[Antibiotic Stewardship - From Bench to Bedside]. / Antibiotic Stewardship ­ From Bench to Bedside.

The article explains the practical implementation of Antibiotic Stewardship (ABS) in the clinic. With increasing prevalence of resistant bacteria, the medical profession is challenged to critically question and reduce antibiotic prescriptions. ABS programs are designed to support this. In particular, the involvement of clinic management in the ABS has to improve. There has to be a greater awareness of problems associated with antibiotic use and the data about it must be communicated transparently within the hospital. However, there is also a need for training in the medical profession. The pathophysiological understanding as well as the accurate diagnosis of infectious diseases must be improved. Doctors need courage to forego the use of antibiotics. The consensus within a department and a hospital for withholding antibiotics must be strengthened. However, the awareness of sepsis as an emergency needs to be raised as well, and it is important to focus on hygiene issues and not just on the rapid antibiotic therapy. Microbiological pre-analysis is of crucial importance. In this case, fewer swabs, but more meaningful analytical methods, such as blood cultures or invasive probes, must be attempted. Finally, interactions between clinicians, microbiologists and hospital hygienists are of great importance.

Parathyroid hormone gene variant and calcific aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: Calcific aortic stenosis (AS) is the most frequently acquired valvular disease of the elderly in the Western world. A genetic background for AS has been proposed. The deposition of calcium hydroxyapatite is the key problem of valve calcification; vitamin D and parathyroid hormone are major factors in calcium homeostasis. The vitamin D receptor (VDR) gene and parathyroid hormone (PTH) gene variants were selected as candidate genes. METHODS: A total of 538 patients with severe calcific AS (identified echocardiographically) were characterized by left heart catheterization. A group of 536 patients in whom heart disease had been excluded by left heart catheterization served as a control population. The cardiovascular risk profile was assessed, and three gene variants were analyzed, namely VDR rs1544410, VDR rs1073810, and PTH rs6254. RESULTS: Patients with AS were found to have a higher prevalence of the PTH AA genotype (108 +/- 20.1% versus 71 +/- 13.2%; p = 0.007), while the VDR gene revealed a marginal, but statistically non-significant, association. The age and risk profile was similar in both groups. CONCLUSION: To date, the association of the PTH gene variant has been the only positive association studied in patients with AS in a large population. Hence, the polymorphism is within an intron; the molecular mechanisms of altered gene expression should undergo further investigation.

Maternal factor V Leiden mutation is associated with HELLP syndrome in Caucasian women.

OBJECTIVE: There is growing evidence that hypertensive pregnancy complications and other adverse pregnancy outcomes are associated with the presence of inherited or acquired thrombophilias. As hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome is one of the most severe forms of pre-eclampsia we aimed to assess the prevalence of the factor V Leiden, the prothrombin 20210G >A mutation and the methylenetetrahydrofolate reductase (MTHFR) 677C >T polymorphism in women with HELLP syndrome and in their fetuses from the same index pregnancy. DESIGN: The study was performed retrospectively in a case-control design. SAMPLE: Seventy-one mother-child pairs with HELLP syndrome and 79 control mother-child pairs with uncomplicated pregnancies were included in the study. METHODS: Genotyping of the three thrombophilic mutations was performed using the LightCycler technology. The chi-squared test was used for statistical analysis. Main outcome measures were maternal and fetal genotypes and their correlation with clinical parameters. RESULTS: Maternal heterozygosity for factor V Leiden was significantly more prevalent in the HELLP group than in controls (OR 4.45, 95% CI 1.31-15.31). No significant association was observed for maternal prothrombin mutation or MTHFR polymorphism (p=0.894, p=0.189, respectively). The fetal genotype was not associated with HELLP syndrome for any of the three mutations investigated. Analysis of gene-gene interactions and genotype-phenotype correlation with respect to clinical parameters and perinatal outcome revealed no further differences. CONCLUSIONS: Our study confirms that women heterozygous for factor V Leiden have an increased risk of developing HELLP syndrome, while the most frequent mutations of the prothrombin and MTHFR gene do not play a major role in the pathogenesis of HELLP syndrome.

