Publications by authors named "Sebastian Appelbaum"

25 Publications

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The INTREST registry: protocol of a multicenter prospective cohort study of predictors of women's response to integrative breast cancer treatment.

BMC Cancer 2021 Jun 23;21(1):724. Epub 2021 Jun 23.

Department of Psychology, Chair of Research Methodology and Statistics in Psychology, Witten / Herdecke University, Witten, Germany.

Background: Cancer registries usually assess data of conventional treatments and/or patient survival. Beyond that, little is known about the influence of other predictors of treatment response related to the use of complementary therapies (CM) and lifestyle factors affecting patients' quality and quantity of life.

Methods: INTREST is a prospective cohort study collecting register data at multiple German certified cancer centers, which provide individualized, integrative, in- and outpatient breast cancer care. Patient-reported outcomes and clinical cancer data of anticipated N = 715 women with pTNM stage I-III breast cancer are collected using standardized case report forms at the time of diagnosis, after completing neo-/adjuvant chemotherapy, after completing adjuvant therapy (with the exception of endocrine therapy) as well as 1, 2, 5, and 10 years after baseline. Endpoints for multivariable prediction models are quality of life, fatigue, treatment adherence, and progression-based outcomes/survival. Predictors include the study center, sociodemographic characteristics, histologic cancer and comorbidity data, performance status, stress perception, depression, anxiety, sleep quality, spirituality, social support, physical activity, diet behavior, type of conventional treatments, use of and belief in CM treatments, and participation in a clinical trial. Safety is recorded following the Common Terminology Criteria for Adverse Events.

Discussion: This trial is currently recruiting participants. Future analyses will allow to identify predictors of short- and long-term response to integrative breast cancer treatment in women, which, in turn, may improve cancer care as well as quality and quantity of life with cancer.

Trial Registration: German Clinical Trial Register DRKS00014852 . Retrospectively registered at July 4th, 2018.
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http://dx.doi.org/10.1186/s12885-021-08468-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220783PMC
June 2021

Low testosterone concentrations and prediction of future heart failure in men and in women: evidence from the large FINRISK97 study.

ESC Heart Fail 2021 Aug 2;8(4):2485-2491. Epub 2021 May 2.

Department for Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany.

Aims: The increased incidence of heart failure in men suggests that endogenous sex hormones might play a role in the development of heart failure, but epidemiological data remain sparse. Here, we evaluated the predictive value of low testosterone levels on future heart failure in the large population-based FINRISK97 study.

Methods And Results: Baseline serum testosterone concentrations were measured in 7855 subjects (3865 men and 3990 women) of the FINRISK97 study. During a median follow-up (FU) of 13.8 years, a total of 564 heart failure events were recorded. The age-adjusted baseline testosterone levels did not differ significantly between subjects developing incident heart failure during FU and those without incident events during FU (men: 16.6 vs. 17.1 nmol/L, P = 0.75; women: 1.15 vs. 1.17 nmol/L, P = 0.32). Relevant statistically significant correlations of testosterone levels were found with high-density lipoprotein cholesterol levels (R = 0.22; P < 0.001), body mass index (R = -0.23; P < 0.001), and waist-to-hip ratio (R = -0.21; P < 0.001) in men, while statistically significant correlations in women were negligible in effect size. In sex-stratified Cox regression analyses, taking age into account, a quite strong association between low testosterone and incident heart failure was found in men [hazard ratio (HR) 1.51 (95% confidence interval, CI: 1.09-2.10); P = 0.020 for lowest vs. highest quarter], but not in women [HR 0.70 (95% CI: 0.49-0.98); P = 0.086 for lowest vs. highest quarter]. Nevertheless, this association turned non-significant after full adjustment including body mass index and waist-to-hip ratio, and testosterone levels were no longer predictive for incident heart failure-neither in men [HR 0.99 (95% CI: 0.70-1.42); P = 0.77 for lowest vs. highest quarter] nor in women [HR 0.92 (95% CI: 0.64-1.33); P = 0.99 for lowest vs. highest quarter]. Accordingly, Kaplan-Meier analyses did not reveal significant association of testosterone levels with heart failure.

Conclusions: Low levels of testosterone do not independently predict future heart failure.
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http://dx.doi.org/10.1002/ehf2.13384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318459PMC
August 2021

Comparison of histomorphometric and radiographic effects of growth guidance with tension-band devices (eight-Plate and FlexTack) in a pig model.

Acta Orthop 2021 06 19;92(3):364-370. Epub 2021 Jan 19.

Department of Pediatric Orthopaedics, Deformity Reconstruction and Foot Surgery, University Hospital Muenster, Germany.

Background and purpose - Temporary hemiepiphysiodesis for growth modulation in skeletally immature patients is a long-known technique. Recently the use of tension-band devices has become popular. This study compares 2 tension-band implants (eight-Plate and FlexTack) regarding their effects on the growth plate.Animals and methods - 12 pigs in 2 equally sized groups (A and B) were investigated. The right proximal medial tibia was treated with either eight-Plate or FlexTack. The left tibia of the same pig was treated with the opposite implant. After 9 weeks all implants were removed. Animals in group B were then hosted for another 5 weeks. Histomorphometric analysis of the growth plate was carried out after 9 and 14 weeks, respectively. Radiographs were taken at implantation, removal, and after 14 weeks.Results - Both tension-band devices achieved a statistically significant and clinically relevant growth inhibition, whereas the effect appeared to be more distinct after the use of FlexTack. Implant-related complications or physeal damage was not observed. After implant removal, rebound phenomenon was radiologically observed in all cases. The growth plates treated with eight-Plate showed a paradox reversal of the zonal distributions, with an increase of the proliferative zones at the previously arrested medial aspect of the physis and a decrease laterally.Interpretation - Both eight-Plate and FlexTack proved to be appropriate devices for growth-guiding treatment. The radiographic evaluation showed a change in angular axes after treatment with each implant, while the correction appeared to be faster with FlexTack. The paradox cartilaginous reaction observed after removal of the eight-Plate might be a histopathological correlate for rebound phenomenon.
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http://dx.doi.org/10.1080/17453674.2021.1873603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231350PMC
June 2021

Iron Metabolism Contributes to Prognosis in Coronary Artery Disease: Prognostic Value of the Soluble Transferrin Receptor Within the AtheroGene Study.

