Mild Atherosclerotic Lesions Research Articles

Features of Lipid Metabolism in Humanized ApoE Knockin Rat Models.

Apolipoprotein E (ApoE), an essential plasma apolipoprotein, has three isoforms (E2, E3, and E4) in humans. E2 is associated with type III hyperlipoproteinemia. E4 is the major susceptibility gene to Alzheimer’s disease (AD) and coronary heart disease (CHD). We investigated lipid metabolism and atherosclerotic lesions of novel humanized ApoE knockin (hApoE KI) rats in comparison to wide-type (WT) and ApoE knockout (ApoE KO) rats. The hApoE2 rats showed the lowest bodyweight and white fat mass. hApoE2 rats developed higher serum total cholesterol (TC), total triglyceride (TG), and low- and very low density lipoprotein (LDL-C&VLDL-C). ApoE KO rats also exhibited elevated TC and LDL-C&VLDL-C. Only mild atherosclerotic lesions were detected in hApoE2 and ApoE KO aortic roots. Half of the hApoE2 rats developed hepatic nodular cirrhosis. A short period of the Paigen diet (PD) treatment led to the premature death of the hApoE2 and ApoE KO rats. Severe vascular wall thickening of the coronary and pulmonary arteries was observed in 4-month PD-treated hApoE4 rats. In conclusion, hApoE2 rats develop spontaneous hyperlipidemia and might be suitable for studies of lipid metabolism-related diseases. With the PD challenge, hApoE4 KI rats could be a novel model for the analysis of vascular remodeling.

The importance of cardiac tomography in the evaluation of cardiac changes and coronary atherosclerosis in patients with betathalassemia major

Betathalassemic patients demonstrate an increased rate of extracardiac vascular complications, but very low prevalence for coronary artery disease. Computed tomography (CT) achieves excellent tissue characterization, with high spatial resolution and has developed as a gold standard for noninvasive angiography and calcium score assessment. Methods. We examined 7 patients with major beta-thalassemia and 7 patients who had an indication for cardiac CT for resting ECG changes, without symptoms of angina pectoris. We investigated the coronary atherosclerosis by assessing the coronary artery calcium (CAC) and arterial stifness. Usual tests and echocardiography measurement were performed. Cardiac computed tomography determined left ventricular mass, left ventricular ejection fraction (LVEF), coronary calcium score and coronary anatomy. An analysis of myocardial density was also performed. Artery stiffness was assessed by the cardio ankle vascular index (CAVI). Results. Arterial stiffness index in betathallasemic group was higher than control group, R-CAVI index was 6.21± 0.49 vs 5.65±0.37 and L-CAVI index was 6.21± 0.38 vs 5.71±0.31. The assessment of systolic function by echocardiography and cardiac CT examination in the 2 groups, shows that the LVEF in the betathallasemic group was significantly lower than in the control group, which means that some patients already had cardiomyopathy. LV myocardial mass was significantly higher in the group with beta-thalassemia, which is explained by the appearance of myocardial remodeling. The calcium score in patients with major beta-thalassemia was 0 and 8,5± 5,9 in the control group. Only 3 patients (42,8%) in the control group had a calcium score > 10U. No atherosclerotic lesions were observed in patients with major beta-thalassemia, whereas the control group showed mild coronary atherosclerotic lesions. If myocardial density can be determined, calcium or iron deposits can be detected in the myocardium. In patients with beta-thalassemia, the density of the myocardium was higher, both in the left ventricle (49.29 8.87±HU) and in the septum (56.71± 8.1 HU). Calculation of Pearson’s correlation coefficient revealed a good association between CT and echocardiography, reproducibility of CT was significantly higher on an intra-observer level for LVEF and LV Mass. Conclusions: Patients with β–thalassemia major have a similar calcium score compared to control subjects, but they have an increase in arterial stiffness. However, zero frequencie of coronary heart disease, denotes coronary protection mechanisms in thalassemia, so future research should focus on the anti-atherogenic potential of blood lipids at these patients. The ability of cardiac tomography to detect calcifications and changes in myocardial density should be valued, as it can be a good tool for establishing the diagnosis of cardiomyopathy by iron loading.

