Left ventricular contractile function after distal protection in primary percutaneous coronary intervention: results from the Drug Elution and Distal Protection in ST-Elevation Myocardial Infarction trial.

BACKGROUND: Coronary intervention (PCI) may result in an increased infarct size. We evaluated the effect of distal protection during PCI for ST-segment elevation myocardial infarction (STEMI) on myocardial function. METHODS: Patients with STEMI were randomly referred within 12 h for PCI with (N = 312) or without distal protection (N = 314). Left ventricular (LV) contractile function was assessed with echocardiography 8 months after PCI. Global LV myocardial wall motion index (WMI) was calculated as the average wall motion score of all myocardial segments. The occurrence of death, nonfatal re-infarction, and stroke 8 months after PCI were also recorded. RESULTS: The occurrence of death, nonfatal re-infarction, and stroke 8 months after PCI was 7.1% after distal protection and 5.7% after conventional treatment (p = 0.17). WMI improved by 4.1% at 8 months in patients treated with distal protection compared to patients receiving conventional PCI (p < 0.01). In myocardium supplied by a culprit artery treated by distal protection regional LV function was 9-11% higher than myocardial regions treated conventionally ( p < 0.02). CONCLUSIONS: Routine use of distal protection during primary PCI is associated with a significant improvement in LV contractile function, with no detectable impact on intermediate term clinical outcome.

Predictors of coronary in-stent restenosis: importance of angiotensin-converting enzyme gene polymorphism and treatment with angiotensin-converting enzyme inhibitors.

OBJECTIVES: This study aimed to clarify the role of the angiotensin-converting enzyme (ACE) gene polymorphism in the development of in-stent restenosis. BACKGROUND: In-stent restenosis occurs after treatment of coronary artery stenosis in 12% to 32% of coronary interventions with stents. Experimental and clinical studies have suggested that the deletion/insertion (D/I) polymorphism of the ACE gene plays a role in this. METHODS: Quantitative coronary angiography before, immediately after and six months after stent implantation were compared in 369 patients, in whom D/I typing of the ACE gene was performed. RESULTS: At follow-up we found no differences between the three genotypes in minimal lumen diameter (homozygotes with two deletion alleles in the ACE gene [DD], 2.20 mm; heterozygotes with one deletion and one insertion allele in the ACE gene [DI], 2.19 mm; and homozygotes with two insertion alleles in the ACE gene [II], 2.25 mm). The corresponding diameter stenoses were: DD: 25%, DI: 27%, II: 27% (p = NS), and the frequency of restenosis (>50% diameter stenosis) was: DD: 15.7%, DI: 11.0% and II: 16.4% (p = NS). Logistic regression analysis identified diabetes (odds ratio [OR]: 3.0, 95% confidence interval [CI]: 1.0 to 8.7), lesion length (OR: 1.1, 95% CI: 1.01 to 1.30) and minimal lumen diameter immediately after the intervention (OR: 0.3, 95% CI: 0.14 to 0.85) as predictors of in-stent restenosis. In a post hoc analysis of patients treated versus those not treated with an ACE-inhibitor antagonist or an angiotensin receptor antagonist, we found an increased frequency of in-stent restenosis in the DD genotypes (40% vs. 12%, p = 0.006). CONCLUSIONS: The D/I polymorphism is not an independent predictor of coronary in-stent restenosis in general, but it may be of clinical importance in patients treated with ACE inhibitors or angiotensin receptor antagonists.

[Clinical studies on glycoprotein IIb/IIIa receptor antagonist]. / Kliniske studier med glycoprotein IIb/IIIa-receptorantagonist.

Platelet activation plays a major role in the pathophysiology of acute coronary syndromes (ACS), and inhibition of platelet function is the basic pharmacological treatment of ACS. Platelet membrane glycoprotein IIb/IIIa inhibitors, a new class of potent antiplatelet agents, have been used in the treatment of ACS, as well as in the prevention of complications after percutaneous coronary interventions. The aim of this article is to describe the potential possibilities of platelet inhibition and to review the pharmacology of glycoprotein IIb/IIIa inhibitors, the results of the clinical trials with these agents, and their current use in the pharmacological treatment of ACS and in relation to percutaneous coronary intervention.

[Secondary prevention of ischemic heart disease. A questionnaire study and suggestions to improved cooperation between hospitals and general practice]. / Sekundaerprofylakse af iskaemisk hjertesygdom. En spørgeskemaundersøgelse og forslag til forbedret samarbejde mellem hospital og almen praksis.

