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We examined the cytotoxic effect of iNOS-generated NO in cultured cardiac myocytes treated with IL-1β , IFN- γ and LPS. Treatment of the myocytes with cytokines for 48 h resulted in a marked NO production, a significant decline in cellular ATP content, and a significant increase in myocyte death with morphological characteristics of necrosis. Moreover, immunohistochemical examination showed that the cytokines caused nitrotyrosine formation in the injured myocytes. Uric acid and L-cysteine which have the ability to quench peroxynitrite significantly attenuated these cytokine-induced effects, although they did not alter NO production or the decline in cellular ATP. These data suggest that NO production induced by cytokines can not only cause deleterious effects in the myocardial energy balance but also induce myocytes necrosis, through the formation of peroxynitrite. [Copyright &y& Elsevier]

Introduction: Although several etiopathogenetic mechanisms have been proposed, the causes of left ventricular apical ballooning syndrome are still controversial.Case Presentation: A 51-year-old Japanese woman consulted the emergency room complaining of the sudden onset of anterior chest pain while shopping. We initially suspected her disease as left ventricular apical ballooning syndrome based on her clinical background and laboratory examinations. However, the initial coronary angiogram demonstrated diffuse lesions in her distal left anterior descending coronary artery, and she was finally diagnosed with apical myocardial infarction. The blood flow in her distal left anterior descending coronary artery had markedly improved in the chronic phase. If the reduced blood flow in her distal left anterior descending coronary artery was induced by coronary vasospasm and the vasospasm was relieved before the coronary angiogram was performed, this case must be diagnosed as left ventricular apical ballooning syndrome.Conclusion: We think this case may promote discussion regarding the pathophysiology of left ventricular apical ballooning syndrome. [ABSTRACT FROM AUTHOR]

The mechanism responsible for cardiac depression in septic shock remains unknown. The present study examined whether nitric oxide (NO) overproduced by inducible NO synthase (iNOS) can inhibit aerobic energy metabolism and impair the myocardial function in endotoxin-treated rat hearts. Lipopolysaccharide (LPS) significantly decreased systolic blood pressure (BP) to 44% of control during the 48 h treatment. Hearts from control and LPS-treated rats were perfused in a Langendorff apparatus. After LPS injection, left ventricular (LV) developed pressure (LVDP) was significantly depressed, plasma (NOx) concentration was markedly increased, and myocardial adenosine 5''-triphosphate (ATP), creatine phosphate (CrP), and the ratio of ATP/adenosine 5''-diphosphate were progressively decreased with time. Immunological examination showed a significant expression of iNOS protein in the LPS-treated myocytes. Aminoguanidine, an inhibitor of iNOS, significantly attenuated these LPS-induced functional and metabolic changes. Myocardial cyclic guanosine 3'',5''-monophosphate (cGMP) content was significantly increased after LPS injection. Methylene blue, an inhibitor of soluble guanylate cyclase, blunted this increase in cGMP and significantly restored the LPS-induced contractile dysfunction 6 h after LPS injection. In addition, there was a significant negative correlation between LVDP and myocardial cGMP levels as well as a significant negative correlation between LVDP and plasma NOx levels. In contrast, 48 h after LPS injection, methylene blue no longer affected cardiac performance, and there was a significant positive correlation between LVDP and myocardial ATP content. Furthermore, the normalized activities (as a ratio of the citrate synthase activity) of mitochondrial NADH-CoQ reductase, succinate-CoQ reductase, and ATPase, were significantly inhibited, and the swelling or disruption of mitochondria cristae was seen in the 48 h LPS treatment. These LPS-induced functional and morphological disorders in the mitochondria were significantly improved by aminoguanidine. The findings suggest that sustained production of NO by iNOS leads to contractile dysfunction via cGMP in the early stage, but that it can directly impair the mitochondrial function, lower myocardial energy production, and contribute significantly to the myocardial dysfunction in the later stage of septic shock. [Copyright &y& Elsevier]