Selective inhibition of endothelial NF-κB signaling attenuates chronic intermittent hypoxia-induced atherosclerosis in mice

Background and aimsChronic intermittent hypoxia (CIH) exposure causes atherosclerosis, although the underlying mechanisms are poorly understood. This study defines the role of endothelial intrinsic NF-κB signaling in the atherogenic response to CIH. MethodsWe created ApoE-ECI-κBmt mice that are deficient in the apolipoprotein E gene (ApoE−/−) and overexpress an I-κBα mutant (I-κBmt) selectively in endothelial cells. ApoE−/− and ApoE-ECI-κBmt mice were fed a normal chow diet (NCD) or high cholesterol diet (HCD) and exposed to sham or CIH, and atherosclerotic lesions were quantified. ResultsCIH exposure activated NF-κB in aortas, and induced the expression of endothelial-specific and NF-κB-dependent genes, E-selectin and vascular cell adhesion molecule (VCAM)-1, in the aortas and hearts. Endothelial I-κBmt overexpression in ApoE-ECI-κBmt mice significantly inhibited CIH-induced NF-κB activity, and suppressed E-selectin and VCAM-1 expressions, confirming endothelial NF-κB inhibition in ApoE-ECI-κBmt mice. ApoE−/− mice, on NCD, developed mild atherosclerotic lesions spontaneously, and developed advanced and larger areas of atherosclerotic plaques when exposed to CIH. ApoE−/− mice also developed advanced atherosclerotic lesions when fed an HCD alone. The HCD-induced atherosclerotic plaques became more advanced, and plaque area was doubled in mice exposed to HCD + CIH. Endothelial I-κBmt overexpression in ApoE-ECI-κBmt mice attenuated spontaneously developed atherosclerotic lesions, abrogated CIH-induced atherosclerosis and mitigated CIH-mediated facilitation of HCD-induced atherosclerosis. ConclusionsThese results suggest that endothelial intrinsic NF-kB signaling may play a pivotal role in CIH-induced atherosclerosis.

Effect of exercise-based cardiac rehabilitation on non-culprit mild coronary plaques in the culprit coronary artery of patients with acute coronary syndrome.

Approximately, 70% of acute myocardial infarctions are known to develop from mild atherosclerotic lesions. Therefore, it is important to evaluate mild coronary plaques to prevent acute coronary syndrome (ACS). The aim of the present study was to investigate the effects of exercise-based cardiac rehabilitation (CR) on mild coronary atherosclerosis in non-culprit lesions in patients with ACS. Forty-one men with ACS who underwent emergency percutaneous coronary interventions and completed a 6-month follow-up were divided into CR and non-CR groups. Quantitative coronary angiography (QCA) was performed using the automatic edge detection program. The target lesion was a mild stenotic segment (10-50% stenosis) at the distal site of the culprit lesion, and the segment to be analyzed was determined at a segment length ranging from 10 to 15mm. The plaque area was significantly decreased in the CR group after 6months, but was significantly increased in the non-CR group (P<0.05). The low-density lipoprotein (LDL) cholesterol, LDL/high-density lipoprotein (HDL) ratio and high-sensitivity C-reactive protein (Hs-CRP) levels were significantly reduced in both groups (P<0.01). Peak VO2 in the CR group was significantly increased (P<0.01). Changes in the plaque area correlated with those in Hs-CRP in both groups, while that association with those in HDL-C was observed in only CR group. Stepwise regression analysis revealed the decrease in Hs-CRP as an independent predictor of plaque area regression in the CR group. CR prevented the progression of mild coronary atherosclerosis in patients with ACS.

Infectious Agents, Inflammation, and Growth Factors: How Do They Interact in the Progression or Stabilization of Mild Human Atherosclerotic Lesions?

