Bernhard O Boehm

Publications of Bernhard O Boehm

• Influence of Resting Heart Rate on Mortality in Patients Undergoing Coronary Angiography (from the Ludwigshafen Risk and Cardiovascular Health [LURIC] Study).

  Authors: Bríain O Hartaigh, Jos A Bosch, Stefan Pilz, Adrian Loerbroks, Marcus E Kleber, Tanja B Grammer, Joachim E Fischer, Bernhard O Boehm, G Neil Thomas, Winfried März

  The American journal of cardiology. 05/2012;

  Several epidemiologic studies have reported an association between elevated heart rate (HR) at rest and reduced survival. The usefulness of HR at rest in predicting end points in high-risk patientsSeveral epidemiologic studies have reported an association between elevated heart rate (HR) at rest and reduced survival. The usefulness of HR at rest in predicting end points in high-risk patients is yet to be definitively established. The purpose of this study was to clarify the relation between HR at rest with total and cardiovascular mortality in patients who underwent coronary angiography. A total of 3,316 Caucasian patients with available coronary angiograms were prospectively followed from 2001 to 2011 (median 9.9 years). The effect of HR at rest on total and cardiovascular mortality was explored, while correcting for a number of confounders. Patients in the highest quartile (HR at rest ≥84 beats/min) had survival times reduced by 1.2 and 1.4 years for overall and cardiovascular mortality, respectively. Likewise, these patients had significantly elevated adjusted risk for total (hazard ratio 1.39, 95% confidence interval 1.17 to 1.67, p for trend <0.001) and cardiovascular mortality (hazard ratio 1.38, 95% confidence interval 1.08 to 1.78, p for trend = 0.004). In conclusion, HR at rest is an inexpensive, easily measured, and modifiable predictor of mortality.

• Combination of low free testosterone and low vitamin D predicts mortality in older men referred for coronary angiography.

  Authors: Elisabeth Lerchbaum, Stefan Pilz, Bernhard O Boehm, Tanja B Grammer, Barbara Obermayer-Pietsch, Winfried März

  Clinical endocrinology. 02/2012;

  CONTEXT: Low levels of 25-hydroxyvitamin D (25(OH)D) and free testosterone (FT) are both associated with increased mortality. Experimental studies show a complex interplay of vitamin D and androgenCONTEXT: Low levels of 25-hydroxyvitamin D (25(OH)D) and free testosterone (FT) are both associated with increased mortality. Experimental studies show a complex interplay of vitamin D and androgen metabolism suggesting that a deficiency of both hormones may be associated with a particularly adverse clinical outcome. OBJECTIVE: To evaluate the impact of parallel FT and 25(OH)D deficiency in a large cohort of older men. DESIGN: We measured total testosterone (TT), SHBG, and 25(OH)D levels in 2069 men who were routinely referred for coronary angiography (1997-2000). MAIN OUTCOME MEASURES: Cox proportional hazard ratios (HRs) (with 95% confidence intervals) for mortality from all causes, cardiovascular, and non-cardiovascular causes according to combined deficiency of FT and 25(OH)D. RESULTS: In multivariate adjusted analyses, we found an increased risk for all-cause mortality, cardiovascular and non-cardiovascular mortality for men in the lowest FT (HR 1.26 [1.03-1.54], 1.24 [0.96-1.60], and 1.39 [1.00-1.93], respectively) and 25(OH)D quartile (HR 1.77 [1.47-2.13], 1.65 [1.29-2.10], and 1.89 [1.38-2.60] respectively) compared to men in higher FT and 25(OH)D quartiles. There was no independent association of TT levels with mortality. Multivariate adjusted HRs progressively increased with the number of hormones (FT and 25(OH)D) in the lowest quartile (0 vs 2 hormone deficiencies: 2.11 [1.60-2.79] for all cause, 1.77 [1.23-2.55] for cardiovascular, and 2.33 [1.45-3.47] for non-cardiovascular mortality respectively). CONCLUSION: A combined deficiency of FT and 25(OH)D is significantly associated with fatal events in a large cohort of men referred for coronary angiography. © 2012 Blackwell Publishing Ltd.

• Duration of type 2 diabetes strongly predicts all-cause and cardiovascular mortality in people referred for coronary angiography.

