Atsunori Okamura

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.

Upregulation of renin-angiotensin system during differentiation of monocytes to macrophages.

BACKGROUND We have demonstrated that accumulated macrophages in human coronary arteries strongly express angiotensin converting enzyme in accordance with the development of atheromatous plaques. However, there are few reports on the regulation of the renin-angiotensin system in macrophages and in monocytes as their source. OBJECTIVE To examine whether the renin-angiotensin system is upregulated during the differentiation of monocytes to macrophages, and whether it is further regulated by angiotensin II and cytokines. MATERIALS AND METHODS We used a human leukemia cell line, THP-1, for monocytes. Differentiated THP-1, induced by adding phorbol 12-myristate 13-acetate for 24 h, were used as macrophages. Expression of messenger RNA of the renin-angiotensin system components was measured by quantitative reverse-transcriptase polymerase chain reaction. Angiotensin converting enzyme activity and subtype-specific angiotensin-binding sites of cultured cells, and angiotensin II production in the culture medium were measured. RESULTS Macrophages expressed all components of the renin-angiotensin system except chymase. Cellular angiotensin converting enzyme activity and angiotensin II in the medium were increased 3.2- and 4.5-fold during differentiation, respectively. Expression of angiotensin II type 1 (AT1) and type 2 (AT2) receptors was increased 6.2-and 6.4-fold during differentiation, and was sustained for 7 days. Incubation with angiotensin II for 24 h caused downregulation of both AT1 and AT2 receptor messenger RNA, but the expression levels were still more than threefold higher compared with monocytes. The density of binding sites of AT1 and AT2 receptors in macrophages was 0.26 +/- 0.02 and 0.15 +/- 0.01 fmol/10(6) cells, respectively. CONCLUSION The renin-angiotensin system is markedly activated during monocyte/macrophage differentiation, and may participate in the development of atherosclerosis.

Quantitative Ultrasonic Tissue Characterization Can Identify High-Risk Atherosclerotic Alteration in Human Carotid Arteries

BACKGROUND Recently, ultrasonic tissue characterization of the composition of plaques has been performed in a quantitative fashion on the basis of integrated backscatter (IBS) analysis, but most of those studies have used high-frequency ultrasound to obtain microscopic images. METHODS AND RESULTS We performed B-mode measurement and IBS signal analysis with acoustic densitometry with a 7.5-MHz linear-array transducer in freshly excised human aortas (n=58) (normal, atheromatous, and fibrous tissue) obtained at autopsy. Atheromatous and fibrous tissue had a similar intima-media thickness (IMT), but the IBS value in atheromatous specimens was lower than that in fibrous specimens. We further applied this method to human carotid ultrasonography. The subjects were young (80 regions), middle aged with 1 or no coronary risk factors (low risk) (120 regions), middle aged with >/=2 coronary risk factors (high risk) (240 regions), or elderly (80 regions) or were patients with myocardial infarction (MI) with multivessel disease (90 regions). The IMT was similar in middle-aged, elderly, and MI subjects. In contrast, the IBS value was significantly higher in elderly subjects and lower in high-risk middle-aged and MI subjects compared with that in low-risk middle-aged subjects. The percent of regions diagnosed as atheromatous (IBS less than mean minus 2-SD value of IBS in young subjects) was 11% in low-risk middle-aged subjects, 29% in high-risk middle-aged subjects, and 63% in the MI group. CONCLUSIONS In conjunction with conventional B-mode imaging, IBS analysis with carotid ultrasonography appeared to provide prognostic information to identify a high-risk group with systemic atherosclerosis, which could lead to coronary heart disease in individuals with early-stage disease.