Genetic analysis of the angiotensinogen gene in pre-eclampsia: study of german women and review of the literature.

AIMS: To evaluate the influence of the angiotensinogen (AGT) gene on the individual predisposition to pre-eclampsia, we screened the AGT gene for pathogenic mutations and an association of identified polymorphisms in German women with pre-eclampsia. METHODS: The study population consisted of 67 German primi- and multigravid patients with pre-eclampsia or superimposed pre-eclampsia and 100 controls with uncomplicated singleton pregnancies. The initial screening for mutations was carried out in a subgroup of pre-eclampsia patients by single-strand conformation polymorphism analysis and direct sequencing. RESULTS: Fifteen single nucleotide polymorphisms (SNPs) were detected, of which 14 had been described before. Allelic frequencies of the detected SNPs were estimated in the total study population. Only the promoter polymorphism g.-570C>T was associated with pre-eclampsia (p = 0.038) but after adjustment for multiple testing p was >0.05. The well-known M268T [M235T] polymorphism was not associated with pre-eclampsia. CONCLUSION: Our results do not indicate an association of the AGT gene with pre-eclampsia. Data from previously published studies are conflicting: positive results were reported in at least 4 studies, negative results in 10 studies. A possible influence, if existing at all, is obviously very small. AGT therefore does not play a major role in the etiology of pre-eclampsia.

Prevalence and Strain Characterization of Clostridioides (Clostridium) difficile in Representative Regions of Germany, Ghana, Tanzania and Indonesia - A Comparative Multi-Center Cross-Sectional Study.

Clostridioides (Clostridium) difficile infections (CDI) are considered worldwide as emerging health threat. Uptake of C. difficile spores may result in asymptomatic carrier status or lead to CDI that could range from mild diarrhea, eventually developing into pseudomembranous colitis up to a toxic megacolon that often results in high mortality. Most epidemiological studies to date have been performed in middle- and high income countries. Beside others, the use of antibiotics and the composition of the microbiome have been identified as major risk factors for the development of CDI. We therefore postulate that prevalence rates of CDI and the distribution of C. difficile strains differ between geographical regions depending on the regional use of antibiotics and food habits. A total of 593 healthy control individuals and 608 patients suffering from diarrhea in communities in Germany, Ghana, Tanzania and Indonesia were selected for a comparative multi-center cross-sectional study. The study populations were screened for the presence of C. difficile in stool samples. Cultured C. difficile strains (n = 84) were further subtyped and characterized using PCR-ribotyping, determination of toxin production, and antibiotic susceptibility testing. Prevalence rates of C. difficile varied widely between the countries. Whereas high prevalence rates were observed in symptomatic patients living in Germany and Indonesia (24.0 and 14.7%), patients from Ghana and Tanzania showed low detection rates (4.5 and 6.4%). Differences were also obvious for ribotype distribution and toxin repertoires. Toxin A+/B+ ribotypes 001/072 and 078 predominated in Germany, whereas most strains isolated from Indonesian patients belonged to toxin A+/B+ ribotype SLO160 and toxin A-/B+ ribotype 017. With 42.9-73.3%, non-toxigenic strains were most abundant in Africa, but were also found in Indonesia at a rate of 18.2%. All isolates were susceptible to vancomycin and metronidazole. Mirroring the antibiotic use, however, moxifloxacin resistance was absent in African C. difficile isolates but present in Indonesian (24.2%) and German ones (65.5%). This study showed that CDI is a global health threat with geographically different prevalence rates which might reflect distinct use of antibiotics. Significant differences for distributions of ribotypes, toxin production, and antibiotic susceptibilities were observed.

Systemic and local levels of fetuin-A in calcific aortic valve stenosis.

