Martina Bröcker-Preuss

Coronary Risk Stratification, Discrimination, and Reclassification Improvement Based on Quantification of Subclinical Coronary Atherosclerosis: The Heinz Nixdorf Recall Study

OBJECTIVES The purpose of this study was to determine net reclassification improvement (NRI) and improved risk prediction based on coronary artery calcification (CAC) scoring in comparison with traditional risk factors. BACKGROUND CAC as a sign of subclinical coronary atherosclerosis can noninvasively be detected by CT and has been suggested to predict coronary events. METHODS In 4,129 subjects from the HNR (Heinz Nixdorf Recall) study (age 45 to 75 years, 53% female) without overt coronary artery disease at baseline, traditional risk factors and CAC scores were measured. Their risk was categorized into low, intermediate, and high according to the Framingham Risk Score (FRS) and National Cholesterol Education Panel Adult Treatment Panel (ATP) III guidelines, and the reclassification rate based on CAC results was calculated. RESULTS After 5 years of follow-up, 93 coronary deaths and nonfatal myocardial infarctions occurred (cumulative risk 2.3%; 95% confidence interval: 1.8% to 2.8%). Reclassifying intermediate (defined as 10% to 20% and 6% to 20%) risk subjects with CAC <100 to the low-risk category and with CAC ≥400 to the high-risk category yielded an NRI of 21.7% (p = 0.0002) and 30.6% (p < 0.0001) for the FRS, respectively. Integrated discrimination improvement using FRS variables and CAC was 1.52% (p < 0.0001). Adding CAC scores to the FRS and National Cholesterol Education Panel ATP III categories improved the area under the curve from 0.681 to 0.749 (p < 0.003) and from 0.653 to 0.755 (p = 0.0001), respectively. CONCLUSIONS CAC scoring results in a high reclassification rate in the intermediate-risk cohort, demonstrating the benefit of imaging of subclinical coronary atherosclerosis. Our study supports its application, especially in carefully selected individuals with intermediate risk.

Running: the risk of coronary events Prevalence and prognostic relevance of coronary atherosclerosis in marathon runners

AIMS To quantify the prevalence of coronary artery calcification (CAC) in relation to cardiovascular risk factors in marathon runners, and to study its role for myocardial damage and coronary events. METHODS AND RESULTS In 108 apparently healthy male marathon runners aged >or=50 years, with >or=5 marathon competitions during the previous three years, the running history, Framingham risk score (FRS), CAC, and presence of myocardial late gadolinium enhancement (LGE) were measured. Control groups were matched by age (8:1) and FRS (2:1) from the Heinz Nixdorf Recall Study. The FRS in marathon runners was lower than in age-matched controls (7 vs. 11%, P < 0.0001). However, the CAC distribution was similar in marathon runners and age-matched controls (median CAC: 36 vs. 38, P = 0.36) and higher in marathon runners than in FRS-matched controls (median CAC: 36 vs. 12, P = 0.02). CAC percentile values and number of marathons independently predicted the presence of LGE (prevalence = 12%) (P = 0.02 for both). During follow-up after 21.3 +/- 2.8 months, four runners with CAC >or= 100 experienced coronary events. Event-free survival was inversely related to CAC burden (P = 0.018). CONCLUSION Conventional cardiovascular risk stratification underestimates the CAC burden in presumably healthy marathon runners. As CAC burden and frequent marathon running seem to correlate with subclinical myocardial damage, an increased awareness of a potentially higher than anticipated coronary risk is warranted.

Chronic Residential Exposure to Particulate Matter Air Pollution and Systemic Inflammatory Markers

Background Long-term exposure to urban air pollution may accelerate atherogenesis, but mechanisms are still unclear. The induction of a low-grade systemic inflammatory state is a plausible mechanistic pathway. Objectives: We analyzed the association of residential long-term exposure to particulate matter (PM) and high traffic with systemic inflammatory markers. Methods We used baseline data from the German Heinz Nixdorf Recall Study, a population-based, prospective cohort study of 4,814 participants that started in 2000. Fine PM [aerodynamic diameter ≤ 2.5 μm (PM2.5)] exposure based on a small-scale dispersion and chemistry transport model was assigned to each home address. We calculated distances between residences and major roads. Long-term exposure to air pollution (annual PM2.5 and distance to high traffic) and concentration of inflammatory markers [high-sensitivity C-reactive protein (hs-CRP) and fibrinogen] on the day of the baseline visit were analyzed with sex-stratified multiple linear regression, controlling for individual-level risk factors. Results In the adjusted analysis, a cross-sectional exposure difference of 3.91 μg/m3 in PM2.5 (interdecile range) was associated with increases in hs-CRP of 23.9% [95% confidence interval (CI), 4.1 to 47.4%] and fibrinogen of 3.9% (95% CI, 0.3 to 7.7%) in men, whereas we found no association in women. Chronic traffic exposure was not associated with inflammatory markers. Short-term exposures to air pollutants and temperature did not influence the results markedly. Conclusions Our study indicates that long-term residential exposure to high levels of PM2.5 is associated with systemic inflammatory markers in men. This might provide a link between air pollution and coronary atherosclerosis.