J Am Heart Assoc 2020 05 23;9(9):e015480. Epub 2020 Apr 23.

Department of General and Interventional Cardiology University Heart Center Hamburg Hamburg Germany.

Background Coronary heart disease is a leading cause of mortality worldwide. Iron deficiency, a frequent comorbidity of coronary heart disease, causes an increased expression of transferrin receptor and soluble transferrin receptor levels (sTfR) levels, while iron repletion returns sTfR levels to the normal physiological range. Recently, sTfR levels were proposed as a potential new marker of iron metabolism in cardiovascular diseases. Therefore, we aimed to evaluate the prognostic value of circulating sTfR levels in a large cohort of patients with coronary heart disease. Methods and Results The disease cohort comprised 3423 subjects who had angiographically documented coronary heart disease and who participated in the AtheroGene study. Serum levels of sTfR were determined at baseline using an automated immunoassay (Roche Cobas Integra 400). Two main outcomes were considered: a combined end point of myocardial infarction and cardiovascular death and cardiovascular death alone. During a median follow-up of 4.0 years, 10.3% of the patients experienced an end point. In Cox regression analyses for sTfR levels, the hazard ratio (HR) for future cardiovascular death and/or myocardial infarction was 1.27 (95% CI, 1.11-1.44, <0.001) after adjustment for sex and age. This association remained significant (HR, 1.23; 95% CI, 1.03-1.46, =0.02) after additional adjustment for body mass index, smoking status, hypertension, diabetes mellitus, dyslipidemia, C-reactive protein, and surrogates of cardiac function, size of myocardial necrosis (hs-Tnl), and hemoglobin levels. Conclusions In this large cohort study, sTfR levels were strongly associated with future myocardial infarction and cardiovascular death. This implicates a role for sTfR in secondary cardiovascular risk prediction.
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http://dx.doi.org/10.1161/JAHA.119.015480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428563PMC
May 2020

Cardio-Renal Biomarker Soluble Urokinase-Type Plasminogen Activator Receptor Is Associated With Cardiovascular Death and Myocardial Infarction in Patients With Coronary Artery Disease Independent of Troponin, C-Reactive Protein, and Renal Function.

J Am Heart Assoc 2020 04 17;9(8):e015452. Epub 2020 Apr 17.

Clinic of Cardiology University Heart and Vascular Center Hamburg Hamburg Germany.

Background Risk stratification among patients with coronary artery disease (CAD) is of considerable interest due to the potential to guide secondary preventive therapies. Thus, we evaluated the predictive value of soluble urokinase-type plasminogen activator receptor (suPAR) levels for cardiovascular mortality and nonfatal myocardial infarction in patients with CAD. Methods and Results Plasma levels of suPAR were measured in a cohort of 1703 patients with documented CAD as evidenced by coronary angiography-including 626 patients with acute coronary syndrome and 1077 patients with stable angina pectoris. Cardiovascular death and/or nonfatal myocardial infarction were defined as main outcome measures. During a median follow-up of 3.5 years, suPAR levels reliably predicted cardiovascular death or myocardial infarction in CAD, evidenced by survival curves stratified for tertiles of suPAR levels. In Cox regression analyses, the hazard ratio for the prediction of cardiovascular death and/or myocardial infarction was 2.19 (<0.001) in the overall cohort and 2.56 in the acute coronary syndrome cohort (<0.001). Even after adjustment for common cardiovascular risk factors, renal function and the biomarkers C-reactive protein, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I suPAR still enabled a reliable prediction of cardiovascular death or myocardial infarction with a hazard ratio of 1.61 (=0.022) in the overall cohort and 2.22 (=0.005) in the acute coronary syndrome cohort. Conclusions SuPAR has a strong and independent prognostic value in secondary prevention settings, and thereby might represent a valuable biomarker for risk estimation in CAD.
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http://dx.doi.org/10.1161/JAHA.119.015452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428542PMC
April 2020

A Systematic Review and Meta-Analysis on the Survival of Cancer Patients Treated with a Fermented Viscum album L. Extract (Iscador): An Update of Findings.

Complement Med Res 2020 10;27(4):260-271. Epub 2020 Jan 10.

Institute of Integrative Medicine, Faculty of Health, Witten/Herdecke University, Herdecke, Germany,

Purpose: We aimed at updating the evidence found in controlled studies addressing general and event-free survival of cancer patients treated with the fermented mistletoe extract Iscador.

Methods: The databases Embase, PubMed, CAMbase, Scopus, AMED and Cochrane were searched for clinical studies on cancer patients treated with Iscador. Quality of studies and risk of bias were evaluated according to the Cochrane guidelines and the Newcastle Ottawa Scale. Outcome data were expressed as hazard ratios (HR) and the respective 95% confidence intervals (CI). Meta-analysis was carried out using a random-effects model.

Results: Eighty-two controlled studies met the inclusion criteria, of which 32 with 55 strata provided data for extracting HR and CI. The overall HR was 0.59 (95% CI: [0.53; 0.65], p < 0.0001) in favour of Iscador treatment. Heterogeneity of study results was moderate (I2 = 50.9%; p < 0.0001, τ2 = 0.053). Meta-regression did not reveal significant effects of sample size or study design. However, significant differences were found between cancer entities (p < 0.01), with most pronounced effects in cervical (HR = 0.43) and less pronounced effects in lung cancer (HR = 0.84).