  Authors: Guenther Silbernagel, Silke Rosinger, Tanja B Grammer, Marcus E Kleber, Bernhard R Winkelmann, Bernhard O Boehm, Winfried März

  Atherosclerosis. 01/2012;

  OBJECTIVE: Type 2 diabetes represents a major cardiovascular risk factor. However, few studies have addressed the impact of the disease duration on mortality. Thus, we aimed to investigate theOBJECTIVE: Type 2 diabetes represents a major cardiovascular risk factor. However, few studies have addressed the impact of the disease duration on mortality. Thus, we aimed to investigate the predictive value of diabetes duration for all-cause and cardiovascular mortality in subjects undergoing coronary angiography. METHODS: We studied 2455 participants of the LUdwigshafen RIsk and Cardiovascular health study (1768 males/687 females). They had a mean±standard deviation (SD) age of 63.1±9.0 years (range: 40.0-79.9) and a mean±SD body mass index of 27.7±4.0kg/m(2). 704 subjects were newly diagnosed with type 2 diabetes according to the 2010 criteria of the American Diabetes Association and 446 subjects had a known history of type 2 diabetes. The mean±SD duration of the follow-up for all-cause and cardiovascular mortality was 7.4±2.3 years. RESULTS: A total of 543 deaths occurred during the follow-up. Among these, 343 were accounted for by cardiovascular diseases. The duration of type 2 diabetes was strongly and positively correlated with all-cause and cardiovascular mortality (both P<0.001). The multivariate adjusted hazard ratios (95% confidence intervals) for cardiovascular mortality compared to subjects without diabetes were 1.76 (1.34-2.32), 2.86 (2.00-4.08), 2.96 (1.85-4.74), and 4.55 (3.24-6.39) for subjects with new onset type 2 diabetes and subjects with known type 2 diabetes (duration ≤5, >5 and ≤10, >10 years), respectively. CONCLUSIONS: The data emphasise the need to consider the diabetes duration for the prediction of mortality in subjects at intermediate to high cardiovascular risk.

• A genome-wide association search for type 2 diabetes genes in African Americans.

  Authors: Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock [......] Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Robert Sladek

  PloS one. 01/2012; 7(1):e29202.

  African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was toAfrican Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

• Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome.

  Authors: Thomas M Morgan, John A House, Sharon Cresci, Philip Jones, Hooman Allayee, Stanley L Hazen, Yesha Patel, Riyaz S Patel, Danny J Eapen, Salina P Waddy, Arshed A Quyyumi, Marcus E Kleber, Winfried März, Bernhard R Winkelmann, Bernhard O Boehm, Harlan M Krumholz, John A Spertus

  BMC medical genetics. 09/2011; 12:127.

  Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yetGenome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated. We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients. After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086). We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease.

• Additional use of glycated hemoglobin for diagnosis of type 2 diabetes in people undergoing coronary angiography reveals a subgroup at increased cardiovascular risk.

  Authors: Guenther Silbernagel, Marcus E Kleber, Tanja B Grammer, Bernhard R Winkelmann, Bernhard O Boehm, Winfried März

  Diabetes care. 09/2011; 34(11):2471-3.

  To study the prognosis of people with newly diagnosed type 2 diabetes as per the American Diabetes Association (ADA) 2010 definition but without diabetes as per the ADA 2009 definition. A total ofTo study the prognosis of people with newly diagnosed type 2 diabetes as per the American Diabetes Association (ADA) 2010 definition but without diabetes as per the ADA 2009 definition. A total of 2,002 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study without a history of diabetes were studied. During the follow-up of a mean duration ± SD of 7.7 ± 2.0 years, 346 people died (202 cardiovascular deaths). Subjects with type 2 diabetes as per the ADA 2009 definition (n = 468) had significantly increased all-cause and cardiovascular mortality compared with people without diabetes as per the ADA 2010 definition (both P ≤ 0.003). Subjects with type 2 diabetes as per the ADA 2010 definition but without diabetes as per the ADA 2009 definition (n = 150) were at significantly increased risk to die of cardiovascular diseases (P = 0.029). Use of the ADA 2010 diabetes definition may be instrumental in improving cardiovascular risk stratification in people undergoing coronary angiography.

