Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized ldl: a possible role for interleukin-6.

The goal of the present study was to elucidate mechanisms for angiotensin II (Ang II) induction of oxidized low density lipoprotein (Ox-LDL) uptake by macrophages, the hallmark of early atherosclerosis. Compared with placebo treatment, Ang II injections (0.1 mL, 10(-7) mol/L per day) for 2 weeks to apolipoprotein E-deficient mice significantly increased Ox-LDL degradation, CD36 mRNA expression, and CD36 protein expression by their peritoneal macrophages (MPMs). These effects were abolished by treatment with losartan (5 to 50 mg/kg per day) before Ang II administration. Because no such effect was obtained in vitro, the ex vivo effect of Ang II on macrophage uptake of Ox-LDL could be mediated by a factor that is not expressed at a significant level in vitro. Because Ang II stimulates cellular production of interleukin-6 (IL-6), we analyzed the possible role of IL-6 as a mediator of Ang II-mediated cellular uptake of Ox-LDL by using several approaches. First, incubations of IL-6 with MPM or IL-6 administration in mice increased macrophage Ox-LDL degradation and CD36 mRNA expression. Second, injection of IL-6 receptor antibodies in mice during Ang II treatment reduced macrophage Ox-LDL uptake and CD36 expression compared treatment with Ang II alone. Finally, Ang II treatment of IL-6-deficient mice did not affect their MPM Ox-LDL uptake and CD36 protein levels. Thus, we conclude that a novel mechanism for Ang II atherogenicity, related to macrophage cholesterol accumulation and foam cell formation, may involve its stimulatory effect on macrophage uptake of Ox-LDL, a process mediated byIL-6.

The MB fraction of creatine phosphokinase. An indicator of myocardial involvement in acute pericarditis.

An elevated level of the MB fraction of creatine phosphokinase (CPK) with normal serum myoglobin and normal CPK values was found in a case of acute idiopathic pericarditis. The elevated serum CPK-MB isozyme is suggested to be an indicator of myocardial involvement accompanying acute pericarditis. The normal CPK and serum myoglobin values and the pattern of rapid decrease of CPK-MB level ruled out the possibility of acute myocardial infarction.

The angiotensin-converting enzyme inhibitor, fosinopril, and the angiotensin II receptor antagonist, losartan, inhibit LDL oxidation and attenuate atherosclerosis independent of lowering blood pressure in apolipoprotein E deficient mice.

OBJECTIVE: To investigate the possible mechanisms of the antiatherosclerotic effects of the angiotensin-converting enzyme (ACE) inhibitor, fosinopril, in apolipoprotein (apo) E deficient mice. METHODS: Apo E deficient (E0) mice at the age of 8 weeks received either placebo or a high dose (25 mg/kg/d) of fosinopril supplemented in their drinking water. RESULTS: After 12 weeks of treatment, fosinopril reduced the aortic lesion size by 70%, compared with the placebo group. At this dosage, fosinopril significantly reduced blood pressure from 93 +/- 2 mmHg before treatment to 70 +/- 2 mmHg at the end of the treatment period (P < 0.005). Fosinopril also increased the resistance of the mice plasma low density lipoprotein (LDL) to CuSO4-induced oxidation, as shown by a 90% reduction in the LDL content of malondialdehyde (MDA) and also by a prolongation of the lag time required for the initiation of LDL oxidation (from 100 min in the placebo-treated mice to more than 240 min in the fosinopril-treated mice; P < 0.001). In addition, fosinopril inhibited CuSO4-induced oxidation of LDL that was obtained from the aortas of the treated mice, as shown by an 18% and 37% reduction in the LDL content of lipid peroxides and hydroperoxy-cholesterol linoleate, respectively, compared with the placebo-treated mice (P < 0.01). A low dosage of fosinopril (5 mg/kg/d) that was still adequate to reduce their plasma ACE activity and LDL propensity to lipid peroxidation was insufficient to lower their blood pressure. This dosage also reduced the aortic lesion size in the apo E deficient mice by 40% (P < 0.01). CONCLUSIONS: The antiatherogenic effects of fosinopril in apo E deficient mice are due not only to blood pressure reduction but also to the direct inhibition of angiotensin II-dependent effects, which are probably also associated with the inhibition of LDL oxidation.

