Sudden Cardiac Arrest as the First Manifestation in a Patient with Catastrophic Antiphospholipid Syndrome.

We herein report a 26-year-old woman with sudden cardiac arrest who had no remarkable medical history. While resuscitation was successfully performed with adrenalin administration and extracorporeal membrane oxygenation, the cause of cardiac arrest could not be determined for over two weeks. Given the presence of autoimmune disease along with the findings of refractory renal insufficiency and thrombocytopenia, a kidney biopsy and blood examinations, including lupus anticoagulant testing, were performed, which proved the presence of antiphospholipid syndrome. The patient was successfully treated with steroid pulse therapy. This drastic case scenario highlighted the fact that autoimmune disease can be the cause of sudden cardiac arrest.

Neutrophil Elastase Inhibition Ameliorates Endotoxin-induced Myocardial Injury Accompanying Degradation of Cardiac Capillary Glycocalyx.

Myocardial injury in sepsis may be caused by a burst of several inflammatory mediators, leading to vascular endothelial injuries. However, the contribution of neutrophil elastase (NE) to myocardial injury in sepsis is still unknown. We aimed to evaluate whether endotoxemia-induced myocardial injury is associated with NE. Lipopolysaccharide (LPS) was injected intraperitoneally at a dose of 20 mg/kg into granulocyte-colony-stimulating-factor knockout mice (G-CSF-KO), which have few neutrophils, and littermate control mice. The survival rate of G-CSF-KO mice 48 hours after LPS injection was significantly greater than that of control mice. The serum level of troponin I in G-CSF-KO mice was significantly lower than that in control mice. In addition, the concentration of inflammatory cytokine interleukin-6 (IL-6) was significantly decreased 6 and 12 hours after LPS administration compared with that in control mice. Ultrastructural analysis revealed that vascular endothelial structures and the endothelial glycocalyx in G-CSF-KO mice were clearly preserved. Next, mice were injected with 0.2 mg/kg sivelestat (an NE inhibitor) after LPS administration. The survival rate was significantly higher and the serum level of troponin I was lower in sivelestat-injected mice than in control mice, respectively. Furthermore, IL-6 levels were significantly decreased 6 and 12 hours after LPS administration compared with those in control mice. Vascular endothelial structures and the endothelial glycocalyx in sivelestat-treated mice were clearly preserved at the ultrastructural level. In conclusion, NE is significantly associated with myocardial injury in endotoxemia. Inhibition of NE may be a useful tool for the management of endotoxemia.

Effect of high-flow high-volume-intermittent hemodiafiltration on metformin-associated lactic acidosis with circulatory failure: a case report.

BACKGROUND: Metformin-associated lactic acidosis is a well-known life-threatening complication of metformin. We here report the case of a patient who developed metformin-associated lactic acidosis without organ manifestations, due to the simultaneous ingestion of an overdose of metformin and alcohol, and who recovered with high-flow high-volume intermittent hemodiafiltration. CASE PRESENTATION: A 44-year-old Asian woman with type 2 diabetes attempted suicide by ingesting 10 tablets of metformin 500 mg and drinking approximately 600 mL of Japanese sake containing 15% alcohol. She was transferred to our emergency department because of disturbed consciousness. Continuous intravenous administration of noradrenalin (0.13 µg/kg per minute) was given because she was in shock. Laboratory findings included a lactate level of 119 mg/dL (13.2 mmol/L), bicarbonate of 14.5 mmol/L, and serum metformin concentration of 1138 ng/mL. She was diagnosed as having metformin-associated lactic acidosis worsened by alcohol. After 4560 mL of bicarbonate ringer (Na+ 135 mEq/L, K+ 4 mEq/L, Cl- 113 mEq/L, HCO3- 25 mEq/L) was administered, high-flow high-volume intermittent hemodiafiltration. (dialysate flow rate: 500 mL/min, substitution flow rate: 3.6 L/h) was carried out for 6 h to treat metabolic acidosis and remove lactic acid and metformin. Consequently, serum metformin concentration decreased to 136 ng/mL and noradrenalin administration became unnecessary to maintain normal vital signs. On hospital day 12, she was moved to the psychiatry ward. CONCLUSIONS: HFHV-iHDF may be able to remove metformin and lactic acid efficiently and may improve the condition of hemodynamically unstable patients with metformin-associated lactic acidosis.