• Large-scale gene-centric analysis identifies novel variants for coronary artery disease

  Authors: Adam S Butterworth, Peter S Braund, Martin Farrall, Robert J Hardwick, Danish Saleheen, John F Peden, Nicole Soranzo, John C Chambers, Suthesh Sivapalaratnam, Marcus E Kleber [......] Anders Hamsten, Alistair S Hall, Jaspal S Kooner, Simon G Thompson, John R Thompson, Panos Deloukas, Willem H Ouwehand, Hugh Watkins, John Danesh, Nilesh J Samani

  PLoS Genetics. 09/2011; 7(9):e1002260.

  Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematicCoronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.

• Low free testosterone levels are associated with all-cause and cardiovascular mortality in postmenopausal diabetic women.

  Authors: Elisabeth Wehr, Stefan Pilz, Bernhard O Boehm, Tanja B Grammer, Winfried März, Barbara Obermayer-Pietsch

  Diabetes care. 06/2011; 34(8):1771-7.

  Hyperandrogenemia is associated with cardiovascular risk factors in women but evidence about the relationship of testosterone levels with mortality is sparse. We aimed to evaluate whether totalHyperandrogenemia is associated with cardiovascular risk factors in women but evidence about the relationship of testosterone levels with mortality is sparse. We aimed to evaluate whether total testosterone (TT), free testosterone (FT), and sex hormone-binding globulin (SHBG) are associated with all-cause and cardiovascular mortality in a cohort of postmenopausal women. We measured TT and SHBG levels in 875 postmenopausal women who were referred for coronary angiography (during 1997-2000). FT was calculated according to the Vermeulen method. The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes and from cardiovascular causes. After a median follow-up time of 7.7 years, 179 women (20.5%) had died. There were 101 deaths due to cardiovascular disease (56.4% of all deaths). We found no association of FT, TT, and SHBG levels with mortality in all postmenopausal women. In postmenopausal diabetic women, multivariable-adjusted HRs (with 95% CIs) in the fourth compared with the first FT quartile for all-cause and cardiovascular mortality were 0.38 (0.08-0.90), P = 0.025, and 0.28 (0.08-0.90), P = 0.032, respectively. We found no association of TT and SHBG with mortality in diabetic postmenopausal women. In postmenopausal diabetic women referred for coronary angiography, low FT levels are independently associated with increased all-cause and cardiovascular mortality.

• Lipopolysaccharide-binding protein (LBP) is associated with total and cardiovascular mortality in individuals with or without stable coronary artery disease--results from the Ludwigshafen Risk and Cardiovascular Health Study (LURIC).

  Authors: Philipp M Lepper, Marcus E Kleber, Tanja B Grammer, Kristina Hoffmann, Simone Dietz, Bernhard R Winkelmann, Bernhard O Boehm, Winfried März

  Atherosclerosis. 06/2011; 219(1):291-7.

  Atherosclerosis of coronary arteries is hallmarked by non-specific local inflammatory processes accompanied by a systemic response. Lipopolysaccharide-binding protein (LBP) has been suggested to beAtherosclerosis of coronary arteries is hallmarked by non-specific local inflammatory processes accompanied by a systemic response. Lipopolysaccharide-binding protein (LBP) has been suggested to be associated with coronary artery disease (CAD) in a previous study without follow-up. LBP plasma levels were measured in 2959 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort study referred to coronary angiography at baseline between 1997 and 2000. Median follow-up time was 8.0 years. Primary and secondary end points were cardiovascular and all-cause mortality, respectively. Multivariable adjusted logistic regression analyses were conducted to investigate the role of LBP. Serum LBP concentration was significantly increased in 2298 patients with angiographically confirmed CAD compared to 661 individuals without coronary atherosclerosis (6.78 μg/mL (5.46-8.84) vs. 6.13 μg/mL (5.05-7.74), respectively; p<0.001). Moreover in multivariable logistic regression analyses, adjusted for established cardiovascular risk factors and markers of systemic inflammation, LBP was a significant and independent predictor of total and cardiovascular mortality (hazard ratio (HR) for all cause mortality: 1.43, 95% CI: 1.06-1.94, p=0.024; HR for cardiovascular mortality in the 4th quartile of LBP: 1.55, 95% CI: 1.06-2.27, p=0.025). The present results add information on LBP in CAD. The data underscore the potential importance of innate immune mechanisms for atherosclerosis. Further studies are needed to clarify the pathways between innate immune system activation and atherosclerosis.

