Age-related changes in serum/plasma biochemical parameters of WHHLMI rabbits.

We developed myocardial infarction-prone rabbits (WHHLMI rabbits) by selectively breeding coronary atherosclerosis-prone WHHL rabbits. To examine the serum/plasma biochemical parameters of this animal model, we assayed the lipid and glucose levels, and enzyme activities of WHHLMI rabbits from 2 to 26 months of age using solid phase analysis. The results showed a good correlation with those measured with a conventional method. The serum enzyme activities and lipid levels varied with aging despite almost no change in the plasma glucose levels. Gender differences were observed in the total cholesterol, triglyceride, and lactate dehydrogenase activity levels. The data on these serum/plasma biochemical parameters will be useful in studies of myocardial infarction or pharmacological studies using this model.     

Discrimination of Recent Ischemic Myocardial Changes in WHHLMI Rabbits from the Findings of Postmortem Degeneration.

To distinguish recent ischemic myocardial changes in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits from general postmortem myocardial degeneration, we examined hearts of WHHLMI rabbits after sudden death and postmortem hearts of non-atherogenic rabbits. Hearts of 8 WHHLMI rabbits were excised within 30 min of sudden death and hearts of 27 non-atherosclerotic rabbits were excised at designated periods after sacrifice. A large number of myocardial cells from WHHLMI rabbits exhibited features characteristic of ischemia (intercellular gap, intracellular edema, eosinophilia, disappearance of myocardial cells, indistinct nuclei, wavy myocardial fibers) simultaneously at regions close to proximal occluded coronary arteries. Although postmortem hearts of non-atherosclerotic rabbits exhibited similar characteristics, several features characteristic of autolyzed myocytes were also randomly observed in the left ventricle wall. Each feature was detected independently in myocardial cells or regions of the ventricle wall. In conclusion, we found several unique characteristics associated with myocardial infarction which enable discrimination between recent ischemic myocardial changes and myocardial degeneration following death.     

Electrocardiograms Corresponding to the Development of Myocardial Infarction in Anesthetized WHHLMI Rabbits (Oryctolagus cuniculus), an Animal Model for Familial Hypercholesterolemia

