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Eicosapentaenoic acid (EPA) has antiarrhythmic effects. The J-wave on an electrocardiogram is associated with a high incidence of ventricular tachycardia/fibrillation (VT/VF). We evaluated relationships between EPA and J-waves, and their involvement in the occurrence of VT/VF in acute myocardial infarction (AMI). Two hundred consecutive patients undergoing successful percutaneous coronary intervention within 12 h after AMI onset were enrolled. Serum EPA level and J-waves at admission were evaluated. The patients were divided into two groups according to the optimal cutoff value (2.94) of serum EPA level (% of total fatty acids): LOW (<2.94, 61 ± 11 years, n = 103) and HIGH groups (≥2.94, 70 ± 13 years, n = 81). J-waves were observed more frequently in the LOW (36/103, 35 %) than in HIGH group (16/81, 20 %) (P = 0.020). The 30-day incidence of VT/VF including those occurring before admission was higher in the LOW (19.5 %) than in HIGH group (6.2 %) (P = 0.009). The patients with J-waves showed a higher incidence of VT/VF (23.1 %) than those without J-waves (9.9 %) (P = 0.019). Kaplan-Meier analysis showed that the highest incidence of VT/VF was observed in the LOW with J-wave group (27.8 %), followed by the LOW without J-wave (15.0 %), HIGH with J-wave (12.5 %), and HIGH without J-wave (4.6 %) (P = 0.013). Cox proportional hazard analysis revealed that Killip grade and low serum EPA level or presence of J-waves were significantly associated with the incidence of VT/VF. Low serum EPA level is a risk for incidence of VT/VF in the acute phase of myocardial infarction. Involvement of the J-wave and its possible link with EPA in the pathogenesis of ischemia-induced VT/VF are suggested.

Background: It is still controversial whether intravenous administration of β-blocker in the very acute phase of acute myocardial infarction (AMI) is beneficial. Landiolol is an ultra-short-acting β-blocker that has less effect on blood pressure, but little is known about its efficacy and safety for patients with AMI undergoing primary percutaneous coronary intervention (PCI)., Methods and Results: A consecutive 96 patients with AMI not manifesting cardiogenic shock were prospectively randomized to landiolol (n = 47) or a control group (n = 49). Continuous administration of landiolol (3 µg·kg(-1)·min(-1) for 24 h) was done just after PCI in the landiolol group, but not in the control group. Heart rate decreased by 9.4 ± 1.7 beats/min after initiation of landiolol (P<0.01), but was unchanged in the control group. Left ventricular ejection fraction assessed 6 months later was greater than that at 2 weeks in the landiolol group (52.0 ± 1.5 vs. 49.1 ± 1.5%, P = 0.01), but remained unchanged in the control group. Left ventricular end-diastolic volume index assessed 6 months later was increased compared with that at 2 weeks in the control group (78.0 ± 2.7 vs. 72.5 ± 2.8 ml/m(2), P = 0.02), whereas it was unchanged in the landiolol group., Conclusions: Early intravenous administration of landiolol in patients with AMI undergoing PCI is safe and has the potential to improve cardiac function and inhibit cardiac remodeling in the chronic phase.

Enalapril is effective in the suppression of left ventricular remodeling after acute myocardial infarction (AMI), but the effect of telmisartan is unclear. The consecutive 163 AMI patients underwent primary percutaneous coronary intervention and were randomized to telmisartan (n = 82) or enalapril (n = 81). Left ventriculography was performed in the acute and chronic (6 months) phases. Matrix metalloproteinase (MMP)-2 and MMP-9 activities were measured by zymography in the acute (days 1, 7, and 14) and chronic (6 months) phases. Plasma pentraxin3 (PTX3), a marker of vascular inflammation, was also measured. There were no adverse effects in the telmisartan group. The analysis of the left ventriculograms in the acute and chronic phases revealed no difference between the two groups. MMP-9 activities at days 7 and 14 and in the chronic phase were decreased compared to that at day 1 in both groups. MMP-2 activity was also decreased in the acute phase, but increased in the chronic phase in both groups. There was no difference in the plasma PTX3 level in the acute phase, but in the chronic phase, PTX3 was significantly lower in telmisartan than in enalapril group (2.6 ± 1.4 vs. 3.2 ± 1.6 ng/ml, p = 0.04). Telmisartan is well tolerated, shows similar effects on the markers of left ventricular remodeling to those of enalapril, and suppresses vascular inflammation more effectively than enalapril in AMI patients. Telmisartan can be an alternative to angiotensin converting enzyme inhibitor in patients with AMI.