Circulating progenitor cells decrease immediately after marathon race in advanced-age marathon runners

Introduction Exercise is thought to stimulate the release of hematopoietic and endothelial progenitor cells (EPC) from the bone marrow. Little is known about the influence of strenuous exercise on the content of circulating progenitor cells. The aim of this study was to investigate the influence of a marathon race on the amount of circulating progenitor cells immediately after the race in advanced-aged runners. Methods Sixty-eight healthy marathon runners (age: 57 ± 6 years) were included in this study. Blood cell counts were evaluated by standard methods, and circulating progenitor cells before and immediately after the race were quantified by fluorescence-activated cell sorter (FACS). Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) was quantified by enzyme-linked immunosorbent assay. Results A marathon race led to a significant increase in white blood cell count (5283 ± 155 vs. 13706 ± 373 cells/μl; P < 0.001). Fluorescence-activated cell sorter analysis revealed a significant decrease of CD34pos cells (1829 ± 115 vs. 1175 ± 75 cells/ml blood; P < 0.0001), CD117pos cells (2478 ± 245 vs. 2193 ± 85 cells/ml blood; P < 0.05), and CD133pos cells (3505 ± 286 vs. 2239 ± 163 cells/ml blood; P < 0.001). No significant change was observed for EPCs defined as CD34pos/VEGF-R2pos cells (117 ± 8 vs. 128 ± 9cells/ml blood; P = 0.33). With respect to VEGF a significant downregulation was evident directly after the race (48.9 ± 8.0 vs. 34.0 ± 7.5 pg/ml; P < 0.05), whereas no change was obvious in EGF levels. Conclusion The results of our study suggest that finishing a marathon race will lead to an inflammatory response and downregulation of circulating hematopoietic stem cells. With respect to EPCs no change is observed, which may be because of a greater differentiation of the remaining CD34pos cells towards EPCs.

Association between source-specific particulate matter air pollution and hs-CRP: local traffic and industrial emissions.

Background: Long-term exposures to particulate matter air pollution (PM2.5 and PM10) and high traffic load have been associated with markers of systemic inflammation. Epidemiological investigations have focused primarily on total PM, which represents a mixture of pollutants originating from different sources. Objective: We investigated associations between source-specific PM and high-sensitive C-reactive protein (hs-CRP), an independent predictor of cardiovascular disease. Methods: We used data from the first (2000–2003) and second examination (2006–2008) of the Heinz Nixdorf Recall study, a prospective population-based German cohort of initially 4,814 participants (45–75 years of age). We estimated residential long-term exposure to local traffic- and industry-specific fine particulate matter (PM2.5) at participants’ residences using a chemistry transport model. We used a linear mixed model with a random participant intercept to estimate associations of source-specific PM and natural log-transformed hs-CRP, controlling for age, sex, education, body mass index, low- and high-density lipoprotein cholesterol, smoking variables, physical activity, season, humidity, and city (8,204 total observations). Results: A 1-μg/m3 increase in total PM2.5 was associated with a 4.53% increase in hs-CRP concentration (95% CI: 2.76, 6.33%). hs-CRP was 17.89% (95% CI: 7.66, 29.09%) and 7.96% (95% CI: 3.45, 12.67%) higher in association with 1-μg/m3 increases in traffic- and industry-specific PM2.5, respectively. Results for PM10 were similar. Conclusions: Long-term exposure to local traffic-specific PM (PM2.5, PM10) was more strongly associated with systemic inflammation than total PM. Associations of local industry-specific PM were slightly stronger but not significantly different from associations with total PM. Citation: Hennig F, Fuks K, Moebus S, Weinmayr G, Memmesheimer M, Jakobs H, Bröcker-Preuss M, Führer-Sakel D, Möhlenkamp S, Erbel R, Jöckel KH, Hoffmann B, Heinz Nixdorf Recall Study Investigative Group. 2014. Association between source-specific particulate matter air pollution and hs-CRP: local traffic and industrial emissions. Environ Health Perspect 122:703–710; http://dx.doi.org/10.1289/ehp.1307081

