Non-invasive peripheral vascular function, incident cardiovascular disease, and mortality in the general population.

AIMS: Evidence suggests that peripheral vascular function is related to cardiovascular disease (CVD) and mortality. We evaluated the associations of non-invasive measures of flow-mediated dilatation and peripheral arterial tonometry with incident CVD and mortality. METHODS AND RESULTS: In a post-hoc analysis of the community-based Gutenberg Health Study, median age 55 years (25th/75th percentile 46/65) and 49.5% women, we measured brachial artery flow-mediated dilatation (N=12 599) and fingertip peripheral arterial tonometry (N=11 125). After a follow-up of up to 11.7 years, we observed 595 incident CVD events, 106 cardiac deaths, and 860 deaths in total. Survival curves showed decreased event-free survival with higher mean brachial artery diameter and baseline pulse amplitude and better survival with higher mean flow-mediated dilatation and peripheral arterial tonometry ratio (all Plog rank <0.05). In multivariable-adjusted Cox regression analyses only baseline pulse amplitude was inversely related to mortality [hazard ratio (HR) per standard deviation increase, 0.86, 95% confidence interval (95% CI), 0.79-0.94; P=0.0009]. After exclusion of individuals with prevalent CVD the association was no longer statistically significant in multivariable-adjusted models (HR 0.91, 95% CI 0.81-1.02; P=0.11). None of the vascular variables substantially increased the C-index of a model comprising clinical risk factors. CONCLUSIONS: In our cohort, non-invasive measures of peripheral vascular structure and function did not reveal clinically relevant associations with incident CVD or mortality. Whether determination of pulse amplitude by peripheral arterial tonometry improves clinical decision-making in primary prevention needs to be demonstrated.

Predicting clinical outcome by indexed mitral valve tenting in functional mitral valve regurgitation.

OBJECTIVES: Mitral valve (MV) tenting parameters are indicators of left ventricular remodelling severity and may predict outcome in functional mitral regurgitation (FMR). We hypothesised that indexing of MV tenting area to body surface area (BSA), to mitral annulus diameter or gender-adjusted analysis of tenting parameters may improve their prognostic value. METHODS: We identified retrospectively 240 patients with consecutive FMR (mean age 68±10 years; men=135) from our institutional database who underwent isolated MV annuloplasty during a period of 7 years (2010-2016). Using preoperative two-dimensional transthoracic echocardiographic images, MV tenting parameters including tenting area, tenting height and annulus diameter were systematically assessed. Follow-up protocol consisted of chart review and structured clinical questionnaire. Primary study endpoint was the composite of death and adverse cardiac events (ie, MV reoperation, cardiac resynchronisation therapy implantation, ventricular assist device implantation or heart transplantation). RESULTS: BSA-indexed MV tenting area was identified as independent predictor of primary study endpoint (HR 1.9; 95% CI 1.1 to 3.5; p=0.02). After cut-off point analysis, BSA-indexed MV tenting area >1.35 cm2/m2 was significantly associated with primary study outcome (HR 2.3; 95% CI 1.3 to 4.0; p=0.003). Annulus-indexed MV tenting area showed only a tendency towards primary study endpoint prediction (HR 2.8; 95% CI 0.6 to 12.6; p=0.17). Between female and male patients, BSA-indexed MV tenting area was similar (1.42±0.4 cm2/m2 vs 1.45±0.4cm2/cm2; p=0.6) and gender was not associated with primary study outcome (HR 0.8; 95% CI 0.5 to 1.4; p=0.5). CONCLUSION: In our FMR cohort, BSA-indexed MV tenting area showed the strongest association with negative outcomes following isolated MV annuloplasty. Patients with BSA-indexed MV tenting area >1.35cm2/m2 could potentially benefit from additional surgical maneuvers addressing left ventricular remodelling.

Risk prediction of in-hospital mortality in patients with venoarterial extracorporeal membrane oxygenation for cardiopulmonary support: The ECMO-ACCEPTS score.

