Early alterations of myocardial blood flow reserve in heart transplant recipients with angiographically normal coronary arteries.

BACKGROUND: The evaluation of the coronary reserve provides valuable information on the status of coronary vessels. Therefore, we studied with positron emission tomography (PET) and 13N-ammonia the myocardial blood flow (MBF) reserve in heart transplant recipients free of allograft rejection and with angiographically normal coronary arteries early after heart transplantation (HTx). The MBF reserve was calculated as the ratio between MBF after dipyridamole injection and basal MBF normalized for the rate-pressure product. METHODS: Patients were studied within 3 months (group A, n = 12) or more than 9 months (group B, n = 12) after HTx. Five patients have been studied both during the early and late period after HTx. Results were compared to those obtained in 7 normal volunteers (NL). RESULTS: Group A recipients had a significantly lower dipyridamole MBF (in ml/min/100 gr of tissue) than that of group B recipients (142+/-34 vs 195+/-59, p<0.05). This resulted in a significant decrease in MBF reserve early after HTx (group A: 1.82+/- 0.33) and a restoration to normal values thereafter (group B: 2.52+/- 0.53 vs NL: 2.62+/-0.51, p = ns). Separate analysis of 5 patients studied twice is consistent with these results. CONCLUSION: This study shows that in heart transplant recipients free of allograft rejection and with normal coronary angiography, MBF reserve is impaired early after HTx. Restoration within one year suggests that this abnormality does not represent an early stage of cardiac allograft vasculopathy.

Coronary vasomotility and myocardial blood flow early after heart transplantation.

Serotonin constricts coronary arteries with endothelial dysfunction, a common abnormality in cardiac transplant recipients. To assess whether endothelial dysfunction is associated with myocardial blood flow (MBF) abnormalities, 24 patients were studied 1 to 12 months after transplantation. Serotonin in increasing doses (1, 10, and 20 micrograms/min for 2.5 min each) was infused into the coronary circulation. Diameters were measured by quantitative angiography. Fourteen patients (group A) had a pronounced artery constriction (diameter reduction > 40%), while in 10 other patients (group B), such a constriction was never reached. No patient had evidence of rejection and all had angiographically normal coronary arteries. MBF was measured at rest and after intravenous dipyridamole with dynamic nitrogen-13 ammonia positron emission tomography (PET). The resting MBF was higher in group A than in group B (94 +/- 12 vs 74 +/- 15 ml/min/100 g of tissue; p < 0.05). During dipyridamole, MBF was not significantly different (191 +/- 53 vs 184 +/- 64 ml/min/100 g; p = NS). Coronary flow reserve (the ratio of perfusion after dipyridamole to perfusion at rest) was significantly lower in group A than in group B (2.08 +/- 0.54 vs 2.66 +/- 0.57; p < 0.05). Thus, coronary hypersensitivity to serotonin in cardiac transplant recipients is associated with elevated resting MBF and reduced coronary flow reserve. Immune mechanisms inducing endothelial injuries and inflammation-related hyperemia may account for these abnormalities.

Synthesis and evaluation of 3',5'-di-tert-butyl-4'-hydroxyflavones as potential inhibitors of low density lipoprotein (LDL) oxidation.

The novel flavones 6-28, which display structural analogies with the two well-known lipid peroxidation inhibitors, probucol [1] and butylated hydroxytoluene [2], were synthesized and studied in vitro for their ability to inhibit the copper sulfate or endothelial cell-induced lipid peroxidation of human low-density lipoprotein (LDL). Most of the flavones were active in the range of 0.1-1 microM.

Cardiovascular effects of moderate normovolaemic haemodilution during enflurane-nitrous oxide anaesthesia in man.

The cardiovascular effects of mild normovolaemic haemodilution during enflurane-nitrous oxide anaesthesia were studied in 20 patients with normal cardiac function before, during and after total hip replacement. After induction of anaesthesia, patients were randomly allocated to one control group (C), or one haemodiluted group (H) where Hct was decreased to 30% by replacement of blood volume by an identical volume of hydroxyethyl starch 200/05. Each patient was monitored with a pulmonary artery catheter allowing the measurement of right ventricular ejection fraction. During haemodilution, stroke index and right ventricular end-diastolic volume index increased from 33.1 +/- 7.9 to 39.3 +/- 7.1 ml.M-2 and from 73.8 +/- 20.3 to 94.9 +/- 18.5 ml.M-2 respectively (mean +/- s.d., both P < 0.05). However, heart rate decreased so that cardiac index did not change. O2 delivery decreased significantly (from 389 +/- 70 to 311 +/- 63 ml.min-1.m-2; P < 0.05), but was not different to the control group. O2 consumption was maintained by an increase in O2 extraction. During the surgical procedure, cardiac index was higher in the haemodiluted group than in the control group, so that O2 delivery was similar in the two groups. O2 consumption tended to be greater in the haemodiluted group. In patients with normal cardiac function, enflurane-nitrous oxide anesthesia could alter the normal physiologic response to mild normovolaemic haemodilution.