Objectives: The present study examined the possibility that intracellular ATP levels dictate whether hypoxic cardiac myocytes die by apoptosis or necrosis. Background: Although apoptosis and necrosis may appear to be distinct forms of cell death, recent studies suggest that the two may represent different outcomes of a common pathway. In ischemic myocardium, apoptosis appears early, while energy stores are presumably still available, followed only later by necrosis. Methods: Neonatal rat cardiac myocytes were exposed to continuous hypoxia, during which the intracellular ATP concentration was modulated by varying the glucose content in the medium. The form of cell death was determined at the end of the hypoxic exposure. Results: Under total glucose deprivation, ATP dropped precipitously and cell death occurred exclusively by necrosis as determined by nuclear staining with ethidium homodimer-1 and smearing on DNA agarose gels. However, with increasing glucose concentrations (10, 20, 50, 100 mg/dl) cellular ATP increased correspondingly, and apoptosis progressively replaced necrosis until it became the sole form of cell death, as determined by nuclear morphology, DNA fragmentation on agarose gels, and caspase-3 activation. The data showed a significantly positive correlation between myocyte ATP content and the percentage of apoptotic cells. Hypoxia resulted in lactate production and cellular acidification which stimulates apoptosis. However, acidification-induced apoptosis was also increased in an ATP-dependent fashion. Loss of mitochondrial membrane potential and cytochrome c release from the mitochondria was observed in both the apoptotic and necrotic cells. Furthermore, translocation of Bax from cytosol into mitochondria preceded these events associated with mitochondrial permeability transition. Increased lactate production and a lack of effect by the mitochondrial inhibitor oligomycin indicated that ATP was generated exclusively through glycolysis. Conclusions: We demonstrate that ATP, generated through glycolysis, is a critical determinant of the form of cell death in hypoxic myocytes, independently of cellular acidification. Our data suggest that necrosis and apoptosis represent different outcomes of the same pathway. In the absence of ATP, necrosis prevails. However, the presence of ATP favors and promotes apoptosis. [Copyright &y& Elsevier]

Examines the role of energy-dependent mitochondrial pathways in cultured rat cardiac myocyte apoptosis. Importance of intracellular energy levels in determining the form of cell death in cardiac myocytes; Definition of apoptosis; Loss of Bax translocation in apoptotic and neurotic cells.

Examines the role of intracellular energy levels in determining the form of cell death in cardiac myocytes. Effect of glucose concentration on adenosine triphosphate content; Effect of staurosporine treatment on cell viability; Mitochondrial transmembrane potential; Effect of glucose concentration on caspase-3 activity.

Recently, there have been increasing opportunities to treat patients with peripheral arterial disease. Of those patients, both pathological conditions, such as acute limb ischemia (ALI) and chronic critical limb ischemia (CLI), are closely associated with high risks of major amputation, disability and death. We encountered a very rare case of CLI subsequent to ALI. An 83-year-old male showed the sudden onset of ALI, probably due to thromboembolism from an abdominal aortic aneurysm during an operation for gastric cancer. The patient was referred to another hospital for Fogarty thrombectomy. About 1 month after ALI onset, necrosis of the left first toe gradually progressed. On angiography of the left lower limb, we noted occlusions of both anterior and posterior tibial arteries. Then, we successfully conducted balloon angioplasty for the below-the-knee arteries. Thereby, favorable blood flow was achieved, which led to successful wound healing without amputations. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Neoatherosclerosis is emerging as a stent‐associated problem that has not yet been fully resolved. Because in‐stent restenosis with a neoatherosclerotic etiology is associated with a high risk of acute coronary syndrome and a poor survival prognosis, it is essential to precisely identify patients at risk using advanced imaging modalities. [ABSTRACT FROM AUTHOR]

Currently, there are more opportunities to treat patients complicated with critical limb ischemia (CLI), which is a very dismal medical condition associated with a high risk of major amputation, disability and death. Because CLI is usually caused by multi-level occlusive atherosclerotic disease, the condition of CLI induced by aorto-iliac occlusive disease (AIOD) alone is thought to be a rare pathological entity. We encountered a patient with severe CLI caused by solitary AIOD. Three vascular access routes were established and stiff guidewires retrogradely passed the occluded arteries on both sides. We deployed two self-expandable bare metal stents and complete revascularization led to wound healing. Recent improvements of catheter devices and procedural techniques related to endovascular treatment (EVT) have enabled us to safely recanalize complex vascular lesions of the lower extremities. Therefore, an EVT strategy is one of the favorable treatment options for CLI patients who are contraindicated for surgical treatments. [ABSTRACT FROM AUTHOR]

