Ischemic Risk Area Research Articles

The Acute Effect of Fructose on Cardiac Hemodynamic Responses and Infarcted Area in Isolated Rat Heart During Ischemia-Reperfusion

Introduction: This study aimed to investigate the effects of fructose on cardiac hemodynamics and infarct size and the role of the antioxidant mechanism in these effects in isolated rat hearts undergoing ischemiareperfusion. Patients and Methods: Isolated hearts obtained from female Wistar rats were perfused with Krebs-Henseleit solution containing 12 mM glucose or solution containing 12 mM fructose or 48 mM fructose and underwent lowflow ischemia followed by reperfusion on the Langendorff apparatus. Left ventricular developed pressure (LVDP), timedependent pressure changes (dp/dt max, dp/dt min) and heart rates were recorded at the 1st, 15th and 120th minutes of reperfusion following ischemia, and the percentage of the infarct area and the size of the risk area were determined. At the end of the reperfusion, total oxidant capacity (TOS), malondialdehyde (MDA) and glutathione (GSH) levels were examined in perfusion fluid samples. Results: Basal dp/dt max values were lower in the high fructose group compared to the glucose group (p= 0.032). When the hearts were perfused with 12 mM fructose, a significant increase was observed in the percentage of the ischemic area and risk area compared to equivalent glucose and high fructose (p< 0.001 and p< 0.001, respectively). MDA, GSH and TOS values were comparable in all groups. Conclusion: The present study shows that fructose perfusion plays a role in reduced ventricular contractile function relative to glucose in isolated rat hearts. This reduction triggered by fructose appears to be independent of antioxidant mechanisms. Furthermore, fructose perfusion at glucose-equivalent concentration causes a greater increase in infarct area in ischemic hearts, whereas an increase in fructose concentration appears to prevent this effect.

Abstract 13279: Effects of SBT-255 on Myocardial Infarct Size and No Reflow in a Rat Myocardial Ischemia/Reperfusion Model

Background: We determined whether mitochondrial protective agents, elamipretide and SBT-255, could limit myocardial infarct (MI) size and the no reflow phenomenon in a standardized rat model. Methods and Results: Anesthetized rats were randomized into 3 groups (n = 15 in each group): (1) Saline control group; (2) Bolus dose of elamipretide (1 mg/kg body weight); (3) Bolus dose of SBT-255 (1 mg/kg body weight). The treatment was administered at 10 minutes after coronary artery occlusion. The coronary occlusion was maintained for 30 minutes followed by 3 hours of reperfusion. MI size (triphenyl tetrazolium chloride staining technique), expressed as a percentage of the ischemic risk zone (blue dye technique) was significantly lower in the SBT-255 treated group at 30.2 ± 5.0% versus 53.1 ± 4.0% in the saline group and 48.1 ± 5.1% in the elamipretide group (p=0.001). Area of no-reflow (thioflavin S technique) as a percentage of the risk zone was significantly smaller in the SBT-255 treated group (22.2 ± 5.4%) compared to the saline (38.0 ± 3.4%) and elamipretide groups (36.4 ± 5.0%; p=0.024). The Figure demonstrates the association between myocardial ischemic risk area and infarct size (panel A) as well as no-reflow size (panel B) among the 3 groups. The regression lines in both infarct size and no-reflow size shift downward in SBT-255 group compared to the saline and elamipretide group, indicating that, for the same size of risk area, the infarct size and no-reflow were smaller in the SBT-255 group than the other groups. Conclusions: SBT-255 treatment significantly reduced infarct size and no-reflow size compared to either saline or elamipretide treatment in an acute rat myocardial ischemia/reperfusion model.

Tissue kallikrein-related peptidase8 protects rat heart against acute ischemia reperfusion injury