S 12340: a potent inhibitor of the oxidative modification of low-density lipoprotein in vitro and ex vivo in WHHL rabbits.

Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in the formation of foam cells and in the initiation and progression of the atherosclerotic plaque. After evaluation of a large number of original drugs, S 12340 was found to be the most potent compound in inhibiting in a dose-dependent manner the human LDL oxidative modification induced either by copper ions or by cultured endothelial cells. Both the electrophoretic mobility and the thiobarbituric acid reactive substances returned to almost normal values in the presence of 0.5 microM of S 12340. Watanabe heritable hyperlipidemic rabbits were treated orally for 3 days or for 1 month with S 12340 to evaluate the potential protective effect of the compound on LDL oxidative modification induced ex vivo. Purified LDL from placebo and treated rabbits were submitted to oxidation, and S 12340 was effectively able to protect LDL in a dose-dependent manner and at doses as low as 10 mg/kg/day. Purified LDL from animals sacrificed at various times after oral administration of S 12340 were protected against oxidation for at least 6 h after the last administration of the compound. These findings are in good agreement with the plasma and LDL levels of S 12340 in these WHHL rabbits. S 12340, probucol and vitamin E were all able to decrease the optical density of the 1,1-diphenyl-2-picrylhydrazyl solution, demonstrating their free radical scavenging properties. The pharmacological properties of the compound suggest that S 12340 may be of potential interest for a new therapeutic approach to atherosclerosis.

Protective effect of S12340 on cardiac cells exposed to oxidative stress.

Oxidative stress induced by reactive oxygen species is one aspect of the deleterious mechanisms involved in myocardial post-ischemic reperfusion injury. The antioxidant properties of the new molecule S12340 (8-[3-(3,5-diterbutyl-4-hydroxyphenyl-thio)propyl]-1-oxa-2- oxo-3,8-diazaspiro[4.5]decane) were evaluated using three successive in vitro approaches mimicking the cardiac cell damages induced by reactive oxygen species released into the reperfused myocardium. (i) The effects of S12340 on lipid peroxidation were evaluated using an original cell-free model of non-enzymatic peroxidation of 1.32 mM arachidonic acid induced by reactive oxygen species generated photochemically. S12340 (13.2 microM) inhibited by 29% the rate of oxidative fragmentation of monohydroperoxidized arachidonic acid into aldehydic products. (ii) S12340 (10 microM) inhibited by 96% and 58% the oxidative necrosis of cultured rat cardiomyocytes induced by xanthine oxidase (20 mU/ml) and monohydroperoxidized arachidonic acid (30 microM), respectively. (iii) Superfusion of guinea-pig papillary muscle with monohydroperoxidized arachidonic acid (20 microM) resulted in marked alterations of their electrophysiological and mechanical activities. These modifications, maximal 15-17 min after the addition of lipid hydroperoxide, were completely abolished by S12340 (30 microM).

In vitro and ex vivo inhibition of the modification of low-density lipoprotein by indapamide.

The effect of an antihypertensive drug, indapamide, on copper- and endothelial cell-induced peroxidation of human low-density lipoprotein (LDL) was studied and compared with that of drugs previously shown to protect LDL against peroxidation: probucol and vitamin E and other thiazidic and nonthiazidic diuretics (clopamide, hydrochlorothiazide, and furosemide). Incubation with indapamide inhibited in a dose-dependent manner LDL peroxidation induced either by copper ions or by cultured endothelial cells. Both electrophoretic mobility and thiobarbituric acid-reactive substances (TBARS) content of LDL returned to almost normal values in the presence of 1 microM indapamide. This drug was at least 10 times more potent than probucol and vitamin E in inhibiting LDL peroxidation. No inhibitory effect has been observed with clopamide, hydrochlorothiazide, and furosemide in the same experimental conditions. Homozygote Watanabe rabbits were treated orally with indapamide (10 mg/kg/d for 3 days) to evaluate the potential protective effect of the compound on LDL peroxidation in vivo. Purified LDL from placebo and treated rabbits were submitted to peroxidation induced by copper ions, and indapamide was effectively able to protect LDL in these experimental conditions. This effect was especially obvious 6 and 8 h after the start of the incubation when LDL of the placebo-treated animals were modified. The mechanism of action of these drugs was examined in vitro using the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) test and in kinetic studies of arachidonic acid photoperoxidation. Indapamide as well as vitamin E and probucol were effective free radical scavengers, but the other diuretic molecules were not.(ABSTRACT TRUNCATED AT 250 WORDS)

Decrease in enkephalinase A number in kidney membranes from hypercholesterolemic and hypertensive rats.