Calcific aortic valve stenosis, the most frequent heart valve disorder in developed countries, is an actively regulated process with similarities to bone formation. Fetuin-A has recently been identified as a potent circulating inhibitor of calcification. While several studies involving patients with end-stage renal disease have shown an association between low serum fetuin-A and cardiovascular calcification, nothing is known about fetuin-A serum levels in non-renal patients with calcific aortic valve stenosis. Furthermore, while fetuin-A has been localized in calcified areas of atherosclerotic arteries, data about fetuin-A deposition in stenotic aortic valves are unavailable at present. Serum fetuin-A levels were determined in patients with (n=31) and without (n=28) calcified aortic valve stenosis by ELISA. Creatinine and CRP levels were determined and glomerular filtration rate (GFR) was calculated by the MDRD formula. Immunohistochemistry for fetuin-A was performed on human calcified stenotic (n=14) and control (n=8) aortic valves using a monoclonal antibody. Serum fetuin-A levels were lower in patients with calcific aortic stenosis as compared to the control group (1.41+/-0.33 versus 1.57+/-0,27 mg/dl; p=0.046). This difference was particularly evident in individuals with a normal GFR >or=60 ml/min (1.36+/-0.24 versus 1.63+/-0.27 mg/dl; p=0.007). Furthermore, specific staining of fetuin-A was found in stenotic valves but not in healthy control valves. The data suggest a role of fetuin-A in the pathogenesis calcific aortic valve stenosis independently of the renal function and support the concept that mechanisms of calcium homeostasis are involved in the development of calcific aortic stenosis.

A double-blind, randomized, placebo-controlled multicenter clinical trial to evaluate the effects of the angiotensin II receptor blocker candesartan cilexetil on intimal hyperplasia after coronary stent implantation.

BACKGROUND: Preclinical data suggest beneficial effects of angiotensin II receptor blockers (ARBs) on neointima formation after vascular injury. Preliminary clinical data, however, revealed conflicting results. The AACHEN trial was a double-blind, randomized, placebo-controlled clinical multicenter trial to evaluate the effects of candesartan cilexetil on intimal hyperplasia after coronary stent implantation. METHODS: A total of 120 patients (61 +/- 9 years, 83% male) were randomized to receive either 32 mg candesartan cilexetil (active) or placebo starting 7 to 14 days before elective coronary stent implantation. A follow-up angiography including intravascular ultrasound assessment of the target lesion was performed 24 +/- 2 weeks after stent implantation. The primary end point was defined as the difference in neointimal area between groups as assessed by intravascular ultrasound. Secondary end points included differences in angiographic parameters (ie, restenosis rate) and incidence of major cardiac events. RESULTS: The mean stent length measured 15.0 +/- 4.9 mm in the active and 14.6 +/- 5.7 mm in the placebo group (P = .81). There was no significant difference in neointimal area between groups (2.1 +/- 1.0 vs 2.1 +/- 1.5 mm2, P = 1.00), nor were there differences in angiographic end point parameters. Major cardiac event rates were not significantly different between treatment groups (8% vs 11%, P = .75). CONCLUSIONS: High-dose candesartan cilexetil therapy in patients with symptomatic coronary artery disease undergoing coronary stent implantation does not reduce clinical event rates, restenosis rates, or neointimal proliferation after elective stent implantation.

Quantification of aortic valve calcification using multislice spiral computed tomography: comparison with atomic absorption spectroscopy.

OBJECTIVES: Multislice spiral computed tomography (MSCT) allows the in vivo detection of valvular calcification. The aim of this study was to validate the quantification of aortic valve calcification (AVC) by MSCT with in vitro measurements by atomic absorption spectroscopy. METHODS: In 18 patients with severe aortic stenosis, 16 detector row MSCT (SOMATOM Sensation 16, Siemens, Forchheim, Germany with scan parameters as follows: 420 milliseconds tube rotation time, 12 x 0.75 mm collimation, tube voltage 120 KV) was performed before aortic valve replacement. Images were reconstructed at 60% of the RR interval with an effective slice thickness of 3 mm and a reconstruction increment of 2 mm. AVC was assessed using Agatston AVC score, mass AVC score, and volumetric AVC score. After valve replacement, the calcium content of the excised human stenotic aortic valves was determined in vitro using atomic absorption spectroscopy. RESULTS: The mean Agatston AVC score was 3,842 +/- 1,790, the mean volumetric AVC score was 3,061 +/- 1,406, and mass AVC score was 888 +/- 492 as quantified by MSCT. Atomic absorption spectroscopy showed a mean true calcification mass (Ca5(PO4)3OH) of 19 +/- 8 mass%. There was a significant correlation between in vivo AVC scores determined by MSCT and in vitro mean true calcification mass (r = 0.74, P = 0.0004 for mass AVC score, r = 0.79, P = 0.0001 for volumetric AVC score and r = 0.80, P = 0.0001 for Agatston AVC score) determined by atomic absorption spectroscopy. Linear regression analysis showed a significant association between the degree of hydroxyapatite (given in mass%) in the aortic valve and the degree of AVC (R = 0.74, F = 19.6, P = 0.0004 for mass AVC score, R = 0.80, F = 29.3, P = 0.0001 for Agatston AVC score and R = 0.79, F = 27.3, P = 0.0001 for volumetric AVC score) assessed by MSCT. CONCLUSION: MSCT allows accurate in vivo quantification of aortic valve calcifications.