Mobilized Muse Cells After Acute Myocardial Infarction Predict Cardiac Function and Remodeling in the Chronic Phase.

BACKGROUND: Multilineage differentiating stress-enduring (Muse) cells are SSEA3+and CD105+double-positive pluripotent-like stem cells. We aimed to examine the mobilization of Muse cells into peripheral blood after acute myocardial infarction (AMI) and their effects on left ventricular (LV) function and remodeling.Methods and Results:In 79 patients with AMI, 44 patients with coronary artery disease (CAD), and 64 normal subjects (Control), we measured the number of Muse cells in the peripheral blood by fluorescence-activated cell sorting. Muse cells were measured on days 0, 1, 7, 14, and 21 after AMI. Plasma sphingosine-1-phosphate (S1P) levels were measured. Cardiac echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI. Muse cell number on day 1 was significantly higher in the AMI (276±137 cells/100 µL) than in the CAD (167±89 cells/100 µL) and Control (164±125 cells/100 µL) groups. Muse cell number peaked on day 1, and had gradually decreased on day 21. Muse cell number positively correlated with plasma S1P levels. Patients with a higher increase in the number of Muse cells in the peripheral blood but not those with a lower increase in number of Muse cells in the acute phase showed improved LV function and remodeling in the chronic phase. CONCLUSIONS: Endogenous Muse cells were mobilized into the peripheral blood after AMI. The number of Muse cells could be a predictor of prognosis in patients with AMI.

Thyrotoxic and pheochromocytoma multisystem crisis: a case report.

BACKGROUND: Thyrotoxic crisis and pheochromocytoma multisystem crisis are rare, life-threatening, emergency endocrine diseases with various clinical manifestations. Here we report a case of a patient who simultaneously developed thyrotoxic crisis and pheochromocytoma multisystem crisis and required intensive cardiovascular management. CASE PRESENTATION: A 60-year-old Asian man experienced nausea and vomiting, and subsequently developed dyspnea and cold sweats while farming. His serum free thyroxine, free triiodothyronine, and thyrotropin receptor antibody levels were elevated at 2.9 ng/dL, 7.2 pg/dL, and 4.7 IU/L, respectively. Serum thyrotropin levels were suppressed at less than 0.01 µIU/mL. Thyroid echography demonstrated no thyroid swelling (23 × 43 mm). A whole body computed tomography was performed for systemic evaluation. This revealed exophthalmos and a mass of size 57 × 64 mm in the anterior pararenal space. Based on these findings, we made an initial diagnosis of thyrotoxic crisis secondary to exacerbation of Grave's hyperthyroidism. Treatment was begun with an iodine agent at a dose of 36 mg/day, thiamazole at a dose of 30 mg/day, and hydrocortisone at a dose of 300 mg daily for 3 consecutive days. To control tachycardia, continuous intravenously administered propranolol and diltiazem infusions were given. At the same time, small doses of doxazosin and carvedilol were used for both alpha and beta adrenergic blockade. On hospital day 5, his blood pressure and serum catecholamine concentrations (adrenalin 42,365 pg/mL, dopamine 6409 pg/mL, noradrenalin 72,212 pg/mL) were still high despite higher beta blocker and calcium channel blocker doses. These findings contributed to the diagnosis of pheochromocytoma multisystem crisis with simultaneous thyrotoxic crisis. We increased the doses of doxazosin and carvedilol, which stabilized his hemodynamic status. On hospital day 16, metaiodobenzylguanidine scintigraphy showed high accumulation in the right adrenal gland tumor. After retroperitoneal laparoscopic adrenalectomy on hospital day 33, his condition stabilized. He was discharged on hospital day 58. CONCLUSIONS: Since he required more intensive cardiovascular management for thyrotoxic crisis, beta blockade was increased under intensive care unit monitoring even though initial alpha blockade is recommended in pheochromocytoma. When these crises occur simultaneously, cardiovascular management can be very challenging.

