Guideline-adherent therapy in patients with acute coronary syndromes. The EPICOR registry in Germany.

BACKGROUND: Representative data on the current management of patients with acute coronary syndromes (ACS) are of high interest. The EPICOR registry aimed to prospectively collect such real-life data with particular focus on antithrombotic drug utilization and outcomes. METHODS: As part of the international prospective EPICOR registry, 29 hospitals in Germany documented 296 patients with ST-elevation myocardial infarction (STEMI)-ACS and 333 with unstable angina or non-STEMI (NSTEMI)-ACS surviving the hospital phase. The statistical analysis was performed in a descriptive manner. The ClinicalTrials.gov identifier is NCT01171404. RESULTS: The mean age of patients was 62 ± 13 years, and 77.4 % were men. Treatment with antithrombotic agents was initiated in the prehospital phase in 50.7 % of STEMI and 33.3 % of NSTEMI patients. During the hospital stay (median 7.0 days), cardiac catheterization was performed in 97.6 %, percutaneous coronary intervention in 85.6 %, thrombolysis in 4.6 %, and coronary bypass surgery in 2.7 % patients. The use of acetylic salicylic acid (ASA) was reported in 95.6 % vs. 96.1 %, clopidogrel in 60.8 % vs. 73.0 %, prasugrel in 45.6 % vs. 22.5 %, any GP IIb/IIIa inhibitor in 52.4 % vs. 18.9 % [any dual combination of ASA+(clopidogrel/prasugrel)in 94.0 vs. 91.0 %], statins in 94.6 % vs. 92.2 %, beta blockers in 96.3 % vs. 94.6 %, and ACE-I/ARB in 91.6 % vs. 87.7 % of STEMI vs. NSTEMI patients, respectively. Combined use of the five drug classes recommended in the guidelines-ASA, P2Y12 antagonists, statin, beta blocker, and ACE-I/ARB-was reported in 81.1 % vs. 69.4 % of STEMI vs. NSTEMI patients, respectively. CONCLUSION: In Germany a high proportion of patients with ACS are treated according to current guidelines, receiving primary revascularization as well as antithrombotic drugs and other agents for prevention of secondary events; associated bleeding complications were less frequent as compared with published registries.

Autoantibodies to HLA B27 in the sera of HLA B27 patients with ankylosing spondylitis and Reiter's syndrome. Molecular mimicry with Klebsiella pneumoniae as potential mechanism of autoimmune disease.

Ankylosing spondylitis (AS) and Reiter's syndrome (RS) both show a strong correlation with the HLA B27 haplotype. We studied whether sharing of homologous amino acid sequences in the HLA B27 antigen with an invading microbe might occur, and if so, what is the biological significance of such homology. In a computer search of the Dayhoff data bank, we found a homology of six consecutive amino acids between HLA B27.1 antigen residues 72-77 and Klebsiella pneumoniae nitrogenase residues 188-193. These shared sequences are hydrophilic, suggesting locations on molecules exposed to the cell surface. Immunochemical analysis showed that 18 of 34 sera from patients with RS (53%) and 7 of 24 sera from patients with AS (29%) contained antibodies that bound to a synthesized peptide sequence representing residues 69-84 of HLA B27.1. In contrast, only 1 of 22 sera from healthy, B27+ controls (5%) contained antibodies to this peptide (p less than 0.01). Sera from three HLA B27- patients with RS did not possess antibodies to the HLA B27 peptide. Additionally, greater than 40% of HLA B27 patients with AS or RS had antibodies to Klebsiella residues 184-193, while none of the normal nonarthritic HLA B27 haplotype subjects did. Our results suggest that an autoimmune response(s) directed against HLA B27.1 may be a pathogenic mechanism in a subset of patients with AS and RS. Further, this response may initially be induced against Klebsiella pneumoniae, a microorganism that shares sequence homology with HLA B27.

Long-term clopidogrel administration following severe coronary injury reduces proliferation and inflammation via inhibition of nuclear factor-kappaB and activator protein 1 activation in pigs.