Enhanced expression of angiotensin-converting enzyme is associated with progression of coronary atherosclerosis in humans

Background The clinical usefulness of angiotensin converting enzyme (ACE) inhibitors in preventing the recurrence of myocardial infarction has been investigated in large randomized trials. Results from many studies using animal models have suggested that ACE inhibitors have vasculoprotective effects, which may contribute to the prevention of coronary atherosclerosis. Objective To examine the association between vascular angiotensin generation and the development of coronary atherosclerosis in humans. Methods We used immunocytochemical techniques to examine frozen sections from 44 coronary artery segments from 19 corpses. Results Three segments were sites of plaque rupture in patients who had died from acute myocardial infarction. Other specimens of coronary artery segments were characterized histologically to be normal artery segments with diffuse intimal thickening (n = 6), hypercellular lesions composed of smooth muscle cells with or without infiltration of macrophages (n = 11), atheromatous plaque (n = 12), and fibrosclerotic plaque (n = 12). In normal arteries with diffuse intimal thickening, ACE was expressed in endothelial cells. In those with hypercellular lesions and atheromatous plaques, however, enhanced ACE expression was found in macrophages and smooth muscle cells. In contrast, arteries with fibrosclerotic plaques exhibited little or no ACE expression within the plaque. All three ruptured plaques expressed ACE strongly in macrophages accumulated around the attenuated fibrous cap. Conclusion The strong association of enhanced ACE expression with the histologic characteristics of plaques suggests that ACE in hypercellular lesions, atheromatous plaques, and ruptured plaques contributes greatly to the further progression of atherosclerosis via an increase in vascular angiotensin II formation and inactivation of bradykinin.

The renin-angiotensin and adrenergic nervous system in cardiac hypertrophy in fructose-fed rats.

BACKGROUND Hyperinsulinemia and insulin resistance are associated with left ventricular hypertrophy (LVH) and cardiovascular complications in hypertensive subjects. The aim of this study was to explore the mechanisms for LVH including activation of the renin-angiotensin system system (RAS) and the sympathetic nervous system and their activation by insulin using a rat model of hyperinsulinemia and insulin resistance. METHODS Male Sprague-Dawley rats were fed a high-fructose or control diet. The fructose-fed rats (FFR) were divided into four subgroups that were administrated either vehicle or the following antihypertensive drugs (n = 6-8) for 4 weeks: 1) olmesartan, an angiotensin II type 1 (AT1) receptor antagonist; 2) bunazosin, an alpha1-receptor blocker; and 3) hydralazine, a direct vasodilator. RESULTS Fructose feeding induced significant increases in mean systolic blood pressure (BP) levels at 4 weeks (control, 117 v fructose, 131 mm Hg), left ventricular weight, and the sum of the insulin level in response to a glucose tolerance test (2 g/kg). Fructose feeding also increased urinary excretion of epinephrine and norepinephrine, the density of cardiac alpha1-adrenergic receptors, and the content of angiotensin II in the left ventricle. All antihypertensive drugs decreased systolic BP, but only the AT1 receptor antagonist attenuated the development of LVH in FFR. The AT1 receptor antagonist did not affect glucose-mediated insulin responses, but did suppress urinary catecholamine excretion and cardiac alpha1-adrenergic receptor density. CONCLUSIONS Left ventricular hypertrophy in FFR may be less dependent on systemic elevations of BP and more dependent on the RAS and the sympathetic nervous system. Use of an AT1 receptor antagonist might be the most beneficial way to prevent progression of LVH through direct effects on tissue RAS and the sympathetic nervous system in FFR. As these changes occur in a rat model with hyperinsulinemia, insulin may have a role in promoting LVH by activating the local RAS and sympathetic nervous system activity.

Upregulation of Angiotensin-Converting Enzyme During the Healing Process After Injury at the Site of Percutaneous Transluminal Coronary Angioplasty in Humans

BACKGROUND Balloon injury models in rat have shown enhanced expression of ACE in the developing neointima. However, neointimal lesions in human coronary arteries are complex due to atherosclerosis and different types of wall laceration. This study was designed to investigate whether ACE is present in the neointima of humans, including patients with restenosis after percutaneous transluminal coronary angioplasty (PTCA). METHODS AND RESULTS Thirty-seven sites with angioplasty injury, obtained at autopsy, were studied using immunocytochemical techniques. Sites with injury limited to a fibrous plaque and those with injury extending into the media (<2 months after PTCA) showed fibrocellular repair tissue composed mainly of smooth muscle cells that were distinctly positive for ACE. In cellular reactions at the site of injury limited to the atheromatous plaque (<2 months after PTCA), the expression of ACE appeared first in accumulated macrophages; once smooth muscle cells appeared in the repair tissue, they also expressed ACE. At a later stage (3 months after PTCA), the number of cells with ACE expression decreased markedly; from 7 months on, ACE was no longer expressed within the repair tissue. Basically, there were no differences with regard to ACE expression during the healing process after PTCA between segments with and those without angiographic evidence of restenosis. CONCLUSIONS These results show that PTCA injury in humans results in upregulation of ACE at sites of active repair and, therefore, ACE could play an important role as one of the mediators of the healing process after PTCA.