The aim of the present study was to examine the extent of secondary prophylaxis in patients following hospitalization under the diagnosis of ischaemic heart (IHD). Our data were based on hospital records and questionnaires sent to patients admitted to the Cardiological Department, Frederiksberg Hospital, under the diagnosis of IHD during the first six months of 1996. One hundred and twenty-five patients were included, of these 106 answered the questionnaire. We found that overall patients were insufficiently treated with aspirin, beta-blockers and antilipidaemic agents. Measures to reduce smoking and to increase physical exercise were sparse. We concluded that secondary intervention instituted from the Cardiological Department in question was not up to generally agreed standards. Suggestions to improve secondary prophylaxis in patients with IHD are presented. The importance of increased co-operation between hospital, general practitioner and patient is emphasized. A patient-born record designed for this purpose is presented.

On the pathogenesis of IDDM.

A model of the pathogenesis of insulin-dependent diabetes mellitus, i.e. the initial phase of beta-cell destruction, is proposed: in a cascade-like fashion efficient antigen presentation, unbalanced cytokine, secretion and poor beta-cell defence result in beta-cell destruction by toxic free radicals (O2- and nitric oxide) produced by the beta cells themselves. This entire process is under polygenetic control.

Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats.

The monokines interleukin-1 alpha and -beta have been implicated as effector molecules in the immune-mediated pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and glucagon release of rat, mouse and human islets exposed to recombinant human interleukin-1 beta, and on interleukin-1 beta induced changes in blood glucose, serum insulin and serum glucagon levels in Wistar Kyoto rats. The interleukin-1 receptor antagonist reduced the co-mitogenic effect of interleukin-1 beta on mouse and rat thymocytes with a 50% inhibitory concentration of 10- and 100-fold molar excess, respectively. Complete inhibition was obtained with a 100-1,000-fold molar excess. However, at a 100-fold molar excess the interleukin-1 receptor antagonist did not antagonise the potentiating effect of interleukin-1 beta on rat islet insulin accumulation during 3 and 6 h of exposure or of interleukin-1 beta-induced inhibition of insulin release after 24 h. In contrast, interleukin-1 beta-stimulated islet glucagon release was completely antagonised by a 100-fold molar excess of interleukin-1 receptor antagonist. A 10,000-fold molar excess of interleukin-1 receptor antagonist was needed to antagonise interleukin-1 beta stimulatory and inhibitory effects on rat beta-cell function in vitro. A 100-fold excess of interleukin-1 receptor antagonist could not counteract interleukin-1 beta effects on mouse and human beta cells, excluding species difference in the efficacy of the human interleukin-1 receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Involvement of interleukin 1 and interleukin 1 antagonist in pancreatic beta-cell destruction in insulin-dependent diabetes mellitus.

In this review we propose that the balance between the action of interleukin 1 (IL-1) and its natural antagonist IL-1ra on the level of the insulin-producing pancreatic beta-cell may play a decisive role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). We argue that IL-1 potentiated by other cytokines (tumor necrosis factor alpha, interferon gamma) is an important effector molecule involved in both early and late events in the immune-mediated process that leads to beta-cell destruction and IDDM. We also point out that surprisingly high molar excesses of IL-1ra over IL-1 are necessary to block the action of IL-1 on islet beta-cells compared to islet alpha-cells in vitro and in animals. We suggest that the selectivity of beta-cell destruction in IDDM may be conferred on several levels: (1) homing of beta-cell antigen specific T cells, (2) targeted delivery of cytokines by lymphocytic and monocytic cells beta-cells, (3) high molar excesses of IL-1ra over IL-1 needed to prevent IL-1 mediated beta-cell toxicity, (4) increased beta-cell sensitivity to free nitric oxide and oxygen radical formation induced by IL-1 and (5) inadequate oxidative stress response by beta-cells to cytokines. Further studies are needed to establish the in vivo role of an imbalance between the amounts of IL-1 and IL-1ra produced relative to their action in the pathogenesis of IDDM.

Heat shock protein induction in rat pancreatic islets by recombinant human interleukin 1 beta.

