollution and coronary heart disease.

PURPOSE OF REVIEW: Air pollution poses a significant health risk. The article focuses on the adverse effects of air pollution on the cardiovascular system. RECENT FINDINGS: Short-term and long-term studies clearly indicate that relatively modest exposures to particulate matter in the ambient air are associated with increased morbidity and mortality due to coronary heart disease. In humans, inhalational exposure to particulate air pollutants decreases heart rate variability, causes ST-segment depression and endothelial dysfunction, increases blood pressure and blood coagulability, and accelerates the progression of atherosclerosis. Mechanisms of air pollution-induced cardiotoxicity include increased generation of reactive oxygen species followed by activation of proinflammatory and prothrombotic pathways. In experimental settings, ultrafine air pollutants instilled directly into the cardiac vasculature depress cardiac contractility and decrease coronary flow. Both effects are attenuated by the use of a free radical scavenger. SUMMARY: Reactive oxygen species-related mechanisms of air pollution cardiotoxicity might become a valid target in developing new pharmacological strategies aimed at decreasing adverse effects of air pollution during extreme episodes (fires, earthquakes, industrial accidents, acts of terrorism). Educating patients and the general population on the negative cardiovascular effects of air pollution might be helpful in decreasing the risk of developing air pollution-related coronary heart disease.

Critical role of nuclear calcium/calmodulin-dependent protein kinase IIdeltaB in cardiomyocyte survival in cardiomyopathy.

Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a central role in cardiac contractility and heart disease. However, the specific role of alternatively spliced variants of CaMKII in cardiac disease and apoptosis remains poorly explored. Here we report that the deltaB subunit of CaMKII (CaMKIIdeltaB), which is the predominant nuclear isoform of calcium/calmodulin-dependent protein kinases in heart muscle, acts as an anti-apoptotic factor and is a novel target of the antineoplastic and cardiomyopathic drug doxorubicin (Dox (adriamycin)). Hearts of rats that develop cardiomyopathy following chronic treatment with Dox also show down-regulation of CaMKIIdeltaB mRNA, which correlates with decreased cardiac function in vivo, reduced expression of sarcomeric proteins, and increased tissue damage associated with Dox cardiotoxicity. Overexpression of CaMKIIdeltaB in primary cardiac cells inhibits Dox-mediated apoptosis and prevents the loss of the anti-apoptotic protein Bcl-2. Specific silencing of CaMKIIdeltaB by small interfering RNA prevents the formation of organized sarcomeres and decreases the expression of Bcl-2, which all mimic the effect of Dox. CaMKIIdeltaB is required for GATA-4-mediated co-activation and binding to the Bcl-2 promoter. These results reveal that CaMKIIdeltaB plays an essential role in cardiomyocyte survival and provide a mechanism for the protective role of CaMKIIdeltaB. These results suggest that selective targeting of CaMKII in the nuclear compartment might represent a strategy to regulate cardiac apoptosis and to reduce Dox-mediated cardiotoxicity.

Ischemic preconditioning maintains cardioprotection in aging normotensive and spontaneously hypertensive rats.

We determined whether ischemic preconditioning could reduce infarct size and improve cardiac function in both aging normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The left anterior descending coronary artery was occluded for 1h followed by 3 h reperfusion in aging ( approximately 16 months old) SHR rats and age-matched WKY rats. Hearts were either preconditioned or not (control group) prior to 1h of coronary artery occlusion. The preconditioning regimen consisted of three cycles of 3 min occlusion followed by 5 min reperfusion applied prior to the subsequent 1h occlusion. In WKY (n=12 each group), the risk zone was similar in the control (51+/-2%) and preconditioned group (46+/-2%; p=0.1). Preconditioning significantly reduced infarct size (as a percentage of the ischemic risk zone) (24+/-6%) compared to controls (51+/-5%; p=0.0026). In SHR rats (n=9 each group), the risk zone was smaller in the preconditioning group (41+/-3%) than in the control group (51+/-3%; p=0.035). Infarct size (as % of ischemic risk zone) was also significantly reduced in the preconditioned group (13+/-4%) compared to controls (62+/-5%; p<0.0001). For both WKY and SHR rats, for any sized risk zone the infarct size was smaller in preconditioned hearts compared with the control hearts. Preconditioning improved aspects of LV function during ischemia and reperfusion phase in SHR rats, but these benefits were not observed in the WKY rats. Preconditioning maintains powerful cardioprotection in aging normotensive hearts as well as aging hypertrophied hearts.