Marshall vein as arrhythmogenic source in patients with atrial fibrillation : Correlation between its anatomy and electrophysiological findings

Background: Atrial fibrillation (AF) may originate from catecholamine‐sensitive vein of Marshall (VOM) or its ligament in addition to pulmonary veins (PVs). The anatomy of VOM and its relation to arrhythmogenic foci in the left atrium are unknown. We studied the anatomy of VOM and its relation to foci in patients with AF.

Japanese multicenter registry evaluating the retrograde approach for chronic coronary total occlusion.

This registry evaluated the current trends and outcomes associated with retrograde percutaneous coronary intervention (PCI) for chronic total occlusion (CTO).

Relative localization of angiotensin-converting enzyme, chymase and angiotensin II in human coronary atherosclerotic lesions.

BACKGROUND Studies using cell cultures and animal models have indicated an important role for angiotensin II in atherosclerosis. In humans, at least two major enzymes are involved in the conversion of angiotensin I to angiotensin II: so-called angiotensin-converting enzyme (ACE) and chymase. Enhanced activation of chymase in atherosclerotic tissue homogenates has been reported in animal models, but its contribution to the generation of angiotensin II has not been studied. OBJECTIVE To clarify the localization of chymase and its pathophysiologic role in the formation of angiotensin II, using human coronary arteries. DESIGN AND METHODS Twenty-four coronary artery segments obtained from 14 autopsied patients were characterized histologically into the following categories: normal coronary arteries with diffuse intimal thickening, hypercellular lesions, atheromatous plaques and fibrosclerotic plaques. We compared the cellular localization of chymase, ACE and angiotensin II expression using immunocytochemical techniques. RESULTS Chymase was expressed only in the cytosole of mast cells in all segments. On the basis of the histologic study, the number of chymase-positive cells in the intima of atheromatous plaques was significantly higher than that in normal coronary arteries with diffuse intimal thickening. The expression of angiotensin II in the intima was enhanced in hypercellular lesions and atheromatous plaques. Localization of angiotensin II in the intima was associated with that of ACE. Immunodouble staining did not show colocalization of angiotensin II and chymase. CONCLUSIONS These results suggest an important role for the production of angiotensin II by ACE in the progression of atherosclerosis in human coronary arteries. Enhanced expression of chymase appears not to be involved in angiotensin II production in the intima.

Clinical Implications of Distal Embolization During Coronary Interventional Procedures in Patients With Acute Myocardial Infarction: Quantitative Study With Doppler Guidewire

OBJECTIVES This study sought to investigate the timing and amount of embolic particles generation during the percutaneous coronary intervention (PCI) procedure and studied the relationship between embolic burden and coronary blood flow and myocardial damage. BACKGROUND Distal embolization is a major complication of PCI. The Doppler guidewire (DGW) can detect the embolic particles as high-intensity transient signals (HITS) during the PCI procedure. METHODS We prospectively studied 37 patients with acute myocardial infarction (MI). Under monitoring with the DGW, we performed first and second balloon angioplasty, followed by stenting and post-high-pressure dilatation. Left ventricular ejection fraction (LVEF) (%) and regional wall motion (RWM) (standard deviation/chord) were measured on days 1 and 22. RESULTS The HITS were detected in 35 of 37 patients. The number of HITS was the greatest after stenting (16 +/- 18) followed by first balloon inflation (5 +/- 4). There was a significant correlation between the total number of HITS and the corrected Thrombolysis In Myocardial Infarction frame count (r = 0.52, p = 0.003) and a significant weak inverse correlation between the total number of HITS and changes in LVEF and RWM (r = 0.37, p = 0.03 and r = 0.35, p = 0.04, respectively). CONCLUSIONS Distal embolization is common during PCI in patients with acute MI, and the majority of HITS were observed after stenting. An increase in the total number of HITS is associated with reduced coronary blood flow, and is weakly associated with poor recovery of left ventricular function.