• Glycated hemoglobin predicts all-cause, cardiovascular, and cancer mortality in people without a history of diabetes undergoing coronary angiography.

  Authors: Guenther Silbernagel, Tanja B Grammer, Bernhard R Winkelmann, Bernhard O Boehm, Winfried März

  Diabetes care. 06/2011; 34(6):1355-61.

  Glycated hemoglobin has been suggested to be superior to fasting glucose for the prediction of vascular disease and death from any cause. The aim of the present work was to analyze and compare theGlycated hemoglobin has been suggested to be superior to fasting glucose for the prediction of vascular disease and death from any cause. The aim of the present work was to analyze and compare the predictive value of glycated hemoglobin and fasting glucose on all-cause and cause-specific mortality in subjects who underwent coronary angiography. We studied 2,686 participants of the Ludwigshafen Risk and Cardiovascular health study without a history of diabetes. The majority of this cohort had coronary artery disease. Glycated hemoglobin was measured at the baseline examination. The mean (± SD) duration of the follow-up for all-cause, cardiovascular, and cancer mortality was 7.54 ± 2.1 years. A total of 508 deaths occurred during the follow-up. Of those, 299 were accounted for by cardiovascular diseases and 79 by cancer. Baseline glycated hemoglobin was predictive of all-cause, cardiovascular, and cancer mortality. The multivariable-adjusted hazard ratios (HR) (95% CI) for glycated hemoglobin values of <5.0, 5.0-5.4, 5.5-5.9, 6.0-6.4, 6.5-7.4, and ≥7.5% for all-cause mortality were 1.36 (0.85-2.18), 1.00 (0.76-1.32), 1.00 (reference), 1.11 (0.88-1.41), 1.39 (1.07-1.82), and 2.15 (1.32-3.53), respectively. Similar J-shaped relationships were found between glycated hemoglobin and cardiovascular and cancer mortality. The associations of glycated hemoglobin with all-cause and cardiovascular mortality remained significant after inclusion of fasting glucose as a covariate. However, fasting glucose was not significantly related to mortality when adjusting for glycated hemoglobin. Glycated hemoglobin significantly and independently of fasting glucose predicts all-cause and cardiovascular mortality in whites at intermediate to high cardiovascular risk.

• Associations of plasma renin with 10-year cardiovascular mortality, sudden cardiac death, and death due to heart failure.

  Authors: Andreas Tomaschitz, Stefan Pilz, Eberhard Ritz, Alberto Morganti, Tanja Grammer, Karin Amrein, Bernhard O Boehm, Winfried März

  European heart journal. 05/2011; 32(21):2642-9.

  Renin is the key regulator of the renin-angiotensin-aldosterone system. Previous studies have reported conflicting results on the relation of plasma renin with fatal cardiovascular events. This studyRenin is the key regulator of the renin-angiotensin-aldosterone system. Previous studies have reported conflicting results on the relation of plasma renin with fatal cardiovascular events. This study in a large cohort of patients sought to evaluate the association between plasma renin concentration (PRC) and cardiovascular mortality after long-term follow-up of almost 10 years. Plasma renin concentration [median: 11.4 (6.0-24.6) pg/mL] was measured in 3303 patients (mean age: 62.7 ± 10.6 years; 30.3% women) referred to coronary angiography. After a median follow-up of 9.9 years, 554 participants (16.8%) with PRC measurement at baseline had died due to fatal cardiovascular events. Multivariable-adjusted Cox analysis revealed that when compared with participants in the lowest PRC quartile, those in the highest quartile were at increased risk of cardiovascular mortality (hazard ratio: 1.79, 95% CI 1.28-2.48). Analyses of specific causes of cardiovascular death showed that for each standard deviation increase in log-PRC there was a 22% (P = 0.006) increase in risk of sudden cardiac death and a 23% (P = 0.033) greater risk of death due to heart failure. The association of PRC with cardiovascular mortality remained stable after adjustment for established cardiovascular risk factors, ongoing antihypertensive medication, immunoreactive angiotensin II, and aldosterone levels. Age, N-terminal pro-B-type natriuretic peptide levels, coronary artery disease, the use of angiotensin-converting enzyme-inhibitors, beta-blockers, diuretics, and kidney function were important effect modifiers. Plasma renin concentration is associated with long-term cardiovascular mortality in patients referred to coronary angiography. Further intervention studies should determine whether renin is a potential therapeutic target or only a marker of mortality risk in various cardiovascular risk groups.