Prevalence of atherosclerosis of the coronary and extracranial cerebral arteries in patients undergoing aortic valve replacement for calcified stenosis.

BACKGROUND AND AIM OF THE STUDY: The study aim was to investigate the coexistence of various atherosclerotic changes in patients with non-rheumatic calcific aortic valve stenosis (AS), since calcific AS shares various clinical risk factors with atherosclerosis. METHODS: In 282 consecutive patients with severe calcific stenosis of a tricuspid aortic valve scheduled for aortic valve replacement, the prevalence of atherosclerotic changes of the coronary and extracranial cerebral arteries were assessed using coronary angiography and Doppler sonography, respectively. RESULTS: The severities of coronary and extracranial cerebral artery atherosclerosis were significantly associated (p = 0.005). The prevalence and severity of both coronary and extracranial cerebral artery atherosclerosis were age-dependent. Coronary or extracranial cerebral artery stenosis was present in 59% and 16% of patients, respectively, while 91% of the study population and all patients aged > 80 years showed atherosclerosis of the coronary and/or extracranial cerebral arteries. CONCLUSION: The data obtained indicated a very high prevalence of atherosclerotic changes in patients with calcific AS, suggesting pathogenetic similarities of both disorders. Routine screening of the extracranial cerebral arteries is warranted in all patients with calcific AS and scheduled for valve replacement.

Lower serum calcium levels are associated with greater calcium hydroxyapatite deposition in native aortic valves of male patients with severe calcific aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the relationship between serum calcium levels and the degree of calcification found in stenotic aortic valves. METHODS: Using atomic absorption spectroscopy, the hydroxyapatite content of 228 excised human stenotic aortic valves was determined and expressed as a percentage of valve mass. Left heart catheterization preceded valve replacement. In addition, serum levels of calcium and creatinine were determined before native calcific aortic valve excision. RESULTS: Valves from male patients contained more hydroxyapatite than those of female patients (26 +/- 9 versus 22 +/- 9 mass%; p < 0.001). Patients presenting with lower serum calcium levels showed a slight trend towards higher levels of valve calcification (r = -0.15, p = 0.026), but this association appeared only within the subgroup of male patients. Male patients with lowest serum calcium levels displayed greatest valvular hydroxyapatite deposition (1st calcium tertiary: 29.5 +/- 8.9 mass% versus 2nd calcium tertiary 26.4 +/- 7.8 mass% versus 3rd calcium tertiary 21.4 +/- 8.9 mass%; n = 122; p = 0.001; r = -0.25; p = 0.006). This association was even more distinct in male patients with normal serum creatinine levels. Furthermore, serum calcium was inversely and significantly associated with serum C-reactive protein in male patients (r = - 0.34; p < 0.001). CONCLUSION: Serum calcium levels appear to be inversely related to valve calcification in patients with severe calcific aortic stenosis (AS). This finding indicates the importance of systemic calcium metabolism in calcific AS, independent of manifest disorders of calcium metabolism or renal function. Interestingly, this association was evident only in male patients, suggesting a gender-dependent pathogenesis.