Advanced complicated atherosclerotic lesions have been related to many factors, including inflammation, infectious agents, and growth factors. Mycoplasma pneumoniae (MP) and Chlamydia pneumoniae (CP), inflammation, and growth factors have been associated with severe atherosclerotic lesions in necropsy material in recent work at our lab. The present study intends to clarify the pathogenesis of atherosclerosis, analyzing which of these elements (macrophages, MP, CP, lymphocytes, and growth factors) are associated with initial development of atherosclerotic lesions, discriminating elements related to stabilization of the plaque versus those related to subendothelial active accumulation of macrophages in living patients. Surgical ascending aorta fragments presenting mild atherosclerotic lesions from 30 coronary atherosclerotic patients were immunohistochemically quantified regarding CP, MP, T cells (CD4, CD8), B cells (CD20), macrophages (CD68), and growth factors [platelet-derived growth factor A (PDGF-A), PDGF-B, transforming growth factor-beta (TGF-beta), granulocyte-macrophage colony-stimulating factor (GM-CSF)]. Cases were grouped according to the presence or not of active accumulation of macrophages at the subendothelium that indicates atheroma in development: group I (GI) fragments with <4 CD68+ cells/x400 field, in normal distribution (mean 1.8 +/- 1) representing stable atherosclerotic mild lesion, and GII fragments presenting >or=4 CD68+ cells/x400 field, in a non-normal distribution, mean (8.9 +/- 4.8, atheromas in progress), which was followed by increased number of lymphocytes. The median number in GI was significantly lower than that in GII: CD4 T (2.5 vs. 7.7), CD8 T (1.0 vs. 5.5), and CD20 B (1.5 vs. 5.5) cells/x400 field, p < 0.001. Percentage area positive for CP antigens was significantly lower in GI than in GII: 1.0 vs. 9.2, p < 0.001. There was a higher percentage area occupied by MP than CP in both GI and GII (7.8 vs. 13.8). There was no difference regarding mean number of growth factor-positive cells/x400 field: PDGF-A, 1.4 vs. 3.9; PDGF-B, 3.4 vs. 5.7; TGF-beta, 0.9 vs. 2.2; and GM-CSF, 2.0 vs. 2.2. Considering all cases, a positive correlation was seen between inflammatory cells and CP+ cells (r > 0.5 and p < 0.01). Growth factors did not correlate with inflammatory cells, CP, or MP and were usually seen in smooth muscle cell and fibrotic areas. Study of initial atherosclerotic lesions showed that MP is present in both kinds of lesion: stable and active subendothelial accumulation of macrophages. Stabilization was related to proportional increase of both infectious agents, which were also related to increased amount of PDGF-A and PDGF-B. Active macrophage accumulation lesions were related to higher elevation in CP concentration at subendothelial regions, in association with B cells, but not of MP and growth factors. MP and CP, inflammation, and growth factors, which were already described in severe atherosclerotic lesions in necropsy material, are also present in mild lesions in living patients, strongly favoring a pathogenetic role for these bacteria in the pathogenesis of atherosclerosis. Predominance of CP in relation to MP may favor progression of the plaque, which is associated with increased B-cell proliferation. PDGF-A and PDGF-B are associated with plaque stability, at least in arterial segments not prone for development of complicated lesions.

Effect of Low Dose Atorvastatin Versus Diet-Induced Cholesterol Lowering on Atherosclerotic Lesion Progression and Inflammation in Apolipoprotein E*3–Leiden Transgenic Mice

To evaluate whether low-dose atorvastatin suppresses atherosclerotic lesion progression and inflammation in apolipoprotein E*3 (apoE*3)-Leiden mice beyond its cholesterol-lowering effect. ApoE*3-Leiden mice were fed a high-cholesterol (HC) diet until mild atherosclerotic lesions had formed. Subsequently, HC diet feeding was continued or mice received HC supplemented with 0.002% (w/w) atorvastatin (HC+A), resulting in 19% plasma cholesterol lowering, or mice received a low-cholesterol (LC) diet to establish a plasma cholesterol level similar to that achieved in the HC+A group. HC+A and LC diet reduced, significantly and to the same extent, lesion progression and complication in the aortic root, as assessed by measuring total atherosclerotic lesion area, lesion severity, and macrophage and smooth muscle cell area. In the aortic arch, HC+A but not LC blocked lesion progression. HC+A and LC reduced vascular inflammation (ie, expression of macrophage migration inhibitory factor , plasminogen activator inhibitor- 1, matrix metalloproteinase-9), but HC+A additionally suppressed vascular cell adhesion molecule-1 expression and, in parallel, monocyte adhesion. In contrast, low-dose atorvastatin showed no antiinflammatory action toward hepatic inflammation markers (serum amyloid A, C-reactive protein [CRP]) in apoE*3-Leiden mice and human CRP transgenic mice. Low-dose atorvastatin cholesterol-dependently reduces lesion progression in the aortic root but shows antiinflammatory vascular activity and tends to retard atherogenesis in the aortic arch beyond its cholesterol-lowering effect.

