Tadao Yasugi

Regression of coronary atherosclerosis by combined LDL-apheresis and lipid-lowering drug therapy in patients with familial hypercholesterolemia: a multicenter study

The purpose of the LDL-Apheresis Regression Study (LARS) group, which included 13 institutions in Japan, was to investigate the effects on coronary atherosclerosis of LDL-apheresis combined with cholesterol-lowering drugs. Changes in coronary artery stenosis were assessed angiographically in 37 patients with familial hypercholesterolemia (7 homozygotes and 25 heterozygotes) and hypercholesterolemia which had not been defined as familial hypercholesterolemia (5 patients) by visual judgement and computer analysis. Definite regression was observed in 14 cases, including 4 homozygotes and 10 heterozygotes and others. Regression occurred as often in patients with severe coronary artery disease (2 or more vessel disease) as in those having less severe disease. Our results encourage initiation of aggressive cholesterol-lowering therapy to produce regression of coronary atherosclerosis in FH patients at high risk for cardiovascular events.

Small polydisperse low density lipoproteins in familial hyperalphalipoproteinemia with complete deficiency of cholesteryl ester transfer activity

Lipoprotein abnormalities were analyzed in 3 cases of marked hyperalphalipoproteinemia caused by complete deficiency of cholesteryl ester transfer activity. The probands were all men, aged 34, 43 and 48 years, respectively. The serum high density lipoprotein (HDL)-cholesterol levels of these patients were higher than 150 mg/dl (157-254 mg/dl), while serum total cholesterol levels ranged from 227 to 360 mg/dl. Sequential flotation-ultracentrifugation analysis disclosed that low density lipoprotein (LDL)-cholesterol was slightly decreased and that cholesteryl ester accumulated solely in the HDL2 fraction, which was also enriched with apolipoprotein E. Cholesteryl ester transfer activity was completely absent in all of these cases. High-performance liquid chromatography showed a decrease of LDL particle size in combination with a marked enlargement of HDL particle size. Analytical ultracentrifugation disclosed heterogeneity of LDL with the presence of small LDL subpopulations. We conclude that hyperalphalipoproteinemia due to complete deficiency of cholesteryl ester transfer activity is characterized by the presence of both small polydisperse LDL and markedly large HDL enriched with cholesteryl ester and apolipoprotein E.

Chemical stimulation of the locus coeruleus: inhibitory effects on hemodynamics and renal sympathetic nerve activity

We examined the role of the locus coeruleus (LC) in the regulation of the hemodynamics and sympathetic nerve activity in anesthetized rats. Unilateral microinjection into the LC of the excitatory amino acid, L-glutamate (Glu), elicited dose-dependent decreases in arterial pressure (AP) and heart rate (HR). The bradycardic response was partially attenuated after intravenous injection of atropine sulfate, but the greater part of this response still remained. Interruption of the ascending projections of the LC by midbrain transection did not affect the depressor and bradycardic responses elicited by chemical stimulation. The renal sympathetic nerve activity showed transient but strong inhibition with this stimulation. Cardiac output was measured using an electromagnetic flowmeter implanted in the ascending aorta. The stroke volume and total peripheral resistance (TPR) were calculated. Microinjection of Glu elicited a significant decrease in TPR and slight decreases in cardiac output and stroke volume. Microinjection of the inhibitory amino acid, gamma-aminobutyric acid (GABA), or the alpha 2-adrenergic agonist, clonidine, exerted no effect on AP and HR. The present results therefore suggest that: (1) the LC neurons have an inhibitory influence on the sympathetic nervous system, and stimulation of these neurons can elicit depressor and bradycardic responses; (2) the depressor response was produced predominantly as a result of a decrease in vascular resistance, rather than a decrease in cardiac output; (3) these inhibitory responses may be provided not via the ascending projections of the LC; and (4) the LC neurons do not have a tonic influence on the cardiovascular system.