Increased uptake of LDL by oxidized macrophages is the result of an initial enhanced LDL receptor activity and of a further progressive oxidation of LDL.

Iron ions were recently shown to induce cellular lipid peroxidation in macrophages, and these oxidized cells can convert native low-density lipoprotein (LDL) to oxidized LDL (Ox-LDL). The present study demonstrates that deoxycholic acid (DCA) and angiotensin II (ANG-II) can also induce oxidative modification of macrophages via metal ions independent mechanisms. Furthermore, incubation of LDL (200 micrograms of protein/ml) for 24 h at 37 degrees C with DCA, ANG-II, as well as FeSO4-induced oxidized macrophages, resulted in oxidative modification of the lipoprotein as evidenced by increased TBARS formation in LDL (by 50, 105, and 258%, respectively), decreased TNBS reactivity (by 45, 56, and 42%, respectively), and increased cellular uptake (by 60, 166, and 230%, respectively). A positive correlation (n = .88) was found between the extent of the cellular lipid peroxidation and the increment in the cellular uptake of the LDL. The oxidative modification of LDL by oxidized macrophages was found to be a progressive process. Incubation of LDL with oxidized macrophages for increasing periods of time up to 24 h resulted in progressive increment in: (1) the electrophoretic mobility of the LDL; (2) the TBARS formation in LDL; (3) the cellular uptake of LDL by the oxidized macrophages via the Ox-LDL receptor. Upon fractionation on a heparin-sepharose column of LDL that was incubated for different periods of time with oxidized macrophages, a gradual increment in the unbound LDL fraction was obtained, up to 72% after 24 h of incubation. During the first hour of LDL incubation with the oxidized macrophages a twofold increase in the cellular uptake of LDL by these cells was detected, although no significant oxidation of the lipoprotein occurred during this short time period. This effect could be attributed to an increased number of LDL receptors on the cell surface of the oxidized macrophages. In conclusion, increased uptake of LDL by oxidized macrophages results from two routes: (1) enhanced uptake via the LDL receptor due to increased LDL receptor activity; (2) lipoprotein uptake via the Ox-LDL receptors due to cellular modification of LDL. Both of these processes lead to macrophage cholesterol accumulation and foam cell formation, and thus contribute to accelerated atherosclerosis under oxidative stress.

Apolipoprotein E-rich HDL in patients with homozygous familial hypercholesterolemia.

Ordinarily, HDL1, a fraction of HDL enriched in apoE, is a minor fraction of plasma, but in human subjects and experimental animals eating diets high in fat and cholesterol and in patients with homozygous familial hypercholesterolemia (HFH) or CETP deficiency, HDL1 (or HDLc) concentrations in plasma are increased. However, little is known about the structures, compositions and metabolic sources of HDL1 in HFH patients. To obtain HDL1 for the study, we surveyed several fractions in the HDL density range for apoE by SDS-PAGE. The ratio of apoE to apoAI in the HDL (d = 1.063-1.21 g/ml) of 8 HFH patients was 0.14 +/- 0.03 compared to 0.03 +/- 0.005 in a control group of 8 normolipidemic subjects (P less than 0.001) suggesting that an apoE-rich fraction indeed was present in increased amounts. ApoE/apoAI ratios of lipoproteins of the density range 1.050-1.090 were even higher at 1.5 and 2.0 in 2 patients compared to 0.4 +/- 0.1 in controls, indicating that this density fraction may be particularly enriched with apoE-rich lipoproteins. By contrast, d = 1.020-1.050 g/ml and d greater than 1.090 fractions contained very little apoE. Therefore, we further characterized the d = 1.050-1.090 g/ml lipoproteins of HFH patients and controls. Fractionation of an d = 1.050-1.090 fraction by concanavalin-A chromatography (CONA) yielded an unbound apoE-rich fraction that contained apoE, apoAI and apoC but no apoB, and a bound LDL-like fraction that contained mostly apoB-100, as determined by SDS-PAGE and by solid phase immunoassays, containing monoclonal antibodies directed against apoB, apoE and apoAI. The apoE/apoAI ratio of the CONA unbound fraction of HFH patients was greater, and the fraction also contained more free cholesterol and phospholipids than the fraction of control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II stimulates macrophage-mediated oxidation of low density lipoproteins.