Detection of Chlamydia pneumoniae in atherosclerotic coronary arteries.

Chlamydia pneumoniae has recently been associated with the development of coronary heart diseases by sero-epidemiological studies and by direct detection of the organism in atherosclerotic tissues. The aim of our study was to employ a semi-nested PCR approach to investigate the presence of C. pneumoniae in both normal and atherosclerotic coronary arteries of humans obtained at autopsy. Moreover, we have evaluated the role of infection with C. pneumoniae in relation to the extent of coronary atherosclerosis. One hundred and eighty coronary artery specimens were collected at autopsy from 60 consecutive subjects (three arterial segments from each subject). Atherosclerosis in each arterial segment was graded histologically by the Stary classification. Thirty normal coronary arteries were also taken at autopsy as control. PCR results evidenced the presence of C. pneumoniae DNA in atherosclerotic coronary arteries in 19 (31.7%) of 60 subjects examined, while none of the 30 subjects with non-atherosclerotic tissues was positive (p=0.001). Moreover, of the 180 atherosclerotic specimens examined, C. pneumoniae DNA was detected in 3.4% (2/59) of mild atherosclerotic lesions, and in 14.0% (17/121) of advanced atherosclerotic lesions (p=0.05). Our results demonstrate that the presence of C. pneumoniae DNA may be associated with the severity of coronary atherosclerosis.

Immunohistochemical detection of apolipoprotein A-I and B-100 in canine atherosclerotic lesions.

We attempt to determine and compare the localization of apolipoproteins (apo) apoA-I and B-100 in atherosclerotic lesions of canine aortas, coronary arteries, and the peripheral arteries, using immunohistochemical techniques. Histopathologically, atherosclerotic lesions were characterized by deposition of lipids and infiltration of lipid-laden foamy cells in the tunica intima and tunica media, sometimes forming fibrofatty plaques containing abundant sudanophilic and mineralized material. Canine apoA (CapoA)-I and canine apoB (CapoB)-100 immunopositive signals were simultaneously observed in mild and severe atherosclerotic lesions of the aorta, coronary arteries, splenic arteries, and renal arteries in the double-immunolabeled sections. Both CapoA-I and CapoB-100 positive signals were seen in the cytoplasm of endothelial cells, smooth muscle cells, and macrophages. The subendothelial space and extracellular matrix in the tunica intima and media were also positive. Neither CapoA-I nor CapoB-100 positive signals were seen in normal arteries. These findings closely resemble those of the localization of apoA-I and apoB-100 in human atherosclerotic lesions.

HMG-CoA reductase inhibitors reduce vascular monocyte chemotactic protein-1 expression in early lesions from hypercholesterolemic swine independently of their effect on plasma cholesterol levels

