Yuzo Takeuchi

Long-Term (>10 Years) Clinical Outcomes of First-in-Human Biodegradable Poly-l-Lactic Acid Coronary Stents Igaki-Tamai Stents

Background— The purpose of this study was to evaluate the long-term safety of the Igaki-Tamai stent, the first-in-human fully biodegradable coronary stent made of poly-l-lactic acid. Methods and Results— Between September 1998 and April 2000, 50 patients with 63 lesions were treated electively with 84 Igaki-Tamai stents. Overall clinical follow-up (>10 years) of major adverse cardiac events and rates of scaffold thrombosis was analyzed together with the results of angiography and intravascular ultrasound. Major adverse cardiac events included all-cause death, nonfatal myocardial infarction, and target lesion revascularization/target vessel revascularization. During the overall clinical follow-up period (121±17 months), 2 patients were lost to follow-up. There were 1 cardiac death, 6 noncardiac deaths, and 4 myocardial infarctions. Survival rates free of all-cause death, cardiac death, and major adverse cardiac events at 10 years were 87%, 98%, and 50%, respectively. The cumulative rates of target lesion revascularization (target vessel revascularization) were 16% (16%) at 1 year, 18% (22%) at 5 years, and 28% (38%) at 10 years. Two definite scaffold thromboses (1 subacute, 1 very late) were recorded. The latter case was related to a sirolimus-eluting stent, which was implanted for a lesion proximal to an Igaki-Tamai stent. From the analysis of intravascular ultrasound data, the stent struts mostly disappeared within 3 years. The external elastic membrane area and stent area did not change. Conclusion— Acceptable major adverse cardiac events and scaffold thrombosis rates without stent recoil and vessel remodeling suggested the long-term safety of the Igaki-Tamai stent.

Anti-Ischemic Effect of a Novel Cardioprotective Agent, JTV519, Is Mediated Through Specific Activation of δ-Isoform of Protein Kinase C in Rat Ventricular Myocardium

BACKGROUND A new 1,4-benzothiazepine derivative, JTV519, has a strong protective effect against Ca(2+) overload-induced myocardial injury. We investigated the effect of JTV519 on ischemia/reperfusion injury in isolated rat hearts. METHODS AND RESULTS At 30 minutes of reperfusion after 30-minute global ischemia, the percent recovery of left ventricular developed pressure was improved, and the creatine phosphokinase and lactate dehydrogenase leakage was reduced in a concentration-dependent manner when JTV519 was administered in the coronary perfusate both at 5 minutes before the induction of ischemia and at the time of reperfusion. The myocardial protective effect of JTV519 was completely blocked by pretreatment of the heart with GF109203X, a specific protein kinase C (PKC) inhibitor. In contrast, the effect of JTV519 was not affected by alpha(1)-, A(1)-, and B(2)-receptor blockers that couple with PKC in the cardiomyocyte. Both immunofluorescence images and immunoblots of JTV519-treated left ventricular myocardium and isolated ventricular myocytes demonstrated that this agent induced concentration-dependent translocation of the delta-isoform but not the other isoforms of PKC to the plasma membrane. CONCLUSIONS The mechanism of cardioprotection by JTV519 against ischemia/reperfusion injury involves isozyme-specific PKC activation through a receptor-independent mechanism. This agent may provide a novel pharmacological approach for the treatment of patients with acute coronary diseases via a subcellular mechanism mimicking ischemic preconditioning.

Endothelin-1 Has a Unique Oxygen-Saving Effect by Increasing Contractile Efficiency in the Isolated Rat Heart

BackgroundThe effect of endothelin (ET)-1 on cardiac energetics is not fully understood. Methods and ResultsIn isolated, coronary-perfused rat hearts, we measured left ventricular contractility index (Emax), pressure-volume area (PVA), and myocardial oxygen consumption (M˙V>o2) before and after administration of ET-1 (1×10−9 mol/L). ET-1 increased Emax by 48±16% (P <0.01) and the total M˙Vo2 by 24±11% (P <0.01). The M˙Vo2-PVA relations were linear both before and after ET-1 (r >0.99). ET-1 shifted M˙Vo2-PVA upward, increasing the M˙Vo2 intercept by 24±13%. At the same time, ET-1 decreased the slope (S), with 1/S (contractile efficiency) being 46±5% before and 56±5% after ET-1 (P <0.01). ET-1–induced increases in Emax and in contractile efficiency were abolished by an ETA receptor blocker (S-0139) but not by an ETB blocker (BQ-788). Although high [Ca2+] perfusion increased Emax and the intercept to the same extent as ET-1, it did not change S. NG-Nitro-l-arginine (an inhibitor of nitric oxide synthase) increased the coronary perfusion pressure as much as ET-1, but S again remained unchanged. Dimethylamyloride (Na+/H+ exchanger inhibitor) partially blocked the positive inotropic effect of ET-1 but not the ET-1–induced increase in the contractile efficiency. ConclusionsAgonistic effects of ET-1 on the ETA receptor economized the chemomechanical conversion efficiency of the left ventricular unit myocardium by a mechanism independent of the Na+/H+ exchanger. This unique oxygen-saving effect of ET-1 may play an adaptive role in the failing myocardium, in which local accumulation of ET-1 is present.