Ranolazine as an adjunct to cardioplegia: a potential new therapeutic application.

The purpose of this study was to examine the therapeutic potential of ranolazine, a novel antianginal drug, as an adjunctive therapy to hyperkalemic cardioplegia. Rat hearts were Langendorff-perfused and exposed to 40 minutes of ischemia and 30 minutes of reperfusion without (control) or with cardioplegia or cardioplegia with 50 micromol/L ranolazine. During ischemia, cardioplegia prolonged time to contracture, defined as the time to reach an intraventricular pressure of 20 mm Hg, from 12 +/- 1 minute (control) to 25 +/- 2 minutes (P < .05). Ranolazine supplement further lengthened the time to contracture to 34 +/- 2 minutes (P < .05). Ischemia/reperfusion caused a dramatic elevation in left ventricular end diastolic pressure (LVEDP) during reperfusion. Cardioplegia lessened the LVEDP elevation measured at 30 minutes of reperfusion from 76 +/- 3 mm Hg (control) to 32 +/- 3 mm Hg (P < .05). The increase in LVEDP was reduced even further to 17 +/- 2 mm Hg in hearts receiving cardioplegia plus ranolazine (P < .05). These results suggest that addition of ranolazine during hyperkalemic ischemic cardioplegic arrest is beneficial and provides further protection against contracture.

Air pollution and cardiovascular injury epidemiology, toxicology, and mechanisms.

Recent epidemiologic studies show that increased levels of air pollutants are positively associated with cardiovascular morbidity and mortality. Inhalation of air pollutants affects heart rate, heart rate variability, blood pressure, vascular tone, blood coagulability, and the progression of atherosclerosis. Several categories within the general population (i.e., people with pre-existing cardiovascular disease and diabetic and elderly individuals) are considered to be more susceptible to air pollution-mediated cardiovascular effects. Major mechanisms of inhalation-mediated cardiovascular toxicity include activation of pro-inflammatory pathways and generation of reactive oxygen species. Although most studies focus on the influence of systemic effects, recent studies indicate that ultrafine particles may be translocated into the circulation and directly transported to the vasculature and heart where they can induce cardiac arrhythmias and decrease cardiac contractility and coronary flow.

Direct and acute cardiotoxic effects of ultrafine air pollutants in spontaneously hypertensive rats and Wistar--Kyoto rats.

It is hypothesized that preexisting cardiovascular disease could affect the susceptibility to direct and acute cardiotoxic effects of ultrafine air pollutants. Ultrafine particles (UFP) isolated from 12.5 mg of diesel particulate matter (National Institute of Standards and Technology) were infused into isolated Langendorffperfused hearts obtained from spontaneously hypertensive rats (SHR) and normotensive control Wistar- Kyoto rats (WKY). Perfusion for 30 minutes with UFP reduced cardiac function in both groups-but to a greater extent in WKY. In SHR, developed pressure was reduced by 24.1 +/- 4.4% of baseline and maximal dP/dt was reduced by 19.8 +/- 4.9%; in WKY, developed pressure was reduced by 43.5 +/- 7.3% and maximal dP/dt by 41.8 +/- 8.2% (P < .05 for maximal dP/dt in SHR vs WKY). Coronary flow was decreased by 30.3% versus 53.7% in SHR versus WKY ( P < .05). The results of this study suggest that although UFP depress myocardial contractile response and coronary flow in both SHR and WKY the underlying hypertension does not necessarily worsen the response.

Direct and acute cardiotoxicity of ultrafine particles in young adult and old rat hearts.

BACKGROUND: Air pollution is associated with significant increases in cardiac morbidity and mortality in the general population. The elderly cohort within the general population is considered at high risk for cardiac diseases. However the degree to which air pollutants affect cardiac responses in old hearts vs. their young adult counterparts has not been systematically addressed. OBJECTIVES: We sought to investigate the response of young adult vs. old rat hearts to the direct exposure of ultrafine particles (UFP); i.e. when the UFP are directly instilled into the cardiac vasculature, and their effects are not dependent upon UFP inhalation. METHODS: The study was performed in isolated Langendorff-perfused rat hearts obtained from young adult (4 months old) and aged (26 months old) Fisher 344/Brown Norway rats. Two treatment groups (control and UFP-treated) were studied, and two ages (young adult and old) were studied within each group. Control hearts were perfused with buffer only, UFP-treated hearts were perfused with buffer containing ultrafine particles isolated from industrial diesel reference particulate matter. Systolic and end-diastolic pressures, positive and negative dP/dt, and coronary flow were measured. RESULTS: Young adult and old hearts demonstrated equal functional deterioration in response to direct infusion of UFP. Developed pressure in young adult UFP-treated hearts fell from 101+/-4 to 68+/-8 mmHg (a decrease by 33%, p<0.05). In the old UFP-treated hearts developed pressure fell by 35% (from 101+/-7 to 67+/-9 mm Hg, p<0.05). Positive dP/dt was equally affected in the young adult and old UFP-treated hearts and was decreased by 28% in both groups. CONCLUSION: Ultrafine particles when instilled directly into the cardiac vasculature were equally cardiotoxic in young adult and old rat hearts.

