Effect of remote ischemia or nicorandil on myocardial injury following percutaneous coronary intervention in patients with stable coronary artery disease: A randomized controlled trial.

BACKGROUND: The effect of remote ischemic preconditioning (RIPC) and nicorandil on periprocedural myocardial injury (pMI) in patients with planned percutaneous coronary intervention (PCI) remains controversial. The aim of this randomized trial was to evaluate the effect of RIPC or nicorandil on pMI following PCI in patients with stable coronary artery disease (CAD) compared with a control group. METHODS: Patients with stable CAD who planned to undergo PCI were assigned to a 1:1:1 ratio to control, RIPC, or intravenous nicorandil (6mg/h). Automated RIPC was performed by a device, which performs intermittent arm ischemia through three cycles of 5min of inflation and 5min of deflation of a pressure cuff. The primary outcome was the incidence of pMI, determined by an elevation in high-sensitive troponin T or creatine kinase myocardial band at 12 or 24h after PCI. The secondary outcomes were ischemic events during PCI and adverse clinical events at 8months after PCI. RESULTS: A total of 391 patients were enrolled. The incidence of pMI following PCI was not significantly different between the control group (48.9%) and RIPC group (39.5%; p=0.14), or between the control group and nicorandil group (40.3%; p=0.17). There were no significant differences in ischemic events during PCI or adverse clinical events within 8months after PCI among the three groups. CONCLUSIONS: This study demonstrated moderate reductions in biomarker release and pMI by RIPC or intravenous nicorandil prior to the PCI consistently, but may have failed to achieve statistical significance because the study was underpowered.

Intermittent arm ischemia induces vasodilatation of the contralateral upper limb.

Intermittent arm ischemia before percutaneous coronary intervention induces remote ischemic preconditioning (RIPC) and attenuates myocardial injury in patients with myocardial infarction. Several studies have shown that intermittent arm ischemia increases coronary flow and is related to autonomic nerve system. The aim of this study was to determine whether intermittent arm ischemia induces vasodilatation of other arteries and to assess changes in the autonomic nerve system during intermittent arm ischemia in humans. We measured change in the right brachial artery diameter during intermittent left arm ischemia through three cycles of 5-min inflation (200 mmHg) and 5-min deflation of a blood-pressure cuff using a 10-MHz linear array transducer probe in 20 healthy volunteers. We simultaneously performed power spectral analysis of heart rate. Ischemia-reperfusion of the left arm significantly dilated the right brachial artery time-dependently, resulting in a 3.2 ± 0.4% increase after the 3rd cycle. In the power spectral analysis of heart rate, the high-frequency domain (HF), which is a marker of parasympathetic activity, was significantly higher after the 3rd cycle of ischemia-reperfusion than baseline HF (P = 0.02). Intermittent arm ischemia was accompanied by vasodilatation of another artery and enhancement of parasympathetic activity. Those effects may play an important role in the mechanism of RIPC.

Impact of hypertriglyceridemia on endothelial dysfunction during statin ± ezetimibe therapy in patients with coronary heart disease.

Despite the use of statin therapy and achieving the target for low-density lipoprotein cholesterol, a substantial number of coronary events are not prevented, and residual risk factors remain unsettled. Recently, ezetimibe has been shown to reduce not only low-density lipoprotein cholesterol but also triglyceride (TG) levels. The aim of this study was to investigate the associations of residual risk factors, mainly hypertriglyceridemia, with endothelial function during statin therapy in patients with coronary heart disease and examine the effect of ezetimibe add-on therapy. A total of 109 consecutive patients with coronary heart disease during statin therapy were enrolled. Lipid profile was measured and endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery in a fasting state. Next, 32 patients with high TG levels (≥150 mg/dl) were prospectively assigned to the ezetimibe add-on group or the no-ezetimibe group, and endothelial function was assessed after 3 months. Multivariate linear regression analysis demonstrated that serum TG and high-density lipoprotein cholesterol levels were independent determinants of percentage FMD (ß = -0.210 and 0.208, respectively, p <0.05). In patients with high TG levels, ezetimibe add-on therapy significantly improved percentage FMD (from 3.3 ± 1.1% to 4.0 ± 1.1%, p <0.005), whereas no significant change was observed in the no-ezetimibe group. Moreover, the improvement in percentage FMD was significantly associated with reduction in serum TG levels (ß = -0.387, p <0.05) independent of the change in serum low-density lipoprotein cholesterol levels. In conclusion, hypertriglyceridemia is independently associated with endothelial dysfunction in patients with coronary heart disease during statin therapy. Ezetimibe add-on therapy improves endothelial function in these high-risk populations.

Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction.

OBJECTIVE: Postprandial hyperlipemia has been shown to impair endothelial function and contribute to the development of atherosclerosis. We investigated the association between postprandial lipid profiles and endothelial function, and we examined the effects of ezetimibe on postprandial hyperlipemia and lipemia-induced endothelial dysfunction. METHODS: A randomized prospective trial in which 10 mg/day of ezetimibe was administered to 10 subjects for 4 weeks and not administered to 10 subjects (control group) was performed. Lipid profiles and endothelial function, assessed by brachial artery flow-mediated dilation (FMD) during a fasting state and at 2, 4, 6 and 8 h after an oral cookie loading test, were determined before and after treatment for 4 weeks. RESULTS: In all subjects before treatment, the maximum reduction in postprandial %FMD was significantly correlated with the maximum increases in postprandial triglyceride (TG) (r=-0.499, P<0.05) and apolipoprotein B-48 (apoB-48) concentrations (r=-0.551, P<0.05). Ezetimibe treatment for 4 weeks significantly suppressed postprandial elevation in TG (area under the incremental curve, from 1419±594 to 968±32 1 mg h/dl, P<0.05), remnant lipoprotein cholesterol (from 66.9±27.6 to 38.9±15.4 mg h/dl, P<0.01) and apoB-48 (from 58.8±27.5 to 36.2±17.0 µg h/ml, P<0.05) concentrations, and postprandial endothelial dysfunction assessed by %FMD (maximum reduction in %FMD, from -2.6±1.1% to -1.2±0.8%, P<0.05), whereas no significant changes were observed in the control group. CONCLUSION: Postprandial hyperlipemia is closely correlated with transient endothelial dysfunction. Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction.

Beta-Blockers and Oxidative Stress in Patients with Heart Failure.

Oxidative stress has been implicated in the pathogenesis of heart failure. Reactive oxygen species (ROS) are produced in the failing myocardium, and ROS cause hypertrophy, apoptosis/cell death and intracellular Ca(2+) overload in cardiac myocytes. ROS also cause damage to lipid cell membranes in the process of lipid peroxidation. In this process, several aldehydes, including 4-hydroxy-2-nonenal (HNE), are generated and the amount of HNE is increased in the human failing myocardium. HNE exacerbates the formation of ROS, especially H2O2 and ·OH, in cardiomyocytes and subsequently ROS cause intracellular Ca(2+) overload. Treatment with beta-blockers such as metoprolol, carvedilol and bisoprolol reduces the levels of oxidative stress, together with amelioration of heart failure. This reduction could be caused by several possible mechanisms. First, the beta-blocking effect is important, because catecholamines such as isoproterenol and norepinephrine induce oxidative stress in the myocardium. Second, anti-ischemic effects and negative chronotropic effects are also important. Furthermore, direct antioxidative effects of carvedilol contribute to the reduction of oxidative stress. Carvedilol inhibited HNE-induced intracellular Ca(2+) overload. Beta-blocker therapy is a useful antioxidative therapy in patients with heart failure.

Fulminant eosinophilic myocarditis associated with visceral larva migrans caused by Toxocara canis infection.

A 19-year-old man was transferred to hospital because of myocarditis with cardiogenic shock. Echocardiography showed a left ventricular ejection fraction of 23.8% and an intermediate amount of pericardial effusion. The patient immediately received an intra-aortic balloon pump and percutaneous cardiopulmonary support. Right ventricular endomyocardial biopsy was performed in the acute phase and showed extensive eosinophilic inflammatory cell infiltration, severe interstitial edema and moderate myocardial necrosis. High-dose corticosteroids were administered. Because the patient's antibody titer against Toxocara canis was high and his symptoms had appeared after eating raw deer meat, the diagnosis was fulminant eosinophilic myocarditis caused by a hypersensitivity reaction to visceral larval migrans. After starting high-dose corticosteroids, the ejection fraction dramatically improved, the eosinophilia decreased and the patient made a full recovery.