Long-Term (>10 Years) Clinical Outcomes of First-In-Man Biodegradable Poly-l-lactic Acid Coronary Stents: Igaki-Tamai Stents

Background— The purpose of this study was to evaluate the long-term safety of the Igaki-Tamai stent, the first-in-human fully biodegradable coronary stent made of poly-l-lactic acid. Methods and Results— Between September 1998 and April 2000, 50 patients with 63 lesions were treated electively with 84 Igaki-Tamai stents. Overall clinical follow-up (>10 years) of major adverse cardiac events and rates of scaffold thrombosis was analyzed together with the results of angiography and intravascular ultrasound. Major adverse cardiac events included all-cause death, nonfatal myocardial infarction, and target lesion revascularization/target vessel revascularization. During the overall clinical follow-up period (121±17 months), 2 patients were lost to follow-up. There were 1 cardiac death, 6 noncardiac deaths, and 4 myocardial infarctions. Survival rates free of all-cause death, cardiac death, and major adverse cardiac events at 10 years were 87%, 98%, and 50%, respectively. The cumulative rates of target lesion revascularization (target vessel revascularization) were 16% (16%) at 1 year, 18% (22%) at 5 years, and 28% (38%) at 10 years. Two definite scaffold thromboses (1 subacute, 1 very late) were recorded. The latter case was related to a sirolimus-eluting stent, which was implanted for a lesion proximal to an Igaki-Tamai stent. From the analysis of intravascular ultrasound data, the stent struts mostly disappeared within 3 years. The external elastic membrane area and stent area did not change. Conclusion— Acceptable major adverse cardiac events and scaffold thrombosis rates without stent recoil and vessel remodeling suggested the long-term safety of the Igaki-Tamai stent.

Calcium handling and sarcoplasmic-reticular protein functions during heart-failure transition in ventricular myocardium from rats with hypertension.

The objective of this study was to determine the primary event that occurs in Ca2+-regulatory sarcoplasmic-reticular (SR) proteins during subacute transition from concentric/mechanically-compensated left ventricular (LV) hypertrophy to eccentric/decompensated hypertrophy. Using Dahl salt-sensitive rats with hypertension, changes of myocardial contraction, intracellular Ca2+ transients, SR Ca2+ uptake, protein levels of SR Ca2+ ATPase (SERCA2), phospholamban, and calsequestrin (CSQ), and mRNA levels of SERCA2 and CSQ were serially determined and compared between the established stage of LV hypertrophy (LVH) and the subsequent stage of overt LV dysfunction (CHF). In LVH, isolated LV papillary muscle preparations showed an equal peak-tension level and a mild prolongation of the isometric tension decay compared to those of age-matched controls. The Ca2+ transients as measured by aequorin were unchanged. The Ca2+ uptake of isolated SR vesicles and the protein/mRNA levels of SR proteins were also equivalent to those of the controls. In contrast, in CHF, the failing myocardium showed a further prolongation of the contraction time course and a 39% reduction of the peak-tension development. The Ca2+ transients showed changes consisting of a decrease in the peak level and a prolongation of the time course. In addition, the SR Ca2+ uptake was decreased by 41%. Despite these functional changes, the protein and mRNA levels of the SR components remained equivalent to those of the age-matched controls. Thus, in this hypertensive animal, 1) at the LVH stage, myocardial contractility and intracellular capability to regulate Ca2+ remained normal; 2) at the CHF stage, impaired SR Ca2+ handling and the subsequent reduction of myocardial contraction were in progress; and 3) impairments of SR function occurred at the post-translational protein level rather than at the transcriptional/translational levels. Our findings support the role of SR proteins as the primary determinant of the contractile dysfunction that occurs during the heart-failure transition; however, post-translational modulators of these SR elements may also be critical.

Long-term effects of early statin therapy for patients with acute myocardial infarction treated with stent implantation.