The variation of enkephalinase A number on the hypertensive and hypercholesterolemia rats kidney membranes is studied using the [3H]-acetorphan, a potent inhibitor of enkephalinase A to label the protease in rat kidney. The binding of [3H]-acetorphan to kidney membrane determined in vitro with both equilibrium and kinetic methods is saturable and reversible involving a single class of sites with a dissociation constant of 4-5.3 nM. The [3H]-acetorphan binding capacity is identical, Bmax approximately 51 pmoles per mg of proteins, for kidney membranes from Sprague Dawley and Wistar Kyoto rats. In contrast, the enkephalinase A number is decreased in the pathological states studied: 20% for hypertensive rats and 50% for hypercholesterolemic rats. Such pharmacological results provide a great deal of information about the modification appeared in the metabolism of peptidic substrates of enkephalinase A in hypercholesterolemia and hypertension.

Calcium antagonists prevent monocyte and endothelial cell-induced modification of low density lipoproteins.

Low density lipoprotein (LDL) incubated in the presence of the calcium antagonists verapamil, nifedipine and flunarizine were more resistant than control LDL to human monocyte- or endothelial cell-induced modification, as assessed by electrophoretic mobility in agarose gel, thiobarbituric acid reactive substance content, and degradation by J774 macrophages. The efficiency of the drugs was: flunarizine greater than nifedipine greater than verapamil. Moreover, a 24 h preculture with calcium antagonists significantly impaired the ability of cells to modify LDL in the absence of the drugs. All the studied drugs also inhibited copper-induced autooxidation of LDL. None of the studied calcium antagonists, at concentrations up to 10(-4) M, significantly reacted with free radicals as assessed by the 1,1-diphenyl-2-picrylhydrazyl test. It is suggested that such a protective effect of calcium antagonists against LDL peroxidation could play a role in the previously reported antiatherogenic effect of these drugs.

High cardiac output as a paraneoplastic syndrome.

A high cardiac output (17 1 min-1) was recorded in a young man suffering from lymphoplasmatocytotic lymphoma. The evolution of the blood disease was characterized by two relapses, during which clinical signs of heart failure were prominent but resolved with efficient blood chemotherapy. The known aetiologies of high cardiac output were excluded. The complete normalization of the cardiac parameters with blood remission suggests that the high cardiac output represented an unusual paraneoplastic syndrome, the pathogenesis of which still remains unknown, although several hypotheses were tested.

Phenothiazines inhibit copper and endothelial cell-induced peroxidation of low density lipoprotein. A comparative study with probucol, butylated hydroxytoluene and vitamin E.

The effect of two phenothiazines, chlorpromazine (CPZ) and trifluoperazine (TFP) on the copper and endothelial cell-induced peroxidation of low density lipoprotein (LDL) has been studied and compared to that of drugs previously shown to protect LDL against peroxidation: probucol (PBC) and butylated hydroxytoluene (BHT). Incubation with CPZ or TFP inhibited in a dose-dependent manner LDL peroxidation induced either by copper ions or by cultured endothelial cells. Both the electrophoretic mobility and the thiobarbituric reactive substance content of LDL returned to almost normal values in the presence of 50 microM CPZ or TFP. The two studied phenothiazines also strongly inhibited the hydrolysis of LDL phosphatidylcholine which accompanies copper or endothelial cell-induced peroxidation of the particle. CPZ and TFP were as effective as PBC and BHT in inhibiting the LDL peroxidation. Whereas copper or endothelial cell-oxidized LDL were recognized and rapidly catabolized by mouse peritoneal macrophages, CPZ- or TFP-, as well as PBC- or BHT-treated LDL were not. Moreover, it was found that, in contrast to vitamin E, neither CPZ nor PBC reacted with model peroxy radicals formed by gamma irradiation of aerated ethanol. The possible mechanisms underlying this protective effect of phenothiazines against LDL oxidative modification are discussed.

Mass concentration of creatine kinase MB isoenzyme and lactate dehydrogenase isoenzyme 1 in diagnosis of perioperative myocardial infarction after coronary bypass surgery.

Recent advances in methodology allow the mass concentration of creatine kinase MB isoenzyme (CK-MB), and of lactate dehydrogenase isoenzyme 1 (LD1) to be determined quickly and easily as routine, emergency tests. We evaluated these tests as diagnostic criteria of perioperative myocardial infarction (PMI) after coronary bypass surgery. These tests were compared with the usual measurements of CK-MB activity by immunoinhibition and LD1 by electrophoresis and with other biological markers of myocardial infarction such as total CK, total LD, and aspartate aminotransferase. Sixty-one patients who underwent coronary bypass grafting were followed pre- and postoperatively by enzyme determinations and electrocardiography; a subgroup was monitored by myocardial scintigraphy. CK-MB mass appeared to be the best marker of PMI during the first 48 h, although LD1 was the marker of choice from days 2 to 4.