Conclusions: We found almost identical effects on cancer survival based on a broader database of higher quality. However, none of the studies was blinded and, therefore, there might be risk of performance bias. Implications for cancer survivors are as follows: findings indicate that adjuvant treatment of cancer patients with Iscador can be associated with a better survival.
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http://dx.doi.org/10.1159/000505202DOI Listing
April 2021

Do patients of integrative anthroposophic pediatric inpatient departments differ? Comparative analysis to all pediatric inpatients in Germany considering demographic and clinical characteristics.

BMC Public Health 2019 Dec 3;19(1):1623. Epub 2019 Dec 3.

Department of Pediatrics, Gemeinschaftskrankenhaus Herdecke, Gerhard-Kienle-Weg 4, 58313, Herdecke, Germany.

Background: Integrative medicine (IM) is a patient-centered, evidence-based, therapeutic paradigm which combines conventional and complementary approaches. The use of IM in pediatrics has increased in the past two decades and parents' demand for it is growing. An IM whole systems approach is anthroposophic medicine. Considering the growing demand for integrative approaches in children, it is relevant from a public health perspective to find out which kind of children use IM in Germany and whether they differ from the entirety of pediatric inpatients in Germany. Moreover, it would be interesting to known, whether these patients are willing to travel a longer distance to gain integrative treatment.

Methods: The present study investigates the standard ward documentation datasets of 29,956 patients of all German integrative anthroposophic pediatric inpatient wards from 2005 to 2016 and compares them systematically to collect data of the entirety of all pediatric inpatient wards in Germany. Apart from patients' age and gender, and the ICD-10 admission diagnoses, the geographical catchment area of the hospitals were analyzed.

Results: Sociodemographic characteristics of pediatric inpatients in the integrative anthroposophic departments (IAH) did not differ from the entirety of all pediatric inpatients. Regarding clinical characteristics, higher frequencies were found for endocrine, nutritional and metabolic diseases (IAH: 7.24% vs. 2.98%); mental, behavioral, and neurodevelopmental disorders (IAH: 9.83% vs. 3.78%) and nervous diseases (IAH: 8.82% vs. 5.16%) and lower frequencies for general pediatric diseases such as respiratory diseases (IAH: 17.06% vs. 19.83%), digestive diseases (IAH: 3.90% vs. 6.25%), and infectious and parasitic diseases (IAH: 12.88% vs. 14.82%) in comparison to the entirety of all pediatric inpatients in Germany. The IAH showed a broad catchment area, with most patients being from former, Western federal republic of Germany. Large catchment areas (> 100 km) for the IAH are merely covered by severe and chronic diseases.

Conclusion: Pediatric inpatients of IAH do not differ from the entirety of pediatric inpatients in Germany regarding sociodemographic characteristics but show differences regarding clinical characteristics. Parents are willing to travel further distance to get specialized integrative anthroposophic medical care for children with severe and chronic diseases.
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http://dx.doi.org/10.1186/s12889-019-7972-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889203PMC
December 2019

Differential Item Functioning for Boys and Girls in a Screening Instrument for Attention Deficit Hyperactivity Disorder.

Stud Health Technol Inform 2019 Sep;267:3-8

Department for Psychology and Psychotherapy, Witten/Herdecke University, Germany.

Differential item functioning (DIF) indicates differential response probabilities of items for different subgroups. While there is a vast amount of research and literature on DIF in the field of educational screening and career assessment, DIF analysis has hardly been applied in the field of clinical assessment. This paper aims at analyzing the presence of gender related DIF in a cross-sectional survey of children assessed by a structured questionnaire containing items on attention deficit and hyperactivity. A total of 1449 children (mean age: 1.94 ± 0.14 years; 51.2% male) were included. Almost no significant variations in parameters were found between boys and girls. Results based on a Partial Credit Model indicate an absence of DIF in eight out of nine items. Consistent with other studies in attention deficit hyperactivity disorder (ADHD) our results imply that the same level of rating for a symptom has the same meaning for boys and girls.
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http://dx.doi.org/10.3233/SHTI190797DOI Listing
September 2019

Verbal Probabilities: Linear or Logistic? - A Regression Analysis Approach.

Stud Health Technol Inform 2018 ;253:117-121

Department for Psychology and Psychotherapy, Witten/Herdecke University, Alfred Herrhausen-Straße 50, 58448 Witten, Germany.

Verbal probability expressions are quite intuitive and used in a variety of clinical important issues like adverse drug causality appraisal. However, there is insufficient evidence of their numerical meaning and whether they have a linear or logistic relationship with them. We aimed at contributing to answering these questions by means of a comparative regression analysis based on a sample of N=683 participants between 10 and 82 years (mean age 20.33±11.77; median: 18 years) who were asked to numerically rate a given set of sixteen verbal probability phrases on a visual analogue scale. With respect to the explained variance, we found an R2 for the linear model of 0.574 while R2 for the logistic model was only 0.392 indicating a superiority of linear model compared to the logistic model. Although we were able to show that ranked verbal phrases are more likely to behave in a linear that in a logistic way other regression options like the double logistic model should be taken into consideration for further research.
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November 2018

Testosterone Levels and Type 2 Diabetes-No Correlation with Age, Differential Predictive Value in Men and Women.

Biomolecules 2018 08 20;8(3). Epub 2018 Aug 20.

Department of General and Interventional Cardiology, University Heart Center, 20246 Hamburg, Germany.