Key Clinical Message Catheter-induced coronary dissection involving left main bifurcation is a rare complication during cardiac catheterization but can become lethal unless it is treated appropriately. Interventional cardiologists always have to pay attention to the risk of complications related to cardiac catheterization and prepare for determining the best bailout strategy for the situation. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the practical usefulness of dual lumen catheter-facilitated reverse wire technique.Background: We sometimes encounter difficulty in introducing a guidewire to the highly angulated side branch. In those cases, the reverse wire technique is considered as a last resort to overcome the situation.Methods: Between January 2013 and June 2015, we performed the reverse wire technique for guidewire crossing into an extremely angulated side branch in consecutive seven cases with true bifurcated lesions. We retrospectively evaluated patients' backgrounds, lesion characteristics, and details of the percutaneous coronary intervention (PCI) procedures.Results: Three interventional cardiologists with various levels of experience in coronary intervention performed this technique. A polymer-jacket hydrophilic-coated guidewire was used for the reverse wire system excluding in one case, and we adopted a sharp curve for the tip shape in all cases. After crossing the reverse wire into a highly angulated side branch, we usually deliver a flexible micro catheter over the guidewire for the purpose of guidewire exchange. We deployed a stent in the side branch in three cases. We successfully performed all PCI procedures without any complications and no major adverse cardiac event was observed during hospitalization.Conclusions: We could safely and effectively perform the reverse wire technique for guidewire crossing into a markedly angulated side branch. We recommend a polymer-jacket hydrophilic-coated guidewire with a sharp curve in the tip shape for this technique. All interventional cardiologists should acquire knowledge and skills regarding this guidewire manipulation technique. [ABSTRACT FROM AUTHOR]

It is well known that silent myocardial ischemia (SMI) often complicates patients with cerebral infarction and that stroke patients often die of ischemic heart disease. Therefore, it is considered important to treat myocardial ischemia in stroke patients. This study investigated SMI complicating Japanese patients with fresh stroke, using Tc-tetrofosmin myocardial scintigraphy with pharmacologic stress testing to elucidate their clinical manifestations. This study included 41 patients (26 men, mean age 76.0 ± 10.7 years) with acute cerebral infarction and no history of coronary artery disease. All patients underwent Tc-tetrofosmin myocardial scintigraphy with intravenous administration of adenosine to diagnose SMI. Of the 41 patients, myocardial ischemia was confirmed in 17 patients (41.5%). Atherosclerotic etiology was the major cause of stroke in the ischemia(+) group and embolic origin was the major cause in the ischemia(−) group. Patients with myocardial ischemia had a higher incidence of diabetes mellitus (52.9 vs 20.8%; P = 0.0323) and more than two conventional cardiovascular risk factors (64.7 vs 25.0%; P = 0.0110) compared with the nonischemic patients. Infarction subtype of atherosclerotic origin was an independent positive predictor of asymptomatic myocardial ischemia in patients with stroke. These findings indicate that the prevalence of asymptomatic myocardial ischemia is relatively high, especially in patients with stroke of atherosclerotic origin. Therefore, it is beneficial for us to narrow the target population who are at the highest risk when screening for SMI in Japanese patients with acute cerebral infarction. [ABSTRACT FROM AUTHOR]