• Low homoarginine concentration is a novel risk factor for heart disease.

  Authors: Stefan Pilz, Andreas Meinitzer, Andreas Tomaschitz, Christiane Drechsler, Eberhard Ritz, Vera Krane, Christoph Wanner, Bernhard O Boehm, Winfried März

  Heart (British Cardiac Society). 05/2011; 97(15):1222-7.

  Homoarginine is an amino acid which may play a role in nitric oxide and energy metabolism. Low homoarginine concentrations have previously been linked to increased mortality, but the underlyingHomoarginine is an amino acid which may play a role in nitric oxide and energy metabolism. Low homoarginine concentrations have previously been linked to increased mortality, but the underlying mechanisms remain unknown. To investigate whether serum homoarginine concentrations are associated with myocardial function, energy metabolism and fatal events. Serum homoarginine concentrations were measured in 3305 Caucasian patients who were referred for coronary angiography at a tertiary care centre in Germany. After baseline examinations (1997-2000), patients were followed-up with respect to specific causes of death. Homoarginine concentration correlated positively with angiographic ejection fraction and was inversely associated with N-terminal pro-B-type natriuretic peptide (p<0.001 for both). Variables of energy metabolism (guanidinoacetate and creatine) were significantly associated with homoarginine concentration (p<0.001 for both). Over a median follow-up time of 9.9 years, 991 patients died, including 258 sudden cardiac deaths, 148 heart failure deaths and 105 fatal myocardial infarctions. Multivariable adjusted Cox proportional HRs (with 95% CI) for the first versus the fourth homoarginine quartile were 2.44 (1.60 to 3.73) for sudden cardiac deaths, 3.44 (1.89 to 6.24) for heart failure deaths, and 3.78 (1.77 to 8.06) for fatal myocardial infarctions. Homoarginine deficiency is associated with myocardial dysfunction and significantly increased risk of fatal cardiovascular events and may be related to poor energy metabolism. Further studies are warranted to explore the significance of homoarginine metabolism in risk stratification and treatment of heart diseases.

• Arginine bioavailability ratios are associated with cardiovascular mortality in patients referred to coronary angiography.

  Authors: Harald Sourij, Andreas Meinitzer, Stefan Pilz, Tanja B Grammer, Bernhard R Winkelmann, Bernhard O Boehm, Winfried März

  Atherosclerosis. 05/2011; 218(1):220-5.

  Arginine is the only source for nitric oxide (NO) synthesis. The bioavailability of NO plays a pivotal role in endothelial function and consequently in cardiovascular disease. The aim of the currentArginine is the only source for nitric oxide (NO) synthesis. The bioavailability of NO plays a pivotal role in endothelial function and consequently in cardiovascular disease. The aim of the current study is to investigate the association of arginine bioavailability ratios with markers of endothelial function and cardiovascular mortality in patients referred to coronary angiography. We investigated 2236 patients recruited within the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study that were followed up for a median of 7.7 years. Arginine, ornithine and citrulline were chromatographically determined after precolumn-derivatisation followed by postcolumn continuous reaction with ninhydrin. Global arginine bioavailability (GABR) was calculated by arginine divided by the sum of ornithine plus citrulline. We observed a significant rise in cardiovascular mortality with decreasing GABR and arginine to ornithine ratio quartiles. The adjusted Cox proportional HRs for GABR were 1.27 (0.88-1.83), 1.27 (0.89-1.80) and 1.75 (1.24-2.45) for the 3rd, the 2nd and the 1st quartile respectively in comparison to the 4th quartile. The HRs for the quartiles of the arginine to ornithine ratio were 1.83 (1.25-2.67), 2.17 (1.50-3.20) and 2.02 (1.39-2.92) respectively. Patients with type 2 diabetes mellitus had a significantly lower GABR than persons without diabetes (0.88 ± 0.23 vs. 0.94 ± 0.24, p<0.001). GABR was found to be inversely correlated with endothelial markers as VCAM-1 (r=-0.301, p<0.001) or ICAM-1 (r=-0.136, p<0.001). GABR and the arginine to ornithine ratio are associated with markers of endothelial dysfunction and increased risk of cardiovascular mortality. Further studies are warranted to elucidate the pathobiology and clinical relevance of the arginine bioavailability ratios in cardio-metabolic diseases.

