Zenshiro Onouchi

Quantitative histological analysis of the human sinoatrial node during growth and aging.

BackgroundFibrosis or fatty infiltration of the human sinoatrial (SA) node is generally believed to represent replacement of the SA nodal cells by connective tissue. Quantitative analysis, however, has not been performed precisely to validate the interpretation of such histological changes. Methods and ResultsThe actual volume of the SA node and its components were calculated according to the sum of the pixel number representing the colors of SA nodal cells and connective tissue in serial sections using a digital color image analyzer. Average volume occupied by the total SA nodal cells in adolescents and adults (n=7) was 3.55±0.45 mm3, which was 2.4 times greater than that in infants (n=3). The rate of increase was smaller than that of the total SA node (4.2 times, 16.68±2.56 mm3 in adolescents and adults). The considerable discrepancy in the growth ratio between the SA nodal cells and the total SA node resulted from an increase in the volume of connective tissue (7.4 times). In the elderly (n=9), the volume of total SA node and SA nodal cells actually decreased (13.10±1.85 mm3 and 2.18±0.44 mm3), whereas that of fibrous connective tissue remained unchanged. Constant DNA ploidy patterns of SA nodal cells determined by cytofluorometry indicated that SA nodal cells never synthesize DNA during growth. ConclusionsUntil adulthood, the actual volume of SA nodal cells does not decrease, although the increase in volume ratio of the interstitial tissue to the total SA node has merely given a false impression of involution of SA nodal cells. Atrophy of SA nodal cells, however, occurs during aging together with reduction of the SA node and/or infiltration of fatty tissue.

Evaluation of Coronary Flow Velocity Dynamics and Flow Reserve in Patients With Kawasaki Disease by Means of a Doppler Guide Wire

OBJECTIVES To assess the pathophysiologic effects of the coronary sequelae of Kawasaki disease on coronary hemodynamic variables, we regionally evaluated the flow velocity dynamics and flow reserve in coronary vessels with lesions using an intracoronary Doppler flow guide wire. BACKGROUND The pathophysiologic effects of the coronary sequelae of Kawasaki disease on coronary hemodynamic variables have not been completely clarified, and we previously reported some discrepancies between coronary angiographic findings and exercise stress tests in Kawasaki disease. METHODS Doppler phasic coronary flow velocity was determined using an 0.018-in. (0.046-cm) intracoronary Doppler flow guide wire at rest and during the adenosine triphosphate-induced hyperemic response in 95 patients (75 male, 20 female, mean age 9.8+/-6.2 years) with Kawasaki disease. RESULTS In 25 patients with coronary aneurysms in 29 vessels, the average peak velocity and diastolic to systolic velocity ratio were significantly (p < 0.05) decreased in the moderate-sized and large-sized aneurysms. Significantly lower values in coronary flow reserve (CFR) were noted in 3 of 10 vessels with moderate aneurysms and in 4 of 7 vessels with large aneurysms. A significant positive correlation (y = 0.53x + 14.6, r2 = 0.91) was observed between the percent diameter stenosis evaluated by angiography and that calculated from the flow velocity measurement. However, the percent diameter stenosis calculated from the flow velocity measurement was underestimated compared with that determined by angiography in the stenotic lesions of intermediate severity. A reduced CFR was noted in five of seven vessels with intermediate stenosis ranging from 50% to 75%, and also in three vessels with mild stenosis ranging from 30% to 40%. A reduced CFR was also observed in six of the eight angiographically normal vessels associated with the area of reduced perfusion on exercise thallium-201 myocardial scintigraphy. CONCLUSIONS Abnormalities in flow dynamics and a reduction in flow reserve were revealed in coronary aneurysms of intermediate to large size and in stenotic lesions, even of mild to intermediate severity, in patients with Kawasaki disease. Abnormalities in the coronary microcirculation, as well as epicardial lesions, contribute to the pathophysiologic responses in Kawasaki disease.

Congenital ventricular aneurysm and diverticulum in children

SummaryClinical profiles were analysed of 18 children with congenital ventricular aneurysm (CVA) and diverticulum (CVD) (nine with CVA and nine with CVD). Of 18 children, only six had any symptoms, consisting of chest discomfort, palpitation, or convulsion. Heart murmurs were heard in nine of the 18 children, and a nonspecific systolic ejection murmur in one. A systolic click was heard in only four children. Dyskinesia of an abnormal protrusion of the cardiac silhouette on the chest x-ray film was detected in only three. The ECG revealed abnormal findings in all children. In those with CVA, signs of myocardial damage or left axis deviation (LAD) and left bundle branch block (LBBB) were the main findings. Among those with CVD, multiple premature ventricular contractions (PVCs) were present in four; some signs of myocardial damage were present in three. None of those with CVD had LAD or LBBB. Among the four children with right ventricular diverticulum, multiple PVCs were present in three. The lesions were detected by two-dimensional echocardiography (2DE) before angiography in 13 (72%) of 18 children. The wall kinetics of the lesions, as seen on 2DE, were in agreement with the subsequent angiographic findings.