Additive effects of the chemokine receptor 2, vitamin D receptor, interleukin-6 polymorphisms and cardiovascular risk factors on the prevalence of myocardial infarction in patients below 65 years.

BACKGROUND: Cardiovascular risk factors (CRF) have been associated with myocardial infarction (MI), while the role of genetic risk factors (GRF) remains undetermined. METHODS: Cineventriculograms of 3436 were analyzed for presence of regional function impairment as sign of MI. Genotyping for genetic polymorphism (vitamin D receptor VDR BsmI, interleukin-6 IL6-174 G/C, chemokine receptor 2 CCR2 64 V/I) was performed. CRF were assessed (hypertension, hypercholesterolemia, smoking, and diabetes mellitus). RESULTS: In patients <65 years (n=1946) genotypes (VDR BB, IL6 GC/CC, CCR2 VI/II, defined as GRF) were significantly associated with the presence of MI (BB: OR 1.38, 95%CI 1.07-1.79, p=0.016 GC/CC: 1.28, 95%CI 1.03-1.60, p=0.028 VI/II: 1.49, 95%CI 1.17-1.88, p=0.001). Combining four CRF (14% vs. 21% vs. 27% vs. 31% vs. 38%, p<0.0001) and three GRF (21% vs. 25% vs. 32% vs. 44%, p<0.0001) revealed additive effects on the prevalence of MI. The more combined CRF and GRF were present (from 0 to 7) the higher was the prevalence of MI (11% vs. 12% vs. 21% vs. 27% vs. 30% vs. 34% vs. 59%, p< 0.0001). Age was not associated with MI. In patients > or =65 years (n=1490) the combination of CRF was only weakly associated with MI, while GRF were not. In these patients age was a predictor of MI. CONCLUSION: Certain GRF might have additive but small effects on the disposition for MI before the age of 65. In older patients the tested GRF had no effect, possibly indicating a mechanism of aging rather than a purely genetic determined entity. Given the small effect of the tested genetic polymorphisms the value of testing GRF remains uncertain.

Chemokine receptor (CCR2) genotype is associated with myocardial infarction and heart failure in patients under 65 years of age.

Inflammation is associated with atherosclerosis of coronary arteries. Chemokines have an important role in inflammation. The CCR2 chemokine receptor mediates leukocyte chemoattraction, which is involved in the pathogenesis of coronary heart disease. We prospectively studied 1960 consecutive patients aged under 65 years and referred for a first-time left ventricular catheter. Left heart catheters were analyzed by two independent cardiologists for the presence of myocardial infarction (regional wall motion abnormality) and moderate or severely reduced left ventricular function on cineventriculography and presence of coronary atherosclerosis on angiography. Genotyping for CCR2 V64I polymorphism was performed. The presence of the rare allele of the CCR2 gene was significantly associated with a higher prevalence of myocardial infarction on cinventriculography (32.0% vs. 24.2%, moderately or severely reduced left ventricular function (14.0% vs. 9.5%) and NYHA class III or IV (16.7% vs. 12.2%). The association of the CCR2 genotype with heart failure was not independent of the presence of myocardial infarction in multivariate analysis. There was no association of the CCR2 genotype with coronary atherosclerosis. The CCR2 genotype seems to predispose patients for myocardial infarction before the age of 65 years. The higher prevalence of heart failure in gene carriers with the rare alle might be a consequence of myocardial infarction. If the CCR2 genotype is associated with higher mortality in the general population must be investigated in further studies.

Relationship of five inflammatory gene polymorphisms with morbidity and mortality in 533 patients admitted to an ICU.