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase are widely used in the treatment of dyslipemias and have shown beneficial effects in primary and secondary prevention of cardiovascular diseases. There is new information that seems to suggest that the beneficial effects observed may not be solely attributable to plasma cholesterol reduction. Our objective has been to evaluate the effect of two statins at similar dose, although unequivalent plasma lipid lowering potential, on vessel wall expression of two proteins involved in atherosclerotic lesion progression. We have studied the effects of treatment on vessel wall expression of monocyte chemotactic protein-1 (MCP-1) and the inducible form of nitric oxide synthase (NOS II). Atherosclerosis was induced in pigs by feeding a high cholesterol and saturated fatty acid diet for 50 days. Mild atherosclerotic lesions were found at this early stage of induction. Animals were simultaneously treated with atorvastatin (3 mg/kg/day), pravastatin (3 mg/kg/day) or placebo. Non-HDL-cholesterol levels induced by diet were reduced in the atorvastatin-treated group (63±8%, P=0.03) and not as much in the pravastatin treated group (44±3, P=0.08). The average MCP-1 expression in carotid, femoral and thoracic aorta was significantly reduced with both statins by 37% ( P<0.05), while NOS II expression was unaffected. Therefore, vascular MCP-1 expression was downregulated by statins regardless of their lipid lowering potential and lipo/hydrophilic characteristics. Early downregulation of MCP-1 could attenuate the inflammation within the vascular wall and prevent the development of atherosclerotic lesions.

Chronic Renal Artery Occlusion: Nephrectomy Versus Revascularization

Renal artery occlusion (RA-OCC) represents the final expression of anatomically progressive atherosclerotic renovascular occlusive disease. When a highgrade stenosis progresses to occlusion, the event may be clinically silent or previously controlled hypertension may worsen and serum creatinine levels may elevate.1 Given that as much as 35% of mild contralateral renal artery atherosclerotic lesions progress to sigChronic renal artery occlusion: Nephrectomy versus revascularization

812-1 The Number of Stenoses on Coronary Arteriography is Related to more Widespread and Numerous Milder Lesions

The extent of significant (&gt;50%) coronary narrowings assessed by angiography has served as a useful prognostic index. Recent studies have shown, however, that most myocardial infarctions are caused by milder stenoses. To explain the paradox that severe stenoses at angiography can predict cardiovascular prognosis, we tested the hypothesis that the extent of severe stenoses relates to the number of mild lesions. We assessed the burden of mild atherosclerotic lesions in angiographically normal arteries by intravascular ultrasound (IVUS) in 37 patients divided in 3 groups: Group 1 comprised subjects with normal coronary angiograms throughout, Group 2 patients with single-vessel disease and Group 3 patients with two-vessel disease. For each patient, an angiographically normal (smooth) vessel was examined using a 4.3F monorail catheter with a 30 MHz mechanical transducer, connected to an image console (CVIS Inc., Sunnyvale, CA). The number and extent of milder lesions were quantified in all segments by the intimal index (Ii = Intimal area/intimal + luminal area × 100%). Results are expressed as mean Ii and maximal Ii per patient. Mean and maximal Ii from the 3 groups were compared by ANOVA. Results are as follow: n = 37 Group 1 Group 2 Group 3 p value Mean Ii (%) 7.4 17.0 33.5 0.0014 Max.li(%) 15.7 30.4 49.8 0.0006 Patients with angiographic evidence of focal CAD also have less severe but more numerous and diffuse atherosclerotic lesions. The number of coronary arteries with significant angiographic stenoses correlates directly with the burden of mild lesions which may explain its relation to cardiovascular prognosis.

Effect of Cholesterol-Lowering Medications on Progression of Mild Atherosclerotic Lesions of the Carotid Arteries and on the Risk of Stroke

The Asymptomatic Carotid Artery Progression Study (ACAPS) compared the usefulness of lovastatin alone or in combination with warfarin in the prevention of 3-year progression of mean maximum intimal-medial thickness (IMT), which is a measure of early atherosclerosis. The factorally designed, placebo-controlled study enrolled 919 men and women aged 40–79 who had moderately elevated low-density-lipoprotein (LDL) cholesterol and a single maximum IMT of 1.5–3.5 mm in the carotid arteries. Lovastatin significantly reduced LDL cholesterol. The mean maximum IMT declined at an annual rate of 0.009 mm among those persons taking lovastatin while the mean maximum IMT increased by 0.006 mm in the controls (p = 0.001). In addition, deaths and the combined frequency of coronary deaths, nonfatal myocardial infarctions and strokes were significantly lowered among the lovastatin-treated groups. Only 5 strokes (3 hemorrhages) were detected in the study; all occurred among those persons who were receiving lovastatin placebo. Our study suggests that early administration of lipid-lowering drugs halts the progression of early atherosclerosis in the carotid artery. In turn, such early primary preventive treatment may lessen the risk of important ischemic vascular events including stroke.

