Stefan Möhlenkamp

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.

Update on Myocardial Bridging

Muscle overlying the intramyocardial segment of an epicardial coronary artery, first mentioned by Reyman1 in 1737, is termed a myocardial bridge, and the artery coursing within the myocardium is called a tunneled artery (Figure 1). It is characterized by systolic compression of the tunneled segment, which remains clinically silent in the vast majority of cases. An in-depth analysis of autopsy samples was first presented by Geiringer et al2 in 1951, but clinical interest and systematic research was triggered by an observed association of myocardial bridging with myocardial ischemia.2–5 Figure 1. Typical systolic compression (arrows) of the mid LAD at two sites in series. Diastolic lumen dimensions are normal. The coronary tree shows no angiographic signs of coronary atherosclerosis. New imaging techniques have led to improved identification and functional quantitation of myocardial bridging in vivo, which is crucial for establishing a link between systolic compression and the clinical presentation, and hence for commencing appropriate therapy. In the present article, we summarize clinically relevant aspects of myocardial bridging with an emphasis on morphological and hemodynamic alterations and their representation in imaging techniques. The prevalence varies substantially among studies with a much higher rate at autopsy versus angiography (Table).2,4–28 Variation at autopsy may in part be attributable to the care taken at preparation and the selection of hearts. Polacek, who included myocardial loops, reports the highest rate with bridges or loops in 86% of cases.29 On average, myocardial bridges are present in about one third of adults. View this table: Prevalence of Myocardial Bridging at Autopsy and Angiography The rate of angiographic bridging is <5%, attributable to thin bridges causing little compression. In subjects with angiographically normal coronary arteries, the use of provocation tests may enhance systolic myocardial compression and thereby reveal myocardial bridges in ≤40% of cases.26,30 A …

Common variants in KCNN3 are associated with lone atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 × 10−12), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40–1.64; P = 1.83 × 10−21). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

Common variants at ten loci modulate the QT interval duration in the QTSCD Study

The QT interval, a measure of cardiac repolarization, predisposes to ventricular arrhythmias and sudden cardiac death (SCD) when prolonged or shortened. A common variant in NOS1AP is known to influence repolarization. We analyze genome-wide data from five population-based cohorts (ARIC, KORA, SardiNIA, GenNOVA and HNR) with a total of 15,842 individuals of European ancestry, to confirm the NOS1AP association and identify nine additional loci at P < 5 × 10−8. Four loci map near the monogenic long-QT syndrome genes KCNQ1, KCNH2, SCN5A and KCNJ2. Two other loci include ATP1B1 and PLN, genes with established electrophysiological function, whereas three map to RNF207, near LITAF and within NDRG4-GINS3-SETD6-CNOT1, respectively, all of which have not previously been implicated in cardiac electrophysiology. These results, together with an accompanying paper from the QTGEN consortium, identify new candidate genes for ventricular arrhythmias and SCD.

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.

Association of epicardial fat with cardiovascular risk factors and incident myocardial infarction in the general population: the Heinz Nixdorf Recall Study.

OBJECTIVES This study sought to determine whether epicardial fat volume predicts coronary events in the general population. BACKGROUND Epicardial adipose tissue (EAT) is suggested to promote plaque development in the coronary artery tree. METHODS We quantified EAT volume in participants from the prospective population-based Heinz Nixdorf Recall cohort study free of cardiovascular disease. Incident coronary events were assessed during a follow-up period of 8.0 ± 1.5 years. Multivariable association of EAT with cardiovascular risk factors, coronary artery calcification (CAC), and coronary events was assessed using regression analysis. RESULTS From the overall 4,093 participants (age 59.4 years, 47% male), 130 subjects developed a fatal or nonfatal coronary event. Incidence of coronary events increased by quartile of EAT (0.9% vs. 4.7% for 1(st) and 4th quartile, respectively, p < 0.001). Doubling of EAT was associated with a 1.5-fold risk of coronary events when adjusting for cardiovascular risk factors (hazard ratio [HR] [95% confidence interval (CI)]: 1.54 [1.09 to 2.19]), which remained unaltered after further adjustment for CAC score (HR [95% CI]: 1.50 [1.07 to 2.11]). For discrimination of subjects with events from those without, we observed a trend for improvement of Harrells C and explained variance by EAT over traditional cardiovascular risk factors, which, however, did not reach statistical significance (0.720 to 0.730 for risk factors alone and with EAT added, respectively, p = 0.10, R(2) = 2.73% to R(2) = 2.92%, time-dependent integrated discrimination improvement = 0.196%). CONCLUSIONS Epicardial fat is associated with fatal and nonfatal coronary events in the general population independent of traditional cardiovascular risk factors and complements information from cardiac computed tomography above the CAC score.