BACKGROUND: The optimal duration of clopidogrel treatment following percutaneous coronary intervention (PCI) and the patient population that would benefit most are still unknown. In a porcine coronary injury model, we tested two different durations of clopidogrel treatment on severely or moderately injured arteries and examined the arterial response to injury. To understand the molecular mechanism, we also investigated the effects on transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1). MATERIALS AND METHODS: In 24 cross-bred pigs, one coronary artery was only moderately injured by percutaneous transluminal coronary angioplasty (PTCA) and one coronary artery was severely injured by PTCA and subsequent beta-irradiation (Brachy group). Animals received 325 mg aspirin daily for 3 months and 75 mg clopidogrel daily for either 28 days [short-term (ST) clopidogrel group] or 3 months [long-term (LT) clopidogrel group]. RESULTS: After 3 months, the number of proliferating cells per cross-section differed significantly between ST and LT in both injury groups (PTCA(ST) 90.2 +/- 10.3 vs. PTCA(LT )19.2 +/- 4.7, P < 0.05; Brachy(ST) 35.8 +/- 8.4 vs. Brachy(LT) 7.5 +/- 2.0, P < 0.05). Similar results were seen for inflammatory cells (CD3(+) cells): PTCA(ST) 23.5 +/- 3.55 vs. PTCA(LT )4.67 +/- 0.92, P < 0.05; Brachy(ST) 83.17 +/- 11.17 vs. Brachy(LT) 20 +/- 4.82, P < 0.05). Long-term administration also reduced the activity of NF-kappaB and AP-1 by 62-64% and 42-58%, respectively. However, the effects of different durations of clopidogrel administration on artery dimensions were not statistically significant. CONCLUSIONS: Regarding inflammation and transcription factor activity at the PCI site, long-term clopidogrel administration is superior to short-term administration, especially in severely injured arteries. Transferring our results to the human situation, patients with more severely diseased arteries may benefit from a prolonged clopidogrel medication after PCI.

Inhibition of diabetes in BB rats by virus infection.

BB rats serve as a model for human insulin-dependent diabetes mellitus (IDDM), since without insulin treatment, most 60-140-d-old animals die within 1 to 2 wk of developing polyuria, polydypsia, hyperglycemia, and hypoinsulinemia. Lymphoid cells accumulate in the islets of Langerhans and beta cells undergo destruction. We report that inoculation of such BB rats with lymphocytic choriomeningitis virus (Armstrong strain, clone 13) reduces over a prolonged period the incidence of IDDM, normalizes the concentration of blood sugar and pancreatic insulin, prevents the mononuclear cell infiltration in the islets of Langerhans, and for a short time after inoculation alters T lymphocyte subsets. Thus, a virus might be programmed to carry out useful functions.

Molecular mimicry and myasthenia gravis. An autoantigenic site of the acetylcholine receptor alpha-subunit that has biologic activity and reacts immunochemically with herpes simplex virus.

The large majority of patients with the autoimmune disease myasthenia gravis characteristically have detectable antibodies against the acetylcholine receptor (AChR). We used synthetic peptides to identify antibodies in sera of myasthenia gravis patients reactive with the human acetylcholine receptor (HuAChR) alpha-subunit, residues 160-167. Affinity purification of these antibodies, using the HuAChR alpha-subunit 157-170 peptide immobilized on thiopropyl-Sepharose, yielded IgG antibodies that bound to the native AChR and inhibited the binding of alpha-bungarotoxin to the receptor. The HuAChR alpha-subunit 160-167 peptide demonstrated specific immunological cross-reactivity with a shared homologous domain on herpes simplex virus glycoprotein D, residues 286-293, by both binding and inhibition studies. Thus, HuAChR alpha-subunit, residues 160-167, elicits antibodies in myasthenic patients that binds to the native AChR protein and is capable of eliciting a biologic effect. Immunologic cross-reactivity of this "self" epitope with herpes simplex virus suggest that this virus may be associated with the initiation of some cases of myasthenia.

High prevalence of cardiac parvovirus B19 infection in patients with isolated left ventricular diastolic dysfunction.

BACKGROUND: The etiology of left ventricular (LV) isolated diastolic dysfunction often remains unclear. In the present study, we report a strong association between parvovirus B19 (PVB19) genomes and isolated LV diastolic dysfunction. METHODS AND RESULTS: In 70 patients (mean+/-SD age, 43+/-11 years) admitted with exertional dyspnea and/or reduced exercise tolerance despite preserved LV systolic contractility (ejection fraction=68%), isolated diastolic dysfunction was clinically suspected. Patients with classic risk factors for diastolic dysfunction such as hypertension, coronary heart disease, diabetes mellitus, or pulmonary disease had been excluded. Diastolic function was assessed by echocardiography and LV and RV catheterization. Endomyocardial biopsies (EMBs) were analyzed for the presence of storage or infiltrative diseases or myocarditis, including molecular screening for cardiotropic virus genomes. In a substudy of 24 patients who reported atypical angina, coronary endothelial function was additionally investigated with a coronary Doppler flow-wire technique. In 37 of 70 patients (53%), isolated diastolic dysfunction was confirmed as the cause of their clinical symptoms. No evidence for cardiac storage or infiltrative diseases was found in these cases, but in 35 of 37 of these patients (95%), cardiotropic virus genomes were detected in EMBs (P<0.001). PVB19 was the most frequent pathogen in 31 of 37 patients (84%). In a subgroup of 10 patients with diastolic dysfunction and coexisting endothelial dysfunction, all 10 (100%) were PVB19 positive. CONCLUSIONS: PVB19 genomes were predominant in patients with unexplained, isolated diastolic dysfunction. A strong association with the incidence of endothelial dysfunction was obvious, consistent with the hypothesis that PVB19-induced endothelial dysfunction may be a possible pathomechanism underlying diastolic dysfunction.