Abstract: Nicorandil has been shown to inhibit myocyte apoptosis by opening of mitochondrial ATP-sensitive potassium (mitoKATP) channels and nitrate-like effect against oxidative stress. However, the detailed mechanism of nicorandil-mediated cardioprotection under hypoxic conditions remains to be largely unknown. The present study examined whether nicorandil can inhibit apoptosis via regulation of Bcl-2 family proteins in hypoxic myocytes. Neonatal rat cardiac myocytes were exposed to hypoxia for 7 hours. Hypoxia-induced myocyte apoptosis (13.9±0.9%) under glucose-rich conditions. Myocyte apoptosis was accompanied by loss of mitochondrial membrane potential (Δψm), cytochrome c release from mitochondria into cytosol, and activation of caspase-3. Hypoxia also significantly increased Bax and decreased Bcl-2 mRNA and protein expression, thereby increasing Bax/Bcl-2 ratio. Nicorandil 100 μmol/l significantly decreased the percentage of apoptotic myocytes (7.2±0.5%) by inhibiting loss of Δψm and translocation of cytochrome c. These effects of nicorandil were partially but significantly inhibited by cotreatment of either 500 μmol/l 5-hydroxydecanoate, a selective mitoKATP channel antagonist, or 10 μmol/l 1H-[1,2,4]oxidazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase. Moreover, nicorandil significantly inhibited the hypoxia-induced changes in Bax and Bcl-2 expression, and concomitant increased Bax and decreased Bcl-2 immunoreactivity in mitochondria. These effects of nicorandil in Bax and Bcl-2 expression were significantly blunted by cotreatment of ODQ and 5-HD, respectively. Cotreatment of KT5823, an inhibitor of protein kinase G, significantly blocked the effect of nicorandil on Bax expression and 8-bromo-cyclic guanosine 3′,5′ monophosphate (8-bromo-cGMP), a cGMP analog, mimicked the effect of nicorandil on Bax expression. The present study demonstrates that nicorandil regulates Bcl-2 family proteins via opening of mitoKATP channels and nitric oxide-cGMP signaling and inhibits hypoxia-induced mitochondrial death pathway. [Copyright &y& Elsevier]

Objective. Nitric oxide (NO) is known to act as a mediator of tissue injury as well as being a potent endogenous vasodilator. The functional and metabolic effects of NO on ischemia-reperfusion injury are still controversial. The aim of this study was to clarify the relationship between the degree of NO synthase (NOS) inhibition and the effects on ischemia-reperfusion injury. Methods and results. Langendorff-perfused rat hearts were subjected to 30 minutes of global ischemia followed by 30 minutes of reperfusion. The recovery of left ventricular developed pressure (LVDP), creatine kinase (CK) release, and myocardial high energy phosphates were measured in hearts perfused with or without NOS inhibitors, L-NG-monomethyl arginine (L-NMMA) or NGnitro-L-arginine methylester (L-NAME). NOS inhibitors exerted different effects on the recovery of LVDP and CK release depending on the concentration. The low dose of L-NMMA improved the recovery of LVDP, decreased the CK release during reperfusion, and preserved the myocardial adenosine triphosphate content after reperfusion. In contrast, the high dose of L-NMMA had adverse effects. L-NMMA reduced NO release in coronary effluent in a dose-dependent fashion. Both effects of L-NMMA were abolished by excessive co-administration of L-arginine and the same doses of D-NG-monomethyl arginine (D-NMMA) showed no effect on ischemia-reperfusion injury. Therefore, both effects were due to NOS inhibition. In addition, L-NMMA suppressed the myocardial malondialdehyde accumulation, an indicator of oxidative stress, which might be attributed to the beneficial effects by partial NOS inhibition. On the other hand, the high dose L-NMMA significantly decreased coronary flow during aerobic perfusion and reperfusion. Therefore, it is conceivable that the vasoactive NOS inhibition contributes to the harmful effects, which might exceed the beneficial effects due to a decrease in oxidative stress. Conclusion. The present results showed that NO inhibitors had dual effects on mechanical function and energy metabolism depending on the concentration. Non-vasoactive inhibition of NOS had beneficial effects due to the suppression of oxidative injury. However, strong vasoactive inhibition of NOS exacerbated the ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