HDL-Bound Sphingosine 1-Phosphate (S1P) Predicts the Severity of Coronary Artery Atherosclerosis

Background: We have recently demonstrated a reduction in HDL-bound sphingosine 1-phosphate (S1P) in patients with stable coronary artery disease (CAD). In the current study, we tested whether HDL-associated S1P is predictive for the degree of coronary stenosis, restenosis and overall CAD severity on follow up in patients undergoing elective percutaneous coronary intervention (PCI). Methods: Coronary angiography of patients with CAD (n=59) undergoing elective PCI and presenting for a follow up after 6 months (n=48) was graded for disease severity defined clinically as 1- or multi-vessel disease. Target lesion stenosis was quantified by quantitative coronary angiography (QCA). S1P in plasma and isolated HDL were measured by mass spectrometry in the initial samples and in 32 available follow up samples. Results: HDL-bound S1P levels remained stable over time and correlated closely at first visit and follow up. While not associated with the extent of target lesion stenosis or restenosis, HDL-bound S1P correlated negatively with the overall severity of CAD and discriminated 1-vessel-disease from multi-vessel disease. Furthermore, low HDL-bound S1P was predictive for CAD extent. Conclusion: In stable CAD, HDL-bound S1P does not predict the degree of stenosis or restenosis of the target lesion but constitutes a marker of clinically defined disease burden.

Coronary atherosclerosis and cardiovascular risk in masters male marathon runners : Rationale and design of the marathon study

Background:Regular physical exercise is recommended to reduce cardiovascular mortality. And yet, atherosclerosis is the main cause of exercise-associated death in persons beyond age 35. The need for risk stratification in marathon runners is under discussion. The predictive value of modern imaging- and non-imaging-based markers of risk that can be used for risk stratification in masters endurance athletes still deserves exploration.Methods:Male runners > 50 years who have completed at least five marathon races during the preceding 3 years and do not suffer from coronary artery disease, angina nor diabetes mellitus are studied to assess the predictive value of established and modern imaging- based and biochemical cardiovascular risk factors. Laboratory parameters including clinical chemistry, hematology and hormone measurements are determined. Lifestyle-related risk factors, psychosocial and socioeconomic variables are explored using standardized questionnaires. Coronary, carotid, femoral and aortic atherosclerosis is measured using electronbeam computed tomography and ultrasound. In addition, a resting ECG, a bicycle stress test and heart rate variability are performed. Myocardial morphology and function are assessed using echocardiography and magnetic resonance imaging. Participants are invited to compete in a marathon race to quantify the association of coronary atherosclerosis with marathon-related changes of cardiac troponin levels and the extent of marathon-induced inflammation. At the cellular level, the effect on the amount of circulating progenitor cells (EPCs) is determined by FACS analysis. Changes in laboratory parameters and hormone levels are also studied. Annual long-term follow-up including hospital records and death certificates is performed. Data are compared with those from a general unselected cohort from the Heinz Nixdorf Recall Study.Conclusion:This study should contribute to cardiovascular risk assessment in the growing number of masters marathon runners with a focus on assessing the predictive value of modern imaging techniques and biochemical markers for comprehensive risk stratification.ZusammenfassungHintergrund:Regelmäßige körperliche Aktivität eignet sich zur Prävention der Arteriosklerose und kardiovaskulärer Ereignisse. Und dennoch ist die Arteriosklerose die Hauptursache sportassoziierter Todesfälle jenseits des 35. Lebensjahrs. Der prädiktive Nutzen moderner bildgebender Verfahren und biochemischer Marker, die für eine Risikostratifizierung in Frage kommen, wurde bei älteren Ausdauersportlern bislang nicht hinreichend untersucht.Methodik:Es werden Männer > 50 Jahre untersucht, die in den vergangenen 3 Jahren mindestens fünf Marathonläufe absolviert haben und keine bekannte Herzkrankheit oder Angina pectoris und keinen Diabetes mellitus aufweisen. Etablierte Risikofaktoren sowie moderne bildgebende und biochemische Risikomarker werden gemessen. Lebensstilassoziierte, psychosoziale und sozioökonomische Risikofaktoren werden mit standardisierten Fragebögen erhoben. Die Arteriosklerose der Koronararterien, der Karotiden, der Femoralarterien und der Aorta wird mittels Elektronenstrahltomographie und Ultraschall quantifiziert. Zusätzlich werden ein Ruhe-EKG, eine Fahrradergometrie und eine Messung der Herzfrequenzvariabilität durchgeführt. Morphologie und Funktion des linken Ventrikels werden echokardiographisch und magnetresonanztomographisch erfasst. Die Teilnehmer wurden gebeten, an einem Marathonwettkampf teilzunehmen, um die Assoziation von Koronarsklerose und dem marathoninduzierten Anstieg von kardialem Troponin in Abhängigkeit von der erwarteten Entzündungsreaktion zu untersuchen. Auf zellulärer Ebene wird der Effekt auf die Anzahl zirkulierender endothelialer Vorläuferzellen (EPCs) mittels FACS-Analyse bestimmt. Die Ereignisrate im Verlauf wird jährlich erfragt. Es werden auch Krankenhausdokumente und Sterbeunterlagen ausgewertet. Die Daten können im Vergleich zur Allgemeinbevölkerung aus der Heinz-Nixdorf-Recall-Studie analysiert werden.Schlussfolgerung:Diese Studie kann einen Beitrag zur kardiovaskulären Risikostratifikation in der wachsenden Gruppe älterer Marathonläufer leisten. Der prädiktive Wert der bildgebenden und biochemischen Marker für kardiovaskuläre Ereignisse wird untersucht.