Risk factors related to the wall thickness of carotid artery assessed by ultrasonography

Progression of atherosclerotic lesion of the carotid artery is suggested to induce the development of cerebrovascular events. We evaluate the risk factors related to carotid artery, wall thickness by ultrasonography. A total of 159 patients, who had received no medication for hypertension or hyperlipidemia were enrolled in this study. The wall thickness of carotid artery was evaluated as an intima-media (IM) complex measured by B-mode ultrasonography with a 7.5 MHz probe. Simple regression analysis demonstrated significant correlation between the IM complex and both age and systolic blood pressure, but not with fasting levels of plasma glucose, hemoglobin A1c, total and HDL cholesterol, triglyceride or gender. Stepwise regression analysis showed age and systolic blood pressure contribute to IM thickness (r = 0.623). However, in patients aged 60 or over, blood pressure did not contribute to the IM wall thickness. Smoking was not a risk factor for IM thickness, but the Brinkman Index (daily consumption of cigarettes x years smoking) was significantly higher in patients with plaques in the carotid artery than those without it. These results suggest that high blood pressure is a risk factor for mild atherosclerotic lesions of the carotid artery for those aged under 60. Smoking may contribute to the formation of plaque, which may consequently lead to the ischemic cerebrovascular disease.

Visualisation of arterial structure in vivo with intravascular ultrasound

Contrast angiography provides a silhouette of the arterial lumen, but does not give information about arterial wall structure. Catheter-tip ultrasound transducers can now provide a cross-sectional image of the arterial wall. This study examined the pathological correlation of intravascular ultrasound images and the accuracy of ultrasound measurements of vascular geometry. Intravascular ultrasound images were obtained with a mechanically rotated catheter-tip transducer and recorded on videotape. Initial validation studies were performed in fresh, post-mortem arterial specimens, which were filled with saline at physiological pressures. Ultrasound images at specific sites were compared with the pathological findings at that site and measurements of luminal diameter were compared with corresponding angiographic measurements. Subsequently, intravascular ultrasound was employed to examine the aorta, ilio-femoral and coronary arteries in patients undergoing balloon angioplasty. The pathological correlations showed that intravascular ultrasound can detect early initial thickening and mild atherosclerotic lesions that do not result in luminal deformation. Ultrasound images provided definition of calcified, fibrotic and lipid-filled lesions. Ultrasound measurements of luminal diameter correlated well with pathology measurements (r = 0.93), as did ultrasound measurements of plaque area (r = 0.89). The in vivo studies demonstrated that intravascular ultrasound can define atheroma lesions not evident on contrast angiography and permits detailed evaluation of the results of interventions such as balloon angioplasty. Intravascular ultrasound provides a unique window upon arterial structure and pathology in humans. Ultrasound images allow accurate measurements of vascular geometry and define early atheromatous lesions that are not evident with angiography.

Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions.

We examined whether coronary risk factors and atherosclerotic lesions in the study artery were associated with impaired endothelium-dependent dilation of coronary resistance arteries. Acetylcholine (ACH) at graded doses (1, 3, 10 and 30 micrograms/min) and papaverine (10 mg) were selectively infused into the left anterior descending coronary artery of 28 patients, in whom the study artery was angiographically normal (n = 16) or with mild stenosis < or = 40% (n = 12). Coronary blood flow (CBF) was estimated from the product of mean CBF velocity measured by an intracoronary Doppler catheter and the arterial cross-sectional area of the study artery determined by quantitative arteriography. ACH increased CBF in a dose-dependent manner. However, the maximum CBF response to ACH varied widely among patients (from 50% to 660%). By multivariate analysis, the presence of atherosclerotic lesions in the study artery was an independent predictor for impaired CBF response to ACH (P < 0.01). Hypertension (P < 0.001), hypercholesterolemia (r = -0.52, P < 0.005), age > or = 50 yr (P < 0.01) and total number of coronary risk factors (r = -0.62, P < 0.001) were associated with the impaired increase in CBF with ACH by univariate analysis. The percent increase in CBF evoked with papaverine did not correlate with these risk factors. The results suggest that mild atherosclerotic lesions in the study artery and coronary risk factors are accompanied by impaired endothelium-dependent dilation of coronary resistance arteries evoked with ACH. Endothelial dysfunction of coronary resistance arteries may result in altered regulation of myocardial perfusion in patients with mild coronary atherosclerosis and coronary risk factors.