In vivo and in vitro models to test the hypothesis of particle-induced effects on cardiac function and arrhythmias.

Exposure to ultrafine particles (UFPs) by inhalation increases the number and severity of cardiac events. The specific mechanism(s) of action are unknown. This study was designed to examine whether UFPs could exert a direct effect on the cardiovascular system without dependence upon lung-mediated responses. The direct effects of UFPs were determined in normal rats (infused intravenously with UFPs), and in the isolated Langendorff perfused rat heart. UFPs from either ambient air (UFAAs) or diesel engine exhaust (UFDGs) were studied. Infusion of UFDGs prepared in our laboratory caused ventricular premature beats (VPBs) in 2 of 3 rats in vivo. Ejection fraction increased slightly (approximately 4.5%) in rats receiving UFPAA and was unchanged in the UFDG and saline groups in vivo. In the isolated rat heart, perfused according to Langendorff, UFDGs caused a marked increase in left-ventricular end-diastolic pressure (LVEDP; from 12.0 +/- 4.6 mmHg to 24.8 +/- 11.2 mmHg, p < 0.05) after 30 min of exposure. UFPs isolated from industrial diesel particulate matter (UFIDs), obtained from the National Institute of Standards and Technology, caused a significant decrease in left-ventricular systolic pressure (LVSP; from 85.7 +/- 4.0 mmHg to 37.9 +/- 20.3 mmHg, p < 0.05) and +/- dP/dt (from 2,365 +/- 158 mmHg/s to 1,188 +/- 858 mmHg/s, p < 0.05) at 30 min after the start of infusion. This effect was absent when the soluble fraction (containing no particles) isolated from the UFIDs was studied. These findings indicate that UFPs can have direct effects on the cardiovascular system that are independent of effects of particles on the lungs.

Molecular aspects of ischemic heart disease: ischemia/reperfusion-induced genetic changes and potential applications of gene and RNA interference therapy.

Molecular biologic techniques have a variety of applications in the study of ischemic heart disease, including roles in elucidating cardiac genetic changes resulting from ischemia as well as in developing therapeutic interventions to treat ischemic heart disease. This review describes recent studies documenting genetic changes associated with myocardial ischemia and infarction as well as those investigating the safety and effectiveness of gene therapy for stimulating angiogenesis, protecting the heart against reperfusion injury, and treating heart failure. Also discussed are future research directions, including the potential use of RNA interference and combined stem cell therapy and gene therapy for the treatment of cardiovascular disease.

Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics.

Mildronate is a fatty acid oxidation inhibitor approved as an antianginal drug in parts of Europe. We carried out the first study to determine whether a 10-day course of mildronate could reduce myocardial infarct size (IS) during acute myocardial ischemia. Sprague Dawley rats received 200 mg/kg/d of mildronate (treated group, n = 16) or sterile water (control group, n = 14) subcutaneously for 10 days before ischemia-reperfusion. Rats were then subjected to 45 minutes of left coronary artery occlusion and 2 hours of reperfusion. The 2 groups had identical areas at risk: treated 38 +/- 3%; controls 38 +/- 2%. The amount of necrosis was smaller in the mildronate group at 16 +/- 2% of the left ventricle versus controls, 22 +/- 2% (P = 0.05); and for any amount of risk >25%, necrosis was smaller in the treated group (P = 0.0035). Myocardial IS (% of risk zone) was 43+/-3% in the mildronate-treated rats, and 57+/-4% in controls (P = 0.004). During occlusion, there were no differences between the 2 groups in heart rate (216 +/- 12 bpm, mildronate and 210 +/- 9 bpm, control), in mean arterial pressure (60 +/- 2 mm Hg, mildronate and 64 +/- 3 mm Hg, control) or in the frequency of arrhythmias. Our study for the first time demonstrated that a 10-day treatment with mildronate reduced myocardial IS in an experimental model of acute myocardial ischemia, without any effect on hemodynamics.