PURPOSE: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is an increasingly used treatment option for patients in need of mechanical cardiopulmonary support, while available outcome data is limited. The aim of this study was to identify predictors for 30-day in-hospital mortality. MATERIAL AND METHODS: We analyzed baseline characteristics and outcomes of 8351 VA-ECMO procedures performed in Germany from 2007 to 2015. Using a multivariable model, we identified the ten most important variables to allow for prediction of 30-day in-hospital mortality. Based on these variables, we created a mortality prediction score (ECMO-ACCEPTS score) to enhance decision making in patients considered for or treated with VA-ECMO support. RESULTS: Of 8351 patients (71.7% male) 3567 had prior CPR. Mean age was 62 years in the present cohort. The overall 30-day in-hospital mortality was 61%. The ECMO-ACCEPTS score, derived among randomly selected 4175 patients, included ten independent predictors for in-hospital mortality. Internal validation in the remaining 4176 patients confirmed strong differentiation between low and high risk of 30-day in-hospital mortality (r = 0.97 for correlation of predicted with observed mortality, p < .001). CONCLUSIONS: The ECMO-ACCEPTS score might help clinicians to improve risk prediction among VA-ECMO patients for refractory cardiogenic shock.

Left ventricular geometry and function in early repolarization: results from the population-based Gutenberg Health Study.

AIMS: The electrocardiographic pattern of early repolarization (ER) is related to increased cardiac mortality in the general population. The pathophysiological basis of ER is largely unknown. We investigated the association of echocardiographic structural and functional parameters of the left ventricle with the presence of ER in the community. METHODS AND RESULTS: The presence of ER (ER+) was assessed in 13,878 participants (mean age 54.6 years, 51.1% women) of the Gutenberg Health Study and related to left ventricular structure and function derived from standard echocardiography. The prevalence of ER was 5.0% (694/13,878), with higher prevalence in men than women (6.6% vs. 3.5%, p < 0.001). In men baseline characteristics differed including a lower BMI and a lower heart rate in ER+ individuals, whereas in women there were only minor differences. Multivariable-adjusted logistic regression analysis in men showed an association of ER with smaller diameters (left-ventricular end-diastolic diameter: OR 0.77 95% CI 0.69-0.86, p < 0.001; left-ventricular end-systolic diameter: OR 0.86 95% CI 0.78-0.95, p = 0.0035), and lower left-ventricular end-diastolic and end-systolic volume (OR 0.72 95% CI 0.65, 0.80, p < 0.001 and OR 0.80 95% CI 0.72, 0.89, p < 0.001). In women, the associations of ER with left ventricular diameters and volumes showed a similar direction, but were not as pronounced. CONCLUSION: In the community, the ER pattern predominantly occurs in men with a low heart rate and a slender habit. Furthermore, ER is not associated with higher left ventricular mass or size but rather with smaller left ventricular diameters and volumes with a regular systolic and diastolic function. Patterns were comparable in women, but less strong.

Cross-Sectional Associations between Homoarginine, Intermediate Phenotypes, and Atrial Fibrillation in the Community-The Gutenberg Health Study.

Homoarginine has come into the focus of interest as a biomarker for cardiovascular disease. Atrial fibrillation (AF) causes a substantial increase in morbidity and mortality. Whether circulating homoarginine is associated with occurrence or persistence of AF and may serve as a new predictive biomarker remains unknown. We measured plasma levels of homoarginine in the population-based Gutenberg health study (3761 patients included, of them 51.7% males), mean age 55.6 ± 10.9 years-old. Associations between homoarginine and intermediate electrocardiographic and echocardiographic phenotypes and manifest AF were examined. Patients with AF (124 patients, of them 73.4% males) had a mean age 64.8 ± 8.6 years-old compared to a mean age of 55.3 ± 10.9 in the population without AF (p-value < 0.001) and showed a less beneficial risk factor profile. The median homoarginine levels in individuals with and without AF were 1.9 µmol/L (interquartile range (IQR) 1.5⁻2.5) and 2.0 µmol/L (IQR 1.5⁻2.5), respectively, p = 0.56. In multivariable-adjusted regression analyses homoarginine was not statistically significantly related to electrocardiographic variables. Among echocardiographic variables beta per standard deviation increase was -0.12 (95% confidence interval (CI) -0.23⁻(-0.02); p = 0.024) for left atrial area and -0.01 (95% CI -0.02⁻(-0.003); p = 0.013) for E/A ratio. The odds ratio between homoarginine and AF was 0.91 (95% CI 0.70⁻1.16; p = 0.45). In our large, population-based cross-sectional study, we did not find statistically significant correlations between lower homoarginine levels and occurrence or persistence of AF or most standard electrocardiographic phenotypes, but some moderate inverse associations with echocardiographic left atrial size and E/A. Homoarginine may not represent a strong biomarker to identify individuals at increased risk for AF. Further investigations will be needed to elucidate the role of homoarginine and cardiac function.