Increased incidence of myocardial infarction was found in hypertensive patients with high plasma renin activity and increased susceptibility to oxidation was demonstrated in low density lipoprotein (LDL) that was obtained from hypertensive patients. As lipid peroxidation was demonstrated in areas of the atherosclerotic lesion, we sought to analyze the effect of angiotensin II (AN-II) on LDL oxidation, both in vitro and in vivo. Preincubation of J-774 A.1 macrophage-like cell line or mouse peritoneal macrophages (MPM) with AN-II (10(-7) M) for 1 h at 37 degrees C, followed by the addition of LDL for a further 18 h of incubation, resulted in a substantial increase in macrophage-mediated oxidation of LDL (by 55% and 19%, respectively). Similarly, incubation of LDL with MPM harvested from AN-II-injected mice resulted in a substantially increased oxidation of the lipoprotein by up to 90% in comparison to saline-injected mice. Analysis of cellular lipid peroxidation in the MPM themselves, in both the in vitro and the in vivo studies, revealed a 25% or 90% increased macrophage lipid peroxidation, respectively. The mechanism of AN-II-mediated cellular lipid peroxidation involved AN-II binding to its receptor on macrophages as saralasin, an AN-II receptor antagonist, completely inhibited this effect. Inhibitors of phospholipases A2, C and D substantially reduced macrophage lipid peroxidation, suggesting the involvement of phospholipases A2, C and D substantially reduced macrophage lipid peroxidation, suggesting the involvement of phospholipid metabolites in AN-II-mediated macrophage lipid peroxidation, suggesting the involvement of phospholipid metabolites in AN-II-mediated macrophage lipid peroxidation. Extracellular calcium ions, which active phospholipases, were also essential for AN-II-mediated macrophage lipid peroxidation since calcium channel blockers substantially inhibited cellular lipid peroxidation. Finally, the nature of the oxidant and oxygenase involved in AN-II-mediated cellular lipid peroxidation was studied using oxygenase inhibitors. Angiotensin II-mediated macrophage lipid peroxidation was found to involve the action of cellular NADPH oxidase as well as 15-lypoxygenase. We conclude that AN-II stimulates macrophage-mediated mediated oxidation of LDL secondary to cellular lipid peroxidation, and this may have a role in the accelerated atherosclerosis found in hypertensive patients.

Low density lipoprotein isolated from patients with essential hypertension exhibits increased propensity for oxidation and enhanced uptake by macrophages: a possible role for angiotensin II.

In patients with essential hypertension, the increased risk for atherosclerosis is related not only to the blood pressure levels per se, but also to other, unknown, factors. Recent observations have indicated that oxidation of low density lipoprotein (LDL) and macrophage uptake of oxidized LDL are implicated in human atherosclerosis. We tested both the susceptibility of LDL, derived from hypertensive patients, to lipid peroxidation as well as its uptake by macrophages, in comparison with control LDL obtained from healthy subjects. The LDL that was derived from 25 patients with essential hypertension demonstrated increased propensity for lipid peroxidation with a 63%, 91% and 69% elevation in the content of the lipoprotein malondialdehyde, peroxides and conjugated dienes, respectively, in comparison with control LDL. Minimally modified LDL (MM-LDL) (prepared by 6 months' storage of the LDL at 4 degrees C) derived from the hypertensive patients also demonstrated increased lipid peroxidation with a 94%, 130% and 96% elevation in lipoprotein malondialdehyde, peroxides and conjugated dienes, respectively, compared with the control LDL. The susceptibility of the patients' LDL to lipid peroxidation decreased by 32% and 44% (measured as malondialdehyde) after 3 weeks of therapy with the angiotensin converting enzyme inhibitors captopril and enalapril, respectively, with no parallel reduction in the patients' blood pressure. The patients' LDL was shown to contain increased content of lipid peroxides and unsaturated fatty acids, which may explain its increased susceptibility to lipid peroxidation. In vitro experiments revealed that LDL can bind angiotensin II, and that angiotensin II has a stimulatory effect on copper-mediated oxidation of LDL, as well as on LDL degradation by macrophages. These results were secondary to cell-mediated oxidation of the LDL and to its cellular uptake via the scavenger receptor. We conclude that LDL derived from patients with essential hypertension is more susceptible to lipid peroxidation than control LDL, and this may be secondary to angiotensin II stimulation of LDL lipid peroxidation in these patients. Furthermore, this LDL demonstrates enhanced cellular uptake by macrophages in comparison with normal LDL which can also be related to angiotensin II-mediated LDL oxidation. Both these phenomena have been shown to be associated with accelerated atherosclerosis, and thus suggest a new mechanism for increased atherogenecity in hypertensive patients.