Tissue kallikrein-related peptidases (KLKs) play important roles in acute cardiac injury and cardiac remodeling. However, the exact cardiac actions of KLK8 have not been determined.Transgenic rat overexpressing KLK8 was established to examine the role of KLK8 in the heart. Cardiac injury was induced by ischemia/reperfusion (I/R) and examined by infarct size measurement and TUNEL staining. The molecular mechanisms were investigated in cultured neonatal rat cardiomyocytes (CMs). Western blot analysis was used to determine the protein levels.KLK8 protein level was significantly increased in the cardiac ischemic risk area. KLK8 overexpression mitigated I/R-induced cardiac injury, as evidenced by decreased infarct size and apoptosis in cardiac ischemic risk area in vivo. Via in vitro studies, it was found that KLK8 overexpression attenuated the Hypoxia/Reoxygenation (H/R) injury in CMs; both B2R and PAR2 antagonist significantly attenuated KLK8-induced protective actions under H/R injury. Moreover, KLK8 overexpressed CMs showed significant higher phosphorylation levels of Akt, ERK1/2 and PKA under H/R stimulation; B2R antagonist attenuated the phosphorylation levels of Akt and ERK1/2, while PAR2 antagonist attenuated the phosphorylation levels of PKA and ERK1/2.KLK8 protects the heart against I/R-induced cardiac injury, which may represent a new therapeutic target in cardiac medicine.

Abstract 12589: Delayed Therapeutic Hypothermia Protects Against the Myocardial No-reflow Phenomenon Independent of Infarct Size in a Rat Ischemia/reperfusion Model

Background: Adjunctive therapy in addition to reperfusion to reduce myocardial infarct size has been disappointing based on clinical trials. New therapeutic targets independent of infarct size modification are needed. No-reflow predicts poor clinical outcome. In this study, we investigate the effects of a single application of delayed (post-reperfusion) therapeutic hypothermia (TH) on no-reflow in rats. Methods: Rats were subjected to 60 min of coronary artery occlusion followed by 3 hours of reperfusion. Rats were divided into normothermic (n=5) and TH (n=5) groups. In the TH, hypothermia was initiated at 1 minute after coronary artery reperfusion by pumping room-temperature (22 °C) saline into and out of the thoracic cavity for 1 hour. This decreased intra-thoracic temperature to around 27 °C within a few minutes. At 3 hours after reperfusion, hearts were excised for infarct size (tetrazolium staining) and no-reflow zone (Thioflavin S technique) measurement. Results: Ischemic risk area (expressed as % of LV area, assessed by blue dye technique) was 52.4 ± 2.9% in normothermic group and 44.8±3.7% in TH group (p=0.15). Infarct size (expressed as % of risk area) was similar between normothermic (73.8 ±3.8% ) and TH (72.0± 4.0%, p = 0.76) groups. No-reflow area (expressed as % of risk area) was significantly reduced in TH group (18.0 ± 4.4%) compared with normothermic group (39.5 ± 2.9%, P = 0.005). When expressed as % of necrotic area, no-reflow area was reduced by more than half in TH group (25.5 ± 6.4%) versus in normothermic group (54.4 ± 5.3%, P = 0.01). Conclusions: A single delayed TH markedly diminishes reperfusion induced microvascular damage and no-reflow even when initiated after reperfusion, and independent of infarct size.

Cardioprotective Effects of Mitochondria-Targeted Peptide SBT-20 in two Different Models of Rat Ischemia/Reperfusion.

Dysfunctional mitochondria are considered to be the major source of intracellular reactive oxygen species and play a central role in the pathophysiology of myocardial ischemia/reperfusion. This study sought to determine effects of mitochondria-targeted cytoprotective peptide SBT-20 on myocardial infarct size in two different models of ischemia/reperfusion. For in vivo studies, anesthetized Sprague Dawley rats were subjected to 30min of coronary artery occlusion followed by 3h of reperfusion. Rats received saline (control), low dose SBT-20 (0.3mg/kg/h) or high dose SBT-20 (3mg/kg/h) treatment (n=15 rats in each group). Saline or SBT-20 were delivered into the jugular vein starting 5min after coronary artery occlusion and were continued for one hour post coronary artery reperfusion. Body temperature, heart rate and blood pressure were monitored during the procedure. At the end of 3h reperfusion, the ischemic risk area, no-reflow area, and infarct size were measured. In separate in vitro studies, isolated rat hearts were exposed to 20min global ischemia, followed by SBT-20 administration (1μM) or no SBT-20 (control) throughout the 2h reperfusion. In vitro studies were conducted in cells and heart mitochondria to ascertain the mitochondrial effects of SBT-20 on mitochondrial respiration and reactive oxygen species production. In the in vivo study, the ischemic risk areas (as a percentage of the left ventricle) were similar among the saline (49.5±2.3%), low dose SBT-20 (48.6±2.1%), and high dose SBT-20 groups (48.7±3.0%). Treatment with SBT-20 significantly reduced infarct size ( as a percentage of risk area) in low dose (62.1±4.4%) and high dose (64.0±4.9%) compared with saline treatment (77.6±2.6%, p=0.001 for both doses). There was no difference in infarct size between low and high dose SBT-20 treatment. The no-reflow areas (as a percentage of the risk area) were comparable among the saline (23.9±1.7%), low dose SBT-20 (23.7±2.8%), and high dose groups (25.0±2.1%). Body temperature, heart rate and blood pressure were comparable among the 3 groups at baseline, during ischemia, and at the end of 3h of reperfusion. In the in vitro study, infarct size was reduced from 43.3±2.6% in control group (n=11) to 17.2±2.8% in the SBT-20 treatment group (n=5, p<0.05). There were no benefits of SBT-20 on recovery of left ventricular developed pressure, coronary flow, or maximal rates of contraction/relaxation. In cell studies, treatment with SBT-20 significantly improved maximal mitochondrial respiration in response to an H2O2 challenge. In isolated mitochondria, reactive oxygen species production was significantly blunted following treatment with SBT-20. In summary, SBT-20 significantly reduced infarct size in two different models of myocardial injury, but did not affect hemodynamics or no-reflow area in rat heart. The reduction in injury is postulated to involve stabilization of mitochondrial function and reduced mitochondrial production of ROS.