Washout of transplanted cells from the heart: a potential new hurdle for cell transplantation therapy.

OBJECTIVE: The number of viable transplanted cells in the heart is sharply decreased shortly after cell injection. The exact mechanics of cell loss are unclear. We hypothesized that immature cardiac cells transplanted directly into rat heart could be washed out via the cardiac vasculature, and carried to other organs. METHODS: Female Fischer rats were subjected to 60 min of coronary artery occlusion followed by 3 h of reperfusion (OR group) or 4 h or permanent coronary artery occlusion (PO group). Neonatal rat cardiac cells (5x10(6)) were injected directly into the free wall of the left ventricle at either 15 min post-reperfusion (OR group) or 75 min after occlusion (PO group). At the end of the protocol, a histological analysis for transplanted cells in the heart (i.e. microscopic examination for cells in approximately 790 histogic fields within each heart) and polymerase chain reaction (PCR)-based determination of the Sry gene (a male cell marker) in the heart and other organs were performed. RESULTS: In the OR group, only 3.39+/-0.69% fields contained immature cells compared to 6.57+/-1.33% fields in the PO group (p<0.05). Cardiac blood vessels contained round, immature cardiomyocytes. PCR analysis revealed that 100% of the animals (5 of 5) in both groups had cells present in their hearts and lungs, 40% of the OR group and 60% of the PO group demonstrated cells in the liver and kidneys, and 40% of the PO group had cells in the spleen. CONCLUSION: Neonatal cardiomyocytes injected directly into the area at risk of the heart escape acutely from the infract to other organs through the vascular system of the heart; loss of cells is more prominent with reperfusion.

New cellular and molecular approaches for the treatment of cardiac disease.

Similar to the kidney in uremia, end-stage cardiac failure is an outcome common to many disparate disease processes including hypertension, various inflammatory pathologies, as well as ischemic loss of tissue. In regard to the heart, cellular and molecular mechanisms responsible for heart failure have been investigated with renewed intensity over the past several years with newer techniques of molecular genetics, genomic analysis, and cell biology. Although this article reviews some recent advances made in our understanding of molecular and cellular events in the heart leading to heart failure and explores possible new targets for therapeutics, the main point is to stress the importance of investigative interactions between organ physiologists and molecular and cellular biologists. These interactions between organ physiologists and molecular geneticists is stressed and supported as a mechanism for rapid advancement for both understanding the underlying pathophysiology of human disease and the development of therapeutic strategies.

Metabolic mechanism by which mild regional hypothermia preserves ischemic tissue.

BACKGROUND: Our laboratory demonstrated that mild regional hypothermia reduced myocardial infarct size by an average of 65% in the rabbit model of regional ischemia. The exact mechanism for this benefit has not been explored. We hypothesized that a moderate reduction in regional myocardial temperature could preserve cardiac energy metabolism and thus protect the myocardium from sustained ischemic insult. METHODS AND RESULTS: Anesthetized open-chest rabbits were randomized to normothermic sham-operated (NS, n = 6), hypothermic sham-operated (HS, n = 6), normothermic ischemic (NI, n = 10), and hypothermic ischemic (HI, n = 10) groups. Both sham-operated groups received no occlusions, and both ischemic groups were subjected to 20 minutes of coronary occlusion. To achieve regional cooling of the hearts in the hypothermic groups, a bag of ice water was placed directly on the risk area 15 minutes prior to coronary artery occlusion/no intervention and maintained for the duration of the subsequent 20 minutes of ischemia/no intervention (in the HI and HS groups respectively). Hypothermia preserved adenosine triphosphate (ATP) and glycogen stores in the ischemic area by 42.9% and 84.2%, respectively (1.20 +/- 0.11 micromoles ATP/g wet tissue vs 0.84 +/- 0.06 micromoles ATP/g wet tissue and 8.16 +/- 0.95 micromoles of glucosyl unit/g wet tissue vs 4.43 +/- 0.44 micromoles of glucosyl unit/g wet tissue in the HI and the NI groups, respectively). In addition, hypothermia resulted in a trend toward creatine phosphate preservation in the nonischemic area. CONCLUSIONS: This is the first demonstration that local therapy with mild reductions in myocardial temperature preserves energy metabolism both in the ischemic and the nonischemic areas as well. The preservation in ATP is the likely mechanism by which regional hypothermia is preserving ischemic myocardium.