Most studies reporting on the association of circulating testosterone levels with type 2 diabetes in men are of cross-sectional design. Reports on the relevance of altered testosterone levels in women are scarce. Here, we evaluate the role of low serum testosterone levels for incident diabetes in men and women in a population setting of 7706 subjects (3896 females). During a mean follow up time of 13.8 years, 7.8% developed type 2 diabetes. Significant correlations of testosterone with high density lipoprotein (HDL)-cholesterol ( = 0.21, < 0.001), body-mass-index ( = -0.23, < 0.001), and waist-to-hip-ratio ( = -0.21, < 0.001) were found in men. No correlation was found with age in men; in women, the correlation was negligible ( = 0.04, = 0.012). In men, low testosterone levels predicted high risk of type 2 diabetes, while in women this relationship was opposite. Men with low testosterone levels showed increased risk of future diabetes (hazard ratio (HR) 2.66, 95% confidence interval (CI) 1.91⁻3.72, < 0.001 in basic model; HR 1.56 95%, CI 1.10⁻2.21, = 0.003). In women, low testosterone levels indicated lower risk with (HR 0.53, 95% CI 0.37⁻0.77, = 0.003), while the association lost significance in the fully adjusted model (HR 0.72, 95% CI 0.49⁻1.05, = 0.09). Low levels of testosterone predicted future diabetes in men. A borderline opposite association was found in women.
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http://dx.doi.org/10.3390/biom8030076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165105PMC
August 2018

Prognostic Value of Iron-Homeostasis Regulating Peptide Hepcidin in Coronary Heart Disease-Evidence from the Large AtheroGene Study.

Biomolecules 2018 06 28;8(3). Epub 2018 Jun 28.

Department of General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany.

Iron is essential in terms of oxygen utilization and mitochondrial function. The liver-derived peptide hepcidin has been recognized as a key regulator of iron homeostasis. Since iron metabolism is crucially linked to cardiovascular health, and low hepcidin was proposed as potential new marker of iron metabolism, we aimed to evaluate the prognostic value of hepcidin in a large cohort of patients with coronary heart disease (CHD). Serum levels of hepcidin were determined at baseline in patients with angiographically documented CHD. The main outcome measure was non-fatal myocardial infarction (MI) or cardiovascular death. During a median follow-up of 4.1 years, 10.3% experienced an endpoint. In Cox regression analyses for hepcidin the hazard ratio for future cardiovascular death or MI was 1.03 (95% confidence interval (CI) 0.91⁻1.18, = 0.63) after adjustment for sex and age. This association virtually did not change after additional adjustment for body mass index (BMI), smoking status, hypertension, diabetes, dyslipidemia, and surrogates of cardiac function (NT-proBNP), size of myocardial necrosis (troponin I), and anemia (hemoglobin). In this study, by far the largest evaluating the predictive value of hepcidin, hepcidin levels were not associated with future MI or cardiovascular death. This implicates a limited, if any, role for hepcidin in secondary cardiovascular risk prediction.
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http://dx.doi.org/10.3390/biom8030043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165548PMC
June 2018

Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men, but protective in women - results from the FINRISK study.

Eur J Prev Cardiol 2018 07 29;25(11):1133-1139. Epub 2018 May 29.

1 Department of General and Interventional Cardiology, University Heart Center Hamburg, Germany.

Background Atrial fibrillation is the most common serious abnormal heart rhythm, and a frequent cause of ischaemic stroke. Recent experimental studies, mainly in orchiectomised rats, report a relationship between sex hormones and atrial electrophysiology and electroanatomy. We aimed to evaluate whether low testosterone levels are predictive for atrial fibrillation and/or ischaemic stroke in men and women. Design and methods The serum total testosterone levels were measured at baseline in a population cohort of 7892 subjects (3876 male, 4016 female), aged 25-74 years, using a commercially available immunoassay. The main outcome measure was atrial fibrillation or ischaemic stroke, whichever came first. Results During a median follow-up of 13.8 years, a total of 629 subjects (8.0%) suffered from incident atrial fibrillation ( n = 426) and/or ischemic stroke ( n = 276). Cox regression analyses, adjusted for age (used as time-scale), geographical region, total cholesterol (log), high-density lipoprotein-cholesterol (log), hypertension medication, known diabetes, smoking status, waist-hip-ratio, and time of blood drawn, documented differential predictive value of low sex-specific testosterone levels for atrial fibrillation and/or ischaemic stroke, in men and in women: Increasing levels were associated with lower risk in men (hazard ratio per one nmol/l increase 0.98 (95% confidence interval 0.93-1.00); p = 0.049). On the other hand, increasing testosterone levels were associated with higher risk in women (hazard ratio per one nmol/l increase 1.17 (95% confidence interval 1.02-1.36); p = 0.031). Conclusion Our study indicates that low testosterone levels are associated with increased risk of future atrial fibrillation and/or ischaemic stroke in men, while they are protective in women.
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http://dx.doi.org/10.1177/2047487318778346DOI Listing
July 2018

Circulating microRNAs strongly predict cardiovascular death in patients with coronary artery disease-results from the large AtheroGene study.

Eur Heart J 2017 Feb;38(7):516-523

Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.

Introduction: Stratification for subsequent coronary events among patients with coronary artery disease (CAD) is of considerable interest because of the potential to guide secondary preventive therapies. Recently, we identified eight microRNAs (miRNAs), which facilitated acute coronary syndrome (ACS) diagnosis. In this study, we aimed to evaluate their potential role as prognostic biomarkers for cardiovascular disease.

Methods: The serum concentrations of eight candidate miRNAs -miR-19a, miR-19b, miR-132, miR-140-3p, miR-142-5p, miR-150, miR-186, and miR-210 were measured in a cohort of 1112 patients with documented CAD-including 430 patients with ACS and 682 patients with stable angina pectoris. Cardiovascular death was the main outcome measure.

Results: During a median follow-up of 4.0 years, most miRNAs reliably predicted cardiovascular death in ACS patients. Cox regression analyses indicated that in particular miR-132 (HR 2.85 per 1 SD increase, P = 0.022), miR-140-3p (HR 2.88 per 1 SD increase, P = 0.022), and miR-210 (HR 3.10 per 1 SD increase, P = 0.039) were able to precisely predict cardiovascular death. Circulating miR-132, miR-140-3p, and miR-210 clearly improved various model performance measures, including C-statistics (AUC [area under the receiver-operating characteristic curve] for miR-132: 0.737; AUC for miR-140-3p: 0.756; AUC for miR-210: 0.754).