The aim of this study was to determine whether features indicative of myocardial ischemia occur in the electrocardiograms (ECG) in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits, an animal model for human familial hypercholesterolemia. ECG were recorded in 110 anesthetized WHHLMI rabbits (age, 10 to 39 mo) by using unipolar and bipolar limb leads with or without chest leads. We noted the following electrocardiographic changes: T wave inversion (37.4%), ST segment depression (31.8%), deep Q wave (16.3%), reduced R wave amplitude (7.3%), ST segment elevation (2.7%), and high T wave (1.8%). These ECG changes resembled those in human patients with coronary heart disease. Histopathologic examination revealed that the left ventricular wall showed acute myocardial lesions, including loss of cross-striations, vacuolar degeneration, coagulation necrosis of cardiac myocytes, and edema between myofibrils, in addition to chronic myocardial lesions such as myocardial fibrosis. The coronary arteries that caused these ECG changes were severely stenosed due to atherosclerotic lesions. Ischemic ECG changes corresponded to the locations of the myocardial lesions. Normal ECG waveforms were similar between WHHLMI rabbits and humans, in contrast to the large differences between rabbits and mice or rats. In conclusion, ischemic ECG changes in WHHLMI rabbits reflect the location of myocardial lesions, making this model useful for studying coronary heart disease.Abbreviations: CHD, coronary heart disease; ECG, electrocardiogram; WHHL, Watanabe heritable hyperlipidemic; WHHLMI, myocardial infarction-prone Watanabe heritable hyperlipidemicCoronary heart disease (CHD) is prevalent in developed countries, including the United States.^16,24 Although potent compounds (for example, statins to inhibit cholesterol synthesis) have been developed to reduce the public health burden of this disease, CHD remains a leading cause of death, and further efforts are needed to reduce associated morbidity and mortality.²⁵ In evaluating the therapeutic effects of CHD interventions, the electrocardiogram (ECG) is an essential tool for examining myocardial function.³⁹In humans, various ischemic ECG changes occur in association with myocardial ischemia and infarction, such as high T wave, ST segment elevation, emergence of the deep Q wave, reduction of R wave amplitude, resolution of ST segment elevation, and T wave inversion.^21,39 In addition, ST segment depression is a typical change observed with subendocardial ischemia.^2,7In the study of myocardial ischemia, animal models that show ECG waveforms comparable to those of human patients with CHD play an important role. This similarity is important not only for assessing the effects of agents for the treatment of CHD but also for assessing adverse effects of newly developed agents on cardiac function. Although ECG have been used to study myocardial ischemia in several species including pigs, dogs, rabbits, rats, and mice,^{3,9,10,14,18,23} most of these studies used coronary ligation models. These models do not fully reflect the events that occur during myocardial ischemia caused by atherosclerotic coronary stenosis, which is seen typically in patients with CHD.The Watanabe heritable hyperlipidemic (WHHL) rabbit⁴⁰ and the myocardial infarction-prone WHHL (WHHLMI) rabbit³³ are animal models for the study of human myocardial ischemia. WHHLMI rabbits spontaneously develop hypercholesterolemia due to a deficiency of receptors for low-density lipoproteins and manifest severe coronary atherosclerosis and myocardial infarction. Importantly, lipoprotein metabolism in WHHL and WHHLMI rabbits resembles that in humans.^28,30 Using these advantages of the WHHL and WHHLMI models, we and others have been studying the effects of hypocholesterolemic and antiatherosclerotic agents on coronary atherosclerosis.^29,32,34 However, ECG were not examined in these studies. Because the rabbit heart is electrophysiologically similar to the human heart,^27,38 using ECG to monitor myocardial function in the WHHLMI rabbit may be valuable.In the present study, we examined whether ECG changes observed in WHHLMI rabbits reflect myocardial ischemia and whether those changes correspond to ECG features in human patients with CHD.     

Suppression of Coronary Atherosclerosis by Helix B Surface Peptide,a Nonerythropoietic,Tissue-Protective Compound Derived from Erythropoietin

Erythropoietin (EPO), a type I cytokine originally identified for its critical role in hematopoiesis, has been shown to have nonhematopoietic, tissue-protective effects, including suppression of atherosclerosis. However, prothrombotic effects of EPO hinder its potential clinical use in nonanemic patients. In the present study, we investigated the antiatherosclerotic effects of helix B surface peptide (HBSP), a nonerythropoietic, tissue-protective compound derived from EPO, by using human umbilical vein endothelial cells (HUVECs) and human monocytic THP-1 cells in vitro and Watanabe heritable hyperlipidemic spontaneous myocardial infarction (WHHLMI) rabbits in vivo. In HUVECs, HBSP inhibited apoptosis (≈70%) induced by C-reactive protein (CRP), a direct mediator of atherosclerosis. By using a small interfering RNA approach, Akt was shown to be a key molecule in HBSP-mediated prevention of apoptosis. HBSP also attenuated CRP-induced production of tumor necrosis factor (TNF)-α and matrix metalloproteinase-9 in THP-1 cells. In the WHHLMI rabbit, HBSP significantly suppressed progression of coronary atherosclerotic lesions as assessed by mean cross-sectional stenosis (HBSP 21.3 ± 2.2% versus control peptide 38.0 ± 2.7%) and inhibited coronary artery endothelial cell apoptosis with increased activation of Akt. Furthermore, TNF-α expression and the number of M1 macrophages and M1/M2 macrophage ratio in coronary atherosclerotic lesions were markedly reduced in HBSP-treated animals. In conclusion, these data demonstrate that HBSP suppresses coronary atherosclerosis, in part by inhibiting endothelial cell apoptosis through activation of Akt and in association with decreased TNF-α production and modified macrophage polarization in coronary atherosclerotic lesions. Because HBSP does not have the prothrombotic effects of EPO, our study may provide a novel therapeutic strategy that prevents progression of coronary artery disease.     