[Short- and long-term prognosis of myocardial infarct. Contributions and limitations of the clinical aspects and non-invasive technics]. / Pronostic à court et à long terme de l'infarctus du myocarde. Apports et limitations de la clinique et des techniques non invasives.

Clinical variables and those obtained by non-invasive techniques were recorded in a series of 306 patients discharged from hospital after an acute myocardial infarction. We studied the prognostic value at 2 and 12 months of these variables (alive/dead). The results of simple clinical data were as discriminant as those from more elaborated techniques. When the prognostic value of the same data at 12 months was studied in those surviving for two months, most of the predictive variables lost their discriminant power. The study shows that the predictive value of many of the predischarge variables usually taken into account in the assessment of long term risk, does not extend beyond the first two months.

[MRI of acute myocardial infarction with injection of Gd-DOTA (15 patients)]. / IRM de l'infarctus myocardique aigu avec injection de Gd-DOTA (quinze patients).

We studied 15 patients 4 to 8 days after myocardial infarction by using ECG gated MR before and after administration of 0.2 mmol/kg Gd-DOTA. The diagnosis in each patient was confirmed by electrocardiographic criteria, elevated levels of fractionated creatine kinase (CK) isoenzyme, thallium scintigraphy, ventriculography and coronarography. T1-weighted, spin-echo images, were obtained before and immediately after injection of Gd-DOTA and were repeated 15 min later. The site of infarction was visualised in 10 patients as an area of high signal intensity after the injection of Gd-DOTA. Contrast between normal and infarcted myocardium was greatest 15 min after injection. Three patients were excluded because of failure to acquire adequate MR studies. In 2 other patients, the infarct were not detected. Before injection of Gd-DOTA, only 2 infarcts were detected. These results suggest that Gd-DOTA can improve MR visualisation and detection of acute myocardial infarction.

Daflon 500 mg depresses bradykinin-ischemia-induced microvascular leakage of FITC dextran in rat cremaster muscle.

We studied the in vivo effects of Daflon 500 mg on transvascular movement of macromolecules induced by bradykinin (BK) and ischemia. The experimental preparation involved the rat cremaster muscle. The muscle was fashioned as a single bag (new procedure), placed in a transparent chamber and superfused with a bicarbonate buffer solution equilibrated with a 5% CO2 95% N2 gas mixture in order to obtain pH 7.40, PCO2 = 40 mmHg, PO2 = 20-40 mmHg and thermostated at 35 degrees C. FITC-Dextran 150 (MW 150,000) was injected i.v. as a macromolecular tracer. BK was added to the buffer solution at the concentration of 2 micrograms/ml five minutes after a control period of 60 minutes. Ischemia was performed during 60 min by a clamp positioned on the main artery of the cremaster muscle. Animals treated with Daflon 500 mg (100 mg/kg) 18 and 2 hours before experiments showed a significant reduction in FITC-Dextran 150 leakage in both BK and ischemia protocols. Leakage of FITC-Dextran 150 started 2-3 min after application of BK in the two animal groups but the response was less important (+ 270%) and the preparation returned to control appearance after 40 min in the treated rats in contrast with control rats (+ 450% and 70 min). The amplitude of FITC-Dextran 150 leakage was identical just one hour after ischemia in the two animal groups, but microvascular permeability returned to basal state in treated animals (30 min), a fact non observed in non treated animals. These data demonstrate the protective effect of Daflon 500 mg on the microvascular muscle network in vivo.

Limitations on the prognostic value of predischarge data after myocardial infarction.

Clinical variables and those obtained by non-invasive techniques were studied prospectively in a series of 306 patients discharged from hospital after an acute myocardial infarction. The predictive value of the data at two and 12 months was assessed by univariate and multivariate analyses. The best correlation was found for age, hypertension, bundle branch block, early and late heart failure, x ray cardiothoracic ratio, digoxin use, the number of metabolic equivalents reached during the stress test, echocardiographic wall motion score index, left ventricular end diastolic diameter, left ventricular ejection fraction, and the presence of an aneurysm. The prognostic value of the same data at 12 months was studied in those surviving for two months. There was a noticeable decline in the relative risk of all but two of the factors (number of metabolic equivalents, ventricular arrhythmias). All of the predictive variables except the x ray cardiothoracic ratio, number of metabolic equivalents, and the presence of an aneurysm lost their discriminant power. The explanation for this is the strength of statistical relations of these variables with the outcome at two months. They continued to influence the score at 12 months even when the entire patient series was considered. In conclusion, the study shows that the predictive value of most of the predischarge variables usually taken into account in the assessment of risk in patients one year after infarction does not extend beyond the first two months.