Conclusions: This is the largest study so far evaluating the prognostic value of circulating miRNAs in cardiovascular disease. Our study shows that single miRNAs derived from peripheral blood predict mortality in secondary prevention settings, and thereby represent valuable biomarkers for risk estimation in CAD.
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http://dx.doi.org/10.1093/eurheartj/ehw250DOI Listing
February 2017

Transcatheter Mitral Valve Repair in Surgical High-Risk Patients: Gender-Specific Acute and Long-Term Outcomes.

Biomed Res Int 2016 2;2016:3934842. Epub 2016 Mar 2.

Department of General and Interventional Cardiology, University Heart Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.

Background: Analyses emphasizing gender-related differences in acute and long-term outcomes following MitraClip therapy for significant mitral regurgitation (MR) are rare.

Methods: 592 consecutive patients (75 ± 8.7 years, 362 men, 230 women) underwent clinical and echocardiographic follow-up for a median of 2.13 (0.99-4.02) years.

Results: Significantly higher prevalence of cardiovascular comorbidities, renal failure, and adverse echocardiographic parameters in men resulted in longer device time (p = 0.007) and higher numbers of implanted clips (p = 0.0075), with equal procedural success (p = 1.0). Rehospitalization for heart failure did not differ (p[logrank] = 0.288) while survival was higher in women (p[logrank] = 0.0317). Logarithmic increase of NT-proBNP was a common independent predictor of death. Hypercholesterolemia and peripheral artery disease were predictors of death only in men while ischemic and dilative cardiomyopathy (CM) and age were predictors in women. Independent predictors of rehospitalization for heart failure were severely reduced ejection fraction and success in men while both ischemic and dilative CM, logistic EuroSCORE, and MR severity were predictive in women.

Conclusions: Higher numbers of implanted clips and longer device time are likely related to more comorbidities in men. Procedural success and acute and mid-term clinical outcomes were equal. Superior survival for women in long-term analysis is presumably attributable to a comparatively better preprocedural health.
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http://dx.doi.org/10.1155/2016/3934842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793092PMC
December 2016

miRNA-197 and miRNA-223 Predict Cardiovascular Death in a Cohort of Patients with Symptomatic Coronary Artery Disease.

PLoS One 2015 31;10(12):e0145930. Epub 2015 Dec 31.

Department of General and Interventional Cardiology, University Heart Center Hamburg Eppendorf, Hamburg, Germany.

Background: Circulating microRNAs (miRNAs) have been described as potential diagnostic biomarkers in cardiovascular disease and in particular, coronary artery disease (CAD). Few studies were undertaken to perform analyses with regard to risk stratification of future cardiovascular events. miR-126, miR-197 and miR-223 are involved in endovascular inflammation and platelet activation and have been described as biomarkers in the diagnosis of CAD. They were identified in a prospective study in relation to future myocardial infarction.

Objectives: The aim of our study was to further evaluate the prognostic value of these miRNAs in a large prospective cohort of patients with documented CAD.

Methods: Levels of miR-126, miR-197 and miR-223 were evaluated in serum samples of 873 CAD patients with respect to the endpoint cardiovascular death. miRNA quantification was performed using real time polymerase chain reaction (RT-qPCR).

Results: The median follow-up period was 4 years (IQR 2.78-5.04). The median age of all patients was 64 years (IQR 57-69) with 80.2% males. 38.9% of the patients presented with acute coronary syndrome (ACS), 61.1% were diagnosed with stable angina pectoris (SAP). Elevated levels of miRNA-197 and miRNA-223 reliably predicted future cardiovascular death in the overall group (miRNA-197: hazard ratio (HR) 1.77 per one standard deviation (SD) increase (95% confidence interval (CI) 1.20; 2.60), p = 0.004, C-index 0.78; miRNA-223: HR 2.23 per one SD increase (1.20; 4.14), p = 0.011, C-index 0.80). In ACS patients the prognostic power of both miRNAs was even higher (miRNA-197: HR 2.24 per one SD increase (1.25; 4.01), p = 0.006, C-index 0.89); miRA-223: HR 4.94 per one SD increase (1.42; 17.20), p = 0.012, C-index 0.89).

Conclusion: Serum-derived circulating miRNA-197 and miRNA-223 were identified as predictors for cardiovascular death in a large patient cohort with CAD. These results reinforce the assumption that circulating miRNAs are promising biomarkers with prognostic value with respect to future cardiovascular events.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145930PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699820PMC
June 2016

ADMA, subclinical changes and atrial fibrillation in the general population.

Int J Cardiol 2016 Jan 19;203:640-6. Epub 2015 May 19.

Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Germany; DZHK (Deutsches Zentrum fuer Herz-Kreislauf-Forschung e.V.), partner site Hamburg/Kiel/Luebeck, Germany. Electronic address:

Background: Pathways of oxidative stress, nitric oxide bioavailability and L-arginine derivatives are hypothesized to be related to atrial fibrillation (AF). Circulating methylated L-arginine metabolites can be assessed in the general population and may show an association with AF.

Methods: We determined L-arginine and its metabolites asymmetric dimethylarginine (ADMA), L-N(ω)-monomethylarginine (NMMA) and symmetric dimethylarginine (SDMA) in the population-based Gutenberg Health Study (n=5000), mean age 55 ± 11 years, 51% men, in association with clinical variables of AF such as electrocardiographic and echocardiographic measures and manifest AF.

Results: Individuals with AF (N=161), 71% men, were older, mean age 64.9 ± 8.3 years. In Bonferroni-corrected multivariable-adjusted regression analyses we observed moderate inverse associations for L-arginine, SDMA, and L-arginine/ADMA ratio with ventricular heart rate, and for L-arginine and L-arginine/ADMA ratio with QTc interval. L-arginine was correlated with QRS duration. In echocardiographic analyses, SDMA was related to left atrial diameter and deceleration time, ADMA and NMMA were correlated with left ventricular mass. ADMA (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.11-1-32; p=0.013) and NMMA (OR 1.17, 95% CI 1.09-1.26, p=0.014) were related to prevalent AF. L-arginine/ADMA ratio was inversely associated (OR 0.8, 95% CI 0.71-0.90, p=0.0082). Results were similar after adjustment for creatinine.