Blunt cardiac injury due to trauma associated with snowboarding: a case report.

BACKGROUND: Cardiac trauma is associated with a much higher mortality rate than injuries to other organ systems, even though cardiac trauma is identified in less than 10% of all trauma admissions. Here we report blunt trauma of the left atrium due to snowboarding trauma. CASE PRESENTATION: A 45-year-old Asian man collided with a tree while he was snowboarding and drinking. He lost consciousness temporarily. An air ambulance was requested and he was transported to an advanced critical care center. On arrival, a pericardial effusion was detected by a focused assessment with sonography for trauma. His presenting electrocardiogram revealed normal sinus rhythm and complete right bundle branch block. Laboratory findings included a white blood cell count of 13.5 × 103/µl, serum creatine kinase level of 459 IU/l, and creatine kinase-myocardial band level of 185 IU/l. Enhanced computed tomography showed a large pericardial effusion and bleeding from his left adrenal gland. There were no pelvic fractures. A diagnosis of cardiac tamponade due to blunt cardiac injury and left adrenal injury due to blunt trauma was made. Subsequently, emergency thoracic surgery and transcatheter arterial embolization of his left adrenal artery were performed simultaneously. A laceration of the left atrial appendage in the lateral wall of his left ventricle was detected intraoperatively and repaired. His postoperative course progressed favorably, although a pericardial effusion was still detected on chest computed tomography on hospital day 35. His electrocardiogram showed normal sinus rhythm and the complete right bundle branch block pattern changed to a narrow QRS wave pattern. He was discharged on hospital day 40. CONCLUSIONS: The present case report illustrates two points: (1) severe injuries resulted from snowboarding, and (2) complete right bundle branch block was caused by blunt cardiac injury. The present report showed blunt trauma of the left atrium with complete right bundle branch block as an electrocardiogram change due to snowboarding trauma. To detect cardiac trauma in snowboarding accidents, an examination of an electrocardiogram is required in all patients who might have a bruised chest.

Intravenous Administration of Endothelial Colony-Forming Cells Overexpressing Integrin ß1 Augments Angiogenesis in Ischemic Legs.

When injected directly into ischemic tissue in patients with peripheral artery disease, the reparative capacity of endothelial progenitor cells (EPCs) appears to be limited by their poor survival. We, therefore, attempted to improve the survival of transplanted EPCs through intravenous injection and gene modification. We anticipated that overexpression of integrin ß1 will enable injected EPCs to home to ischemic tissue, which abundantly express extracellular matrix proteins, the ligands for integrins. In addition, integrin ß1 has an independent angiogenesis-stimulating function. Human endothelial colony-forming cells (ECFCs; late-outgrowth EPCs) were transduced using a lentiviral vector encoding integrin ß1 (ITGB1) or enhanced green fluorescent protein (GFP). We then locally or systemically injected phosphate-buffered saline or the genetically modified ECFCs (GFP-ECFCs or ITGB1-ECFCs; 1 × 10(5) cells each) into NOD/Shi-scid, IL-2Rγnull mice whose right femoral arteries had been occluded 24 hours earlier. Upregulation of extracellular matrix proteins, including fibronectin, was apparent in the ischemic legs. Four weeks later, blood perfusion of the ischemic limb was significantly augmented only in the ITGB1-ECFC group. Scanning electron microscopy of vascular casts revealed increases in the perfused blood vessels in the ischemic legs of mice in the ITGB1-ECFC group and significant increases in the density of both capillaries and arterioles. Transplanted ECFC-derived vessels accounted for 28% ± 4.2% of the vessels in the ITGB1-ECFC group, with no cell fusion. Intravenous administration of ECFCs engineered to home to ischemic tissue appears to efficiently mediate therapeutic angiogenesis in a mouse model of peripheral artery disease. Significance: The intravenous administration of endothelial colony-forming cells (ECFCs) genetically modified to overexpress integrin ß1 effectively stimulated angiogenesis in ischemic mouse hindlimbs. Transplanted ECFCs were observed in the ischemic leg tissue, even at the chronic stage. Moreover, the cells appeared functional, as evidenced by the improved blood flow. The cell type used (ECFCs), the route of administration (intravenous, not directly injected into the affected area), and the use of ligand-receptor interactions (extracellular matrix and integrins) for homing represent substantial advantages over previously reported cell therapies for the treatment of peripheral artery disease.