Multivessel myocardial infarction

A 56-year-old female patient with hypertension, obesity and chronic intermittent cauda equina compression suffered an acute myocardial infarction five days after a lumbar hernia operation. The electrocardiogram (ECG) showed ST-segment elevation in multiple leads, consistent with an extensive acute apical and lateral myocardial infarction (figure 1, panel A). Acute coronary angiography revealed occlusion of the end-arteries of the left coronary artery in the absence of significant atherosclerotic disease (figure 1, panel B).     

G-CSF prevents the progression of atherosclerosis and neointimal formation in rabbits

Granulocyte colony-stimulating factor (G-CSF) prevents left ventricular remodeling after myocardial infarction, but its effect on atherosclerosis is unknown. We examined two kinds of rabbit atherosclerosis models. Myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHL-MI) rabbits were treated with G-CSF or saline for 7 days from 14 months old. The vascular injury models were created by inflating angioplasty balloon in the iliac artery of rabbits and were divided into G-CSF and saline group. G-CSF significantly reduced the stenosis score of coronary artery and lipid plaque area of thoracic aorta in WHHL-MI rabbits at 4 weeks after the treatment. In the vascular injury model, G-CSF significantly prevented an increase in neointima/media ratio at 4 weeks after the treatment. G-CSF accelerated the reendothelialization of denuded arteries, and the pretreatment with nitric oxide synthase inhibitor significantly inhibited it. These results suggest that G-CSF has a therapeutic potential for the progression of atherosclerosis.     

Lipoprotein(a) enhances advanced atherosclerosis and vascular calcification in WHHL transgenic rabbits expressing human apolipoprotein(a)

High lipoprotein(a) (Lp(a)) levels are a major risk factor for the development of atherosclerosis. The risk of elevated Lp(a) concentration is increased significantly in patients who also have high levels of low density lipoprotein (LDL) cholesterol. To test the hypothesis that increased plasma levels of Lp(a) may enhance the development of atherosclerosis in the setting of hypercholesterolemia, we generated Watanabe heritable hyperlipidemic (WHHL) transgenic (Tg) rabbits expressing human apolipoprotein(a) (apo(a)). We report here that Tg WHHL rabbits developed more extensive advanced atherosclerotic lesions than did non-Tg WHHL rabbits. In particular, the advanced atherosclerotic lesions in Tg WHHL rabbits were frequently associated with calcification, which was barely evident in non-Tg WHHL rabbits. To investigate the molecular mechanism of Lp(a)-induced vascular calcification, we examined the effect of human Lp(a) on cultured rabbit aortic smooth muscle cells and found that smooth muscle cells treated with Lp(a) showed increased alkaline phosphatase activity and enhanced calcium accumulation. These results demonstrate for the first time that Lp(a) accelerates advanced atherosclerotic lesion formation and may play an important role in vascular calcification.     

Surgical treatment of impending myocardial infarction: Report of two cases

Two men, aged 29 and 44, presented with clinical and electrocardiographic evidence suggesting impending myocardial infarction. Selective coronary angiography revealed serious obstructive coronary atherosclerosis including gross stenosis of the main left coronary artery in both. Emergency surgical operations were performed, a double aorto-coronary venous bypass in one and a single venous bypass combined with a Vineberg operation in the other. Neither patient sustained myocardial infarction. Both patients are very well more than six months after operation. Clinical, electrocardiographic and angiographic evidence of the effectiveness of these operations is presented.     