Conclusions: In our large, population-based cohort, we observed moderate associations of l-arginine metabolites and intermediate electrocardiographic and echocardiographic variables and AF. Our findings support further investigations to define the role of L-arginine derivatives in AF and their clinical utility.
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http://dx.doi.org/10.1016/j.ijcard.2015.05.102DOI Listing
January 2016

Reference intervals of plasma homoarginine from the German Gutenberg Health Study.

Clin Chem Lab Med 2016 Jul;54(7):1231-7

Background: Low circulating homoarginine has been associated with adverse cardiovascular (CV) outcome and mortality in patients at risk and in the general population. The present study aimed to define plasma homoarginine reference intervals from a representative population sample to improve risk stratification between healthy individuals and individuals at risk.

Methods: We determined age- and sex-specific reference intervals for circulating plasma homoarginine in a subgroup of 786 healthy participants (no CV disease or risk factors) of the Gutenberg Health Study. Homoarginine concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method.

Results: Median EDTA plasma homoarginine concentration was 1.88 [25th; 75th percentile, 1.47; 2.41] μmol/L, with lower concentrations in women (1.77 [1.38; 2.26] μmol/L) than in men (2.01 [1.61; 2.56] μmol/L; p<0.001). Sex-specific 2.5th and 97.5th percentiles of reference intervals were 0.84 and 3.89 μmol/L in women and 0.98 and 4.10 μmol/L in men, respectively. Homoarginine concentrations also depended on age and single nucleotide polymorphisms related to the L-arginine:glycine amidinotransferase gene.

Conclusions: We provide plasma homoarginine reference intervals in men and women of the general population. The determination of homoarginine levels might be favorable for individual risk stratification.
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http://dx.doi.org/10.1515/cclm-2015-0785DOI Listing
July 2016

Predictive value of galectin-3 for incident cardiovascular disease and heart failure in the population-based FINRISK 1997 cohort.

Int J Cardiol 2015 Aug 9;192:33-9. Epub 2015 May 9.

National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland. Electronic address:

Objectives: Galectin-3 is an emerging biomarker playing an important, complex role in intracellular pathways of cardiovascular diseases and heart failure. We aimed therefore to investigate the predictive value of galectin-3 for incident cardiovascular disease and heart failure.

Methods: Galectin-3 levels were measured in 8444 participants of the general population-based FINRISK 1997 cohort. Cox proportional hazards regression analyses, adjusting for traditional Framingham risk factors, prevalent valvular heart disease, eGFR (estimated glomerular filtration rate) as well as NT-proBNP, were used to examine the predictive power of galectin-3. Measurements of discrimination and reclassification using 10-fold cross-validation were performed to control for over-optimism. Cardiovascular death (CD), all-cause mortality, myocardial infarction (MI), ischemic stroke (hemorrhagic strokes were excluded) and heart failure (HF) were used as endpoints.

Results: During the follow-up of up to 15 years there were in total 1136 deaths from any cause, 383 cardiac deaths, 359 myocardial infarctions, 401 ischemic strokes and 641 cases of incident heart failure. Hazard ratios (HR) were statistically significant for all-cause mortality (1.12, p < 0.001), cardiac death (1.15, p = 0.033) and heart failure (1.10, p = 0.049). Statistical significance was lost when analyzing by gender except for all-cause mortality. No significant improvements were observed in model discrimination or overall reclassification upon inclusion of galectin-3. Compared to NT-proBNP, the predictive power of galectin-3 was weaker but both remained significant, independently of each other.

Conclusion: Galectin-3 levels were predictive for future cardiovascular events but improvements in discrimination and reclassifications were modest.
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http://dx.doi.org/10.1016/j.ijcard.2015.05.040DOI Listing
August 2015

ST2 may not be a useful predictor for incident cardiovascular events, heart failure and mortality.

Heart 2014 Nov 30;100(21):1715-21. Epub 2014 Jul 30.

Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

Objectives: We hypothesised that soluble ST2 (sST2) levels can identify people with elevated risk of subsequent cardiovascular disease (CVD) and add to existing risk prediction algorithms.

Background: ST2 is a receptor for the inflammatory cytokine IL33. Increased sST2 levels have been associated with heart failure and death in acute myocardial infarction patients and in the general population.

Methods: We measured high-sensitivity sST2 in 8444 men and women (25-74 years) from the FINRISK97 prospective population cohort. Cox proportional hazards modelling evaluated the ability of sST2 to predict fatal and non-fatal heart failure, CVD (coronary heart disease, stroke), diabetes, and death over 15 years follow-up. Discrimination and reclassification statistics for 10-year absolute risks compared the ability of sST2 to improve upon Framingham risk factors (FRF), N-terminal pro-brain natriuretic peptide (NT-proBNP), renal function (eGFR) and prevalent valvular heart disease (VHD).

Results: sST2 showed suggestive but non-significant associations with heart failure {(HR per 1 SD of log sST2 1.06; 95% CI 0.96 to 1.17 (562 events))}, and with CVD (1.01 95% CI 0.94 to 1.08) (914 events) after adjustment for FRF, NT-proBNP, eGFR and VHD. sST2 significantly predicted death from all causes following similar adjustment ({HR 1.09 (95% CI 1.01 to 1.19) (974 events))}. No improvement in the c-index was observed for models adding sST2 to the risk factors.

Conclusions: In a healthy general population from Finland, sST2 did not improve long-term prediction of cardiovascular events including heart failure or all-cause mortality.
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http://dx.doi.org/10.1136/heartjnl-2014-305968DOI Listing
November 2014

Comparison of three troponins as predictors of future cardiovascular events--prospective results from the FINRISK and BiomaCaRE studies.

PLoS One 2014 4;9(3):e90063. Epub 2014 Mar 4.

National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland.