Reduced susceptibility of low density lipoprotein (LDL) to lipid peroxidation after fluvastatin therapy is associated with the hypocholesterolemic effect of the drug and its binding to the LDL.

Increased plasma cholesterol concentration in hypercholesterolemic patients is a major risk factor for atherosclerosis. The impaired removal of plasma low density lipoprotein (LDL) in these patients results in the presence of their LDL in the plasma for a long period of time and thus can contribute to its enhanced oxidative modification. In the present study we analyzed the effect of the hypocholesterolemic drug, fluvastatin, on plasma and LDL susceptibilities to oxidation during 24 weeks of therapy. Fluvastatin therapy (40 mg/day for 24 weeks) in 10 hypercholesterolemic patients resulted in 30%, 34% and 22% decrements in plasma levels of total cholesterol, LDL cholesterol and triglycerides, respectively. This effect has been achieved after only 4 weeks of therapy. We next studied the effect of fluvastatin therapy on LDL susceptibility to oxidation in vivo and in vitro. 2.2-Azobis, 2-amidinopropane hydrochloride (AAPH, 100 mM)-induced plasma lipid peroxidation was decreased by 70% and 77% after 12 weeks and 24 weeks of fluvastatin therapy respectively. The lag time required for the initiation of CuSO4 (10 microM)-induced LDL oxidation was prolonged by 1.2- and 2.5-fold, after 12 and 24 weeks of fluvastatin therapy respectively. We next analyzed the in vitro effect of fluvastatin on plasma and LDL susceptibilities to oxidation. Preincubation of plasma or LDLs that were obtained from normal subjects with 0.1 microgram/ml of fluvastatin, caused 20% or 57% reduction in AAPH-induced lipid peroxidation, respectively. Similarly, a 1.6- and 2.7-fold prolongation of the lag time required for CuSO4-induced LDL oxidation was found following LDL incubation with 0.1 and 1.0 microgram/ml of fluvastatin, respectively. To find out possible mechanisms that contribute to this inhibitory effect of fluvastatin on LDL oxidizability, we analyzed the antioxidative properties of fluvastatin. Fluvastatin did not scavenge free radicals and did not inhibit linoleic acid peroxidation. Fluvastatin also did not act as a chelator of copper ions. However, fluvastatin was shown to specifically bind mainly to the LDL surface phospholipids and this interaction altered the lipoprotein charge as evident from the 38% decrement in the electrophoretic mobility of fluvastatin-treated LDL, in comparison to nontreated LDL. The inhibitory effect of fluvastatin therapy on LDL oxidation probably involves both its stimulatory effect on LDL removal from the circulation, as well as a direct binding effect of the drug to the lipoprotein. We thus conclude that the antiatherogenic properties of fluvastatin may not be limited to its hypocholesterolemic effect, but could also be related to its ability to reduce LDL oxidizability.

Angiotensin II atherogenicity in apolipoprotein E deficient mice is associated with increased cellular cholesterol biosynthesis.