Interleukin 1 beta, potentiated by tumour necrosis factor alpha, is cytotoxic to pancreatic Beta cells in vitro. We have hypothesized that interleukin 1 beta induces oxygen free radicals in Beta cells. Since cytotoxicity induced by free radicals and by heat may activate the same cellular repair mechanism (the heat shock response), the aim of this study was to investigate the pattern of protein synthesis in isolated islets after exposure to interleukin 1 beta (150 pg/ml, 24 h), tumour necrosis factor alpha (50 ng/ml, 24 h) heat shock (43 degrees C, 30 min) and H2O2 (0.1 mmol/l, 20 min). By polyacrylamide gel electrophoresis, autoradiography, Western-blot analysis and partial peptide mapping of 35S-methionine labelled islets, interleukin 1 beta was found to induce a 73 kilodalton protein belonging to the heat shock protein family heat shock protein 70, a heat shock protein 90, and haem oxygenase. A minor induction of heat shock protein 73 and haem oxygenase was seen after H2O2. Interleukin 1 beta did not induce heat shock proteins in rat thyroid cells, rat mesangial cells or in human monocytes. Tumour necrosis factor alpha did not induce selective protein synthesis. Pre-exposure of islets to heat, tumour necrosis factor alpha, or H2O2 did not prevent the impairment of glucose-stimulated insulin release seen after 24 h of interleukin 1 beta exposure. The data are compatible with free radical induction by interleukin 1 beta. However, the heat shock response is not specific for oxidative injury, and previous studies have shown discrepant effects as to a protective effect of free radical scavengers against interleukin 1 beta-mediated beta-cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Repetitive exposure of pancreatic islets to interleukin-1 beta. An in vitro model of pre-diabetes?

The slowly progressing loss of glucose tolerance over years before clinical onset of Type 1 (insulin-dependent) diabetes mellitus may be due to repetitive immunological attacks on the pancreatic beta-cell mass. Accordingly, we studied the effects of repetitive exposure of isolated rat pancreatic islets to the beta-cytotoxic immune-mediator interleukin-1 beta. Islets were exposed thrice to 60 U/ml of recombinant interleukin-1 beta for 24 hr. The islets were allowed to recover for 6 d between the interleukin-1 beta exposure periods. After each of the three interleukin-1 beta exposure periods, islet capacity to release insulin was decreased to 12, 6 and 3% of control, respectively, and islet insulin content decreased to 75, 56 and 21%, respectively. After the two recovery culture periods, the capacity for insulin release reversed to 75 and 30% of control, respectively. An increase in islet insulin content was only seen after the first recovery culture. During repetitive as well as long-term (6 d) interleukin-1 beta exposure of islets, medium accumulation of glucagon was either increased or unaffected. In analogy, beta-cells exposed to interleukin-1 beta for 6 d showed ultrastructural signs of degeneration and cytolysis, whereas alpha-cells were intact. In conclusion, interleukin-1 beta injury to beta-cells was partially reversible, but successive episodes of islet interleukin-1 beta exposure were increasingly detrimental; alpha-cell function and structure did not show susceptibility to damage by interleukin-1 beta. These findings may contribute to our understanding of islet cell behaviour before and during onset of Type 1 diabetes.

Not all insulin secretagogues sensitize pancreatic islets to recombinant human interleukin 1 beta.

The purpose of this study was to test the influence of different insulin secretagogues on interleukin 1 beta mediated injury to isolated rat pancreatic islets. Islets were exposed to interleukin 1 beta for 6 days. During exposure, beta-cells were stimulated with glucose (11 mmol/l vs 3.3 mmol/l) or with non-nutrients as tolbutamide (250 mumols/l), iso-butyl 1-methyl-xanthine (50 mumols/l), or glucagon (10 mg/l). At 3.3 mmol/l of glucose, 60,000 U/l of interleukin 1 beta caused an inhibition of medium insulin accumulation to 62 +/- 5% of control from 48 h to 6 days of exposure, whereas islet DNA content was unaffected. At 11 mmol/l of glucose, interleukin 1 beta dose-dependently decreased medium insulin accumulation (e.g. 60,000 U/l of interleukin 1 beta, 12 +/- 3% of control) and islet content of DNA (60,000 U/l of interleukin 1 beta, 60 +/- 8% of control). During beta-cell stimulation with tolbutamide, interleukin 1 beta caused inhibition of insulin accumulation to 36 +/- 9% of control. In contrast, on islets stimulated with iso-butyl 1-methyl-xanthine or glucagon, the effects of interleukin 1 beta were equivalent to those on non-stimulated islets. These differences were paralleled by differences in the interleukin 1 beta effect on islet morphology. In conclusion, high beta-cell activity (as measured by islet insulin release) may increase islet susceptibility to interleukin 1 beta, however, depending upon the intracellular pathway through which insulin secretion is activated.

Interleukin 1 beta increases the cytosolic free sodium concentration in isolated rat islets of Langerhans.