Bisphenol A Exposure Enhances Atherosclerosis in WHHL Rabbits

Bisphenol A (BPA) is an environmental endocrine disrupter. Excess exposure to BPA may increase susceptibility to many metabolic disorders, but it is unclear whether BPA exposure has any adverse effects on the development of atherosclerosis. To determine whether there are such effects, we investigated the response of Watanabe heritable hyperlipidemic (WHHL) rabbits to 400-µg/kg BPA per day, administered orally by gavage, over the course of 12 weeks and compared aortic and coronary atherosclerosis in these rabbits to the vehicle group using histological and morphometric methods. In addition, serum BPA, cytokines levels and plasma lipids as well as pathologic changes in liver, adipose and heart were analyzed. Moreover, we treated human umbilical cord vein endothelial cells (HUVECs) and rabbit aortic smooth muscle cells (SMCs) with different doses of BPA to investigate the underlying molecular mechanisms involved in BPA action(s). BPA treatment did not change the plasma lipids and body weights of the WHHL rabbits; however, the gross atherosclerotic lesion area in the aortic arch was increased by 57% compared to the vehicle group. Histological and immunohistochemical analyses revealed marked increases in advanced lesions (37%) accompanied by smooth muscle cells (60%) but no significant changes in the numbers of macrophages. With regard to coronary atherosclerosis, incidents of coronary stenosis increased by 11% and smooth muscle cells increased by 73% compared to the vehicle group. Furthermore, BPA-treated WHHL rabbits showed increased adipose accumulation and hepatic and myocardial injuries accompanied by up-regulation of endoplasmic reticulum (ER) stress and inflammatory and lipid metabolism markers in livers. Treatment with BPA also induced the expression of ER stress and inflammation related genes in cultured HUVECs. These results demonstrate for the first time that BPA exposure may increase susceptibility to atherosclerosis in WHHL rabbits.     

Preventive effect of pravastatin sodium, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on coronary atherosclerosis and xanthoma in WHHL rabbits

In this paper, we examined whether the development of atherosclerosis in the Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model of familial hypercholesterolemia in man, could be prevented by the reduction of serum cholesterol levels. Pravastatin sodium (the generic name of CS-514), a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was used as a cholesterol-lowering drug. The drug was administered orally to 12 WHHL rabbits (2-3 months old) at a dose of 50 mg/kg per day for 24 weeks, and 13 animals were given water as control. In the treated group, serum cholesterol, phospholipid and triacylglycerol levels were significantly reduced by 28%, 32% and 16%, respectively, as compared with those of the control group. Although the prevention of development of the aortic atherosclerosis was not significant, the progression of coronary atherosclerosis was significantly prevented. The incidence of atherosclerosis in four main coronary arteries was reduced from 42% (control group) to 19% (treated group, P less than 0.01), and the development of lesion of coronary arteries evaluated by area of lesion was reduced from 19.7% (control group) to 9.1% (treated group, P less than 0.05). Histopathological findings supported the above observations. In addition, development of xanthoma in digital joints was also reduced from 90.4% (control group) to 58.3% (treated group, P less than 0.005). These results suggest that the development of coronary atherosclerosis and xanthoma in WHHL rabbit was reduced by continuous reduction of serum cholesterol levels treated with pravastatin sodium.     

Recurrent myocardial infarction in a patient with Prinzmetal's angina and normal coronary arteries

A 55-year-old man was referred for the evaluation of frequent chest pain and syncope. While in the hospital, he experienced severe chest pain accompanied by transient ST segment elevation and a slight elevation of cardiac enzyme levels. Multiple coronary arteriograms were recorded at various times during an interval of 2 months. On one occasion, the results were normal; on another occasion, they showed total occlusion of the left anterior descending, diagonal, and circumflex coronary arteries. The occlusion was completely relieved with sublingual nitroglycerin. Because the patient's clinical condition deteriorated rapidly, double aortocoronary saphenous vein bypass was performed to the left anterior descending and circumflex coronary arteries. During the induction of anesthesia, ventricular fibrillation occurred, and the patient died from refractory recurrent fibrillation 4 hours after surgery. Postmortem examination revealed normal coronary arteries, patent vein grafts, and multiple focal areas of recent and old myocardial fibrosis. Thus, it appears that coronary spasm, in the presence of otherwise normal coronary arteries, can produce myocardial infarction with necrosis, and that medical management may provide a more successful method of treating such patients.     

Immunoscintigraphy for detecting acute myocardial infarction without electrocardiographic changes.