Outbreak of carbapenem-resistant Acinetobacter baumannii in the intensive care unit: a multi-level strategic management approach.

An outbreak of carbapenem-resistant Acinetobacter baumannii (CRAb) occurred in an interdisciplinary intensive care unit, affecting 10 patients. Within hours of recognition of the spread of CRAb an intervention team was instituted for collection of available data, decision-making, communication and monitoring of all interventions performed, including cohorting, temporary stop of admissions, staff education, and enforcement of infection control measures. An area was defined for cohortation of patients colonized with CRAb, with a separate nursing team and a second set of mobile equipment. New transmissions were no longer observed after only four days into the institution of enhanced infection control measures.

Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio.

BACKGROUND: It is controversial whether myocardial fibrosis in end-stage dilated cardiomyopathy (DCM) is associated with altered collagen type I/type III (Col I/Col III) ratio. METHODS AND RESULTS: Patients with DCM (ejection fraction [EF] <50%, n=12) and with mild global left ventricular dysfunction (EF >50%, n=18) were examined. Col I, Col III, and transforming growth factors-beta1 (TGF-beta1) and -beta2 (TGF-beta2) gene expression in endomyocardial biopsies was evaluated by quantitative competitive reverse transcriptase-polymerase chain reaction (qRT-PCR). Collagen content was quantified after picrosirius red and immunohistological staining and by hydroxyproline assay. In patients with EF <50%, there was a pronounced 2- to 6-fold increase of myocardial Col I mRNA abundance (P<0.01), with a corresponding 1.6-fold increase at the protein level versus that found in patients with EF >50%. The Col III mRNA abundance showed a 2.0-fold increase (P<0.04). There was a relevant shift in the Col I/Col III mRNA ratio for DCM patients (Col I/Col III, 8.2) compared with patients with an EF >50% (Col I/Col III, 6. 4). In addition, total collagen content was increased in patients with EF <50% (n=3) (4.3+/-0.1%) compared with patients with EF >50% (n=8) (2.7+/-0.9%) (P<0.004). The biochemically determined ratio of hydroxyproline/total protein (n=12) was correlated to the Col I mRNA abundance (P<0.05, r=0.77). TGF-beta1 and TGF-beta2 showed elevated myocardial mRNA abundances (1- to 7-fold and 4- to 5-fold, respectively) in DCM patients. CONCLUSIONS: Differential increase of Col I and Col III leads to an increased Col I/Col III ratio in DCM myocardium. Because Col I provides substantial tensile strength and stiffness, this may contribute to systolic and in particular diastolic dysfunction in DCM.

The shift in the myocardial adenine nucleotide translocator isoform expression pattern is associated with an enteroviral infection in the absence of an active T-cell dependent immune response in human inflammatory heart disease.

OBJECTIVES: This study evaluates the relevance of an enteroviral infection and the intramyocardial T-cell immune response for the alteration in the adenine nucleotide translocator isoform transcription pattern (ANTitp) in patients suspected of having myocardial inflammation. BACKGROUND: The ANT, the only mitochondrial carrier for ADP and ATP, plays a significant role in the energy metabolism and is involved in the apoptosis process. Its function and expression were found to be altered in the myocardium of patients with dilated cardiomyopathy and myocarditis. METHODS: The ANTitp was analyzed in endomyocardial biopsies from 53 patients with clinically suspected inflammatory heart disease (csIHD). Enteroviral RNA was detected in the biopsies using the reverse transcripted polymerase chain reaction technique. The activation of the cellular immune system was assessed by the quantification of T-lymphocytes employing immunohistochemistry. RESULTS: The ANTitp was found to be altered in 21 csIHD patients. Enteroviral genome was found in the heart of 71.4% of these patients, but only 37.5% of the patients with a normal ANTitp were virus-positive (p < 0.02). The infiltration with CD3+, CD45R0+ and CD8+ T-cells was substantially lower in myocardial specimens with an altered ANTitp than in biopsies with a normal ANTitp. Combining the data, an altered ANTitp was primarily found in virus-positive heart tissue, which was less infiltrated with lymphocytes or not at all. CONCLUSIONS: An enteroviral infection is linked to changes in the ANT isoform expression in human heart tissue, which shows little or no evidence of an active T-cell dependent immune response. These results make a contribution to a better understanding of the pathophysiology of enterovirus-induced human inflammatory heart disease.