Interleukin 1 (IL-1) exerts both stimulatory and inhibitory (cytotoxic) effects on insulin-producing beta cells in isolated pancreatic islets. Since alteration in ion fluxes is crucial for endocrine cell activation and is a denominator of cell death, and since IL-1 was recently shown to increase the total sodium content in a murine pre-B-lymphocyte cell line, we investigated the effect of recombinant human IL-1 beta (rhIL-1 beta) on the cytosolic free sodium concentration (fNa+i) in rat islets. Furthermore, long-term rhIL-1 beta effects on islet cell function were studied during exposure of islets to amiloride, a blocker of the plasma membrane Na+/H+ exchange. One hour of islet exposure to 60 U/ml of rhIL-1 beta caused a threefold increase in fNa+i in islet cells, and this effect was abolished by depletion of extracellular sodium. Blockade of Na+/H+ exchange with amiloride abolished the inhibitory effect of rhIL-1 beta on insulin release. In conclusion, rhIL-1 beta was found to increase sodium influx in pancreatic islet cells. This might underlie the widespread effects of rhIL-1 beta on beta-cell function and morphology, possibly related to IL-1-mediated toxic free radical formation.

Lack of predictive value of islet cell antibodies, insulin antibodies, and HLA-DR phenotype for remission in cyclosporin-treated IDDM patients. The Canadian-European Randomized Control Trial Group.

The effect of immunosuppression on the humoral immune response to islet autoantigens and exogenously administered insulin and the predictive value of islet cell cytoplasmic antibodies (ICAs), insulin antibodies (IAs), and HLA-DR phenotype for remission during immunosuppression were studied in a prospective randomized double-blind trial of cyclosporin administration in 98 newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients. HLA-DR phenotype and glycosylated hemoglobin were determined at study entry, and insulin requirement, glucagon-stimulated C-peptide, ICAs, and IAs were measured at entry and after 1, 3, 6, 9, and 12 mo of follow-up. Cyclosporin therapy caused significant suppression of the prevalence and serum concentrations of ICAs and IAs. Cyclosporin-treated IDDM patients ICA+ at study entry had higher levels of stimulated C-peptide after 1 mo of study, but the increased beta-cell function was not associated with a higher frequency of insulin-free remission at 1 mo. ICA and IA status at entry did not predict cyclosporin-insulin-free remission as assessed by the prevalence of insulin-free remission or beta-cell function at 3-12 mo of study, and significant decrements in the titers or total disappearance of ICAs were not associated with an increased prevalence or duration of non-insulin-requiring remission or higher stimulated C-peptide values. There was no correlation between the serum levels of ICAs and IAs at entry and beta-cell function at 12 mo of follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Intra-peritoneal administration of interleukin-1 beta induces impaired insulin release from the perfused rat pancreas.

Previous studies have demonstrated a stimulatory effect of interleukin-1 beta (IL-1 beta) on insulin and glucagon release from the perfused rat pancreas, accompanied by selective lysis of 20% of beta-cells as assessed by electronmicroscopy. However, we have not observed an inhibitory action of IL-1 beta on insulin release from the perfused pancreas as shown for isolated islets. To test whether periodical exposure of the endocrine pancreas to circulating IL-1 beta in vivo affects insulin release from the intact perfused pancreas, rats were treated with daily intraperitoneal injections of 4 micrograms IL-1 beta/kg or saline for 5 days. On day 5 the pancreata were isolated 2 h after the last injection and perfused from 0 to 72 min with 11 mmol/l D-glucose and from 72 to 84 min with 20 mmol/l D-glucose. Saline or IL-1 beta was added from 12 to 72 min. In pancreata from animals pre-treated with IL-1 beta glucose-stimulated as well as IL-1 beta potentiated glucose-stimulated insulin release was almost completely abolished. Furthermore, a decline in insulin release was observed at 11 mmol/l D-glucose, in contrast to an increase in insulin release in controls. The total extractable insulin content in pancreata from IL-1 beta pre-treated rats was higher than in pancreata from saline-treated controls. In contrast to the inhibitory effect of in vivo administration of IL-1 beta on beta-cell function glucagon secretion was stimulated. These observations suggest that circulating IL-1 beta is an important modulator of alpha- and beta-cell secretory function in vivo and that IL-1 beta should be considered a contributory pathogenetic factor in the development of insulin-dependent (type 1) diabetes mellitus.

Interaction of beta-cell activity and IL-1 concentration and exposure time in isolated rat islets of Langerhans.