Importance And Objective: Besides their role in diagnosis of acute myocardial infarction (MI), troponins may be powerful biomarkers for risk stratification in the general population. The objective of our study was to compare the performance of three troponin assays in cardiovascular disease (CVD) risk prediction in a population-based cohort without a history of CVD events.

Design, Setting And Participants: Troponin I concentrations were measured using a contemporary-sensitivity, high-sensitivity, and super-sensitivity assay in 7,899 participants of the general-population based FINRISK 1997 cohort. We used Cox proportional hazards regression to determine relative risks, followed by measures of discrimination and reclassification using 10-fold cross-validation to control for over-optimism.

Main Outcome: As outcome measures we used CVD, MI, ischemic stroke, heart failure (HF), and major adverse cardiac events (MACE). During the follow-up of 14 years 1,074 incident MACE were observed.

Results: Values above the lower limit of detection were observed in 26.4%, 81.5% and 93.9% for the contemporary-sensitivity, high-sensitivity and super-sensitivity assay, respectively. We observed significant associations of troponin concentrations with the risk of future CVD events and the results tended to become stronger with increasing assay sensitivity. For the super-sensitivity assay the multivariate adjusted hazard ratios (per one standard deviation increase) for different outcomes were: MI 1.24 [95% CI 1.11-1.39], stroke 1.14 [1.01-1.28], CVD 1.15 [1.07-1.24], HF 1.28 [1.18-1.39], and MACE 1.18 [1.11-1.25]. In subjects with intermediate risk, we found an improvement of net reclassification for HF (10.2%, p<0.001), and MACE (5.1%, p<0.001).

Conclusion: Using a super-sensitivity assay, cardiac troponin was detectable in almost all healthy individuals. Its concentration improved risk prediction and reclassification for cardiovascular endpoints.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090063PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942371PMC
February 2015

Predictive value of midregional pro-adrenomedullin compared to natriuretic peptides for incident cardiovascular disease and heart failure in the population-based FINRISK 1997 cohort.

Ann Med 2014 May 10;46(3):155-62. Epub 2014 Feb 10.

Hamburg University Heart Center , Hamburg , Germany.

Introduction: To examine whether midregional pro-adrenomedullin (MR-proADM) plasma concentrations predict incident cardiovascular outcomes in the general population. Natriuretic peptides (N-terminal pro-brain natriuretic peptide (NT-proBNP), B-type natriuretic peptide (BNP), and midregional pro-atrial natriuretic peptide (MR-proANP)) were analyzed for comparison.

Material And Methods: MR-proADM plasma concentrations and those of the natriuretic peptides were determined in 8444 individuals of the FINRISK 1997 cohort. Patients were followed for 14 years (median). Cox regression analyses, discrimination, and reclassification analyses adjusting for Framingham risk factors were performed to evaluate the additional benefit from MR-proADM.

Results: MR-proADM concentrations significantly predicted all-cause death (hazard ratio highest quintile versus lowest 1.18, 95% confidence interval 1.08-1.28), stroke (1.20, 1.05-1.38), major adverse cardiac events (MACE) (1.27, 1.17-1.37), and heart failure (1.67, 1.49-1.87). MR-proADM remained associated with MACE, death, and heart failure even after additional adjustment for NT-proBNP and C-reactive protein. Adding MR-proADM to the Framingham risk factors significantly improved discrimination (P < 0.001 for C-statistics and integrated discrimination improvement) and risk reclassification for heart failure (net reclassification improvement 12.12%, P < 0.001).

Conclusions: In a healthy general population sample of the FINRISK 1997 cohort MR-proADM significantly predicted all-cause death, MACE, and especially heart failure even beyond NT- proBNP. It also improved risk reclassification for heart failure.
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http://dx.doi.org/10.3109/07853890.2013.874662DOI Listing
May 2014

Association of multiple biomarkers and classical risk factors with early carotid atherosclerosis: results from the Gutenberg Health Study.

Clin Res Cardiol 2014 Jun 2;103(6):477-85. Epub 2014 Feb 2.

University Hospital Hamburg-Eppendorf, University Heart Center Hamburg, Hamburg, Germany,

Background: In the Gutenberg Health Study, a random sample of the population was scanned with vascular ultrasound for early atherosclerosis. A continuous classical risk marker model (waist circumference, HbA1c, LDL/HDL ratio, pack years and pulse pressure) was compared to a model of modern biomarkers (C-reactive protein, troponin I, N-terminal pro B-type natriuretic peptide, copeptin, mid-regional pro-adrenomedullin, and asymmetric dimethylarginine) with regard to the ability of ruling out abnormal intima-media thickness (IMT), respectively, carotid plaques.

Methods: Data of the first consecutive 5,000 participants (aged 35-74 years; 2,540 men, 2,460 women) were analyzed. IMT was measured at both common carotid arteries using an edge detection system. Plaques were defined as protrusion of ≥1.5 mm in common, internal and external carotid artery.

Results: For classical risk factors, in comparison to a model of six modern biomarkers, regarding the variable (a) IMT>0.85 mm negative and positive predictive value (NPV and PPV) were 0.98 and 0.16 for both the classical risk factor model and the biomarker model. The second variable (b) presence of plaque could be ruled out with an NPV of 0.84 and identified with a PPV of 0.61 for classical risk factors, and 0.84 and 0.58 for biomarkers, respectively. Values were calculated using logistic regression analysis.

Conclusion: Classical risk factors allow ruling out pathologic IMT and presence of carotid plaques in a population of primary prevention in a reliable way. Modern biomarkers performed almost equally well but did not provide further information.
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http://dx.doi.org/10.1007/s00392-014-0674-6DOI Listing
June 2014

High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality.

Eur Heart J 2013 Dec 7;34(46):3563-71. Epub 2013 Sep 7.

Department of Angiology, Swiss Cardiovascular Center, Inselspital, University of Bern, Bern, Switzerland.

Aims: High-density lipoprotein (HDL) cholesterol is a strong predictor of cardiovascular mortality. This work aimed to investigate whether the presence of coronary artery disease (CAD) impacts on its predictive value.