OBJECTIVE--To establish whether immunoscintigraphy with antibody to myosin may detect acute myocardial infarction without electrocardiographic changes. DESIGN--Prospective study of patients with suspected acute myocardial infarction or unstable angina with cardiac imaging with 111indium myosin antibody, estimation of cardiac enzyme concentrations, electrocardiography, 201thallium imaging, and radionuclide ventriculography. SETTING--Coronary care unit in a district general hospital. PATIENTS--119 Consecutive patients with suspected acute myocardial infarction or unstable angina. Patients with cardiomyopathy, myocarditis, valvular heart disease, myocardial infarction or cardiac surgery in the previous two weeks or with left bundle branch block and women of childbearing age were excluded. RESULTS--Of 75 patients with suspected acute myocardial infarction, seven had no diagnostic electrocardiographic changes despite normal conduction patterns. Immunoscintigraphy with myosin antibody disclosed necrosis in all seven patients, which was localised in regions supplied by diseased coronary arteries in all but one. Six patients had abnormal images on 201thallium imaging, and all seven had abnormal wall motion at the site of antibody uptake. One patient with minimal left main stem and right coronary artery atheroma had uptake of antibody at two discrete sites. CONCLUSIONS--Immunoscintigraphy with antibody to myosin confirms myocardial infarction in the absence of electrocardiographic changes and discloses the site of infarction.     

Prevalence of asymptomatic myocardial ischaemia in diabetic subjects.

OBJECTIVE--To compare the prevalence of silent myocardial ischaemia associated with coronary artery disease in diabetic subjects with that in controls of similar age and sex. DESIGN--A controlled study in which subjects with positive findings on exercise electrocardiography, 24 hour electrocardiographic recording, or dynamic thallium scintigraphy (diabetics only) underwent coronary angiography. SETTING--Academic medical centre; referral based cardiology clinic. SUBJECTS--136 Diabetic subjects, of whom 72 (33 women, 39 men (mean age 46.0] were insulin dependent and 64 (19 women, 45 men (mean age 49.3] non-insulin dependent. 80 Controls matched for age and sex; all were clients of the Occupational Health Service of Oulu University Central Hospital or the State Occupational Health Service Station in Oulu in whom diabetes had been excluded by a glucose tolerance test. INTERVENTIONS--Any subject showing signs of myocardial ischaemia was referred for cardiac catheterization. MAIN OUTCOME MEASURES--Exercise electrocardiography and 24 hour electrocardiographic recording were regarded as positive if there were ST depressions of greater than or equal to 1 mm that were planar or downsloping and persisted for 0.08 seconds after the J point. Thallium tomographic imaging. With cardiac catheterisation, coronary artery lesions were classified as significant in half or more of the vessel lumen was narrowed, or insignificant if such narrowing was less than half. RESULTS--40 (29%) diabetes and four (5%) controls had positive results in one or more of the non-invasive tests. Coronary angiography was performed on 34 of the diabetics (six refused); 12 had significant coronary artery narrowing; seven had unimportant atherosclerosis; 15 had patent coronary arteries. Among the controls only one had unimportant atherosclerosis; the other three had patent arteries. CONCLUSIONS--These results confirm the high prevalence of asymptomatic myocardial ischaemia in diabetics. Non-invasive screening of diabetic subjects, however, does not seem justified because of the low preset probability of the presence of the disease and the inaccuracy of the available test methods.     