BACKGROUND: The aim of this study was to analyze the association of polymorphisms of five candidate genes with the outcome of consecutive patients admitted to a medical ICU. MATERIALS AND METHODS: The study population was prospectively recruited. Inclusion criteria were admission to the ICU and written informed consent by the patients or their relatives. A total of 533 patients were recruited. The morbidity was assessed by SAPS II Score. Outcome data of in hospital mortality and length of ICU and hospital stay were obtained. Genotyping for genetic polymorphisms (CRP 1059, IL1B -511, CTGF -477, CCR2 64VI, IL6 -174) were performed by allele-specific fluorogenic oligonucleotide probes (TaqMan analysis). RESULTS: All of the investigated polymorphisms were not associated with an altered outcome. There was no difference in morbidity and ICU or in-hospital mortality (neither in cross tabs analysis nor in Kaplan Meier or Cox regression analysis including age, gender and diagnosis as covariates) between the different genotypes. CONCLUSIONS: Genotyping of the investigated polymorphism for risk stratification of patients admitted to ICU does not seem to be appropriated.

The Reduction in Antibiotic Use in Hospitals.

BACKGROUND: Over 350 000 patients are treated in German hospitals for sepsis or pneumonia each year. The rate of antibiotic use in hospitals is high. The growing problem of drug resistance necessitates a reconsideration of antibiotic treatment strategies. METHODS: Antibiotics were given liberally in the years 2010 and 2011 in a German 312-bed hospital. Special training, standardized algorithms to prevent unnecessary drug orders, and uniform recommendations were used in 2012 and 2013 to lessen antibiotic use. We retrospectively studied the hospital's mortality figures and microbiological findings to analyze how well these measures worked. RESULTS: Antibiotic consumption fell from 67.1 to 51.0 defined daily doses (DDD) per 100 patient days (p <0.001) from the period 2010-2011 to the period 2012-2013. The mortality of patients with a main diagnosis of sepsis fell from 1% (95/305) to 19% (63/327; p = 0.001), while that of patients with a main diagnosis of pneumonia fell from 12% (22/178) to 6% (15/235; p = 0.038). The overall mortality fell from 3.0% (623/ 20 954) to 2.5% (576/22 719; p = 0.005). In patients with nosocomial urinary tract infections with Gram-negative pathogens (not necessarily exhibiting three- or fourfold drug resistance), the rate of resistance to three or four of the antibiotics tested fell from 11% to 5%. CONCLUSION: Reducing in-hospital antibiotic use is an achievable goal and was associated in this study with lower mortality and less drug resistance. The findings of this single-center, retrospective study encourage a more limited and focused approach to the administration of antibiotics.

Intravascular ultrasonic comparative analysis of degree of intimal hyperplasia produced by four different stents in the coronary arteries.

Intravascular ultrasound studies were performed at angiographic follow-up on 121 native coronary lesions treated with 1 bare metal stent (n = 50), high-dose dexamethasone-eluting stents (n = 18), non-polymer-based paclitaxel-eluting stents (n = 18), or sirolimus-eluting stents (n = 35). Paclitaxel- and sirolimus-eluting stents reduced mean intimal hyperplasia thickness compared with bare metal stents by 49% and 90% (p = 0.048 and p <0.001), respectively, whereas mean intimal hyperplasia thickness treated with dexamethasone-eluting stents was similar to those lesions treated with bare metal stents.

Variants of the CYP11B2 gene predict response to therapy with candesartan.

In a prospective trial, patients with an elevated diastolic blood pressure (above 95 mm Hg) received high-dose (16 mg) or low-dose (8 mg) candesartan in addition to standardised medication. A positive response to treatment was defined as a diastolic blood pressure <85 mm Hg at follow-up. Genotyping for two candidate genes was performed in 116 patients. Genotypes of the CYP11B2 promotor polymorphism significantly predicted a positive response to treatment (CC: 67%; TC: 34%; TT: 21%; p=0.005).

Expected and observed mortality in critically ill patients receiving initial antibiotic therapy.