Methods And Results: We studied 3141 participants (2191 males, 950 females) of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. They had a mean ± standard deviation age of 62.6 ± 10.6 years, body mass index of 27.5 ± 4.1 kg/m², and HDL cholesterol of 38.9 ± 10.8 mg/dL. The cohort consisted of 699 people without CAD, 1515 patients with stable CAD, and 927 patients with unstable CAD. The participants were prospectively followed for cardiovascular mortality over a median (inter-quartile range) period of 9.9 (8.7-10.7) years. A total of 590 participants died from cardiovascular diseases. High-density lipoprotein cholesterol by tertiles was inversely related to cardiovascular mortality in the entire cohort (P = 0.009). There was significant interaction between HDL cholesterol and CAD in predicting the outcome (P = 0.007). In stratified analyses, HDL cholesterol was strongly associated with cardiovascular mortality in people without CAD [3rd vs. 1st tertile: HR (95% CI) = 0.37 (0.18-0.74), P = 0.005], but not in patients with stable [3rd vs. 1st tertile: HR (95% CI) = 0.81 (0.61-1.09), P = 0.159] and unstable [3rd vs. 1st tertile: HR (95% CI) = 0.91 (0.59-1.41), P = 0.675] CAD. These results were replicated by analyses in 3413 participants of the AtheroGene cohort and 5738 participants of the ESTHER cohort, and by a meta-analysis comprising all three cohorts.

Conclusion: The inverse relationship of HDL cholesterol with cardiovascular mortality is weakened in patients with CAD. The usefulness of considering HDL cholesterol for cardiovascular risk stratification seems limited in such patients.
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http://dx.doi.org/10.1093/eurheartj/eht343DOI Listing
December 2013

Association of MR-proadrenomedullin with cardiovascular risk factors and subclinical cardiovascular disease.

Atherosclerosis 2013 Jun 19;228(2):451-9. Epub 2013 Mar 19.

Department of General and Interventional Cardiology, Hamburg University Heart Center, Martinistraße 52, 20246 Hamburg, Germany.

Aims And Background: Midregional proadrenomedullin (MR-proADM) is a protein, which exerts various effects on the cardiovascular system. Recent studies underscored its prognostic implications in patients with acute dyspnea and cardiovascular diseases. Therefore, we aimed to determine the distribution of MR-proADM in the general population and to reveal potential associations of MR-proADM with cardiovascular risk factors and measures of subclinical cardiovascular disease.

Methods And Results: MR-proADM plasma concentrations were determined in individuals of the population-based cohort of the Gutenberg Health Study (N = 5000) using a commercially available fluoroimmunoassay. Individuals were enrolled between April 2007 and October 2008. Subclinical cardiovascular disease was assessed using echocardiographic and functional measures of myocardial and vascular function. The mean age of the study population was 55.5 ± 10.9 years. In the overall population we determined a median MR-proADM plasma concentration of 0.44 nmol/L in men and women. MR-proADM concentrations were elevated in individuals with hypertension, diabetes, dyslipidemia, known cardiovascular disease, heart failure, peripheral artery disease, atrial fibrillation, and history of myocardial infarction and stroke. In men, we observed a positive association of MR-proADM with reduced ejection fraction, intraventricular septal diameter, wall thickness, and echocardiographic measures of diastolic dysfunction.

Conclusions: In this study, we present age-dependent reference values for MR-proADM in a representative population sample. Elevated MR-proADM plasma concentrations were strongly associated with classical cardiovascular risk factors and manifest cardiovascular diseases. Furthermore, we revealed a gender-specific association with echocardiographic measures of hypertension. MR-proADM seems to be a promising prognostic biomarker for subclinical and manifest cardiovascular disease.
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http://dx.doi.org/10.1016/j.atherosclerosis.2013.03.006DOI Listing
June 2013

Angiographic score assessment improves cardiovascular risk prediction: the clinical value of SYNTAX and Gensini application.

Clin Res Cardiol 2013 Jul 23;102(7):495-503. Epub 2013 Mar 23.

Department of General and Interventional Cardiology, University Heart Center Hamburg, Martinistr. 52, 20246 Hamburg, Germany.

Background: Severity of coronary artery disease (CAD) is related to cardiovascular outcome. We aimed to assess the long-term follow-up depending on Synergy between percutaneous coronary intervention with Taxus and cardiac surgery (SYNTAX) and Gensini score for prognosis. Both scores increase with complexity and thus reflect risk of cardiovascular events.

Methods And Results: We determined complexity and extent of CAD by the SYNTAX and Gensini score in the AtheroGene cohort (N = 1,974, with 22.6 % women). The endpoint was non-fatal myocardial infarction (N = 132) and cardiovascular death (N = 159) over a median follow-up of 5.4 (Q1: 5.23/Q3: 5.57) years up to 8 years maximum (follow-up rate 99.4%). For SYNTAX score, the following distribution was used: low (≤22, N = 1,404), medium (23-32, N = 314), high score (>32, N = 256). Gensini score was split into thirds. Cox regression analysis showed a hazard ratio (HR) of 1.5 (95% confidence interval 1.16-1.95; p = 0.0024) for the log transformed SYNTAX score in a fully adjusted model and a HR of 1.41 (95% CI 1.13-1.77; p = 0.0025) for the Gensini score. The SYNTAX score alone had a C-index of 0.62, whereas adding clinical variables increased the C-index to 0.67. Similar results were obtained for the Gensini score. Regarding the SYNTAX score using net reclassification index, discrimination of events and non-events was enhanced by 37.2% in a model of clinical variables and biomarkers and by 31.8% for the Gensini score.

Conclusion: The SYNTAX and Gensini score in combination with clinical variables could be used to predict the cardiovascular prognosis during a long-term follow-up of up to 8 years in CAD patients.
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http://dx.doi.org/10.1007/s00392-013-0555-4DOI Listing
July 2013
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