Differential regional hemodynamic changes produced by L-glutamate stimulation of the locus coeruleus

The locus coeruleus (LC) exerts an inhibitory influence on the cardiovascular system. Microinjection of the excitatory amino acid, L-glutamate, into the LC elicits a decrease in arterial pressure as a result of a decrease in total peripheral resistance (TPR). The aim of the present study was to examine the role of the LC in the regulation of the regional hemodynamics. Employing anesthetized rats, the blood flow to the renal, mesenteric and hind-limb vascular beds was measured with an electromagnetic flowmeter. The changes in regional blood flow and vascular resistance evoked by chemical stimulation of the LC were examined separately in each region. During the depressor response elicited by LC stimulation, the hind-limb and renal vascular resistance was significantly decreased, while the mesenteric resistance was unchanged. The vasodilatation appeared to be more prominent in the hind-limb muscle than in the systemic circulation. Renal nerve denervation attenuated the decrease in renal vascular resistance elicited by LC stimulation. However, a small part of this response still remained in the denervated kidney. The present results suggest therefore that: (1) LC neurons exert differential hemodynamic effects on the hind-limb muscle, renal and mesenteric vascular beds; (2) the largest contribution to the decrease in TPR is related to vasodilatation in the hind-limb muscles; and (3) the renal vasodilation elicited by LC stimulation is not mediated solely by the renal innervation.

Detection of late potentials. Comparison of two commercial high-resolution ECG systems.

Signal-averaged electrocardiogram (SAECG) is used for detection of ventricular late potentials (LPs) in cardiac patients. As many commercial SAECG systems become available, it is essential to determine if they provide equivalent diagnostic information. Two high-resolution (Hi-Res) ECG systems (MAC-12, Marquette Electronics, Inc (MEI), Milwaukee, WI and LVP101, Arrhythmia Research Technology (ART), Austin, TX) were tested on 143 subjects (13 controls and 130 cardiac patients, 21 of whom were tested for inducible ventricular tachycardia [VT]). Late potential measurements (total QRS duration, high-frequency low-amplitude signal duration, and root-mean-square voltage) obtained from the two systems were in good agreement in most of the controls and patients. Application of Multicenter criteria for the MEI system and Gomes criteria for the ART system yielded very good agreement in LP diagnosis (at least 2 parameters abnormal). The two Hi-Res systems predicted inducible VT with good accuracy. The MEI system gave slightly higher sensitivity (90% vs 70%) and specificity (91% vs 82%) than the ART system in patients tested for inducible VT. In controls, both systems gave the same specificity (92%) and the LP diagnosis agreed in all controls (100%). Although the number of patients was small, neither sensitivity nor specificity were significantly different between the two systems at p < 0.05. To conclude, MEI and ART Hi-Res systems gave very similar LP diagnoses when appropriate criteria were applied.

Altered basal firing pattern and postactivation inhibition of locus coeruleus neurons in spontaneously hypertensive rats

We compared the spontaneous unit activity and inhibition of impulse activity following antidromic activation (postactivation inhibition, PAI) of locus coeruleus (LC) neurons in spontaneously hypertensive rats (SHR) with those of LC neurons in Wistar-Kyoto rats (WKY). Spontaneous spikes of the LC were analyzed by interspike time histograms. The basal unit activity and variation coefficient of the interspike interval were decreased in SHR. The duration of the PAI which was yielded by antidromic activation from the dorsal noradrenergic bundle was shortened in SHR. These findings suggest that SHR LC neurons possess an altered basal firing pattern and inhibitory mechanism.

Recombinant Granulocyte-Macrophage Colony-Stimulating Factor Modulates in vitro Function of the Peripheral Blood Mononuclear Cells in Lipoid Nephrosis

The effect of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) on the in vitro proliferation of peripheral blood lymphocytes (PBL) was evaluated in patients with lipoid nephrosis (LN). The cytokine increased the proliferation of LN PBL in response to phytohemagglutinin (PHA), measured by the [3H]thymidine uptake. The effects were abrogated by antibody against human GM-CSF. We then investigated the effect of GM-CSF on the release of interleukin-1 (IL-1) from peripheral blood monocytes (PBM) in LN patients and normals. In vitro IL-1 production by LN PBM treated with lipopolysaccharide (LPS) was enhanced by coculture with GM-CSF. Potentiation was approximately 2-fold. The immunological identity of the thymocyte comitogenic activity as IL-1 was confirmed by neutralization with a specific rabbit antihuman IL-1 antiserum. Taken together, these observations suggest that one mechanism by which GM-CSF acts to restore immune responses in LN patients may be enhancing the signals which enable activated monocytes/macrophages to secrete IL-1.