Reduction of Ischemia/Reperfusion Injury With Bendavia, a Mitochondria‐Targeting Cytoprotective Peptide

BackgroundManifestations of reperfusion injury include myocyte death leading to infarction, contractile dysfunction, and vascular injury characterized by the “no-reflow” phenomenon. Mitochondria-produced reactive oxygen species are believed to be centrally involved in each of these aspects of reperfusion injury, although currently no therapies reduce reperfusion injury by targeting mitochondria specifically.Methods and ResultsWe investigated the cardioprotective effects of a mitochondria-targeted peptide, Bendavia (Stealth Peptides), across a spectrum of experimental cardiac ischemia/reperfusion models. Postischemic administration of Bendavia reduced infarct size in an in vivo sheep model by 15% (P=0.02) and in an ex vivo guinea pig model by 38% to 42% (P<0.05). In an in vivo rabbit model, the extent of coronary no-reflow was assessed with Thioflavin S staining and was significantly smaller in the Bendavia group for any given ischemic risk area than in the control group (P=0.0085). Myocardial uptake of Bendavia was ≈25% per minute, and uptake remained consistent throughout reperfusion. Postischemic recovery of cardiac hemodynamics was not influenced by Bendavia in any of the models studied. Isolated myocytes exposed to hypoxia/reoxygenation showed improved survival when treated with Bendavia. This protection appeared to be mediated by lowered reactive oxygen species–mediated cell death during reoxygenation, associated with sustainment of mitochondrial membrane potential in Bendavia-treated myocytes.ConclusionsPostischemic administration of Bendavia protected against reperfusion injury in several distinct models of injury. These data suggest that Bendavia is a mitochondria-targeted therapy that reduces reperfusion injury by maintaining mitochondrial energetics and suppressing cellular reactive oxygen species levels. (J Am Heart Assoc. 2012;1:e001644 doi: 10.1161/JAHA.112.001644.)

Is Inhibition of Phosphodiesterase Type 5 by Sildenafil a Promising Therapy for Volume-Overload Heart Failure?

Phosphodiesterase type 5 (PDE5) is an enzyme that belongs to a large family of cyclic nucleotide PDEs that catalyze cAMP and cGMP. cAMP and cGMP are 2 essential intracellular second messengers regulating many different cellular functions of living cells. PDE5 specifically breaks down the substrate cGMP. Inhibition of PDE5 increases intracellular cGMP levels by inhibiting its degradation. Sildenafil (Viagra) is a potent and selective inhibitor of cGMP-specific PDE5 and is the first oral treatment for men with erectile dysfunction; it was approved by Food and Drug Administration on March 27, 1998. Sildenafil binds to the catalytic site of PDE5 and inhibits the degradation of intracellular cGMP in smooth muscle within the corpus cavernosum, resulting in increased levels of cGMP, which cause smooth muscle cell relaxation and vasodilation and improve erectile function.1,2 Article see p 1390 In recent years, there has been growing interest in therapeutic applications of PDE5 inhibitors for cardiovascular diseases other than erectile dysfunction. Some experimental studies demonstrated direct cardioprotective effects of inhibition of PDE5 in experimental acute myocardial infarction models. In 2002, Ockaili et al3 treated rabbits with sildenafil (0.7 mg/kg given as an intravenous bolus) either 30 minutes or 24 hours before coronary occlusion. The rabbits were then subjected to 30 minutes of left anterior descending coronary artery occlusion followed by 3 hours of reperfusion, and the infarct size was measured by tetrazolium staining. The results demonstrated for the first time that sildenafil had a powerful preconditioning-like effect against myocardial ischemia/reperfusion injury. Our research group4 injected 1.45 mg/kg intravenous sildenafil or saline 30 minutes before ischemia in anesthetized open-chest rabbits subjected to 30 minutes of left anterior descending coronary occlusion followed by 3 hours of reperfusion. Compared with saline, sildenafil significantly decreased coronary resistance in the ischemic risk area, slightly increased …