[Three Patients with Acute Myocardial Infarction Associated with Targeted Therapy of Sorafenib for Metastatic Renal Cell Carcinoma : Case Report].

Sorafenib is a tyrosine kinase inhibitor (TKI) of the vascular endothelial growth factor receptor (VEGFR) used for advanced renal cell carcinoma. Treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal cell carcinoma. However, in spite of its therapeutic efficacy, sorafenib causes a wide range of adverse events. Cardiovascular adverse events have been observed when sorafenib was used with targeted agents. Although these adverse events like hypertension, reduced left ventricular ejection fraction, cardiac ischemia or infarction were manageable with standard medical therapies in most cases, some had a poor clinical outcome. We report three cases of acute myocardial infarction associated with sorafenib in patients with metastatic renal cell carcinoma.

An autopsy report of acute myocardial infarction with hypertrophic obstructive cardiomyopathy-like heart.

An 84-year-old woman, who was followed up as hypertrophic obstructive cardiomyopathy (HOCM) in a local hospital, was transferred to our center because of anterior chest pain and diagnosed with acute myocardial infarction (MI). Coronary angiography showed total occlusion of the mid-left anterior descending, and flow was restored after endovascular thrombectomy. An autopsy was performed after she died on hospital day 6. At autopsy, there was no significant stenosis in this vessel and the absence of plaque rupture was confirmed. Likewise, it was unclear asymmetric hypertrophy at autopsy, it could not deny that a sigmoid deformity of the basal septum occurs in elderly patients and can mimic the asymmetric septal hypertrophy of hypertrophic cardiomyopathy. MI was thought to be caused by coronary spasm or squeezing in HOCM-like heart. Therefore, it may be necessary antithrombosis therapy in HOCM-like patients with no history of paroxysmal atrial fibrillation.

Much caution does no harm! Organophosphate poisoning often causes pancreatitis.

Organophosphate poisoning (OP) results in various poisoning symptoms due to its strong inhibitory effect on cholinesterase. One of the occasional complications of OP is pancreatitis. A 62-year-old woman drank alcohol and went home at midnight. After she quarreled with her husband and drank 100 ml of malathion, a parasympathomimetic organophosphate that binds irreversibly to cholinesterase, she was transported to our hospital in an ambulance. On admission, activated charcoal, magnesium citrate, and pralidoxime methiodide (PAM) were used for decontamination after gastric lavage. Abdominal computed tomography detected edema of the small intestine and colon with doubtful bowel ischemia, and acute pancreatitis was suspected. Arterial blood gas analysis revealed severe lactic acidosis. The Ranson score was 6 and the APACHE II (Acute Physiology and Chronic Health Evaluation) score was 14. Based on these findings, severe acute pancreatitis was diagnosed. One day after admission, hemodiafiltration (HDF) was started for the treatment of acute pancreatitis. On the third hospital day, OP symptoms were exacerbated, with muscarinic manifestations including bradycardia and hypersalivation and decreased plasma cholinesterase activity. Atropine was given and the symptoms improved. The patient's general condition including hemodynamic status improved. Pancreatitis was attenuated by 5 days of HDF. Ultimately, it took 14 days for acute pancreatitis to improve, and the patient discharged on hospital day 32. Generally, acute pancreatitis associated with OP is mild. In fact, one previous report showed that the influence of organophosphates on the pancreas disappears in approximately 72 hours, and complicated acute pancreatitis often improves in 4-5 days. However, it was necessary to treat pancreatitis for more than 2 weeks in this case. Therefore, organophosphate-associated pancreatitis due to malathion is more severe. Although OP sometime causes severe necrotic pancreatitis or pancreatic pseudocysts, it was thought that the present patient had a good clinical course without these complications due to the appropriate intensive care including nafamostat, antibiotics, fluid resuscitation, and HDF. In conclusion, OP-associated pancreatitis requires careful assessment because it may be aggravated, as in this case.