Coronary Atherosclerosis and Cardiovascular Risk in Masters Male Marathon Runners

Background:Regular physical exercise is recommended to reduce cardiovascular mortality. And yet, atherosclerosis is the main cause of exercise-associated death in persons beyond age 35. The need for risk stratification in marathon runners is under discussion. The predictive value of modern imaging- and non-imaging-based markers of risk that can be used for risk stratification in masters endurance athletes still deserves exploration.Methods:Male runners > 50 years who have completed at least five marathon races during the preceding 3 years and do not suffer from coronary artery disease, angina nor diabetes mellitus are studied to assess the predictive value of established and modern imaging- based and biochemical cardiovascular risk factors. Laboratory parameters including clinical chemistry, hematology and hormone measurements are determined. Lifestyle-related risk factors, psychosocial and socioeconomic variables are explored using standardized questionnaires. Coronary, carotid, femoral and aortic atherosclerosis is measured using electronbeam computed tomography and ultrasound. In addition, a resting ECG, a bicycle stress test and heart rate variability are performed. Myocardial morphology and function are assessed using echocardiography and magnetic resonance imaging. Participants are invited to compete in a marathon race to quantify the association of coronary atherosclerosis with marathon-related changes of cardiac troponin levels and the extent of marathon-induced inflammation. At the cellular level, the effect on the amount of circulating progenitor cells (EPCs) is determined by FACS analysis. Changes in laboratory parameters and hormone levels are also studied. Annual long-term follow-up including hospital records and death certificates is performed. Data are compared with those from a general unselected cohort from the Heinz Nixdorf Recall Study.Conclusion:This study should contribute to cardiovascular risk assessment in the growing number of masters marathon runners with a focus on assessing the predictive value of modern imaging techniques and biochemical markers for comprehensive risk stratification.ZusammenfassungHintergrund:Regelmäßige körperliche Aktivität eignet sich zur Prävention der Arteriosklerose und kardiovaskulärer Ereignisse. Und dennoch ist die Arteriosklerose die Hauptursache sportassoziierter Todesfälle jenseits des 35. Lebensjahrs. Der prädiktive Nutzen moderner bildgebender Verfahren und biochemischer Marker, die für eine Risikostratifizierung in Frage kommen, wurde bei älteren Ausdauersportlern bislang nicht hinreichend untersucht.Methodik:Es werden Männer > 50 Jahre untersucht, die in den vergangenen 3 Jahren mindestens fünf Marathonläufe absolviert haben und keine bekannte Herzkrankheit oder Angina pectoris und keinen Diabetes mellitus aufweisen. Etablierte Risikofaktoren sowie moderne bildgebende und biochemische Risikomarker werden gemessen. Lebensstilassoziierte, psychosoziale und sozioökonomische Risikofaktoren werden mit standardisierten Fragebögen erhoben. Die Arteriosklerose der Koronararterien, der Karotiden, der Femoralarterien und der Aorta wird mittels Elektronenstrahltomographie und Ultraschall quantifiziert. Zusätzlich werden ein Ruhe-EKG, eine Fahrradergometrie und eine Messung der Herzfrequenzvariabilität durchgeführt. Morphologie und Funktion des linken Ventrikels werden echokardiographisch und magnetresonanztomographisch erfasst. Die Teilnehmer wurden gebeten, an einem Marathonwettkampf teilzunehmen, um die Assoziation von Koronarsklerose und dem marathoninduzierten Anstieg von kardialem Troponin in Abhängigkeit von der erwarteten Entzündungsreaktion zu untersuchen. Auf zellulärer Ebene wird der Effekt auf die Anzahl zirkulierender endothelialer Vorläuferzellen (EPCs) mittels FACS-Analyse bestimmt. Die Ereignisrate im Verlauf wird jährlich erfragt. Es werden auch Krankenhausdokumente und Sterbeunterlagen ausgewertet. Die Daten können im Vergleich zur Allgemeinbevölkerung aus der Heinz-Nixdorf-Recall-Studie analysiert werden.Schlussfolgerung:Diese Studie kann einen Beitrag zur kardiovaskulären Risikostratifikation in der wachsenden Gruppe älterer Marathonläufer leisten. Der prädiktive Wert der bildgebenden und biochemischen Marker für kardiovaskuläre Ereignisse wird untersucht.