Intra-aortic balloon pump in intensive cardiac care: A registry in Florence

The Intra-aortic Balloon Pump (IABP) is currently the most commonly used mechanical assist device to improve and support hemodynamics in patients with cardiogenic shock; it is widely used also in high-risk patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) [1–9]. However, the impact of IABP on prognosis is so far controversial [5,10]. We assessed the in-hospital mortality and complications in patients treated with IABP consecutively admitted to our Intensive Cardiac Care Unit (ICCU). From Jan. 1, 2005 to Dec. 31, 2008, 3500 patients were consecutively admitted to our ICCU [11–13]. Among them, 414 (11.8%) underwent IABP during their hospitalization and were prospectively enrolled in our Registry. Large ischemic risk area (LIRA)was defined as “ejection fraction less than 40% together with proximal occlusion of left descending anterior coronary artery associated or not with critical lesions in other coronary arteries”. In these patients IABP was deployed after PCI. Patients were defined as “high risk” as if one ormore of the following criteria were present: ventricular ejection fraction (LVEF)<40%, killip class 3, persistent malignant ventricular arrhythmias, acute mitral regurgitation and severe coronary artery disease (left main stem or three vessel or vein graft disease). Major bleeding.Major bleeding was defined according to Replace 2 [14]: Continuous data (Kolmogorov–Smirnov test ) were expressed as mean±SD, categorical data as frequencies and percentages. All data were analysed by means of Fisher's exact test or Student's t test, when appropriate. Variables resulted significantly different between subgroups were entered as covariates in a backward stepwise logistic regression analysis. A p<0.05 was considered statistical significant (SPSS 13.0 statistical software; SPSS Inc., Chicago, ILL, USA). The mean age of patients in the study was 68.5±11.4 years; 69.6% were men. Hypertension was detectable in 51.4% (n=213), dyslipidemia in 32.1% (n=133) and diabetes mellitus in 22.0% (n=91). About one fourth of patients (24.4%) showed prior myocardial infarction and prior PCI in the 20.5%. Table 1 shows indications for IABP in our series. In the majority of patients (67.1%, n=278) IABP was the only device, while in the remaining (32.9%) it was associated to other devices. The device most frequently associated with IABP was mechanical ventilation (41.7%; invasive: 24.6%; non-invasive 17.1%). The continuous veno-venous renal replacement therapy was used in 13.5% (n=56) of patients. Unfractioned heparin was used in 97.8% of patients. The majority of patients received dual antiplatelet therapy; acetylsalicylic acid (90.6%) and clopidogrel (83.8%). Therapy with glycoprotein IIb IIIa inhibitors was administered in 59.7% of cases. Inotropic agents (epinephrine, norepinephrine, dopamine and dobutamine) were used in 40.6% of patients, all with refractory cardiogenic shock. In our series, complications were 13.8% (57/414 patients) (Table 2). Thirtypatients (outof 57, 52.7.%) showed severebleeding, amongwhich half of patients exhibited unknown bleeding site while bleeding at the insertion site occurred in 12 patients. The incidence of IABP-related complications did not differ betweenmales and females (10.6%@versus 13.9% p=0.398). Patients who developed IABP-related complications showed a higher median duration of the device (48 h; 25–75th percentile 24–72 hversus 36 h;25–75thpercentile 24–48 h;p=0.007). In our population, 82 patients died (82/414:19.8%). Among patients who died, IABP was implanted because of: cardiogenic shock in 59 patients (72%), cardiac arrest in 8 patients (9.8%), periprocedural complications of PCI in 5 patients (6.1%), mechanical complication of acute myocardial infarction in 4 patients (4.9%), large ischemic risk area in 3 patients (3.6%), acute pulmonary edema in 2 patients (2.4%) and bridge to CABG in 1 patient (1.2%). Among the 47 patientswhodeveloped IABP-related complications 22 died; two deaths were due to IABP (intestinal ischemia in 1 patients and

