Hideo Tada

Role of myocyte nitric oxide in β-adrenergic hyporesponsiveness in heart failure

Background The positive inotropic response to β-adrenergic stimulation is attenuated at the isolated myocyte level in heart failure. Nitric oxide (NO) has a negative inotropic effect and attenuates the response to isoproterenol. It has been suggested that NO synthesis is increased in failing myocytes. However, the pathophysiological consequences after induction of NO in myocyte contractility are less clear in the setting of heart failure. Methods and Results We examined the effects of an NO synthase (NOS) inhibitor on contractile function in myocytes isolated from 11 dogs with rapid pacing–induced heart failure (ejection fraction, 29±2%) and 8 control dogs (ejection fraction, 74±3%). Sarcomere shortening velocity was measured as an index of contractility under four experimental conditions: at baseline, after adding isoproterenol (ISO; 1 nmol/L), after an NOS inhibitor (Nϖ-nitro-l-arginine methyl ester [L-NAME], 0.1 nmol/L), and after L-NAME plus ISO. L-NAME alone had no effects on basal sarcomere shorteni...

Altered plasma levels of cytokines in patients with ischemic heart disease.

BACKGROUND Cytokines play an important role in mediating inflammatory-proliferative responses, including atherosclerosis. Alterations in the plasma levels of cytokines in patients with ischemic heart disease (IHD) remain to be examined. OBJECTIVE To examine the possible alterations in the plasma levels of cytokines in patients with IHD and in controls. METHODS Thirty-one patients with IHD and 16 controls were studied. The cytokines measured in our study included interleukin-6, macrophage-colony-stimulating factor (MCSF), transforming growth factor-beta (TGF-beta), and seven other major cytokines. The measurements were performed by using an enzyme-linked immunosorbent assay method. RESULTS The MCSF levels were significantly higher in patients with IHD than they were in controls (P < 0.01), whereas the TGF-beta levels were significantly lower in patients with IHD than they were in controls (P < 0.01). Moreover, the levels of MCSF and those of TGF-beta were correlated negatively (P < 0.05). The interleukin-6 levels tended to be higher in patients with unstable angina. The plasma levels of other cytokines were below the detection levels in most cases. CONCLUSIONS Results from studies in vitro suggested that the process of atherosclerosis is accelerated and inhibited by MCSF and TGF-beta, respectively. The present results thus suggest that the alterations in the plasma levels of MCSF and TGF-beta may be involved in the pathogenesis of IHD in humans.

In-hospital and one-year outcomes for patients undergoing percutaneous coronary intervention for acute myocardial infarction

Previous studies have identified risk factors for short- and long-term outcomes for patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). However, it remains unknown whether they can be generalized to current PCI practice for a broader cohort of patients. We analyzed the follow-up information (mortality and revascularization procedures) obtained from a nationwide Japanese registry during 1997 of a total of 2,211 patients with AMI who underwent PCI at 143 facilities. Demographic, clinical, angiographic, and procedural variables were submitted to statistical analysis to detect the risk factors of adverse outcomes. In-hospital and 1-year mortality rates were 7.1% and 10.9%, respectively. The most important risk factor for in-hospital death was attempted PCI of the left main (LM) coronary artery. Further independent risk factors for death were left ventricular (LV) dysfunction (ejection fraction </=40%), LM disease, older age, multivessel disease, cerebrovascular disease, and diabetes. The receiver-operating characteristics curve for the predicted probability of death was 0.88, indicating a good ability to discriminate high-risk patients. Independent risk factors for 1-year postdischarge mortality were LV dysfunction, older age, renal failure, multivessel disease, and diabetes. The incidence of the need for repeat PCI or bypass surgery was significantly higher in patients with multivessel and LM disease. PCI is a valuable treatment strategy for a broad spectrum of patients with AMI. However, the mortality for patients with LM disease and poor LV function is still high even using current practice standards.