Atrial Fibrillation Manifestations Risk Factors and Sex Differences in a Population-Based Cohort (From the Gutenberg Health Study).

Sex differences in cardiovascular risk factors, cardiac structure and function, and disease and symptom burden in the common arrhythmia atrial fibrillation (AF) have not been investigated systematically at the population level. Cross-sectional data of 14,796 subjects (age range 35 to 74 years, 50.5% men) from the population-based Gutenberg Health Study were examined to show the distribution of cardiovascular risk factors by AF status and sex, and to determine sex-specific predictors for AF. The prevalence of AF was higher in men (4.3%) than in women (1.9%). Men had a worse cardiovascular risk factor profile, a higher prevalence of cardiovascular disease, but fewer symptoms than women. Age-adjusted Cox regressions showed sex interactions in the association of high-density lipoprotein-cholesterol, triglycerides, diabetes mellitus, coronary artery disease, myocardial infarction, generalized anxiety disorder, and heart rate with AF. After multivariable adjustment, sex interactions were seen for thickness of interventricular end-diastolic septum, odds ratio (OR) per standard deviation (SD), 95% confidence interval women: 0.9 (0.8, 1.1), men: 1.2 (1.1, 1.4), interaction p value = 0.02; left atrial diameter index, OR per SD women: 1.5 (1.3, 1.8), men: 1.9 (1.7, 2.1), interaction p value = 0.03; and myocardial infarction, OR women: 2.7 (1.3, 5.6), men: 0.7 (0.5, 1.1), interaction p value = 0.002. In conclusion, in our large cohort, we observed substantial sex differences in AF distribution and clinical characteristics including comorbidities, symptom burden, and structural cardiac changes.

FEV1 and FVC predict all-cause mortality independent of cardiac function - Results from the population-based Gutenberg Health Study.

BACKGROUND: Lung function has previously been related to increased mortality. Whether pulmonary impairment is associated with an increased mortality independent of cardiac dysfunction remains unclear. METHODS: In 15010 individuals from the general population (age range 35-74years, 51% men) in the Gutenberg Health Study we performed spirometry and transthoracic echocardiography. N-terminal pro-B-type natriuretic peptide (Nt-proBNP) and high-sensitive troponin I (hsTnI) were measured in all individuals. 1819 individuals with pulmonary diseases were excluded from further analysis. RESULTS: The median for forced expiratory volume in 1s (FEV1) was 94.2% and for forced vital capacity (FVC) 94.2% as a percentage of their predicted values. The median FEV1/FVC ratio was 79.1%. In 13191 subjects, 335 deaths were verified from death certificate over a median follow-up of 5.5years. Multivariable-adjusted Cox regression analyses for common cardiovascular risk factors and heart failure revealed that an increase of one standard deviation (SD) of percent predicted (%pred.) FEV1 was associated with a 22% risk reduction (hazard ratio [HR] per SD 0.78 [95% confidence interval (CI): 0.70, 0.86]). The association remained statistically significant after additional adjustment for diastolic dysfunction, Nt-proBNP or hsTnI. Comparable results were seen for %pred. FVC. After adjustment, no association of FEV1/FVC ratio with mortality could be shown. No significant interaction by heart failure was observed. CONCLUSIONS: The lung function parameters FEV1 and FVC, but not FEV1/FVC ratio, were related to all-cause mortality in individuals from the general population independent of cardiac function.

