Shinji Negoro

Myocardial Perfusion Patterns Related to Thrombolysis in Myocardial Infarction Perfusion Grades After Coronary Angioplasty in Patients With Acute Anterior Wall Myocardial Infarction

BACKGROUND Epicardial coronary flow is occasionally reduced even after coronary intervention despite the absence of vessel obstruction in patients with acute myocardial infarction. Our aim was to clarify the cause and outcomes of radiocontrast slow filling in patients with reperfused acute anterior myocardial infarction by assessing microvascular damage with the use of myocardial contrast echocardiography (MCE) and functional outcomes. METHODS AND RESULTS We carefully reviewed the cineangiograms of 86 patients who achieved coronary revascularization within 12 hours of the onset and underwent MCE before and soon after recanalization with the intracoronary injection of sonicated microbubbles. Antegrade coronary flow after recanalization was graded by two observers based on Thrombolysis in Myocardial Infarction (TIMI) trial flow grades. Left ventricular ejection fraction was measured on the day of infarction and 1 month later. TIMI grade 2 was observed in 18 patients (21%), and the other 68 patients manifested TIMI grade 3 after recanalization. All patients with TIMI 2 showed substantial MCE no reflow, whereas only 11 patients (16%) with TIMI 3 showed MCE no reflow. Functional improvement was worse in patients with TIMI 2 than in those with TIMI 3 (TIMI 2, 38 +/- 8% versus 40 +/- 8%, P = NS [acute versus late]; TIMI 3, 44 +/- 13% versus 55 +/- 13%, P < .001). Among patients with TIMI 3, significant functional improvement was observed only in patients with MCE reflow (MCE reflow, 46 +/- 13% versus 57 +/- 12%, P < .001; MCE no reflow, 35 +/- 11% versus 45 +/- 12%, P = NS). CONCLUSIONS Despite no obstructive lesion of the vessel, TIMI 2 is caused by advanced microvascular damage and is a highly specific, although not sensitive, predictor of poor functional outcomes in patients with acute myocardial infarction. TIMI 3 does not necessarily indicate myocardial salvage, and detection of MCE no reflow in these patients is particularly useful for the prediction of functional outcome.

Glycoprotein 130 Regulates Cardiac Myocyte Survival in Doxorubicin-Induced Apoptosis Through Phosphatidylinositol 3-Kinase/Akt Phosphorylation and Bcl-xL/Caspase-3 Interaction

Background —We recently reported that the activation of glycoprotein (gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown. Methods and Results —We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. Adenovirus transfer of the constitutively active form of Akt to cardiac myocytes restored cardiac myocyte survival after DOX treatment. Conversely, the dominant-negative form of Akt inhibited LIF-induced increase in cell viability and suppression of caspase-9 activation. Conclusions —Activation of gp130 inhibits DOX-induced cell death in cardiac myocytes, resulting in the restoration of PI 3-kinase/Akt activities and in the inactivation of caspase-3, leading to facilitation of the protective function of Bcl-xL.

Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction

OBJECTIVES We reported that the activation of gp130 transduced hypertrophic and cytoprotective signals via Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in cardiac myocytes. Recent in vivo experiments have demonstrated that the JAK/STAT pathway is activated in acute pressure overload hearts. The present study was designed to examine whether the JAK/STAT pathway is also activated in acute myocardial infarction (AMI) and to determine its pathophysiological roles in ischemic heart disease. METHODS AND RESULTS AMI model was generated by the ligation of proximal left anterior descending coronary artery of male Wistar rat. They were sacrificed at various time points ranging from 1 to 24 h after coronary ligation and their hearts were examined. Tyrosine phosphorylation of STAT3 was observed in the myocardium obtained from both the ischemic area and the healthy border area adjacent to the infarcted area. The AMI rats were next randomly assigned to two groups, one with coronary ligation only (group M), and the other with coronary ligation with AG-490 treatment (1 mg/kg i.v., every 4 h), a specific JAK2 inhibitor (group A). In group A, phosphorylation of STAT3 was significantly suppressed and caspase-3 activity and Bax expression were significantly increased in the myocardium after AMI. In group M, few apoptotic myocytes were identified in the border area by means of TUNEL assay. However, a significant increase in apoptotic cells was observed in group A. CONCLUSIONS Administration of JAK2 inhibitor resulted in deterioration of myocardial viability in AMI hearts. The JAK/STAT pathway is activated in AMI myocardium and plays a pivotal role in cytoprotective signaling.