A third-generation, long-acting, dihydropyridine calcium antagonist, azelnidipine, attenuates stent-associated neointimal formation in non-human primates

Background Calcium antagonists have been shown to reduce atherogenesis and improve clinical outcomes in atherosclerotic vascular disease. No study has so far, however, addressed the effects of calcium antagonists on stent-associated neointimal formation. We therefore investigated whether a third-generation calcium antagonist, azelnidipine, attenuates in-stent neointimal formation in non-human primates. Method Male cynomolgus monkeys were fed a high cholesterol diet for 4 weeks, and were randomly assigned to three groups: a vehicle group and two other groups treated with azelnidipine at 3 and 10 mg/kg per day for an additional 24 weeks (n = 12 each). Multi-link stents were then implanted in the iliac artery. Results Azelnidipine at the high dose reduced neointimal thickness (0.25 ± 0.02 versus 0.19 ± 0.02 mm; P < 0.05). Azelnidipine also reduced local oxidative stress and monocyte chemoattractant protein 1 (MCP-1) expression. No difference was found between the three groups in the degrees of injury score, inflammation score, plaque neovascularization, or plasma lipid levels. Azelnidipine also reduced MCP-1-induced proliferation/migration of vascular smooth muscle cells in vitro. Conclusions This study demonstrated for the first time that azelnidipine attenuates in-stent neointimal formation associated with the reduced expression of MCP-1 and smooth muscle proliferation/migration in the neointima. These data in non-human primates suggest potential clinical benefits of azelnidipine as a ‘vasculoprotective calcium antagonist’ in patients undergoing vascular interventions.

Glibenclamide, a specific inhibitor of ATP-sensitive K+ channels, inhibits coronary vasodilation induced by angiotensin II-receptor antagonists.

The purpose of our study was test the hypothesis that endogenous angiotensin II contributes to the basal coronary artery tone by acting at vascular ATP-sensitive K+ (K+ATP) channels. Coronary blood flow (CBF) and other hemodynamic parameters were measured in anesthetized dogs. Intracoronary infusion of the selective antagonists of angiotensin II AT1 receptors (L-158,809 and E4177) increased CHF without affecting other hemodynamic parameters, indicating that endogenous angiotensin II caused coronary vaso-constriction through the AT1 subtype receptors. Coronary vasodilation in response to AT1 receptor antagonists was blunted by pretreatment with glibenclamide (a specific inhibitor of K+ATP channels; p < 0.01) but not by either an adenosine-receptor antagonist or an inhibitor of nitric oxide synthesis. Coronary vasodilation in response to AT1-receptor antagonists was partly reduced (p < 0.01) by PD-123319 (the AT2-receptor antagonist). Glibenclamide had no effect on coronary vasodilation induced by sodium nitroprusside. These results indicate that in dogs in vivo, coronary vasodilation in response to AT 1-receptor antagonists inhibited markedly by glibenclamide and partly by PD-123319, suggesting that endogenous angiotensin II contributes to the maintenance of basal coronary vascular tone by acting at K+ATP channels through its receptors.

Coronary aneurysm associated with coronary perforation after sirolimus-eluting stents implantation: close follow-up exceeding 2 years by coronary 3-dimensional computed tomography.

Both coronary perforation and aneurysms associated with sirolimus-eluting stent (SES) implantations are uncommon complications. We describe an unusual case of a coronary aneurysm associated with a coronary perforation after SES implantation. Although their pathogenesis has not yet been completely elucidated, some technical factors including the use of excessive pressure during the stent deployment, and sirolimus-induced vascular inflammatory reactions and poor healing response at the perforation site may be related to the shape of the aneurismal formation. Fortunately and interestingly, the size of the coronary aneurysm gradually decreased, and finally by 26 months a nearly complete resolution of the aneurysm had taken place. Furthermore, close follow-up by coronary 3-dimensional computed tomography (3DCT) could clearly demonstrate the natural course of this aneurysm. To the best of our knowledge, there have been no reports on the natural course of coronary aneurysm associated with a coronary perforation after SES(s) implantation for more than 2 years using coronary 3DCT as in this present case. The phenomenon of the spontaneous resolution of the coronary aneurysm after SES implantation may have clinical therapeutic implications.