Subclinical impairment of lung function is related to mild cardiac dysfunction and manifest heart failure in the general population.

BACKGROUND: Lung function impairment has previously been related to heart failure, although no overt cardiovascular or structural heart disease is present. The extent to which pulmonary function is related to subclinical left ventricular impairment in the general population remains to be investigated. METHODS: 15010 individuals from the general population (mean age 55±11years, 50.5% men) in the Gutenberg Health Study underwent spirometry, transthoracic echocardiography and biomarker measurement. Forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) in percent of the predicted value and FEV1/FVC ratio were associated with echocardiographic measures of cardiac structure, systolic and diastolic function, biomarkers of cardiac necrosis (high-sensitive troponin I, hsTnI) and stress (N-terminal pro-B-type natriuretic peptide, Nt-proBNP) and heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF). RESULTS: Percent predicted FEV1 and FVC were significantly associated with hsTnI (P<0.001) and Nt-proBNP (P<0.001). Additionally, FEV1/FVC ratio was significantly related to hsTnI (P=0.0043) and Nt-proBNP (P<0.001). In the multivariable-adjusted linear regression analyses strongest associations were observed for percent predicted FEV1 and FVC with LVESD, E/e', SV and EF. FEV1/FVC ratio was significantly related with SV and EF. The three lung function parameters were significantly (P<0.001) associated with HFpEF and HFrEF. Associations remained statistically significant after exclusion of individuals with COPD. CONCLUSIONS: FEV1, FVC and FEV1/FVC ratio were associated with systolic and diastolic function and manifest heart failure. Our observations could show, that subclinical lung function impairment is related to a measurable reduction of left ventricular filling and cardiac output in the general population.

ADMA and arginine derivatives in relation to non-invasive vascular function in the general population.

OBJECTIVE: Nitric oxide produced from l-arginine is central to vascular homeostasis. Little is known about the relationship between arginine derivatives including asymmetric dimethylarginine (ADMA) and non-invasive vascular function measures in the general population. APPROACH AND RESULTS: In 5000 individuals (median age 56; 25th/75th percentile: 46, 65; 49% women) taking part in the population-based Gutenberg Health Study (Mainz area, Germany), we measured the relationship between the arginine derivatives asymmetric dimethylarginine (ADMA), N-monomethyl l-arginine (NMMA), symmetric dimethylarginine (SDMA) and l-arginine with flow-mediated dilation (FMD) and peripheral arterial tonometry (PAT). Weak bivariate correlations were observed between all measured arginine derivatives and vascular function measures, except of l-arginine and FMD and SDMA and PAT ratio. In multivariate adjusted linear regression analyses we could show statistically significant relationships between arginine derivatives and vascular function measures, which were influenced by age, sex and body mass index (BMI). Thus, a negative relationship between ADMA and FMD in females who were normal (beta: -0.095, P < 0.001) to overweight (beta: -0.071, P < 0.001) and a negative association of SDMA and FMD for middle-aged females was seen. The relationship between ADMA and PAT was negative for males who were normal (beta: -0.089, P < 0.001) to overweight (beta: -0.051, P = 0.007) and positive for obese females (beta: 0.073, P = 0.021). CONCLUSIONS: We showed small but significant correlations between ADMA and related arginine derivatives and non-invasive vascular function measures representative of different vascular regions. The associations were markedly influenced by age, sex and BMI. These findings support a complex interplay of arginine metabolism and vascular function.

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

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.

Sex Differences in Correlates of Intermediate Phenotypes and Prevalent Cardiovascular Disease in the General Population.