This study was designed to test the hypothesis that target-cell activity influences the degree and time course of interleukin 1 beta (IL-1 beta)-mediated beta-cell impairment in vitro. Functional and morphological studies were performed in cultured newborn rat islets of Langerhans exposed from 6 h to 6 days to 50-2000 ng/L recombinant human IL-1 beta. Beta-Cell activity was modulated by glucose and nonglucose agents (15 mM L-leucine and 10 microM of long-acting somatostatin analogue SMS 201-995). In 11 mM glucose, 2000 ng/L of IL-1 beta caused inhibition of insulin release after approximately 6 h of exposure to IL-1 beta; in 3.3 mM glucose culture, onset of inhibition was delayed by this IL-1 beta concentration until after 48 h of exposure. Similarly, stimulation and suppression of beta-cell function with L-leucine and SMS 201-995, respectively, resulted in acceleration and delay of IL-1 beta-mediated inhibition. The dose-response curve of the IL-1 beta effect was shifted left- and rightward during high and low beta-cell activity, respectively. In analogy, increasing IL-1 beta concentration, exposure time, and beta-cell activity resulted in increasing islet disintegration. Thus, the resting beta-cell is more resistant to IL-1 beta-mediated impairment than the working beta-cell.

Modulation of calcium flux influences interleukin 1 beta effects on insulin release from isolated islets of Langerhans.

The controlled flux of calcium across the cell membrane is intimately linked to the release of insulin from pancreatic beta-cells, but the uncontrolled influx of calcium is a common final denominator of cell death. Because interleukin 1 has been shown to be cytotoxic to beta-cells in isolated rat islets of Langerhans and since interleukin 1 has a calcium ionophore effect on other cell types, this study was designed to test whether alterations of the calcium flux across the beta-cell membrane would influence the effects of interleukin 1 on isolated rat and mouse islets. Further, the cytosolic free Ca2+ concentration was measured by the fura-2 method in rat islets during acute interleukin 1 exposure. Treatment with 10 mumol/l of verapamil (a potent blocker of the voltage-dependent calcium channel) tended to suppress the inhibitory effect of interleukin 1 on insulin release from rat islets, suggesting protection against cytotoxicity. Conversely, a stimulatory effect of interleukin 1 on mouse islets during 6 days of exposure to interleukin 1 was turned into inhibition by high extracellular calcium concentration. Interleukin 1 did not have any acute effect on cytosolic free Ca2+ concentration. In conclusion, interleukin 1 has no specific calcium ionophore effect on beta-cells, but alterations of the calcium flux across the beta-cell membrane influence the functional effects of interleukin 1, suggesting interference with cell function and toxicity, which would likely be accompanied by an uncontrolled influx of calcium.

Interleukin 1 induces new protein formation in isolated rat islets of Langerhans.

It is hypothesized that interleukin 1 induces toxic free radical formation in pancreatic beta-cells leading to beta-cell degeneration and destruction. Therefore, isolated rat pancreatic islets were examined for interleukin 1 and heat shock induced proteins. Afer exposure to human interleukin 1 beta (0.015 to 10 micrograms/1) or heat (40 degrees C) for up to 24 h, islets were labelled with 35S-methionine and solubilized. Islets proteins were analysed by SDS-polyacrylamide gel electrophoresis. By autoradiography it was shown that both interleukin 1 and heat exposure induced the formation of a 70 kD protein. Further, interleukin 1 induced the formation of two proteins of 32 and 80 kD, respectively, which was not seen after heat exposure. Possibly, the 70 kD protein is a member of the heat shock protein 76 family, participating in unspecific cellular defence and maybe free radical scavenging. Other candidates are the superoxide radical scavenging enzyme manganous superoxidedismutase, MHC class II molecules, and heme oxygenase.

Genetically determined differences in newborn rat islet sensitivity to interleukin-1 in vitro: no association with the diabetes prone phenotype in the BB-rat.

This study was designed to investigate whether the genetic predisposition to insulin-dependent diabetes mellitus (IDDM) might be caused by an inherited increased sensitivity of the pancreatic B-cells to immune effector molecules e.g. the monokine interleukin 1 (IL-1), which is selectively cytotoxic to B-cells in vitro. Islets of Langerhans isolated from newborn diabetes prone and diabetes resistant Bio-Breeding rats, as well as from the inbred non-diabetic rat strains Wistar Furth, Brown-Norway and Lewis-Scripps were exposed to 0-1000 ng/l [corrected] of recombinant human IL-1 beta for 7 days. Strain-related differences in the sensitivity to IL-1 were studied by comparing the dose-responses of insulin release at 11 mmol/l glucose and islet light microscopic morphology to varying concentrations of IL-1. Statistical analyses showed a significant impact of strain on B-cell sensitivity to IL-1, Brown-Norway islets being relatively resistant to the action of IL-1. However, the the diabetes prone islets were not more sensitive to the cytotoxic effect of IL-1 than the non-diabetic control strain islets. We conclude that genetic differences in the response to IL-1 exist in vitro, but that this phenomenon is unrelated to the propensity to develop IDDM.