Molecular mimicry between human leukocyte antigen B27 and Klebsiella. Consequences for spondyloarthropathies.

Ankylosing spondylitis and Reiter's syndrome are the two major spondyloarthropathies highly associated with human leukocyte antigen (HLA) B27. Although the development of spondylitis is unclear, it has been hypothesized that HLA-B27 may predispose to spondyloarthropathies via the phenomenon of molecular mimicry. A computer search for homologies between HLA-B27 and microbes revealed a sequence of six consecutive amino acids (glutamine-threonine-aspartic acid-arginine-glutamic acid-aspartic acid) shared by HLA-B27.1 (residues 72 to 77), and Klebsiella pneumoniae nitrogenase (residues 188 to 193). Antibodies raised against a peptide derived from HLA-B27 containing this six-amino-acid sequence cross-reacted with the peptide derived from Klebsiella that contained these six amino acids, and vice-versa. These antibodies also reacted with articular tissues from HLA-B27-positive patients with ankylosing spondylitis. Sera from 53 percent of Reiter's patients and 27 percent of patients with ankylosing spondylitis showed binding to these same peptides. These results suggest that molecular mimicry may have a role in disease development.

Antibody to synthetic somatostatin-28(1-12): immunoreactivity with somatostatin in brain is dependent on orientation of immunizing peptide.

Rabbits were immunized with synthetic peptides representing the neurotransmitter dodecapeptide somatostatin-28(1-12) (SANSNPAMAPRE) coupled to the carrier protein keyhole limpet hemocyanin (KLH) at either the amino or the carboxyl terminus. Although all rabbits produced high-titer antisera to immunizing peptide, as assayed by ELISA, only rabbits immunized with peptide coupled to carrier at the amino terminus yielded antibodies that bound to native somatostatin in mouse brain slices. This effect of peptide coupling orientation on epitope specificity of peptide antisera is likely to be significant to other investigators who use predetermined peptide sequences to generate immunohistochemical reagents.

The role of sensitized T-cells in myocarditis and dilated cardiomyopathy.

Enteroviruses like coxsackie are known to cause myocarditis both in animals and humans and enteroviral genom was found in endomyocardial biopsies of patients with myocarditis and dilated cardiomyopathy. However, subsequent to the initial viral infection, immune mechanisms seem to play an important role in the pathogenesis of both diseases. Using synthetic peptides, it was possible to identify T-cell epitopes of coxsackie B3 virus and to test their significance in the pathogenesis of myocarditis in the animal model. The T-cell response against coxsackie virus and autoantigens like the adenine nucleotide translocator is also present in the human disease, since sensitized T-cells can be cultured from about 50% of endomyocardial biopsies of patients with myocarditis and dilated cardiomyopathy. The significance of the cellular immune responses in the human disease can be demonstrated by the transfer of peripheral blood leukocytes of patients with chronic myocarditis into severe combined immune deficiency mice that develop human cellular infiltrates of the myocardium and an impairment of the left ventricular function within 60 days. Thus, these results show the presence and importance of cellular immune responses in the pathogenesis of myocarditis and dilated cardiomyopathy.

[Supporting primary stent implantation by angiographic length measurement]. / Unterstützung der primären Stentimplantation durch angiographische Längenmessung.

In this study a procedure for online measurement of a coronary segment length during primary stenting is presented. The spatial segmental axis is calculated from a biplane angiogram and the corresponding projection data by simple delineation of the proximal and distal segment sites in each image. In a clinical evaluation the length error, projectional foreshortening and time frame during measurement of 222 stents or carrier balloons were calculated. The overall percentage length error was 3.3(+)-2.4%. The device length imaged with a mean projectional foreshortening of 18(+)-20% was measured within 18(+)-4 s. The procedure yields the accurate length of coronary segments within a short computation time taking projectional foreshortening into account.

[Severe encephalopathy after taking a "phytopharmacon" from Vietnam]. / Schwere Enzephalopathie nach Einnahme eines "Phytopharmakons" aus Vietnam.