Myocardial late gadolinium enhancement: prevalence, pattern, and prognostic relevance in marathon runners.

PURPOSE To prospectively analyze the myocardial distribution of late gadolinium enhancement (LGE) with delayed-enhancement cardiac magnetic resonance (MR) imaging, to compare the prevalence of this distribution in nonprofessional male marathon runners with that in asymptomatic control subjects, and to examine the prognostic role of LGE. MATERIALS AND METHODS Institutional review board and ethics committee approval were obtained for this study, and all subjects provided written informed consent. Two-dimensional inversion-recovery segmented k-space gradient-echo MR sequences were performed after administration of a gadolinium-containing contrast agent in 102 ostensibly healthy male runners aged 50-72 years who had completed at least five marathons during the past 3 years and in 102 age-matched control subjects. Predominantly subendocardial regions of LGE typical of myocardial infarction (hereafter, coronary artery disease [CAD] pattern) were distinguished from a predominantly midmyocardial patchy pattern of LGE (hereafter, non-CAD pattern). Marathon runners with LGE underwent repeat cardiac MR imaging and additional adenosine perfusion imaging. Runners were followed up for a mean of 21 months +/- 3 (standard deviation) after initial presentation. The chi(2), Fisher exact, and McNemar exact tests were used for comparisons. Event-free survival rates were estimated with the Kaplan-Meier method, and overall group differences were evaluated with log-rank statistics. RESULTS Of the 102 runners, five had a CAD pattern of LGE, and seven had a non-CAD pattern of LGE. The CAD pattern of LGE was located in the territory of the left anterior descending coronary artery more frequently than was the non-CAD pattern (P = .0027, Fisher exact test). The prevalence of LGE in runners was higher than that in age-matched control subjects (12% vs 4%; P = .077, McNemar exact test). The event-free survival rate was lower in runners with myocardial LGE than in those without myocardial LGE (P < .0001, log-rank test). CONCLUSION Ostensibly healthy marathon runners have an unexpectedly high rate of myocardial LGE, and this may have diagnostic and prognostic relevance.

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.

Variability of Repeated Coronary Artery Calcium Measurements by Electron Beam Tomography

In 120 patients, the mean interscan variability of coronary calcium quantification by electron beam tomography was 19.9% (median 7.8%) for the traditional calcium score, and 16.2% (median 5.7%) for volumetric scoring. Although this difference was not significant, there was a significant influence of the total amount of calcium, number of acquired images, and image noise on interscan reproducibility.

Natural History and Topographic Pattern of Progression of Coronary Calcification in Symptomatic Patients An Electron-Beam CT Study

Abstract —Electron-beam CT may assess the progression of coronary atherosclerosis by visualizing changes in calcification. The present investigation analyzes (1) the rate of progression of calcification in symptomatic patients, (2) the topographic pattern, and (3) the influence of baseline plaque burden and risk factors. Progression of calcification during a mean (median) interval of 18 (15) months was measured in 102 symptomatic outpatients (aged 59±9 years, 80% male) with calcification. In 4 patient groups with a baseline total score (Agatston criteria) of 1 to 30, >30 to 100, >100 to 400, and >400, the median was 3.1, 26.1, 58.9, and 109.7, respectively, for absolute annual progression of the score (P <0.05) and 57%, 49%, 32%, and 15%, respectively, for relative progression (P <0.05). On the coronary segmental level, changes were largely restricted to typical predilection sites of coronary atherosclerosis. The presence of angiographically defined coronary narrowing influenced absolute, but not relative, progression. Of the risk factors, only low density lipoprotein cholesterol levels showed a trend, although not significant, for predicting progression. These data indicate that baseline plaque burden determines the rate of progression of calcification. This appears to be a coronary systemic process, reflecting the natural history of coronary atherosclerosis.