Gender-specific association of coronary artery calcium and lipoprotein parameters: The Heinz Nixdorf Recall Study

BACKGROUND Coronary atherosclerosis can be detected by computed tomography. The amount of coronary artery calcification (CAC) is related to cardiovascular risk factors, the strength of the gender specific relation between lipoprotein parameters and CAC has not extensively been studied. Especially, the role of routinely determined lipoproteins in contrast to less common and computed lipid parameters (e.g. ratios) remains to be clarified. METHODS AND RESULTS The study cohort (n = 3956, 52% women, age 45-75 years) was randomly selected from three cities of a German metropolitan area. Lipoproteins-low-and high density lipoprotein (LDL-C/HDL-C), total cholesterol, apolipoprotein A-1 and B (apoA-1/apoB) as well as lipoprotein (a) (Lp(a)) were measured, while non-HDL-C was calculated. All participants received an electron-beam computed tomography (EBCT) for quantification of CAC. Adjusted for age and cardiovascular risk factors, CAC increased by a factor of 1.97 (1.51-2.57, 95% CI) and 1.94 (1.53-2.45, 95% CI) comparing the fourth to the first quartile of LDL-C for men and women, respectively. This association with LDL-C was also found after dichotomization of CAC at thresholds >0, ≥ 100 and ≥ 400. The best association of CAC was, however, found to be apoB and the second best was non HDL-C, in both men and women. For apoB, the model including all risk factors reached an explained variance for CAC of 20.2% in men and of 21.6% in women. When using LDL-C as a given parameter according to the current practice and advice, HDL-C in men and apoB in women provided an additional but small benefit. CONCLUSION ApoB showed the best association with CAC compared to all other tested lipoproteins. Neither the ratio LDL-C/HDL-C nor apoB/apoA-1, or Lp(a) revealed a closer association with CAC. While lipoproteins are related to CAC more closely in women than in men, their association with CAC is, however, not particularly strong. Our results may influence primary and secondary prevention advices in order to improve detection of subclinical atherosclerosis, for which lipoprotein parameters can only play a minor role.

Coronary Artery Calcification and Its Relationship to Validated Genetic Variants for Diabetes Mellitus Assessed in the Heinz Nixdorf Recall Cohort

Objective—To examine the association between genomewide association study–based diabetes mellitus–related single-nucleotide polymorphisms (SNPs) and coronary artery calcification (CAC), a valid risk factor for coronary heart disease, in a large, unselected, population-based cohort. Methods and Results—We genotyped 11 validated genomewide association study–based diabetes SNPs in 4459 participants of the Heinz Nixdorf Recall Study. We applied generalized linear regression models to explore the impact of the diabetes SNPs on CAC and to jointly model the effect of the SNPs and CAC on diabetes status. We observed a significant association between cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) variant rs564398 and quantitative CAC (P=1.81×10−5 and adjusted P=4.02×10−4; odds ratio for the presence of CAC, 1.12 [95% CI, 1.02 to 1.25]). Moreover, we observed no strong impact of CAC on diabetes risk in the presence of the other genetic variants. Conclusion—We show that a genetic variant near CDKN2A/2B that has been reported to be strongly associated with diabetes is strongly associated with CAC. In contrast, variants near insulin-like growth factor-binding protein 2 (IGFBP2), CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1), solute carreir family 30 (zinc transporter), member 8 (SLC30A8), hematopoietically-expressed homeobox (HHEX), and transcription factor 7-like2 (TCF7L2) were clearly associated with diabetes; no evidence for an association to CAC was observable. This differential association pattern underlines the potential of endophenotypes, such as CAC, to extend the scope of disease outcome associations.