HISTORY: A 59-year-old woman went into coma after she had taken a phytopharmacon from Vietnamese generally used as an antidiabetic drug to treat her skin disease. INVESTIGATIONS: CT-scans revealed signs of pneumonia and cerebral edema. Severe brain damage was diagnosed by MRI-investigation. By chemical-toxicological analysis of the drug glibenclamide was identified in a concentration of 1.1 mg/g. DIAGNOSIS, TREATMENT AND COURSE: The patient developed severe irreversible encephalopathy. By neurorehabilitative treatment her physical status slightly improved, but she died after 13 months without regaining consciousness. CONCLUSIONS: The cause of losing consciousness remained unclear, however, severe hypoglycaemia following the use of the drug may be taken into account. An urgent warning against the use of such preparations is highly recommended.

Abrogation of diabetes in BB rats by acute virus infection. Association of viral-lymphocyte interactions.

The BB rat spontaneously develops an insulin-dependent diabetes mellitus (IDDM) that closely resembles this disease in man. The pathogenesis involves autoimmune destruction of pancreatic beta-cells. In the present study, inoculation of diabetes-prone BB rats at 30 days of age with a lymphotropic variant of lymphocytic choriomeningitis virus significantly reduced the incidence of diabetes. Such virus-inoculated, diabetes-free rats had normal levels of pancreatic insulin and little or no mononuclear cell infiltration in the islets. Virus was recovered from lymphocytes by cocultivation with permissive cells. In contrast, virus was not detected in a wide variety of organs, indicating that infection in BB rats was primarily lymphotropic. PBL analyzed by FACS and monoclonal markers showed a marked reduction of pan-T. Th, and T suppressor/cytotoxic lymphocyte subsets restricted to 4 and 7 days after infection when compared with numbers of lymphocytes in uninoculated diabetes-prone rats. To prevent IDDM, replicating virus was required, because the expected incidence of IDDM in diabetes prone rats inoculated with UV-inactivated virus was equivalent to that of untreated animals. These results suggest that a virus can suppress the autoimmune response that would otherwise have caused IDDM and may be useful as a probe in dissecting the molecular basis of this autoimmune disorder.

[Thrombolysis in ST-elevation myocardial infarction. Current role in the light of recent studies]. / Thrombolyse bei ST-Hebungsinfarkt. Aktueller Stellenwert im Licht neuerer Studien.

As acute percutaneous interventions are only performed in about 20% of patients in Germany, thrombolysis will continue to play an essential role in the treatment of ST-elevation infarction. There is no real alternative to thrombolysis in hospitals without catheter facilities or with long transport times, especially for patients with a short duration of symptoms. Prehospital thrombolysis is widely underused despite its proven efficacy and safety. This is especially the case with respect to mortality of patients with symptoms <3 h, where thrombolysis seems to be at least as effective as or even superior to percutaneous coronary intervention (PCI) with respect to mortality (most probably by avoiding cardiogenic shock). "Facilitated PCI", i.e. thrombolysis +/-Gp IIb/IIIa receptor blocker and consecutive routine PCI is attractive and may be an option for the future. However, the logistic burden and problems of availability of EMS have not yet been investigated. Also, the principal value of "rescue PCI"still needs to be clarified. Moreover, defining simple clinical parameters which help to detect ineffective thrombolysis as well as time windows for detection and consecutive rescue intervention are urgent tasks for the near future. In order to guarantee an optimized and individualized therapy for the patient with acute myocardial infarction, peripheral hospitals, intervention centres and emergency medical services should set up networks, which consider the local resources, time lines and the specific conditions of the patient.

High efficiency immunoaffinity purification of anti-peptide antibodies on thiopropyl sepharose immunoadsorbants.

Antibodies to peptides are routinely made by immunizing animals with peptide linked to a carrier protein such as keyhole limpet hemocyanin (KLH) or bovine serum albumin (BSA) via a disulfide bond. The majority of such a polyclonal antibody response is directed against the carrier protein. The presence of such background antibodies often complicates efforts to characterize the desired anti-peptide antibody; hence it is desirable to isolate the specific fraction of immunoglobulin reactive against the peptide of interest. We describe here a simple and efficient technique to purify anti-peptide antibodies from such sera using commercially available reagents. Peptide antigen with a carboxy or amino terminal cysteine is coupled to thiopropyl Sepharose via a disulfide linkage. The bond between peptide and propyl group on Sepharose was stable at neutral and acidic pHs, and affinity bound anti-peptide antibodies were eluted from the column at low pH (pH 3.0). This procedure permits purification of anti-peptide antibodies, separating them from usually high-titered antibodies to the carrier protein. We describe the application of this method for purification of antibodies to two peptides derived from the glycoprotein sequence of lymphocytic choriomeningitis virus, as well as sequences derived from the human acetylcholine receptor.