Hyperlipidemia and atherosclerosis in experimental insulinopenic diabetic monkeys

Chronic insulinopenic diabetes was induced by i.v. streptozotocin in the non-human primate Macaca fuscata. Five diabetic monkeys were kept for 8–19 months and nine for 24–48 months without any insulin treatment. Hyperglycemia (241 ± 22 mg/dl, M ± SE ≤ 1 year) progressed to 376 ± 34 mg/dl (>2 years) and ketosis to 3.5 mM (>2 years) during the course of diabetes; this was roughly inversely proportional to hypoinsulinemia (3.4 μU/ml, 2 years). Serum cholesterol increased from 184 ± 11 (≤1 year) to 328 ± 66 mg/dl (>2 years) with the major increase in LDL-cholesterol (2.7-fold over control, >2 years). HDL-cholesterol did not change at all throughout the experimental period. TG increased from 144 ± 25 (≤1 year) to 676 ± 116 (>2 years) with a major increase in the VLDL fraction (15-fold over control, >2 years). Serum levels of apo B increased to 141 ± 16 (≤2 years) and 223 ± 8 mg/dl (>2 years) in contrast to control, 73 ± 2. Morphologically, lipid deposition in the intima and fatty streaks have been observed in the abdominal aorta of all the diabetic monkeys with duration of more than 2 years. In six of the diabetic monkeys atheromatous changes such as intimal and medial thickening with smooth muscle cell proliferation were observed with foam cell formation. Similar atherosclerotic lesions were observed in renal and coronary arteries in at least six of these monkeys. In diabetic monkeys with duration of less than 2 years, mild atherosclerotic lesions were observed in two out of five. The results indicate that long standing insulinopenia leads to metabolic derangements characterized by hyperglycemia, ketonemia and hyperlipidemia. Elevation of LDL-cholesterol and VLDL TG with an increase of apo B is a characteristic of lipoprotein disorder. Morphologically, early to moderately advanced lesions of atherosclerosis were observed in aorta, renal and coronary arteries as a result of metabolic derangement due to insulin deficiency.

Preserved endothelium-dependent vasodilation at the vasospastic site in patients with variant angina.

Endothelial dysfunction has been implicated as a cause of coronary vasospasm in patients with variant angina. This study aimed to determine if endothelium-dependent vasodilation evoked with substance P (SP) was altered at the spastic site where vasospasm was induced by acetylcholine (ACH) in patients with variant angina. It has been shown that SP evokes endothelium-dependent vasodilation with no direct effect on vascular smooth muscle in excised human coronary arteries. SP and ACH were infused into the coronary arteries in nine patients with variant angina in whom coronary arteriograms showed normal or mild atherosclerotic lesions. The vasomotor responses of coronary arteries were assessed by quantitative arteriography. ACH at a high dose (100 micrograms/min) provoked coronary vasospasm associated with anginal attack in all patients. In contrast, SP at graded doses (13.5, 40, and 135 ng/min) caused the dose-dependent and comparable increases in the coronary diameter at the spastic and control sites. ACH at a low dose (10 micrograms/min) also caused comparable vasodilation at the spastic and control sites in patients with normal coronary arteries. Coronary vasodilating responses to SP were comparable in patients with variant angina and those with atypical chest pain. The results indicate that endothelium-dependent vasodilation evoked with SP and ACH at the low dose was present at the vasospastic site in patients with variant angina. These findings suggest that the ACH-induced coronary vasospasm in patients with variant angina results from hyperreactivity of vascular smooth muscle to ACH but not from endothelial dysfunction.