: ObjectivesWe examined whether amlodipine, a calcium channel antagonist with potent antioxidant activity, inhibits doxorubicin-induced apoptosis in cultured neonatal rat cardiac myocytes.: BackgroundRecent studies have shown that doxorubicin induces apoptosis as well as necrosis in myocytes through generation of reactive oxygen species.: MethodsThe effects of amlodipine and several other antioxidants on doxorubicin-induced oxidative stress and mitochondria-mediated apoptosis were examined.: ResultsTreatment of myocytes with doxorubicin (10−6 mol/l) for 14 h increased the number of cells with elevated peroxides, as histochemically estimated by 2′,7′-dichlorofluorescin (DCF) diacetate, and the percentage of apoptotic myocytes, as estimated by Hoechst 33258 nuclear staining, compared with control myocytes (25.0 ± 1.6% vs. 5.2 ± 1.2%). Moreover, doxorubicin-induced myocyte apoptosis was also confirmed by annexin V–fluorescein isothiocyanate binding assay. Doxorubicin induced a reduction in myocyte adenosine 5′-triphosphate content, a loss of mitochondrial membrane potential, cytochrome c release from the mitochondria into the cytosol, and caspase-3 activation to 1.9-fold of control. Amlodipine significantly attenuated increased DCF fluorescence, inhibited the mitochondria-mediated apoptotic responses described earlier, and decreased apoptosis in the doxorubicin-treated myocytes in a dose-dependent fashion. Amlodipine at 10−6 mol/l significantly decreased apoptosis to 15.4 ± 0.7%, and this antiapoptotic action was more effective than that seen with other antioxidants, including probucol, ascorbic acid, and alpha-tocopherol. In contrast, the calcium channel antagonist nifedipine (10−6 mol/l) did not inhibit apoptosis. Catalase, glutathione, and N-acetylcysteine, but not mannitol or superoxide dismutase, significantly decreased DCF fluorescence and attenuated myocyte apoptosis induced by doxorubicin to 18.7 ± 1.2%, 19.1 ± 1.7%, and 18.7 ± 0.6%, respectively.: ConclusionsAmlodipine significantly inhibits doxorubicin-induced myocyte apoptosis by suppressing the mitochondrial apoptotic pathway. This effect is attributed to the antioxidant properties of amlodipine, affecting mainly hydrogen peroxide. [Copyright &y& Elsevier]

Background: Vascular closure devices have been widely used to achieve rapid hemostasis after percutaneous catheterization procedures via the common femoral artery. The EXOSEAL vascular closure device is a device that can deliver a bioabsorbable polyglycolic acid plug to fill the subcutaneous puncture route at the groin for rapid hemostasis, and this device has a lower risk of arterial occlusion than other vascular closure devices.Case Presentation: An 83-year-old Japanese man underwent percutaneous coronary intervention for a proximal stenosis in his left circumflex artery through a 7-Fr sheath from his right common femoral artery. We encountered acute popliteal artery occlusion associated with EXOSEAL vascular closure device. We detected the plug material of this device at the occluded lesion by intravascular ultrasound, and performed successful bailout stenting after pulling the embolus with an inflated balloon catheter up to the superficial femoral artery from the popliteal artery.Conclusion: Acute limb ischemia caused by an EXOSEAL vascular closure device is a very rare complication. Balloon angioplasty and stenting are considered to be effective options to deal with the plug dislodgement of an EXOSEAL vascular closure device. We must be prepared for every rare complication during endovascular treatment. [ABSTRACT FROM AUTHOR]

Introduction: Because of the unusual anatomy of an anomalous origin of the right coronary artery from the left sinus of Valsalva, selective cannulation of the guiding catheter in percutaneous coronary intervention for these cases is always challenging.Case Presentation: A 58-year-old Japanese man was admitted to our hospital complaining of worsening exertional chest pain. He was suspected of having unstable angina pectoris and underwent cardiac catheterization. We found a subtotal occlusive lesion in the mid-portion of his right coronary artery that originated from the left sinus of Valsalva. On the previous percutaneous coronary intervention, we failed to cannulate the guiding catheter to the anomalous orifice of the right coronary artery. Therefore, we decided to use the GuideLiner catheter for stable back-up support from the beginning. A 6Fr GuideLiner catheter was introduced into the right coronary artery by anchoring it coaxially with a semi-compliant balloon catheter. And we successfully deployed two drug-eluting stents by crossing over the posterior-descending artery. Final angiography demonstrated favorable dilatation of the target lesion, and native blood flow in the right coronary artery was completely recovered.Conclusion: GuideLiner is a monorail-type "child" support catheter that facilitates coaxial guiding catheter engagement and an appropriate back-up force, achieving successful device delivery to target lesions in this kind of complex percutaneous coronary intervention. [ABSTRACT FROM AUTHOR]