Angiotensin II (Ang II) was shown to be an important risk factor for accelerated atherosclerosis. Inhibition of Ang II action on the arterial wall by blocking its production with angiotensin converting enzyme (ACE) inhibitors, or by blocking binding to its receptors on cells with antagonists was shown to attenuate atherogenesis in animal model of atherosclerosis. We questioned whether Ang II atherogenicity is related to a stimulatory effect of Ang II on macrophage cholesterol biosynthesis. Angiotensin II injected intraperitoneally once a day (0.1 ml of 10(-7) M per mouse) for a period of 30 days, to the apolipoprotein E deficient mice increased the atherosclerotic lesion area by 95% (P < 0.01 vs. control), compared to placebo-injected mice, with no significant effect on blood pressure or on plasma cholesterol levels. On using mouse peritoneal macrophages (MPMs) that were harvested after intraperitoneally injection of Ang II, an increased rate of cellular cholesterol biosynthesis (measured as incorporation of [3H]acetate into cholesterol) by up to 90% (P < 0.01 vs. control) was observed. In mice treated with the ACE inhibitor, Fosinopril (25 mg/kg per day) a reduction in their MPM's cholesterol synthesis by up to 70% (P < 0.01 vs. control) was obtained. In vitro studies in human monocyte-derived macrophages (HMDM), in MPMs from control BALB/c mice, and in J-774 A.1 macrophage-like cell line demonstrated up to 44, 34 and 30% stimulation of macrophage cholesterol biosynthesis, respectively, following cell incubation with 10(-7) M Ang II for 18 h at 37 degrees C. The stimulatory effect of Ang II on macrophage cholesterol biosynthesis could be related to its interaction with the macrophage AT1 receptor, as Losartan (10(-5) M), an AT1 blocker, but not PD 123319 (10(-5) M), an AT2 blocker, prevented the stimulatory effect on macrophage cholesterol synthesis. Furthermore, in cells that lack the AT1 receptor (RAW macrophages), Ang II did not increase cellular cholesterol synthesis. Ang II increased macrophage 3-hydroxy-3-methyl glutaryl CoA (HMG CoA) reductase mRNA levels in a dose dependent manner in J-774 A.1 macrophages and in MPM. Losartan, the AT1 receptor antagonist clearly attenuated this mRNA induction. We thus conclude that Ang II stimulation of macrophage cholesterol biosynthesis is related to its interaction with the AT1 receptor, followed by stimulation of macrophage HMG CoA reductase gene expression, which leads to increased cellular cholesterol biosynthesis, and can possibly result in macrophage cholesterol accumulation and foam cell formation.

Polymorphous ventricular tachycardia in acute myocardial infarction.

Polymorphous ventricular tachycardia (VT) is thought to be uncommon in acute coronary heart disease, but its prevalence has not been determined. Seven hundred seventy-one consecutive patients admitted with acute myocardial infarction (MI) were reviewed for the occurrence of this arrhythmia. Nine patients (1.2%) had polymorphous VT. No patient had any of the predisposing factors previously associated with polymorphous VT. The arrhythmia was resistant to multiple drugs, and repeated cardioversion was effective in only 3 patients. Overdrive pacing was ineffective in the 3 patients in whom it was attempted. Verapamil was effective in 3 of 4 patients in whom it was tried. Six patients with polymorphous VT died during hospitalization; the remaining 3 died within 6 months of discharge. It is concluded that, when compared with regular VT, polymorphous VT in MI carries a poor prognosis. When the arrhythmia occurs in the context of acute ischemia, it appears to be more difficult to treat compared with its occurrence due to other predisposing factors. Verapamil, not usually indicated for ventricular arrhythmias, should be tested in a therapeutic trial.

MB isoenzyme of creatine phosphokinase. Indicator of ischemia in coronary arterial disease.

After undergoing a stress test that showed abnormal findings, a patient with severe coronary arterial disease had an elevated concentration of the MB isoenzyme of creatine phosphokinase, in the presence of normal levels of creatine phosphokinase and myoglobin in the serum.

A high carbohydrate-fat free diet alters the proportion of heparin-bound VLDL in plasma and the expression of VLDL-apoB-100 epitopes.