Survival and maturation of human embryonic stem cell-derived cardiomyocytes in rat hearts

Human embryonic stem cell (hESC)-derived cardiomyocytes are a promising cell source for cardiac repair. Whether these cells can be transported long distance, survive, and mature in hearts subjected to ischemia/reperfusion with minimal infarction is unknown. Taking advantage of a constitutively GFP-expressing hESC line we investigated whether hESC-derived cardiomyocytes could be shipped and subsequently form grafts when transplanted into the left ventricular wall of athymic nude rats subjected to ischemia/reperfusion with minimal infarction. Co-localization of GFP-epifluorescence and cardiomyocyte-specific marker staining was utilized to analyze hESC-derived cardiomyocyte fate in a rat ischemia/reperfused myocardium. Differentiated, constitutively green fluorescent protein (GFP)-expressing hESCs (hES3-GFP; Envy) containing about 13% cardiomyocytes were differentiated in Singapore, and shipped in culture medium at 4 °C to Los Angeles (shipping time ∼ 3 days). The cells were dissociated and a cell suspension (2 × 10 6 cells for each rat, n = 10) or medium ( n = 10) was injected directly into the myocardium within the ischemic risk area 5 min after left coronary artery occlusion in athymic nude rats. After 15 min of ischemia, the coronary artery was reperfused. The hearts were harvested at various time points later and processed for histology, immunohistochemical staining, and fluorescence microscopy. In order to assess whether the hESC-derived cardiomyocytes might evade immune surveillance, 2 × 10 6 cells were injected into immune competent Sprague-Dawley rat hearts ( n = 2), and the hearts were harvested at 4 weeks after cell injection and examined as in the previous procedures. Even following 3 days of shipping, the hESC-derived cardiomyocytes within embryoid bodies (EBs) showed active and rhythmic contraction after incubation in the presence of 5% CO 2 at 37 °C. In the nude rats, following cell implantation, H&E, immunohistochemical staining and GFP epifluorescence demonstrated grafts in 9 out of 10 hearts. Cells that demonstrated GFP epifluorescence also stained positive (co-localized) for the muscle marker alpha-actinin and exhibited cross striations (sarcomeres). Furthermore, cells that stained positive for the antibody to GFP (immunohistochemistry) also stained positive for the muscle marker sarcomeric actin and demonstrated cross striations. At 4 weeks engrafted hESCs expressed connexin 43, suggesting the presence of nascent gap junctions between donor and host cells. No evidence of rejection was observed in nude rats as determined by inspection for lymphocytic infiltrate and/or giant cells. In contrast, hESC-derived cardiomyocytes injected into immune competent Sprague-Dawley rats resulted in an overt lymphocytic infiltrate. hESCs-derived cardiomyocytes can survive several days of shipping. Grafted cells survived up to 4 weeks after transplantation in hearts of nude rats subjected to ischemia/reperfusion with minimal infarction. They continued to express cardiac muscle markers and exhibit sarcomeric structure and they were well interspersed with the endogenous myocardium. However, hESC-derived cells did not escape immune surveillance in the xenograft setting in that they elicited a rejection phenomenon in immune competent rats.

Catheter-Based Transcoronary Myocardial Hypothermia Attenuates Arrhythmia and Myocardial Necrosis in Pigs With Acute Myocardial Infarction