Growth hormone (GH)-releasing peptides (GHRPs) are synthetic peptides which induce strong GH release in both animals and humans. Among them, GHRP-2 is known to stimulate GH release by acting at both hypothalamic and pituitary sites, but also induces adrenocorticotropic hormone (ACTH) release in healthy subjects. GHRP-2 may stimulate ACTH release directly via GHRP receptor type 1a in ACTH-producing tumors. GHRP-2 increases ACTH secretion in rat in vivo, but not ACTH release from rat primary pituitary cells. In the present study, in order to elucidate the mechanism underlying ACTH secretion by GHRPs, mouse pituitary cells were stimulated by GHRP-2. GHRP receptor mRNA was expressed in the mouse pituitary, and GHRP-2 directly stimulated secretion and synthesis of ACTH in the mouse anterior pituitary cells. GHRP-2 increased intracellular cyclic AMP production. H89, a potent protein kinase A (PKA) inhibitor, and bisindolylmaleimide I, a selective protein kinase C (PKC) inhibitor, inhibited the GHRP-2-induced ACTH release, and that H89, but not bisindolylmaleimide I, inhibited the GHRP-2-induced proopiomelanocortin mRNA levels. Together, the GHRP-2-induced ACTH release was regulated via both PKA and PKC pathways in the mouse pituitary cells, while ACTH was synthesized by GHRP-2 only via the PKA pathway.

Inflammation caused by activated macrophages and T lymphocytes may trigger plaque rapture in acute coronary syndrome (ACS). Anandamide and 2-arachidonylglycerol (2-AG) are macrophage-derived signal lipids and may be involved in the pathogenesis of ACS, but no clinical relevant data have been reported. In 43 acute myocardial infarction (AMI) patients (66 +/- 2 years), blood samples were obtained from the aortic root and the infarct-related coronary artery (IRA) using a PercuSurge system during primary percutaneous coronary intervention (PCI). In six patients with stable effort angina (SEA) (56 +/- 6 years), blood samples were obtained from the site of stenosis during elective PCI. In 25 of the 43 AMI patients, anandamide was detected in the serum. Serum anandamide level was 35 +/- 20 pmol/mL in the aorta and was significantly increased to 401 +/- 134 pmol/mL in the IRA (P < 0.01). 2-AG was undetectable in most of the patients. In patients with SEA, neither anandamide nor 2-AG was detected in the serum at the plaque site. In AMI patients with anandamide detected, left ventricular ejection fraction at 2 weeks after PCI was increased by 3.7 +/- 2.1% compared with that at the acute phase, while it was decreased by 3.0 +/- 1.8% in those without anandamide detected (P < 0.05). The serum anandamide level at the culprit lesion was elevated compared with the systemic level in a significant number of AMI patients, indicating the synthesis of anandamide at the IRA. Anandamide was suggested to be derived from ruptured plaque and may exert beneficial effects in humans.

Aims: Coupling factor 6 (CF6) induces hypertension by attenuating the endothelial generation of prostacyclin. However, intracellular signalling of CF6 in the resistance arteriole vascular smooth muscle cells (VSMCs) that are directly related to vasoconstriction has not been determined. Here we investigated the direct effect of exogenous CF6 on Ca2+ signalling in cultured VSMCs and the in vivo role of endogenous CF6 in the genesis of hypertension using CF6 transgenic (TG) mice., Methods and Results: CF6 induced a monophasic increase in the intracellular free Ca2+ concentration ([Ca2+]i) through nifedipine-sensitive Ca2+ channels in A7r5 cells, a cell line of VSMCs, and enhanced the angiotensin II-induced spike phase of [Ca2+]i to a greater degree in VSMCs derived from spontaneously hypertensive rats (SHRs). In the mesenteric arterioles obtained from CF6-TG mice that manifested hypertension, angiotensin II-induced vasoconstriction was enhanced, compared with wild-type mice, and its enhancement was abolished by an anti-CF6 antibody. Pre-treatment with PP1, a tyrosine kinase c-Src inhibitor, blocked CF6-induced increase in Ca2+ signalling in VSMCs and vasoconstriction in TG mice. The receptor of CF6 was F1 motor of adenosine triphosphate (ATP) synthase with a higher affinity in SHRs. CF6 decreased intracellular pH via activation of ATPase activity and led to c-Src activation to a greater degree in SHR-derived VSMCs., Conclusion: CF6 causes hypertension by directly enhancing Ca2+ signalling in VSMCs and vasoconstriction in the mesenteric arteriolar network via c-Src activation.