ヒト大動脈壁に見られる泡沫細胞の微細構造(第一報)

The presence of both smooth muscle cell-derived foam cells and blood-borne monocyte-derived foam cells in atherosclerotic plaques was recently shown clearly. We tried to find out blood-borne monocytes just penetrating into the aortic intima, examine the time when they transform into foam cells and investigate the fate of foam cells in the way of observation with electron microscope of the aortic regions having no obvious atherosclerotic lesions of 25 human autopsy cases between 1 month to 80 years old with mild atherosclerotic lesions. We found that monocytes adhering to endothelium had a few lipid droplets. A group of foam cells having many lipid droplets were observed in the intima. So we agree with Gerrity's opinion that blood-borne monocytes transform into foam cells through endocytosis of lipid in aortic intima. On the other hand, we observed that foam cells loading many lipid droplets having atrophic intracytoplasmic organella and, moreover, found ruptured foam cells, so we consider that foam cells may be inactive cells just going to die.

Transient Ischemic Attacks: Racial Differences, Treatment, and Prognosis

Prognosis of transient ischemic attack (TIA) in 45 patients, diagnosed as TIA out of 75 suspected TIAs, was investigated for an average follow-up of 12.9 months. Twelve (27%) of the 45 patients progressed to complete stroke during the follow-up period. Patients with severe atherosclerotic lesions and with intracranial arterial lesions or with lesions of both intracranial and extracranial sites were predominant among the 29 cases examined angiographically, and the majority progressed to stroke. The prognosis was poorer than in the cases with mild atherosclerotic lesions or cases with only extracranial arterial lesions. From such characteristics of cerebral atherosclerosis of TIA in the Japanese with predominant intracranial severe arterial lesions, a different genesis for the development of cerebral atherosclerosis between Japanese and Americans or other Caucasians may be expected in cases with TIAs. With respect to the relation of recurrence of TIA to prognosis, a single episode of TIA in the past placed the patient at a greater risk of early infarction, where a high incidence (57%) of progression to stroke was found during the follow-up period. Treatment by superficial temporal artery to middle cerebral artery anastomosis or anticoagulant drug medication seemed to improve the prognosis of TIA as compared with antiplatelet aggregation therapy. These results suggest that embolus formation from an embolic source of arterial lesions may play some part in the pathogenesis of TIA and occurrence of subsequent stroke.

Genetic susceptibility and resistance to diet-induced atherosclerosis and hyperlipoproteinemia.

To test the hypothesis that genetic susceptibility or resistance to diet-induced atherosclerosis is correlated with serum levels of specific lipids, lipoproteins, or apoproteins, male mice of a genetically susceptible and a genetically resistant strain were fed either a normal or an atherogenic diet. After 20 weeks on a normal diet, neither the resistant nor the susceptible strain mice had atherosclerosis; resistant strain mice had serum cholesterol of 66 +/- 11 while the susceptible strain mice had 90 +/- 1 mg/dl serum cholesterol, and lipoproteins were dominated by a single alpha-migrating HDL. After 20 weeks on an atherogenic diet, resistant strain mice had 185 +/- 55 mg/dl cholesterol, their lipoproteins remained dominated by alpha-migrating HDL, and two of eight mice had mild atherosclerotic lesions; susceptible strain mice had 510 +/- 94 mg/dl cholesterol, multiple alpha- and pre-beta-migrating lipoprotein species, and all 13 had advanced aortic atherosclerosis. The resistant strain mice had an apolipoprotein E/total lipoprotein protein ratio of 0.42 on the normal diet and 0.53 on the atherogenic diet, while the susceptible strain mice had the significantly lower ratios of 0.07 and 0.31, respectively. These data indicate that genetic resistance to diet-induced aortic atherosclerosis in mice is correlated with capacity to prevent large increases in serum cholesterol, to suppress abnormal alpha- and pre-beta-migrating lipoproteins, and to maintain elevated serum apolipoprotein E/total lipoprotein protein ratios. Our data do not preclude the possibility of additional gene control at the level of arterial end organ response.