This study evaluated the efficacy of catheter-based transcoronary myocardial hypothermia (CTMH) in pigs with acute myocardial ischemia. Although it has been suggested that hypothermia therapy can attenuate myocardial necrosis, few applications have been accepted for clinical use. This study comprises 2 substudies. In both studies, pigs underwent 60 min of coronary occlusion and 180 min of reperfusion. In study 1, after 15 min of coronary occlusion with an over-the-wire-type balloon (OTWB), pigs in the hypothermia group (H) (n = 13) were directly infused with 4 degrees C saline into the coronary artery through the OTWB wire lumen (2.5 ml/min) for 60 min. Pigs in the normothermia group (N) (n = 15) received the same amount of 36.5 degrees C saline. In study 2, pigs in the hypothermia-reperfusion group (HR) (n = 5) were infused with 4 degrees C saline through the infusion catheter (8 ml/min) for 30 min with a later start (60 min after coronary occlusion), whereas simple reperfusion was used for the reperfusion group (R) (n = 6). Catheter-based transcoronary myocardial hypothermia was successful in both studies. In study 1, CTMH significantly decreased ventricular arrhythmia and the ratio of necrosis to ischemic risk area (H: 9 +/- 2%; N: 36 +/- 4%; p < 0.0001) with a significant reduction of enzyme leaks. In study 2, CTMH tended to reduce the ratio of necrosis (HR: 33 +/- 2%; R: 45 +/- 5%; p = 0.08). In both studies, CTMH significantly suppressed the increase of 8-iso-prostaglandin F(2alpha) while preserving the coronary flow reserve. Catheter-based transcoronary myocardial hypothermia reduced myocardial necrosis while preserving coronary flow reserve, due, in part, to attenuation of oxidative stress.

Myocardial salvage in patients with non–ST-elevation myocardial infarction determined by myocardial perfusion imaging

We compared acute and late myocardial perfusion imaging using technetium-99m isotopes in 69 patients who had non-ST-elevation myocardial infarction. Among these patients, we found that the ischemic risk area was often large (19% of the left ventricle), and that 67% had significant myocardial salvage, defined as a >25% decrease in risk area, which was associated with an improved ejection fraction.

A nonischemic electrocardiogram does not always predict a small myocardial infarction: Results with acute myocardial perfusion imaging

Background A nonischemic electrocardiogram (ECG) in association with myocardial infarction (MI) indicates a small MI in some but not all cases. Myocardial perfusion imaging using technetium-99m sestamibi offers the ability to better characterize these “electrically silent” infarctions. Methods Patients considered low risk for myocardial infarction with a normal or nonischemic ECG (no significant ST elevation, ST depression, ischemic T-wave inversion, or left bundle branch block) underwent early emergency department perfusion imaging, followed by serial myocardial marker sampling. Risk area (defect size) was quantitated by use of a 50% threshold from multiple short-axis slices. Results A total of 87 patients with nonischemic ECGs had myocardial infarction (mean peak creatine kinase [CK] 710 ± 720 U/L, range 111-3196 U/L). Peak CKs were lower in the 7 patients with negative perfusion imaging (420 ± 290 U/L vs 730 ± 740 U/L, P =.06). Mean risk area was 18% ± 11% of the left ventricle (range 0%-62%) and was not significantly different among the different infarct-related arteries. Patients with normal ECGs had a similar risk area compared with other patients (16% ± 12% vs 19 ± 12%, P =.25). Coronary angiography was performed in 81 patients, with significant stenoses in 74 (91%) (37 one-vessel, 19 two-vessel, 18 three-vessel), with the infarct related artery most commonly the left circumflex (n = 32 [38%]). Conclusions The ischemic risk area in patients with a nonischemic ECG was comparable to patients with inferior ST-elevation myocardial infarction found in previous studies. A nonischemic ECG does not predict a small ischemic risk area. (Am Heart J 2001;141:360-6.)

Estimation of the area at risk in myocardial infarction of rats by means of I-123 beta-methyliodophenyl pentadecanoic acid imaging.

Clinical investigations have suggested that the defects in SPECT images of a free fatty acid analog, I-123 beta-methyliodophenyl pentadecanoic acid (BMIPP) may indicate the ischemic risk area. To elucidate whether I-123 BMIPP can indicate the area at risk of ischemia, ex-vivo autoradiography was performed in rats whose left coronary artery was occluded for 60 min and then reperfused. I-123 BMIPP was injected at the acute stage (n = 10), or the subacute stage (7 days after reperfusion; n = 9). Infarction and the area at risk were identified by triphenyl tetrazolium chloride staining and injection of methylene blue during religation just before sacrifice, respectively. The BMIPP uptake in the risk area was significantly lower than that in the remote area at the acute (risk, 53.7+/-23.3% of the uptake at right ventricle, mean +/- SD; remote, 109.3+/-11.8%; p < 0.01) and subacute (risk, 52.5+/-11.5%; remote, 97.9+/-14.3%; p < 0.01) stages. In addition, the area with reduced uptake of I-123 BMIPP showed a significant correlation with the area at risk both at the acute (r = 0.98, p < 0.01) and subacute (r = 0.92, p < 0.01) stages. In conclusion, the area at risk can be evaluated by I-123 BMIPP both at the acute and subacute stages.