Aneurysms of the coronary arteries in Kawasaki disease. An angiographic study of 30 cases.

Thirty patients with coronary aneurysms associated with Kawasaki disease underwent coronary arteriography. Of 53 aneurysms, five were saccular, 24 sacculofusiform, 19 fusiform and five tubular. When tubular aneurysms were included in the fusiform type, the incidence of each configuration in the right coronary artery was almost the same as that in the left coronary artery. The left anterior descending coronary artery had the most aneurysms, followed by the right coronary, left main and circumflex arteries. Right coronary aneurysms always involved the bifurcation or the region from which a branch vessel arose; 13 of 31 left coronary aneurysms did not involve the bifurcation.

Transformation of coronary artery aneurysm to obstructive lesion and the role of collateral vessels in myocardial perfusion in patients with Kawasaki disease

OBJECTIVES The aim of this study was to examine the transformation of coronary artery aneurysms to obstructive lesions and to assess the role of collateral vessels in patients with Kawasaki disease. BACKGROUND Coronary artery aneurysms, especially giant aneurysms, are known to become obstructive lesions in patients with Kawasaki disease. However, the process of transformation is not yet clear. METHODS Thirty patients (average age 9.9 years) with obstructive lesions secondary to Kawasaki disease underwent repeated coronary artery angiography and thallium myocardial scintigraphy over a mean period of 7.7 years after the acute onset of Kawasaki disease. RESULTS In the 27 patients who were enrolled in the acute phase of the disease because of coronary artery aneurysms, the later transformation to obstructive lesions was not significantly different between the 61 large and 6 medium-sized aneurysms. Obstructive transformation of aneurysms was more rapid in the right than in the left coronary artery (p < 0.001). From the last coronary angiogram obtained, the obstructive lesions were classified as localized stenosis > 90% in 10 vessels, occlusions in 6 vessels and segmental stenosis in 26 vessels. Both localized and segmental stenosis occurred significantly more often in the left anterior descending and the right coronary artery than in other vessels (p < 0.05). The incidence of collateral vessels was significantly correlated with a younger age at onset of Kawasaki disease, especially in patients with segmental stenosis (p < 0.001). Collateral vessels did not develop in the presence of localized stenosis regardless of the occurrence of myocardial ischemia. All occluded vessels had collateral development regardless of the presence of myocardial infarction. CONCLUSIONS The treatment of localized stenosis may play an important role in preventing myocardial infarction in the chronic phase of Kawasaki disease.

Coronary Arterial Flow-Velocity Dynamics in Children With Angiographically Normal Coronary Arteries

BACKGROUND There have been few reports about coronary hemodynamics in children during the process of growth. In the present study, to assess the characteristics of coronary flow dynamics in children, we examined the phasic coronary flow-velocity (CFV) patterns at rest and during peak hyperemic responses in children with angiographically normal coronary arteries. METHODS AND RESULTS Spectral Doppler phasic coronary flow velocity was recorded with a 0.018-in intracoronary Doppler guidewire at rest and during peak responses after intracoronary bolus injection of ATP in 30 patients with Kawasakis disease (age, 8.2 +/- 5.1 years; 24 boys and 6 girls) without angiographic coronary lesions. Average peak velocity (APV), maximum peak velocity (MPV), and diastolic-to-systolic velocity ratio (DSVR) were evaluated in the left anterior descending coronary artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA). Coronary vasodilator reserve (coronary flow reserve [CFR]) was calculated as the ratio of ATP-induced hyperemic to baseline APV. Flow-velocity parameters in RCA were significantly lower than those in the LAD and LCx in both proximal and distal portions. Although the distal LCx had significantly lower values of APV and MPV than did the proximal LCx, there was no significant difference between the proximal and distal portions of the LAD and RCA for APV and MPV. All three coronary vessels showed a diastolic dominant flow pattern in each segment. This coronary flow pattern was less marked in the RCA than in the LCA. All three coronary vessels showed a significant increase in APV and a significantly decrease in DSVR after ATP administration. CFR was significantly lower in the LCx than in the LAD or RCA (P < .01: 1.93 +/- 0.34 in LCx versus 2.32 +/- 0.42 in LAD and 2.37 +/- 0.44 in RCA). From the view of aging, it was revealed that APV values in three vessels were higher in the younger group than in the older group. CFR values in the LAD and LCx were significantly lower in the younger group than in the older group (P < .001 in LAD: 2.01 +/- 0.28 in the younger versus 2.53 +/- 0.37 in the older; P < .01 in LCx: 1.61 +/- 0.15 in the younger versus 2.06 +/- 0.31 in the older). In addition, intracoronary injection of ATP did not increase the absolute angiographic coronary luminal diameter. CONCLUSIONS With the use of an intracoronary Doppler guidewire, we demonstrated that there are some characteristic findings in CFV dynamics in childhood. These physiological characteristics in CFV dynamics that occur with aging and occur in each vessel must be taken into consideration in the study of the coronary circulation in children.