• Association of plasma aldosterone with cardiovascular mortality in patients with low estimated GFR: the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.

  Authors: Andreas Tomaschitz, Stefan Pilz, Eberhard Ritz, Tanja Grammer, Christiane Drechsler, Bernhard O Boehm, Winfried März

  American journal of kidney diseases : the official journal of the National Kidney Foundation. 03/2011; 57(3):403-14.

  We have previously shown that plasma aldosterone levels within the physiologic reference range predicted increased all-cause and cardiovascular disease (CVD) mortality in patients referred forWe have previously shown that plasma aldosterone levels within the physiologic reference range predicted increased all-cause and cardiovascular disease (CVD) mortality in patients referred for coronary angiography. Decreased kidney function is associated with a marked increase in CVD mortality that is not explained fully by known cardiovascular risk factors. We hypothesized that level of kidney function might modify the association between plasma aldosterone level and CVD mortality. Prospective cohort study. 3,153 patients (mean age, 62.7 ± 10.6 years; 30.1% women) free of primary kidney disease at baseline were referred for coronary angiography in a tertiary-care center in Southwest Germany between 1997 and 2000. Plasma aldosterone level, determined using radioimmunoassay. Tertiles of estimated glomerular filtration rate (eGFR) based on creatinine and cystatin C levels. CVD mortality and sudden cardiac death events at 7.75 years. At baseline, median plasma aldosterone concentration was 79.0 (25th-75th percentile, 48.0-124.0) pg/mL. Mean eGFR was 83.8 ± 20.1 (SD) mL/min/1.73 m(2), and mean eGFRs in tertiles 1-3 were 61.9 ± 13.0, 84.7 ± 4.4, and 104.7 ± 10.3 mL/min/1.73 m(2), respectively. After a median follow-up of 7.75 years, 454 (14.4%) patients died of cardiovascular causes and 179 (5.7%) died suddenly. Multivariate Cox proportional hazard analyses showed increased risks of CVD mortality (HR per 50-pg/mL increment in plasma aldosterone concentration, 1.08; 95% CI, 1.03-1.12; P = 0.001) and sudden cardiac death (HR, 1.11; 95% CI, 1.06-1.15; P < 0.001). In tertiles 1-3 of eGFR, adjusted HRs per 50-pg/mL increment in plasma aldosterone concentration for CVD mortality were 1.10 (95% CI, 1.05-1.14; P < 0.001), 1.00 (95% CI, 0.83-1.16; P = 0.8), and 0.97 (95% CI, 0.75-1.26; P = 0.8), respectively (product term for interaction, P = 0.001), and for sudden cardiac death were 1.13 (95% CI, 1.08-1.17; P < 0.001), 0.99 (95% CI, 0.75-1.29; P = 0.9), and 0.90 (95% CI, 0.60-1.34; P = 0.5), respectively (product term for interaction, P < 0.001). No urinary analysis was performed to assess dietary salt intake and proteinuria. Our findings suggest that the association of higher plasma aldosterone concentration with overall CVD mortality and sudden cardiac death is stronger for patients with lower kidney function.

• Vitamin D status and mortality in chronic kidney disease.

  Authors: Stefan Pilz, Andreas Tomaschitz, Claudia Friedl, Karin Amrein, Christiane Drechsler, Eberhard Ritz, Bernhard O Boehm, Tanja B Grammer, Winfried März

  Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 03/2011; 26(11):3603-9.