OBJECTIVES Statins are widely administered to patients with acute myocardial infarction (AMI), but knowledge of the effects of early statin therapy on the long-term mortality of AMI patients after stent implantation is still limited, especially for beyond low-density lipoprotein cholesterol (LDL-C) lowering effects. METHODS Our 378 consecutive AMI patients who were discharged alive from the hospital with successful stent implantation between 1997 and 2005 were included. We retrospectively evaluated the effects of statin therapy on major adverse cardiovascular events (MACE), including all-cause death, reinfarction, coronary artery bypass grafting, heart failure requiring rehospitalization, and target lesion revascularization. RESULTS Statins were given to 271 patients according to the physician to achieve a LDL-C level of less than 100mg/dL. The achieved LDL-C levels in the statin group were 100.7, 95.1, 96.7, and 102.8mg/dL at discharge, 6 months, 1 year, and 3 years, respectively, whereas those in the non-statin group were 103.2, 107.3, 102.8, and 103.0mg/dL. These levels were not significantly different between the groups during 3 years. Based on Kaplan-Meier estimates, statin therapy was associated with a reduction of long-term mortality (log-rank test P=0.007). Multivariate Cox regression analysis revealed that statin therapy (P=0.015, hazard ratio: 0.10; 95% confidence interval: 0.01-0.64) was a significant predictor of favorable prognosis. Multivariate analysis revealed that statin treatment had a beneficial effect against MACE over 3 years (P=0.008). CONCLUSIONS Early statin therapy was beneficial for long-term mortality of AMI patients treated with stenting.

The importance of serial cardiac troponin measurement for evaluating the response to immunosuppressive therapy for myocarditis

A 71-year-old woman was admitted to our department because of acute myocarditis. She was ameliorated with conventional heart failure treatment, however she developed left ventricular dilatation and cardiac troponin T (cTnT) was elevated again to >1.0 ng/ml 6 month after the first admission. She was re-admitted because of recurrent decompensated heart failure in spite of conventional treatment. Right ventricular endomyocardial biopsy revealed active myocarditis. Immunosuppressive therapy with prednisolone and azathioprine improved her symptoms and left ventricular function accompanied by a striking decrease of cTnT levels. The decreased cTnT level indicated an effective response to immunosuppression early after the beginning of treatment. These findings suggested that it is possible to evaluate the response to immunosuppressive therapy by serial measurement of cardiac troponin.

Decade of Histological Follow-Up for a Fully Biodegradable Poly-l-lactic Acid Coronary Stent (Igaki-Tamai Stent) in Humans Are Bioresorbable Scaffolds the Answer?

An 83-year-old male with a history of angina pectoris presented with massive intracranial hemorrhage in June 2011, and he died 2 days after admission. Previously, he was included in the first in-human feasibility study of biodegradable poly- l -lactic acid (PLLA) coronary stents: the Igaki-Tamai stents (Kyoto Medical Planning Co Ltd, Kyoto, Japan).1,2 To assess the long-term behavior of PLLA coronary stents in humans, postmortem examination of his coronary arteries was performed. In November 1999, he was diagnosed with stable angina pectoris, and coronary angiography disclosed a single lesion at the middle part of left anterior descending coronary artery (Figure 1A). One Igaki-Tamai stent had been implanted with successful result (Figure 1B). He received …

Rare case of cardiac hemangioma causing massive pericardial effusion: can a left atrial tumor produce pericardial effusion?

A 35-year-old woman presented to the emergency room with a 2-month history of general malaise and anasarca. The chest x-ray showed cardiomegaly, and transthoracic echocardiography revealed massive pericardial effusion leading to cardiac tamponade (Figure 1A and 1B). Immediately, 1400 mL pericardial effusion (yellow exudate) was removed by needle pericardiocentesis. After the procedure, transthoracic echocardiography showed an immobile, heterogeneous tumor in the left atrium (LA) (Figure 1C and Movie I in the online-only Data Supplement). Figure 1. Multimodality imaging of the left atrial (LA) tumor. Transthoracic echocardiography revealed massive pericardial effusion leading to cardiac tamponade ( A and B ). After removal of the pericardial effusion, the immobile, heterogeneous tumor was observed in the LA ( C and Movie I in the online-only Data Supplement). Cardiac computed tomography (CT) showed a well-circumscribed tumor located in the LA wall near the origin of the left pulmonary veins ( D and …

Factors involved in correct analysis of intracardiac electrograms captured by Medtronic Inc. pacemakers during tachycardias

To thoroughly investigate the diagnostic information obtained by pacemakers, it is important that the stored intracardiac electrograms (EGMs) are analyzed. However, in Medtronic pacemakers, only a single intracardiac recording channel is available and thus EGM channel selection is critical.