Effect of 6-wk estrogen withdrawal or replacement on myocardial ischemic tolerance in rats.

Menopausal status is a risk factor for coronary artery disease death, but the mechanism underlying this association is uncertain. To test whether estrogen ameliorates the effects of acute myocardial ischemia in ways likely to translate into a mortality difference, we compared the response to brief (6-min) and prolonged (45-min) coronary occlusion in vivo in five groups (each n = 16) of rats: ovariectomized females; ovariectomized females after 6 wk 17beta-estradiol replacement; male rats supplemented with estradiol for 6 wk; normal males; and normal females. Coronary occlusion produced a uniform ischemic risk area averaging 53 +/- 3% of left ventricular volume. After a brief occlusion, reperfusion ventricular tachycardia/fibrillation occurred with >85% frequency in all groups. During a prolonged occlusion, ischemic ventricular tachycardia occurred in 100% and sustained tachycardia requiring cardioversion in >75% of rats in all groups. Myocardial infarct size averaged 52 +/- 4% of the ischemic risk area and was similarly unaffected by gender or estrogen status. We conclude that neither short-term estrogen withdrawal, replacement, nor supplementation significantly affects the potentially lethal outcomes from acute coronary occlusion in this species.

Evidence for the delayed effect in human ischemic preconditioning: Prospective multicenter study for preconditioning in acute myocardial infarction

OBJECTIVESThis study aimed to investigate prospectively the protective effect of a first preinfarction angina attack against acute myocardial infarction (AMI) in human hearts without significant collaterals.BACKGROUNDSeveral retrospective studies and the prospective studies have demonstrated the existence of the preconditioning (PC) effect in humans. However, collaterals were not examined in the prospective studies. In animal models, the PC effect on myocardial infarct size appears soon after PC reperfusion (classic) but disappears within 1 to 2 h. It then reappears 24 to 48 h after reperfusion (the delayed PC effect). Meanwhile, the PC effect on stunning appears 12 h after PC reperfusion (the delayed PC effect). The concept of the classic and delayed PC effects has not been investigated in human AMI studies. If the above concept is also correct in humans, the infarct size and/or impairment of the left ventricular function should be inversely correlated with the time interval between the first preinfarction angina attack and the onset of AMI when that time interval is limited to between 2 and 48 h.METHODSThe subjects were 25 patients with first AMI of the proximal left anterior descending artery who underwent successful direct percutaneous transluminal coronary angioplasty (PTCA) 2 to 6 h after the onset and with no (or poor) collateral circulation (grade 0 or 1). They were divided into two groups: preinfarction angina (PA)(+) group: 11 patients with new onset preinfarction angina from 2 to 48 h before the onset, PA(−) group: 14 patients without angina before infarction. Peak creatine kinase (CK) and cumulative CK were examined, and the left ventricular ejection fraction (LVEF) and the regional wall motion (RWM) were determined from the left ventriculograms during the acute (immediately after the coronary reperfusion) and chronic (four weeks after the onset of AMI) phases. The RWM index (RWMI) was then calculated as the mean motion of chords (standard deviation [SD]/chord) lying in the area of chords of RWM ≤ −2 SD in the acute phase (ischemic risk area).RESULTSThe increase in the RWMI between the acute and chronic phases was significantly larger in the PA(+) group than in the PA(−) group (1.55 ± 1.32 and 0.69 ± 0.75, p < 0.05, respectively) although no significant difference in the enzymatic infarct size was seen between the two groups. The increases in the LVEF and the RWMI were significantly correlated with the time interval from the first preinfarction angina attack to the onset of AMI (r = 0.622, p < 0.05 and r = 0.646, p < 0.05, respectively), but the enzymatic infarct size was not.CONCLUSIONSThe beneficial effect of preinfarction angina on left ventricular wall motion, independently of collateral flows, indicates the existence of the PC effect in humans. The greater protective effect of a longer time interval between angina pectoris and AMI suggests that the protection is due to a delayed PC effect.