  Vitamin D deficiency is found in the majority of patients with chronic kidney disease (CKD) and may contribute to various chronic diseases. Current guidelines suggest correcting reducedVitamin D deficiency is found in the majority of patients with chronic kidney disease (CKD) and may contribute to various chronic diseases. Current guidelines suggest correcting reduced 25-hydroxyvitamin D [25(OH)D] concentrations in CKD patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2). Whether low 25(OH)D levels in these patients are associated with higher mortality is unclear. This issue was addressed in the present work. We examined 444 patients with eGFR <60 mL/min/1.73 m(2) from the Ludwigshafen Risk and Cardiovascular Health Study. This prospective cohort study includes Caucasian patients without primary kidney disease who were routinely referred to coronary angiography at baseline (1997-2000). During a median follow-up time of 9.4 years, 227 patients died including 159 deaths from cardiovascular causes. Multivariate adjusted hazard ratios (HRs) (with 95% confidence intervals) in severely vitamin D-deficient [25(OH)D <10 ng/mL] compared to vitamin D-sufficient patients [25(OH)D ≥ 30 ng/mL] were 3.79 (1.71-8.43) for all-cause and 5.61 (1.89-16.6) for cardiovascular mortality. Adjusted HRs per 10 ng/mL increase in 25(OH)D levels were 0.63 (0.50-0.79) for all-cause and 0.59 (0.45-0.79) for cardiovascular mortality. There was no significant interaction with parathyroid hormone concentrations. Low 25(OH)D levels are associated with increased all-cause and cardiovascular mortality in CKD patients. These findings support suggestions to correct vitamin D deficiency, but whether vitamin D supplementation improves survival remains to be proven in randomized controlled trials.

• Was the serine protease cathepsin G discovered by S. G. Hedin in 1903 in bovine spleen?

  Authors: David Palesch, Marcin Sieńczyk, Jozef Oleksyszyn, Michael Reich, Ewa Wieczerzak, Bernhard O Boehm, Timo Burster

  Acta biochimica Polonica. 03/2011; 58(1):39-44.

  In the beginning of the 20th century, enzymes with proteolytic activity were classified as peptidases, Erepsin, and proteases. Among these, pepsin, trypsin, and autolytic enzymes were of the proteaseIn the beginning of the 20th century, enzymes with proteolytic activity were classified as peptidases, Erepsin, and proteases. Among these, pepsin, trypsin, and autolytic enzymes were of the protease class. Spleen-derived proteases were poorly characterized until Sven Gustaf Hedin performed several digestion experiments with bovine spleen. He incubated minced bovine spleen under acidic or neutral conditions and characterized two active proteases; the results were published in 1903. The first protease was named α-protease and was active under neutral conditions. The second was named β-protease and was active under acidic conditions. We replicated Hedin's experiments according to his methods and found, by using activity-based probes to visualize proteases, that the historical α-protease is the present-day serine protease cathepsin G (CatG), which is known to be important in several immune processes, including antigen processing, chemotaxis, and activation of surface receptors. The β-protease, however, comprised different proteases including CatX, B, S, and D. We suggest that Hedin described CatG activity in bovine spleen over 100 years ago.

• Association of TCF7L2 SNPs with age at onset of type 2 diabetes and proinsulin/insulin ratio but not with glucagon-like peptide 1.

  Authors: Guenther Silbernagel, Wilfried Renner, Tanja B Grammer, Sigrun R Hügl, Julia Bertram, Marcus E Kleber, Michael M Hoffmann, Bernhard R Winkelmann, Winfried März, Bernhard O Boehm

  Diabetes/metabolism research and reviews. 03/2011; 27(5):499-505.

  Variants in TCF7L2 have been associated with the age at onset of type 2 diabetes in Mexican Americans. However, there is a lack of data on this relationship in Caucasians. Furthermore, risk allelesVariants in TCF7L2 have been associated with the age at onset of type 2 diabetes in Mexican Americans. However, there is a lack of data on this relationship in Caucasians. Furthermore, risk alleles in TCF7L2 have been suggested to account for decreased conversion of proinsulin to insulin and decreased expression of GLP-1. We investigated the effect of the allelic variants rs1225537 and rs7903146 in TCF7L2 on the age at onset of type 2 diabetes, the plasma concentrations of proinsulin and GLP-1, and the ratio of proinsulin to insulin in a German cohort. We studied 3185 participants of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. Among these, 1021 subjects had type 2 diabetes. Data on age at onset of diabetes were available in 925 subjects. OGTTs were performed in a subgroup not previously known to have diabetes. Carriers of the risk alleles in rs1225537 and rs7901346 had increased risk of type 2 diabetes and elevated HbA(1c) (all p < 0.001). The risk alleles were also associated with early onset of type 2 diabetes, decreased insulin secretion and markedly increased proinsulin and proinsulin to insulin ratio (all p < 0.03). GLP-1 was not significantly related to the TCF7L2 genotype. Our data demonstrate that TCF7L2 variants are associated with an early age of onset of type 2 diabetes in Caucasians and affects the conversion of proinsulin to insulin. However, TCF7L2 is not consistently associated with fasting GLP-1.