Species differences of macrophage very low-density-lipoprotein (VLDL) receptor protein expression

Triglyceride-rich lipoproteins (TGRLs) and low-density-lipoprotein (LDL) cholesterol are independent risk factors for coronary artery disease. We have previously proposed that the very low-density-lipoprotein (VLDL) receptor is one of the receptors required for foam cell formation by TGRLs in human macrophages. However, the VLDL receptor proteins have not been detected in atherosclerotic lesions of several animal models. Here we showed no VLDL receptor protein was detected in mouse macrophage cell lines (Raw264.7 and J774.2) or in mouse peritoneal macrophages in vitro. Furthermore, no VLDL receptor protein was detected in macrophages in atherosclerotic lesions of chow-fed apolipoprotein E-deficient or cholesterol-fed LDL receptor-deficient mice in vivo. In contrast, macrophage VLDL receptor protein was clearly detected in human macrophages in vitro and in atherosclerotic lesions in myocardial infarction-prone Watanabe-heritable hyperlipidemic (WHHLMI) rabbits in vivo. There are species differences in the localization of VLDL receptor protein in vitro and in vivo. Since VLDL receptor is expressed on macrophages in atheromatous plaques of both rabbit and human but not in mouse models, the mechanisms of atherogenesis and/or growth of atherosclerotic lesions in mouse models may be partly different from those of humans and rabbits.     

Interpretation of elevated plasma visfatin concentrations in patients with ST-elevation myocardial infarction

Visfatin is a cytokine that is expressed in many tissues, including the heart, and has been proposed to play a role in plaque destabilization leading to acute myocardial injury. The present study evaluates plasma levels of visfatin in acute ST-elevation myocardial infarction (STEMI) patients and examines the temporal changes in visfatin levels from the acute period to the subacute period to determine a correlation with the degree of myocardial ischemia. We evaluated 54 patients with STEMI. Circulating levels of visfatin and brain natriuretic peptide (BNP) were measured by ELISA. In addition, local expression of visfatin and BNP were detected by quantitative real-time polymerase chain reaction and immunohistochemical (IHC) analysis of left ventricular myocytes in a mouse model of myocardial infarction (MI). Plasma levels of visfatin were significantly increased in patients with STEMI on admission, relative to controls (effort angina patients and individuals without coronary artery disease). The visfatin levels reached a peak 24 h after percutaneous coronary intervention (PCI) and then decreased toward the control range during the first week after PCI. The basal plasma visfatin levels were found to correlate with peak troponin-I, peak creatine kinase-MB, total white blood cell count, and BNP levels. Trend analyses confirmed that visfatin levels correlated with the number of diseased coronary arteries. Further, in MI mice, mRNA levels of visfatin and BNP were found to be higher than in sham-treated mice. IHC analysis showed that visfatin and BNP immunoreactivity was diffusely observable in left ventricular myocytes of the MI mice. This study indicates that plasma visfatin levels are significantly higher in STEMI patients and that these higher visfatin levels correlate with elevated levels of cardiac enzymes, suggesting that increased plasma visfatin may be closely related to the degree of myocardial damage.     

Atrial natriuretic peptide levels during development of chronic heart failure after myocardial infarction in rats

Serum levels of atrial natriuretic peptide (ANP) are elevated in chronic heart failure presumably due to dilatation of the left atrium resulting from increases in intracardiac pressures. To define the time course of changes in serum ANP levels and to determine the relationship to left ventricular end-diastolic pressure, rats were subjected to coronary artery ligation to produce myocardial infarction and left ventricular failure. Atrial natriuretic peptide levels were measured weekly for four weeks thereafter. In rats with myocardial infarction and elevation of left ventricular end-diastolic pressure there was no change in ANP levels at 7 and 14 days. However, at day 21 and 28, ANP levels were elevated more than 3 fold. There was a correlation between ANP levels and left ventricular end-diastolic pressures. There was no correlation between ANP levels and right atrial pressures or serum sodium concentrations. We conclude that the chronic elevation of left ventricular end-diastolic pressure is required to produce an increase in ANP after myocardial infarction which results in chronic heart failure.     

Decreased arterial responses in WHHL rabbits, an animal model of spontaneous hypercholesterolemia and atherosclerosis.