Bcl-xl reduces doxorubicin-induced myocardial damage but fails to control cardiac gene downregulation

OBJECTIVE We recently reported that doxorubicin (Dox), an effective anti-cancer drug, induces apoptosis in cardiac myocytes in association with reduction of Bcl-xl expression. In the present study, we further examined whether overexpression of Bcl-xl ameliorates Dox-induced cardiac myocyte damage. METHODS AND RESULTS Overexpression of the Bcl-xl gene by adenovirus vector resulted in an 11-fold increase in Bcl-xl protein in neonatal rat cardiac myocytes (BCL) compared to that in cells with beta-galactosidase gene transfection (CTL). Although Dox treatment generated similar amounts of reactive oxygen species (ROS) in BCL and CTL, cell viability was maintained and the number of apoptotic cardiac myocytes was significantly decreased in BCL. Cytochrome c release and enhanced caspase-3 activity after Dox treatment were significantly suppressed and Bax expression level was decreased in BCL. Cardiac-specific gene expression is known to be inhibited by Dox. The expression of cardiac alpha-actin and sarcoplasmic reticulum Ca(2+)-ATPase 2a mRNA was equally inhibited in BCL and CTL after Dox treatment. CONCLUSIONS Overexpression of Bcl-xl in cardiac myocytes failed to regulate Dox-induced ROS generation and cardiac-specific gene downregulation but inhibited apoptosis accompanied by reduction of Bax protein.

Evaluation of the percusurge guardwire plus temporary occlusion and aspiration system during primary angioplasty in acute myocardial infarction

Thirty patients with acute myocardial infarction (AMI) underwent primary angioplasty under distal protection of PercuSurge GuardWire Plus Temporary Occlusion and Aspiration System. Before angioplasty, protection of the distal circulation was achieved with the system, followed by balloon angioplasty and/or stenting and debris aspiration. Technical device success was 100%. Distal occlusion was well tolerated in all patients. Mean total distal occlusion time was 7.3 ± 5.4 min. Macroscopically visible debris was aspirated from 29 cases (96.7%). Postprocedural Thrombolysis in Myocardial Infarction flow grade 3 was achieved in all cases (100%, vs. 16.7% at baseline). Myocardial blush flow grade 3 was achieved in 26 cases (86.7%). Regression of ST segment elevation ≥ 50% was shown in 23 cases (76.7%). No patient developed angiographic evidence of no‐reflow or distal embolization. Both angiographic and procedural success were 100%. The system is feasible, safe, and effective for distal protection against embolism during primary angioplasty in AMI. Catheter Cardiovasc Interv 2003;60:443–451.

Aldosterone augments endothelin-1-induced cardiac myocyte hypertrophy with the reinforcement of the JNK pathway

Aldosterone is thought to regulate cardiac work independently of sodium retention, though the mechanisms remain to be known. In the present study, we have demonstrated that aldosterone reinforces endothelin‐mediated cardiac hypertrophy with the increase in cell surface area and upregulation of the transcripts characteristic of hypertrophy. We have also shown that aldosterone augments c‐Jun N‐terminal kinase activation induced by endothelin‐1. Taken together, it is suggested that aldosterone modulates cardiac hypertrophy, at least partially, synergistically with extracellular signals that have been shown to be involved in cardiac remodeling.

Clinicopathological characterization of cardiac free wall rupture in patients with acute myocardial infarction: difference between early and late phase rupture

Differences in morphological characteristics have been described in early phase and late phase post-infarction cardiac rupture. In this study, the clinicopathological characteristics of early and late phase rupture have been clarified by reviewing the clinical records of 1450 consecutive patients with acute myocardial infarction (AMI). Rupture of the left ventricular free wall (blow-out type) developed in 27 of the 1450 patients, and these patients were divided into two groups on the basis of the rupture time: early phase (< 72 h) and late phase (> 4 days). Only one patient had a history of prior infarction. Early phase rupture was characterized by an abrupt slit-like tear in the infarcted myocardium, a preference for anterior infarction sites, no prior myocardial infarction, and no difference in incidence in conventional and reperfusion therapy, while late phase rupture was characterized by the presence of infarct expansion, no preferential infarct site and a very low incidence in patients with successful reperfusion. Hence, early and late phase cardiac rupture differ in their pathogenesis, and thus the approach to the prevention and prediction of early and late phase cardiac rupture should be different.