OBJECTIVE: To evaluate the predictors of mortality in critically ill patients receiving initial antibiotic therapy (IAT; < 48 h after admission). METHODS: Six hundred thirty-one consecutive patients admitted to an intermediate care (IMC) unit were included. IAT was initiated in 227 patients. Laboratory markers, interventions, medications, systemic inflammatory response syndrome (SIRS) and sepsis criteria, length of stay, and hospital mortality as well as expected mortality, based on the SAPSII-expanded score, were assessed retrospectively. Failure of IAT was defined as a rise in C-reactive protein (CRP) or leukocyte count on day 3 compared with the values on admission. RESULTS: Patients with IAT were significantly older (67 ± 14 vs. 64 ± 14 years; p = 0.006) and had a higher prevalence of chronic renal failure (33 vs. 23 %; p = 0.015), chronic obstructive pulmonary disease (COPD; 27 vs. 16 %; p = 0.002), malignoma (17 vs. 9 %; p = 0.007), acute renal failure (11 vs. 4 %; p = 0.001), respiratory failure (22 vs. 7 %; p < 0.001), and a shock index < 1.0 (21 vs. 8 %; p < 0.001). Although patients with IAT did not have significantly different expected mortality compared with patients without IAT (19.2 vs. 14.5 %; p = 0.144), they did have a significantly higher observed mortality (16.7 vs. 3.7 %; p < 0.0001). Based on the number of SIRS criteria (0, 1, 2, or 3-4) or sepsis criteria (no sepsis, sepsis, or severe sepsis) fulfilled, expected mortality (16.4, 18.2, 20.6, or 21.0 %, respectively; p = 0.955/17.5, 18.3, or 23.4 %, respectively; p = 0.689) did not differ in IAT patients. In contrast, observed mortality differed significantly (4.8, 10.6, 20.6, or 29.4 %, respectively; p = 0.029/8.3, 19.7, or 29.3 %, respectively; p = 0.013). Patients who responded to IAT did not differ regarding comorbidities, SIRS or sepsis criteria, but they had a lower observed mortality (11.9 vs. 26.3 %; p = 0.008) than patients who failed to respond to IAT. Central venous lines were more frequently present in patients with failure to IAT when compared with those with response (51 vs. 22 %; p = 0.009). In the subgroup of patients with acute myocardial infarction (AMI), those with IAT (n = 41) were treated less frequently according to the current cardiac guidelines than those without (n = 124) CONCLUSIONS: Patients with IAT have a high morbidity burden and higher observed than expected mortality. The SAPSII-expanded score does not seem to precisely estimate the risk of in-hospital mortality in these patients. Failure of response to IAT was associated with an even higher mortality. Whether central venous lines and nonadherence to cardiac care guidelines influence the mortality of patients with IAT should be investigated in further studies.

Genetic variation at chromosome 1p13.3 affects sortilin mRNA expression, cellular LDL-uptake and serum LDL levels which translates to the risk of coronary artery disease.

BACKGROUND: A single nucleotide polymorphism (SNP) rs599839 located at chromosome 1p13.3 has previously been associated with risk of coronary artery disease (CAD) and with serum levels of low-density lipoprotein cholesterol (LDL-C). A functional link explaining the association of SNP rs599839 with LDL-C levels and CAD risk has not yet been elucidated. METHODS: We analyzed the association of rs599839 with LDL-C in 6605 individuals across a wide age spectrum and with CAD in four case-control studies comprising 4287 cases and 7572 controls. Genome-wide expression array data was used to assess the association of SNP rs599839 with gene expression at chromosome 1p13. Finally, we overexpressed sortilin in transfected cells to study LDL-uptake in vitro. RESULTS: Each copy of the G-allele of rs599839 associated with a decrease of serum LDL-C by 0.14 mmol/L (90% confidence interval (CI) 0.09-0.17 mmol/L, p=2.6 x 10(-11)). Moreover, each copy of the G-allele associated with a 9% decrease of CAD risk (90% CI 4-14%) in the presently studied four case-control samples and with a 13% decrease (90% CI 10-17%, p=2.18 x 10(-9)) in a pooled meta-analysis including recent genome-wide association studies on CAD. The same allele was associated with higher mRNA-expression levels of the multiligand receptor sortilin (log transformed mRNA AA vs. GG=8.31 vs. 8.55; p=0.01). Overexpression of SORT1 cDNA resulted in a significant increase in LDL-particle uptake (+23%, p=0.01). CONCLUSIONS: Rs599839 associates with decreased LDL-C and a lower risk of CAD. Effects appear to be mediated by increased sortilin expression and subsequently enhanced LDL-uptake into cells.