BACKGROUND: There are marked sex differences in cardiovascular disease (CVD) manifestation. It is largely unknown how the distribution of CVD risk factors or intermediate phenotypes explain sex-specific differences. METHODS AND RESULTS: In 5000 individuals of the population-based Gutenberg Health Study, mean age 55 ± 11 years, 51% males, we examined sex-specific associations of classical CVD risk factors with intima-media thickness, ankle-brachial index, flow-mediated dilation, peripheral arterial tonometry, echocardiographic, and electrocardiographic variables. Intermediate cardiovascular phenotypes were related to prevalent CVD [coronary artery disease, heart failure, stroke, myocardial infarction, lower extremity artery disease (LEAD) N = 561]. We observed differential distributions of CVD risk factors with a higher risk factor burden in men. Manifest coronary artery disease, stroke, myocardial infarction, and LEAD were more frequent in men; the proportion of heart failure was higher in women. Intermediate phenotypes showed clear sex differences with more beneficial values in women. Fairly linear changes toward less beneficial values with age were observed in both sexes. In multivariable-adjusted regression analyses, age, systolic blood pressure, and body mass index were consistently associated with intermediate phenotypes in both sexes with different ranking according to random forests, maximum model R(2) 0.43. Risk factor-adjusted associations with prevalent CVD showed some differences by sex. No interactions by menopausal status were observed. CONCLUSION: In a population-based cohort, we observed sex differences in risk factors and a broad range of intermediate phenotypes of non-invasive cardiovascular structure and function. Their relation to prevalent CVD differed markedly. Our results indicate the need of future investigations to understand sex differences in CVD manifestation.

Multiple biomarkers and atrial fibrillation in the general population.

BACKGROUND: Different biological pathways have been related to atrial fibrillation (AF). Novel biomarkers capturing inflammation, oxidative stress, and neurohumoral activation have not been investigated comprehensively in AF. METHODS AND RESULTS: In the population-based Gutenberg Health Study (n = 5000), mean age 56 ± 11 years, 51% males, we measured ten biomarkers representing inflammation (C-reactive protein, fibrinogen), cardiac and vascular function (midregional pro adrenomedullin [MR-proADM], midregional pro atrial natriuretic peptide [MR-proANP], N-terminal pro-B-type natriuretic peptide [Nt-proBNP], sensitive troponin I ultra [TnI ultra], copeptin, and C-terminal pro endothelin-1), and oxidative stress (glutathioneperoxidase-1, myeloperoxidase) in relation to manifest AF (n = 161 cases). Individuals with AF were older, mean age 64.9 ± 8.3, and more often males, 71.4%. In Bonferroni-adjusted multivariable regression analyses strongest associations per standard deviation increase in biomarker concentrations were observed for the natriuretic peptides Nt-proBNP (odds ratio [OR] 2.89, 99.5% confidence interval [CI] 2.14-3.90; P<0.0001), MR-proANP (OR 2.45, 99.5% CI 1.91-3.14; P<0.0001), the vascular function marker MR-proADM (OR 1.54, 99.5% CI 1.20-1.99; P<0.0001), TnI ultra (OR 1.50, 99.5% CI 1.19-1.90; P<0.0001) and. fibrinogen (OR 1.44, 99.5% CI 1.19-1.75; P<0.0001). Based on a model comprising known clinical risk factors for AF, all biomarkers combined resulted in a net reclassification improvement of 0.665 (99.3% CI 0.441-0.888) and an integrated discrimination improvement of >13%. CONCLUSIONS: In conclusion, in our large, population-based study, we identified novel biomarkers reflecting vascular function, MR-proADM, inflammation, and myocardial damage, TnI ultra, as related to AF; the strong association of natriuretic peptides was confirmed. Prospective studies need to examine whether risk prediction of AF can be enhanced beyond clinical risk factors using these biomarkers.

Depression in atrial fibrillation in the general population.