Postinfarction Cardiac Remodeling Proceeds Normally in Granulocyte Colony-Stimulating Factor Knockout Mice.

Treatment with granulocyte colony-stimulating factor (G-CSF) reportedly mitigates postinfarction cardiac remodeling and dysfunction. We herein examined the effects of G-CSF knockout (G-CSF-KO) on the postinfarction remodeling process in the hearts of mice. Unexpectedly, the acute infarct size 24 hours after ligation was similar in the two groups. At the chronic stage (4 weeks later), there was no difference in the left ventricular dimension, left ventricular function, or histological findings, including vascular density, between the two groups. In addition, expression of vascular endothelial growth factor (VEGF) was markedly up-regulated in hearts from G-CSF-KO mice, compared with wild-type mice. Microarray failed in detecting up-regulation of VEGF mRNA, whereas G-CSF administration significantly decreased myocardial VEGF expression in mice, indicating that G-CSF post-transcriptionally down-regulates VEGF expression. When G-CSF-KO mice were treated with an anti-VEGF antibody (bevacizumab), cardiac remodeling was significantly aggravated, with thinning of the infarct wall and reduction of the cellular component, including blood vessels. In the granulation tissue of bevacizumab-treated hearts 4 days after infarction, vascular development was scarce, with reduced cell proliferation and increased apoptosis, which likely contributed to the infarct wall thinning and the resultant increase in wall stress and cardiac remodeling at the chronic stage. In conclusion, overexpression of VEGF may compensate for the G-CSF deficit through preservation of cellular components, including blood vessels, in the postinfarction heart.

Phenotype and physiological significance of the endocardial smooth muscle cells in human failing hearts.

BACKGROUND: Extravascular smooth muscle cells are often observed in the endocardium of human failing hearts. Here, we characterized the phenotype of those cells and investigated their physiological significance. METHODS AND RESULTS: We examined left ventricular biopsy specimens obtained from 44 patients with dilated cardiomyopathy and 6 nonfailing hearts. In Masson trichrome-stained histological preparations, bundles of smooth muscle cells were seen localized in the endocardium in 23 of the 44 specimens (none of the 6 controls). These cells were immunopositive for α-smooth muscle actin, type 2 smooth muscle myosin, desmin, and calponin, but were negative for embryonic smooth muscle myosin, vimentin, fibronectin, and periostin. This profile is indicative of a late differentiation (contractile) smooth muscle phenotype. Electron microscopy confirmed that phenotype, revealing the cells to contain abundant myofilaments with dense bodies but little rough endoplasmic reticulum or Golgi apparatus. In the endocardial smooth muscle-positive group, the left ventricular end-systolic volume index (73±34 versus 105±50 mL/m(2); P=0.021), left ventricular peak wall stress (164±47 versus 196±43 dynes 10(3)/cm(2); P=0.023), and left ventricular end-systolic meridional wall stress (97±38 versus 121±37 dynes 10(3)/cm(2); P=0.036) were all significantly smaller, and the ejection fraction was larger (41±8.8 versus 33±9.3%; P=0.005) than in the endocardial smooth muscle-negative group. However, no histological parameters differed between the 2 groups. CONCLUSIONS: Endocardial smooth muscle cell bundles in hearts with dilated cardiomyopathy exhibit a mature contractile phenotype and may play a compensatory role mitigating heart failure by reducing left ventricular wall stress and systolic dysfunction.