Coronary Artery Aneurysms Develop in Weanling Rabbits with Serum Sickness But Not in Mature Rabbits An Experimental Model for Kawasaki Disease in Humans

The involvement of the cardiovascular system in rabbits with serum sickness is similar of that in Kawasaki disease, both with respect to the histologic changes of the myocardium, the valves, the coronary arteries, and the aorta and to the sequence with which they appear. Although coronary arteritis appears the same histologically, aneurysms did not occur in mature rabbits, even in case of necrosis of an arterial segment with deletion of muscle and elastic tissue. On the other hand, weanling rabbits with serum sickness had a tendency to develop aneurysms of coronary arteries, despite little cellular infiltration and reactive fibrocellular hyperplasia. The age factor thus appears to play an important role in the development of coronary aneurysms in Kawasaki disease, irrespective of the underlying mechanism, be it a markedly increased permeability to mediators through degenerated endothelial cells, or primary degenerated muscle cells with marked thinning of the media without much inflammatory cellular reaction. Furthermore, this study provides an insight into the long-term prognosis of transient dilatation of coronary arteries in the acute stage of Kawasaki disease.

Coronary flow reserve in children with Kawasaki disease without angiographic evidence of coronary stenosis

Abstract The presence of coronary lesions due to Kawasaki disease has been anatomically confirmed by selective coronary angiography. We recently encountered 11 patients with Kawasaki disease with ischemic findings on exercise stress tests, but without a stenotic lesion on coronary angiography. To clarify the pathogenesis of the ischemic changes shown by exercise electrocardiography and myocardial scintigraphy in these patients without angiographic evidence of coronary stenosis, we studied the coronary flow reserve by measuring the changes in coronary blood flow and vascular resistance during rapid atrial pacing using coronary sinus catheterization.

Asymptomatic myocardial infarction in Kawasaki disease: Long-term prognosis

SummaryEight patients with Kawasaki disease who had sustained asymptomatic myocardial infarction 8–15 years ago (mean, 13.1 years) were reexamined by various noninvasive cardiac function tests to assess long-term prognosis.At present, electrocardiograms (ECGs) are normal in six patients. However, all eight patients had a prolonged preejection period (PEP) to left ventricular ejection time (LVET) ratio 30 s after amylnitrate (AN) inhalation. Six patients had perfusion defects by exercise thallium-201 myocardial scintigraphy, and two patients developed ST segment depression in treadmill exercise testing.These patients are symptom-free even though their physical activity has not been restricted. Yet they proved to have serious abnormalities suggesting sequelae of myocardial infarction or existing myocardial ischemia. Judging from the results of noninvasive cardiac function tests and recently performed coronary angiography, five of the eight patients require coronary bypass surgery.

Effect of Kawasaki Disease on Migration of Human Umbilical Vein Endothelial Cells

Kawasaki disease, which is characterized by systemic vasculitis causing coronary arterial involvement in childhood, shows a variety of immunoregulatory abnormalities. Especially the direct or indirect deleterious effects on endothelial cells of cytokines and anti-endothelial cell antibodies (AECA) are considered to be involved in the mechanism responsible for production of vasculitis. Intravenous administration of high doses of γ-globulin (IVGG) has been used as an effective therapy for Kawasaki disease. To examine the behavior of endothelial cells affected by cytokines and IVGG in Kawasaki disease, we studied the effects of interferon (IFN), IL-1β, IL-6, and tumor necrosis factor (TNF)-α on the migration of human umbilical vein endothelial cell line (tHUE01) by a modified Boyden chamber method. Plasma from patients with acute Kawasaki disease markedly enhanced the migration of tHUE01 cells. Cytokines, with the exception of TNF-α, also enhanced the migration of tHUE01 cells in a dose-dependent manner. Anti-IFN antibody inhibited the migratory activity in response to not only IFN-γ but also to the plasma from patients with Kawasaki disease. Rabbit AECA (rAECA) also significantly stimulated the migration of tHUE01 cells. Plasma from patients treated with IVGG did not affect the migration of tHUE01 cells. Addition of γ-globulin significantly inhibited the migration of tHUE01 cells induced by the cytokines or rAECA. These results suggest that cytokines and AECA are important in restructuring and destroying vessel walls in Kawasaki disease by enhancing the migration of endothelial cells, and that IVGG may be therapeutically effective for this disease by suppressing this endothelial cell migration.