BACKGROUND: Initial evidence suggests that depressive symptoms are more frequent in patients with atrial fibrillation. Data from the general population are limited. METHODS AND RESULTS: In 10,000 individuals (mean age 56±11 years, 49.4% women) of the population-based Gutenberg Health Study we assessed depression by the Patient Health Questionnaire (PHQ-9) and a history of depression in relation to manifest atrial fibrillation (n = 309 cases). The median (25th/75th percentile) PHQ-9 score of depressive symptoms was 4 (2/6) in atrial fibrillation individuals versus 3 (2/6) individuals without atrial fibrillation, P(X2-Test) = 0.32. Multivariable regression analyses of the severity of depressive symptoms in relation to atrial fibrillation in cardiovascular risk factor adjusted models revealed a relation of PHQ-9 values and atrial fibrillation (odds ratio (OR) 1.04, 95% confidence interval (CI) 1.01-1.08; P = 0.023). The association was stronger for the somatic symptom dimension of depression (OR 1.08, 95% CI 1.02-1.15; P = 0.0085) than for cognitive symptoms (OR 1.05, 95% CI 0.98-1.11; P = 0.15). Results did not change markedly after additional adjustment for heart failure, partnership status or the inflammatory biomarker C-reactive protein. Both, self-reported physical health status, very good/good versus fair/bad, (OR 0.54, 95% CI 0.41-0.70; P<0.001) and mental health status (OR 0.61 (0.46-0.82); P = 0.0012) were associated with atrial fibrillation in multivariable-adjusted models. CONCLUSIONS: In a population-based sample we observed a higher burden of depressive symptoms driven by somatic symptom dimensions in individuals with atrial fibrillation. Depression was associated with a worse perception of physical or mental health status. Whether screening and treatment of depressive symptoms modulates disease progression and outcome needs to be shown.

Sex differences in noninvasive vascular function in the community.

OBJECTIVE: The relation of noninvasive vascular function to sex, sex hormones, and reproductive history in the general population is little understood. METHODS: We simultaneously assessed flow-mediated dilation (FMD) and peripheral arterial tonometry in 454 women (mean age 40.4±16.1 years, age range 19-78 years) and 100 men (mean age 44.7±15.3 years) in a community-based cohort. Plasma estradiol, progesterone, luteinizing hormone, and follicle stimulating hormones were measured, and menstrual cycle and reproductive history were recorded. RESULTS: Vascular function was blunted in men as compared to women irrespective of menopausal status and adjustment for classical cardiovascular risk factors and hormones. Vascular reactivity changed during the menstrual cycle and correlated with estradiol concentrations for FMD, r=0.13 and inversely with progesterone for pulse amplitude, r=-0.14, and brachial artery diameter, r=-0.10. Multivariable-adjusted regressions showed a relation of estradiol with FMD, ß 0.658, 95% confidence interval (CI) 0.084/1.232, P=0.025 in women. Age at menarche (ß 0.070, 95% CI 0.039/0.101, P<0.0001) and breastfeeding duration (ß -0.006, 95% CI -0.011/-0.001, P=0.036) were related to brachial artery diameter, age at menarche also to FMD (ß -0.455, 95% CI -0.886/-0.023, P=0.039). CONCLUSION: Sex differences in noninvasive conduit and peripheral arterial function with better vascular reactivity in women were not fully explained by female sex hormones and menopausal status. Age at menarche and duration of breastfeeding were also related to vascular function and need further investigation.

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

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.

Defining a reference population to determine the 99th percentile of a contemporary sensitive cardiac troponin I assay.

BACKGROUND: Diagnosis of acute myocardial infarction (AMI) according to the universal definition is based on ischemic symptoms, imaging findings and elevated myocardial necrosis markers, preferably cardiac troponin I/T with diagnostic threshold representing the 99th percentile of a reference population. It is not clearly defined if this should be an unselected population-based or a healthy cohort with respect to cardiac diseases. Aim of the current study was to describe the distribution of troponin I using a sensitive assay and to evaluate the impact of cardiac diseases and cardiovascular risk factors in apparently healthy individuals. METHODS: Troponin I was determined using a contemporary sensitive assay (TnI Ultra, Siemens) with 10% coefficient of variation (0.03 ng/mL) below the published 99th percentile (0.04 ng/mL) in 5000 participants (49.2% female) of the Gutenberg Health Study, a community-based, prospective, observational single-center cohort study. The calculated 99 th percentile cut-offs were tested in 1818 patients with suspected AMI. RESULTS: Troponin I concentration representing the 99th percentile of the overall study population was 0.04 ng/mL. Excluding individuals with prevalent cardiovascular disease lowers the 99th percentile to 0.034 ng/mL. Exclusion of individuals with traditional risk factors or elevated natriuretic peptide leads to further reduction with 0.029/0.028 ng/mL. These lower cut-offs detect more patients at risk in individuals with suspected AMI. Correlations of troponin I with age, gender and traditional risk factors were observed. CONCLUSIONS: Troponin I concentrations in apparently healthy individuals are dependent on prevalent cardiovascular diseases, traditional risk factors, gender and age. Application of corresponding cut-offs in diagnosis of AMI alters the group of patients potentially at risk.