High carbohydrate-fat free diets (CHO-diet) induce the secretion of increased numbers of very-low-density lipoprotein (VLDL) particles and alter the composition and metabolism of VLDL. The aims of this study were to examine VLDL in greater detail, specifically to document any CHO-diet-induced alterations of apolipoprotein B-100 (apoB-100) epitope expression of VLDL, and any changes induced in subclasses of VLDL, as defined by heparin Sepharose chromatography. Fifteen normolipidemic subjects participated in the study by eating a basal typical American diet for 7 days and high carbohydrate diet (85% carbohydrate, less than 1% fat) for another 7 days. The sequence was changed in seven subjects. Fasting blood samples were analyzed for lipoprotein lipid and apoprotein concentrations. Heparin affinity VLDL subclasses were characterized chemically and electrophoretically [sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE)]. Immunoreactivities of apoB in VLDL were tested in solid phase competitive-binding radioimmunoassays (RIAs) using five monoclonal anti-B antibodies that react with defined epitopes of apoB-100. The CHO diet produced consistent increases of plasma triglycerides in all subjects by a mean of 66% and decreases in plasma cholesterol by 18%. ApoB in plasma decreased by 21% and apoA-I by 17%; however, apoE and ApoA-II did not change. VLDL was enriched with triglycerides (55.0% +/- 0.8 v 57.0% +/- 0.7, P less than .05) and apoE (3.7% +/- 0.5 to 5.9% +/- 0.7, P less than .007) and the ratio between apoE and apoC in VLDL increased (0.15 +/- 0.03 to 0.25 +/- 0.03, P less than .002).(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoprotein E and lipoprotein lipase reduce macrophage degradation of oxidized very-low-density lipoprotein (VLDL), but increase cellular degradation of native VLDL.

Oxidized low-density lipoprotein (Ox-LDL) has been shown to be taken up by the macrophage-scavenger receptor at an enhanced rate in comparison to native LDL, with consequent cellular cholesterol accumulation. In the present study, we analyzed macrophage interaction with very-low-density lipoprotein (VLDL) from normolipidemic subjects (N-VLDL) that was oxidized in the presence of 10 mumol/L copper ions. Oxidized VLDL (Ox-VLDL) contained increased conjugated dienes and malondialdehyde (MDA) equivalents and showed increased electrophoretic mobility. Gradual fragmentation of VLDL apolipoproteins (apo) was noted, with apo B-100 being the first to be fragmented, followed by apo E and apo C. Degradation of Ox-VLDL by mouse peritoneal macrophages (MPM) was increased almost twofold in comparison to N-VLDL. Upon incubation of VLDL with lipoprotein lipase (LPL), the LPL-treated lipoprotein demonstrated up to 50% increased degradation by macrophages in comparison to control N-VLDL. However, the degradation of LPL-treated Ox-VLDL was decreased by up to 20% in comparison to control Ox-VLDL. Similarly, the addition of apo E to VLDL enhanced its cellular degradation by 56%, whereas a 20% reduction in the degradation of apo E-treated Ox-VLDL was demonstrated in comparison to nontreated Ox-VLDL. These results showed that LPL and apo E, two important regulatory substances in cellular metabolism of plasma lipoproteins, increased macrophage degradation of native VLDL, but reduced the degradation of Ox-VLDL. These inhibitory effects on macrophage uptake of Ox-VLDL suggest that apo E and LPL may possess antiatherogenic potential.

Angiotensin, LDL peroxidation and atherosclerosis.