• The lipid accumulation product is associated with increased mortality in normal weight postmenopausal women.

  Authors: Elisabeth Wehr, Stefan Pilz, Bernhard O Boehm, Winfried März, Barbara Obermayer-Pietsch

  Obesity (Silver Spring, Md.). 03/2011; 19(9):1873-80.

  Lipid accumulation product (LAP) is an emerging cardiovascular risk factor, which is calculated from waist circumference (WC) and triglyceride (TG) levels. The aim of this study was to elucidate theLipid accumulation product (LAP) is an emerging cardiovascular risk factor, which is calculated from waist circumference (WC) and triglyceride (TG) levels. The aim of this study was to elucidate the relationship between LAP and cardiovascular mortality as well as the presence of type 2 diabetes with respect to gender-specific differences. We determined WC and fasting TG levels and the cardiovascular and metabolic phenotypes coronary artery disease (CAD), hypertension, metabolic syndrome, and diabetes mellitus in 2,279 men and 875 postmenopausal women who were routinely referred to coronary angiography. The LAP was calculated as (WC (cm)--65) × (TG (mmol/l)) for men and as (WC (cm)--58) × (TG (mmol/l)) for women. LAP levels were independently associated with congestive heart failure mortality in all postmenopausal women and with all-cause mortality in diabetic postmenopausal women but not in men. Multivariable-adjusted hazard ratios (with 95% confidence intervals) for all-cause, cardiovascular, and congestive heart failure mortality in the third compared to the first LAP tertile were 4.28 (1.94-9.44; P < 0.001), 3.47 (1.28-9.40; P = 0.015), and 10.77 (1.21-95.88; P = 0.033), respectively, in normal weight postmenopausal women, whereas no significant associations were found in men. LAP levels were highly associated with type 2 diabetes in all subjects, postmenopausal women, and men. High LAP values are predictive of mortality independently of other cardiovascular risk factors in normal weight and diabetic postmenopausal women but not in men. Type 2 diabetes (T2DM) was highly associated with LAP in women and men. Our study validates an inexpensive and simple risk profiling that may allow identifying postmenopausal women at high cardiovascular risk.

• Low free testosterone is associated with heart failure mortality in older men referred for coronary angiography.

  Authors: Elisabeth Wehr, Stefan Pilz, Bernhard O Boehm, Winfried März, Tanja Grammer, Barbara Obermayer-Pietsch

  European journal of heart failure. 02/2011; 13(5):482-8.

  Accumulating evidence suggests that androgen deficiency is associated with cardiovascular disease. We aimed at evaluating whether total testosterone (TT) and free testosterone (FT) are associatedAccumulating evidence suggests that androgen deficiency is associated with cardiovascular disease. We aimed at evaluating whether total testosterone (TT) and free testosterone (FT) are associated with specific cardiovascular events. We measured TT and sex-hormone-binding globulin levels in 2078 men who were routinely referred for coronary angiography between 1997 and 2000. Free testosterone was calculated according to Vermeulen. Main outcome measures were Cox proportional hazard ratios (HRs) for sudden cardiac death, fatal myocardial infarction, death from congestive heart failure (CHF), as well as other cardiac deaths according to quartiles of TT and FT. The median follow-up time was 7.7 years. Multivariable adjusted HRs (with 95% confidence intervals) in the fourth compared with the first FT quartile and per 1 SD increase in FT for CHF mortality were 0.38 (0.17-0.87) and 0.37 (0.15-0.89), respectively. We observed no independent significant association of FT with sudden cardiac death, fatal myocardial infarction, or other cardiac death. There was no independent association of TT levels with cardiovascular events or cardiac disease. Low levels of FT are independently associated with increased CHF mortality.

• Corrigendum: Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.

  Authors: Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson [......] Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy

  Nature genetics. 01/2011; 43(4):388.