Aims: We recently demonstrated that aldosterone induces a non-genomic vasoconstrictor effect on rat coronary arterioles and that this effect was blocked by angiotensin II type 1 receptor (AT1) blockers. Intracellular transglutaminase enhances AT1 signalling by cross-linking AT1 homodimers. The purpose of this study was to confirm the AT1-dependency of the vasoconstrictor effect of aldosterone using AT1a knockout (AT1aKO) mice and to investigate the role of intracellular transglutaminase and AT1 dimerization in this effect., Methods and Results: The mesenteric arterioles (60-160 microm) were isolated from C57BL/6J (wild-type, WT) and AT1aKO mice, and the internal diameter was measured by video microscopy. Aldosterone (10(-13) to 10(-6) M), but not hydrocortisone, produced a dose-dependent vasoconstriction in WT mice; the maximal diameter change was -8.6 +/- 0.3% from the baseline (P < 0.001). This vasoconstrictor effect was unaffected by the mineralocorticoid receptor antagonist spironolactone or eplerenone, the AT2 antagonist PD123319, the glucocorticoid receptor antagonist RU486, or endothelium denudation. Aldosterone's vasoconstrictor effect was negligible in AT1aKO mice. The AT1 blockers valsartan or candesartan suppressed aldosterone-induced vasoconstriction in WT mice. The transglutaminase inhibitors cystamine and monodansyl cadaverine also suppressed the vasoconstrictor effect of aldosterone, without affecting the vasoconstrictor effect of angiotensin II in WT mice. AT1 dimer protein levels were increased in WT mesenteric arterioles treated with 10(-7) M aldosterone, and the transglutaminase inhibitor and AT1 blocker blocked this aldosterone-induced formation of AT1 dimer. Treatment with 10(-7) M aldosterone for 10 min increased the transglutaminase activity by 2.5 +/- 0.2-fold in cultured vascular smooth muscle cells and by 1.2 +/- 0.1-fold in the mesenteric arterioles. These increases were abolished by transglutaminase inhibitors., Conclusion: Aldosterone produces a non-genomic, endothelium-independent vasoconstrictor effect by enhancing intracellular transglutaminase activity and presumably inducing AT1 dimer formation in mesenteric arterioles.

Aldosterone is involved in many cardiovascular diseases with increased oxidative stress. Aldosterone-induced cardiac fibrosis is abolished by blockade of angiotensin II Type-1 (AT1) receptor. Recently, non-genomic vasoconstrictor effects of aldosterone were reported in various vascular beds. We tested the hypothesis that aldosterone stimulates angiotensin AT1 receptor, and causes vasoconstriction by increasing oxidative stress in coronary microcirculation. Coronary arterioles (60-120 microm) were isolated from spontaneously hypertensive rats (SHR) and control Wistar Kyoto (WKY) rats, aged 23-26 weeks. They were cannulated, and pressurized at 60 cm H2O. Effect of aldosterone (10(-15) to 10(-6) M) on coronary arteriolar diameter was examined. Aldosterone rapidly and dose-dependently decreased coronary arteriolar diameter in WKY rats and SHR (diameter changes, 8.4+/-0.7% vs 13.9+/-0.8%, P<0.05). Aldosterone-induced vasoconstriction was enhanced by 1.6-folds in SHR compared to WKY rats (P<0.05). Mineralocorticoid receptor antagonist spironolactone (10(-6) M) did not influence aldosterone-induced vasoconstriction. Selective angiotensin AT1 receptor blocker valsartan (10(-4) M) or candesartan (10(-7) M) abolished aldosterone-induced vasoconstriction. Similarly, superoxide dismutase (SOD, 300 U/ml), and NADPH oxidase inhibitor apocynin (10(-4) M) abolished it. Moreover, the vasoconstrictor effect of aldosterone disappeared in denuded vessels. Real-time quantitative RT-PCR revealed that angiotensin AT1 receptor mRNA level in coronary arterioles of SHR was upregulated by 1.5-folds compared to that in WKY rats (P<0.05). Aldosterone causes vasoconstriction in coronary arterioles, and this vasoconstrictor effect is enhanced by genetically defined hypertension. Aldosterone-induced vasoconstriction is mediated by angiotensin AT1 receptor presumably via oxidative stress.

Early reperfusion with angioplasty and stenting is established as a central, effective treatment for acute myocardial infarction (AMI). The role of thrombectomy prior to angioplasty remains to be elucidated. To evaluate its feasibility, safety, and efficacy, thrombectomy using a TVAC aspiration catheter system was attempted prior to angioplasty and stenting in 40 consecutive patients with AMI. Fifty consecutive patients with AMI in whom angioplasty and stenting were performed without prior thrombectomy served as controls. Neither distribution of Killip classification nor culprit lesion was different between the two groups. In patients treated with the TVAC system, the procedure was successful in 39/40 patients (98%) and there were no procedure-related complications. In the final coronary angiogram, TIMI-3 (Thrombolysis in Myocardial Infarction) flow was obtained in 37/40 (93%) in patients treated with the TVAC system and 43/50 (86%) in control patients. Electrocardiograms before and after coronary intervention were analyzed in patients with ST elevation AMI (35 patients treated with the TVAC system and 41 control patients). ST elevation recovery >50% of the initial value was observed after coronary intervention in 26/35 (74%) in patients treated with the TVAC system and 26/41 (63%) in control patients (P = 0.33). In the case of anterior AMI, ST elevation recovery >50% of the initial value was observed in 13/17 (76%) in patients treated with the TVAC system and 8/20 (40%) in control patients (P = 0.045). Thus, thrombectomy using a TVAC system is feasible, safe, and may have the potential to enhance ST-segment resolution in patients with anterior AMI.