Hypertension is a known risk factor for the development of atherosclerosis. However, in most of the studies, no effect of blood pressure reduction was demonstrated on the incidence of coronary artery disease, except in the SHEP study in which it was shown that in older persons, with isolated systolic hypertension, antihypertensive stepped-care drug treatment reduced the incidence of total stroke and major cardiovascular event. In hypertensive patients with elevated plasma renin activity, a 5-fold increased incidence of myocardial infarction was demonstrated. As oxidation of low density lipoprotein (LDL) was suggested to be a major risk factor for atherosclerosis, we studied the relationship between hypertension and LDL oxidation. We demonstrated increased propensity of LDL obtained from hypertensive patients to oxidative modification, in comparison with LDL obtained from normotensive subjects and suggested that angiotensin II (Ang-II) may be involved in this effect. Ang-II was shown to enhance macrophage lipid peroxidation both in vivo and in vitro. This effect was dose-dependent and involved the binding of Ang-II to its receptor on the macrophage surface. In addition, these lipid peroxidized Ang-II-treated macrophages could substantially oxidize LDL. Ang-II was shown to possess additional atherogenic properties such as increasing the activity of the macrophage oxidized LDL receptors. It also binds to LDL, thus leading to the formation of a modified lipoprotein, which is taken up by macrophages at enhanced rate through the scavenger receptor. Inhibition of Ang-II formation by angiotensin converting enzyme inhibitors reduced LDL peroxidation in hypertensive patients as well as in the atherosclerotic apo E deficient mice. The reduction in LDL peroxidation in these mice was accompanied by a 70-90% reduction in the atherosclerotic lesion area. A similar effect in these mice was demonstrated with the Ang-II receptor antagonist, Losartan. Thus, we suggest that Ang-II is involved in the development of atherogenesis in hypertensive patients and inhibition of Ang-II formation or prevention of its interaction with its receptor may attenuate the atherosclerotic process.

Transient electromechanical dissociation in hypertrophic cardiomyopathy.

We describe a patient with hypertrophic cardiomyopathy who experienced several episodes of syncopal attacks, in whom the mechanism was transient electromechanical dissociation.

Non oliguric acute renal failure after treatment with sulfinpyrazone.

Two cases with acute reversible renal failure while receiving sulfinpyrazone after acute myocardial infarction are presented. Sulfinpyrazone 200 mg q.i.d. was started a few days after the myocardial infarction. In both patients BUN and creatinine rose significantly, and returned to previous values when the drug was discontinued. No other known causes of renal failure were present in either of the patients.

Pseudocyst in splenic hilus with splenic vein thrombosis. Case presentation and review.

Pseudocyst of the pancreas involving the spleen is a rare event; occlusion of splenic vein is even rarer. The mortality rate of these complications is high and therefore necessitates early diagnosis. Nuclear medicine, ultrasound and computed tomography are helpful, but definitive diagnosis is done by selective celiac or splenic artery arteriography. A case of splenic vein thrombosis due to pancreatic pseudocyst is presented and the literature on splenic involvement by pseudocyst is reviewed.

Preoperative diagnosis of Mirizzi syndrome.

Mirizzi syndrome is defined as an obstruction of the common hepatic duct by a stone present in the cystic duct or neck of the gallbladder. This entity rarely has been reported, and in only a few cases was the diagnosis made preoperatively. The preoperative diagnosis is of great importance since intraoperative findings may be similar to carcinoma of the extrahepatic biliary system, which requires a different technical approach. Furthermore, unrecognized cholecystobiliary or cholecystoenteric fistula resulting from stone penetration lead to serious postoperative complications, which can be avoided if the condition is properly recognized.

Swallowing induced atrial tachycardia and fibrillation in a patient with a Wolf-Parkinson-White syndrome.

A 56-year-old man with the Wolf-Parkinson-White (WPW) syndrome (type A) is described. His presenting signs were paroxysmal atrial tachycardia and fibrillation induced by swallowing. This supraventricular tachyarrhythmia (SVT) could be abolished by performing the valsalva maneuver or carotid stimulation, and prevented only by treatment with amiodarone.

Regional distribution of the MB isoenzyme of creatine kinase in the human heart.

Human myocardial tissue obtained at autopsy from ten patients was examined for content of the MB isoenzyme of creatine kinase (CK-MB). We wished to determine whether this isoenzyme is distributed homogeneously throughout the heart. In eight cases, there was no history or pathological evidence of heart disease. Two had a history of previous myocardial infarction; in these, tissue was obtained from sites distant from the scar. Difference was found between the CK-MB content of the right atrium and the left atrium, and between the right ventricle and left ventricle. In all cases, the CK-MB content of the right side of the heart significantly exceeded that of the left side of the heart. Statistically significant differences were also found between the CK-MB content of the anterior interventricular septum and that of the posterior septum. These topographical variations in CK-MB content may be related to differences in the density of contractile elements in various parts of the heart and, moreover, are not taken into account in the enzymatic estimation of infarct size.