Restriction of food intake prevents postinfarction heart failure by enhancing autophagy in the surviving cardiomyocytes.

We investigated the effect of restriction of food intake, a potent inducer of autophagy, on postinfarction cardiac remodeling and dysfunction. Myocardial infarction was induced in mice by left coronary artery ligation. At 1 week after infarction, mice were randomly divided into four groups: the control group was fed ad libitum (100%); the food restriction (FR) groups were fed 80%, 60%, or 40% of the mean amount of food consumed by the control mice. After 2 weeks on the respective diets, left ventricular dilatation and hypofunction were apparent in the control group, but both parameters were significantly mitigated in the FR groups, with the 60% FR group showing the strongest therapeutic effect. Cardiomyocyte autophagy was strongly activated in the FR groups, as indicated by up-regulation of microtubule-associated protein 1 light chain 3-II, autophagosome formation, and myocardial ATP content. Chloroquine, an autophagy inhibitor, completely canceled the therapeutic effect of FR. This negative effect was associated with reduced activation of AMP-activated protein kinase and of ULK1 (a homolog of yeast Atg1), both of which were enhanced in hearts from the FR group. In vitro, the AMP-activated protein kinase inhibitor compound C suppressed glucose depletion-induced autophagy in cardiomyocytes, but did not influence activity of chloroquine. Our findings imply that a dietary protocol with FR could be a preventive strategy against postinfarction heart failure.

Elevated plasma GLP-1 levels and enhanced expression of cardiac GLP-1 receptors as markers of left ventricular systolic dysfunction: a cross-sectional study.

OBJECTIVE: We aimed to elucidate usefulness of plasma glucagon-like peptide-1 (GLP-1) levels for the assessment of left ventricular (LV) dysfunction by examining the relationship among plasma GLP-1 levels, expression of cardiac GLP-1 receptors and LV function in patients with impaired and preserved LV function. DESIGN: Prospective study. SETTING: Number of participating center: 1, Gifu, Japan. PARTICIPANTS: Number of patients enrolled: 102 patients who underwent elective cardiac catheterisation for coronary artery disease, cardiomyopathy and valvular heart disease, and 6 patients who underwent cardiac biopsy. RESULTS: The plasma GLP-1 level was significantly increased in patients with impaired LV function (5.7±1.9 pmol/L) as compared with those with preserved LV function (2.7±1.6 pmol/L). Plasma GLP-1 and plasma brain natriuretic peptide (BNP) levels were inversely correlated with the LV ejection fraction(EF), respectively. Plasma GLP-1 level positively correlated with plasma BNP level. Multivariate logistic regression analysis revealed that plasma GLP-1 level was an independent determinant of the impaired LV function, whereas plasma BNP level was not. Intensity of immunostaining for GLP-1 receptor protein was significantly enhanced in patients with impaired LV function compared with those with preserved LV function. CONCLUSIONS: The plasma GLP-1 level was increased in patients with impaired systolic LV function and inversely correlated with the LVEF. The expressions of GLP-1 receptors were enhanced in hearts with impaired LV function. These may suggest that endogenous GLP-1-GLP-1 receptor system serves as a compensatory mechanism for systolic LV dysfunction. TRIAL REGISTRATION: UMIN-CTR, ID=UMIN000009361, registration number: R000011000.

Postinfarct active cardiac-targeted delivery of erythropoietin by liposomes with sialyl Lewis X repairs infarcted myocardium in rabbits.