We examined changes in blood pressure and blood flow of the arteries of WHHL and Japanese white rabbits after intravenous bolus injections of acetylcholine (3.0 micrograms/kg), bradykinin (0.5 microgram/kg), and sodium nitroprusside (3.0 micrograms/kg) under a condition of anesthesia. These vasodilators lowered the blood pressure and increased the blood flow in WHHL and Japanese white rabbits. The changes in the hemodynamic parameters of WHHL rabbits after injection of sodium nitroprusside were similar to those of Japanese white rabbits. This suggests that the relaxation response of the tunica media was not diminished in WHHL rabbits. In contrast, the changes in the hemodynamic parameters of WHHL rabbits after injection of acetylcholine or bradykinin were significantly lower than those in Japanese white rabbits. In the histopathological and immunohistological examination, atherosclerotic lesions were observed in the ascending aortas of WHHL rabbits. In the surface of the atheromatous plaques, CD31-positive endothelial cells disappeared partly and the accumulation of RAM-11-positive macrophages was observed in these regions. In addition, plasma NO2- and NO3- levels of WHHL rabbits were significantly lower than those of Japanese white rabbits. These findings suggest that relaxation responses derived from arterial endothelial cells were probably depressed in WHHL rabbits due to dysfunction or denudation of the arterial endothelial cells.     

Preliminary observations on the structure of the medio-intimal area of the rabbit coronary arteries. (A. Observations on 4-month-old rabbits)

The presence of the diffuse intimal thickening (DIT) is commonly considered the structural basis for the early atherosclerotic involvement of the coronary arteries. In the ambit of a systematic morphometric comparison of experimental atherosclerotic plaques of aorta and coronaries, we have studied the coronary medio-intimal junctions of 4 months old rabbits. Both at sub-epicardic and intra-myocardic coronary arteries level we have found fiber structures similar to DIT. These findings may help explaining why coronary atherosclerosis in rabbits does not represent, in the usual experimental models, a lesion particularly severe nor of precocious appearance.     

Coronary vasoconstrictor influence of angiotensin II is reduced in remodeled myocardium after myocardial infarction

The renin-angiotensin system plays an important role in cardiovascular homeostasis by contributing to the regulation of blood volume, blood pressure, and vascular tone. Because AT(1) receptors have been described in the coronary microcirculation, we investigated whether ANG II contributes to the regulation of coronary vascular tone and whether its contribution is altered during exercise. Since the renin-angiotensin system is activated after myocardial infarction, resulting in an increase in circulating ANG II, we also investigated whether the contribution of ANG II to the regulation of vasomotor tone is altered after infarction. Twenty-six chronically instrumented swine were studied at rest and while running on a treadmill at 1-4 km/h. In 13 swine, myocardial infarction was induced by ligation of the left circumflex coronary artery. Blockade of AT(1) receptors (irbesartan, 1 mg/kg iv) had no effect on myocardial O(2) consumption but resulted in an increase in coronary venous O(2) tension and saturation both at rest and during exercise, reflecting coronary vasodilation. Despite increased plasma levels of ANG II after infarction and maintained coronary arteriolar AT(1) receptor levels, the vasodilation evoked by irbesartan was significantly reduced both at rest and during exercise. In conclusion, despite elevated plasma levels, the vasoconstrictor influence of ANG II on the coronary circulation in vivo is reduced after myocardial infarction. This reduction in ANG II-induced coronary vasoconstriction may serve to maintain perfusion of the remodeled myocardium.     

Tying with thread of the rat coronary arteries, a method for the production of experimental coronary stenosis]

A method is described for producing a localized coronary artery stenosis by tieing two threads around the Ramus descendens of the left coronary artery, which produces progressive cell proliferation of the vascular wall. Studies on 102 male Wistar rats (70 experimental and 32 sham-operated control animals) have shown coronary artery stenosis narrowing the lumen by more than 50% (up to and exceeding 90%) to develop after 7 days in 30% of the animals, after 14 days in 75%, and after 21 days (postoperatively) in 100%. In about one-third of the cases subtotal infarction in the supply area of the left coronary artery occured as a result of post-operative damage to the coronary artery with obturating thrombosis. The induction of effective coronary stenosis limiting the coronary reserve offers possibilities for further experimental studies on the role of relative coronary insufficiency in the pathogenesis of myocardial infarction.