Prognostic information of glycogen phosphorylase isoenzyme BB in patients with suspected acute coronary syndrome.

Early and adequate risk stratification is essential in patients with suspected acute coronary syndrome (ACS). The aim of the present study was to investigate whether glycogen phosphorylase BB (GPBB) could add prognostic information in the context of contemporary sensitive troponin I determination and B-type natriuretic peptide (BNP). Patients with suspected ACS were consecutively enrolled at 3 German study centers from January 2007 through December 2008. Troponin I, GPBB, and BNP were determined at admission. Follow-up information on the combined end point of death, myocardial infarction, revascularization, and hospitalization owing to a cardiovascular cause was obtained 6 months after enrollment. In total 1,818 patients (66% men) were enrolled of whom 413 (23%) were diagnosed as having acute myocardial infarction and 240 (13%) as having unstable angina pectoris, whereas in 1,165 patients (64%) an ACS could be excluded. Follow-up information was available in 98% of patients; 203 events were registered. GPBB measured on admission predicted an unfavorable outcome with a hazard ratio of 1.24 (p <0.05) in an unadjusted Cox regression model and showed a tendency with a hazard ratio of 1.13 (p = 0.07) in a fully adjusted model. Kaplan-Meier analysis revealed a poorer outcome in patients with increased GPBB levels amendatory to the information provided by troponin I or BNP. In conclusion, GPBB measurement provides predictive information on midterm prognosis in patients with chest pain in addition to BNP and troponin I.

Multiple endothelial biomarkers and noninvasive vascular function in the general population: the Gutenberg Health Study.

Vascular reactivity is reflected by blood biomarkers and noninvasive vascular function measurement. The relation of biomarkers to flow-mediated dilation and peripheral arterial tonometry in the general population is little understood. In 5000 individuals (mean age, 56±11 years; age range, 35-74 years; 49% women) of the population-based Gutenberg Health Study we simultaneously assessed 6 biomarkers of cardiovascular function (midregional proadrenomedullin [MR-proADM], midregional pro atrial natriuretic peptide [MR-proANP], N-terminal pro B-type natriuretic peptide, copeptin, C-terminal proendothelin 1, and neopterin) in relation to flow-mediated dilation and peripheral arterial tonometry. Strongest partial correlations (adjusted for age and sex) were observed for baseline pulse amplitude with MR-proADM (r=0.13) and MR-proANP (r=-0.13); hyperemic response variables showed the highest correlation for MR-proADM and peripheral arterial tonometry ratio (r=-0.14). In multivariable linear regression models, strongest associations with baseline vascular function were observed for MR-proANP with baseline pulse amplitude (ß per SD increase [99.17%], -0.080 [-0.115 to -0.044]; P<0.0001 after Bonferroni correction for multiple testing) and MR-proADM (-0.044 [-0.070 to -0.017]; P<0.0001), as well as MR-proANP (-0.033 [-0.057 to -0.009]; P=0.0017) and N-terminal pro B-type natriuretic peptide (-0.027 [-0.051 to -0.003]; P=0.015) with brachial artery diameter. For hyperemic response variables, highest associations were seen for peripheral arterial tonometry ratio with MR-proADM (-0.022 [-0.043 to -0.004]; P=0.043), MR-proANP (0.016 [-0.0034 to 0.035]; P=0.18), and C-terminal proendothelin 1 (-0.025 [-0.043 to -0.008]; P=0.00094]. In our large, population-based study, we identified MR-proADM and MR-proANP as circulating biomarkers of vascular function most strongly related to noninvasive measures of conduit artery and peripheral arterial performance. Whether determination of blood biomarkers helps to better understand vascular pathology and may provide prognostic information needs to be investigated in future studies.