We investigated the effect of cardiac-targeting erythropoietin (EPO)-encapsulated liposomes with sialyl Lewis(X) (SLX) on myocardial infarct (MI) size, left ventricular (LV) remodeling and function, and its molecular mechanism for repairing infarcted myocardium. In rabbits, MI was induced by 30 min of coronary occlusion followed by reperfusion. EPO-encapsulated liposomes with SLX (L-EPO group), EPO-encapsulated liposomes without SLX (L-EPO without SLX group), liposomes with SLX without EPO (L group), or saline (saline group) were intravenously administered immediately after MI. MI sizes and numbers of microvessels were assessed 14 days after MI. Prosurvival proteins and signals were assessed by Western blot analysis 2 and 14 days after MI. Confocal microscopy and electron microscopy showed the specific accumulation of liposomes with SLX in the infarcted myocardium. MI and cardiac fibrosis areas were significantly smaller in the L-EPO group than in the other groups. LV function and remodeling were improved in the L-EPO group. The number of CD31-positive microvessels was significantly greater in the L-EPO group than in the other groups. Higher expressions of EPO receptors, phosphorylated (p)Akt, pERK, pStat3, VEGF, Bcl-2, and promatrix metalloproteinase-1 were observed in the infarct area in the L-EPO group than in the other groups. EPO-encapsulated liposomes with SLX selectively accumulated in the infarct area, reduced MI size, and improved LV remodeling and function through activation of prosurvival signals and by exerting antifibrotic and angiogenic effects. EPO-encapsulated liposomes with SLX may be a promising strategy for active targeting treatment of acute MI.

Sudden reversible pacemaker failure in a patient with cardiac sarcoidosis: an unfortunate case of ventricular septal pacing.

We report a case of sudden marked deterioration of ventricular stimulation threshold resulting in pacemaker failure 16 months after a ventricular septal lead implantation for atrioventricular block. Echocardiography revealed septal wall thinning at the electrode-tissue interface, which was not detected pre-operatively. Endomyocardial biopsy confirmed cardiac sarcoidosis. The increased threshold was reversible with prednisolone.

Cilostazol protects the heart against ischaemia reperfusion injury in a rabbit model of myocardial infarction: focus on adenosine, nitric oxide and mitochondrial ATP-sensitive potassium channels.

1. The present study examined whether or not cilostazol reduces the myocardial infarct size, and investigated its mechanism in a rabbit model of myocardial infarction. 2. Japanese white rabbits underwent 30 min of coronary occlusion, followed by 48 h of reperfusion. Cilostazol (1 and 5 mg/kg) or vehicle was given intravenously 5 min before ischaemia. 8-p-sulfophenyl theophylline (8SPT; an adenosine receptor blocker, 7.5 mg/kg), Nω-nitro-L-arginine methylester (l-NAME; an NOS inhibitor, 10 mg/kg) or 5-hydroxydecanoic acid sodium salt (5-HD; a mitochondrial ATP-sensitive potassium (KATP) channel blocker, 5 mg/kg) was given intravenously 5 min before cilostazol injection. Infarct size was determined as a percentage of the risk area. 3. The myocardial interstitial levels of adenosine and nitrogen oxide (NOx) during ischaemia and reperfusion, and the intensity of myocardial dihydroethidium staining were determined. 4. Infarct size was significantly reduced in the cilostazol 1 mg/kg (38.4% (2.9%)) and cilostazol 5 mg/kg (30.7% (4.7%)) groups compared with that in the control group (46.5% (4.2%)). The infarct size-reducing effect of cilostazol was completely abolished by 8SPT (46.6% (3.5%)), L-NAME (49.0% (5.5%)), or 5HD (48.5% (5.1%)). 8SPT, L-NAME or 5HD alone did not affect the infarct size. Cilostazol treatment significantly increased myocardial levels of adenosine and NOx during ischaemia, and attenuated the intensity of dihydroethidium staining during reperfusion. 5. These findings show that cilostazol reduces the myocardial infarct size by increasing adenosine and NOx levels, attenuating superoxide production and opening the mitochondrial KATP channels. Cilostazol might provide a new strategy for the treatment of coronary heart disease.