Hagen Kälsch

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.

Genetic Associations with Valvular Calcification and Aortic Stenosis

BACKGROUND Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. CONCLUSIONS Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).

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.

Association of pericoronary fat volume with atherosclerotic plaque burden in the underlying coronary artery: A segment analysis

OBJECTIVE We aimed to determine, whether the amount of local pericoronary fat volume is associated with the presence of plaque burden in the underlying coronary artery segment. METHODS We assessed 311 coronary segments from ECG-gated contrast-enhanced dual-source computed tomography for presence of plaque as well as segmental pericoronary fat volume. For pericoronary fat evaluation, regions of interest were manually traced containing any fat surrounding a coronary artery segment, with the myocardial wall, the pericardial sac and other coronary segments as outer border. RESULTS Per each doubling of pericoronary fat volume, we observed an 2.5-fold increase in the presence of plaque in the underlying coronary segment in unadjusted models (95% confidence interval [CI] 1.87-3.27, p<0.001), which remained after adjustment for traditional cardiovascular risk factors (odds ratio [OR] 3.07 [2.16-4.35], p<0.001) and when additionally accounting for overall pericardial fat volume (OR 2.68 [1.90-3.79], p<0.001). Associations were similar in all coronary artery segments and not related to the type of plaque (calcified or non-calcified, p<0.01 for all). CONCLUSION Pericoronary fat is associated with atherosclerosis in the coronary arteries. Our results support the hypothesis that perivascular fat depots may function as a local endocrine risk factor in atherosclerosis development.

Revival of an old method with new techniques: balloon aortic valvuloplasty of the calcified aortic stenosis in the elderly.

Balloon aortic valvuloplasty (BAV), introduced since almost 20 years, has experienced a revival for its use in the treatment of elderly patients with severe calcified aortic stenosis that are associated with high operative risk and co-morbidities. This is due to the introduction of new balloon catheters and techniques. This study reports about 75 such cases performed within the past 28 months. The mean age of our patient group was 78 ± 7 years (median = 80 years). Risk calculation with the EuroSCORE demonstrated an average value of 24.4 ± 19.5%. BAV was performed along with burst pacing to reduce transvalvular blood flow for stabilization of the balloon catheter until blood pressure dropped to less than 50 mmHg. BAV was performed in 72 patients with a procedural success rate of 73%. There was a decrease of 31 mmHg peak-to-peak gradient across the aortic valve from 63 ± 35 to 32 ± 22 mmHg (P < 0.0001). Mean gradient was reduced from 51 ± 24 to 27 ± 15 mmHg (P < 0.0001). Aortic valve area increased by 49% from 0.84 ± 0.33 to 1.25 ± 0.45 cm2 (P < 0.0001). Serious adverse events (SAE) occurred in 17% of the 75 BAV procedures. Follow-up revealed a significant improvement in 6-month and 1-year survival. The improved technology of BAV makes this technique attractive for elderly patients who are at high operative risk or in cases where valve replacement was refused for any reason.

Are air pollution and traffic noise independently associated with atherosclerosis: the Heinz Nixdorf Recall Study

AIMS Living close to high traffic has been linked to subclinical atherosclerosis, however it is not clear, whether fine particulate matter (PM) air pollution or noise, two important traffic-related exposures, are responsible for the association. We investigate the independent associations of long-term exposure to fine PM and road traffic noise with thoracic aortic calcification (TAC), a reliable measure of subclinical atherosclerosis. METHODS AND RESULTS We used baseline data (2000-2003) from the German Heinz Nixdorf Recall Study, a population-based cohort of 4814 randomly selected participants. We assessed residential long-term exposure to PM with a chemistry transport model, and to road traffic noise using façade levels from noise models as weighted 24 h mean noise (Lden) and night-time noise (Lnight). Thoracic aortic calcification was quantified from non-contrast enhanced electron beam computed tomography. We used multiple linear regression to estimate associations of environmental exposures with ln(TAC+1), adjusting for each other, individual, and neighbourhood characteristics. In 4238 participants (mean age 60 years, 49.9% male), PM2.5 (aerodynamic diameter ≤2.5 µm) and Lnight are both associated with an increasing TAC-burden of 18.1% (95% CI: 6.6; 30.9%) per 2.4 µg/m(3) PM2.5 and 3.9% (95% CI 0.0; 8.0%) per 5dB(A) Lnight, respectively, in the full model and after mutual adjustment. We did not observe effect measure modification of the PM2.5 association by Lnight or vice versa. CONCLUSION Long-term exposure to fine PM and night-time traffic noise are both independently associated with subclinical atherosclerosis and may both contribute to the association of traffic proximity with atherosclerosis.

Subclinical Coronary Atherosclerosis Predicts Cardiovascular Risk in Different Stages of Hypertension Result of the Heinz Nixdorf Recall Study

Prehypertension is a frequent condition and has been demonstrated to increase cardiovascular risk. However, the association with coronary atherosclerosis as part of target organ damage is not well understood. We investigated the cross-sectional relationship and longitudinal outcome between blood pressure categories and coronary artery calcification (CAC), quantified by electron beam computed tomography, in 4181 participants from the population-based Heinz Nixdorf Recall Study cohort. At baseline, we observed a continuous increase in calcium scores with increasing blood pressure categories. During a median follow-up period of 7.18 years, 115 primary end points (2.8%; fatal and nonfatal myocardial infarction) and 152 secondary end points (3.6%; stroke and coronary revascularization) occurred. We observed a continuous increase in age- and risk factor-adjusted secondary endpoints (hazard ratios [95% CI]) with increasing blood pressure categories (referent: normotension) in men: prehypertension, 1.80 (0.53–6.13); stage 1 hypertension, 2.27 (0.66–7.81); and stage 2 hypertension, 4.10 (1.27–13.24) and in women: prehypertension, 1.13 (0.34–3.74); stage 1 hypertension, 2.14 (0.67–6.85); and stage 2 hypertension, 3.33 (1.24–8.90), respectively, but not in primary endpoints. Cumulative event rates were determined by blood pressure categories and the CAC. In prehypertension, the adjusted hazard ratios for all of the events were, for CAC 1 to 99, 2.05 (0.80–5.23; P=0.13); 100 to 399, 3.12 (1.10–8.85; P=0.03); and ≥400, 7.72 (2.67–22.27; P=0.0002). Risk of myocardial infarction and stroke in hypertension but also in prehypertension depends on the degree of CAC. This marker of target-organ damage might be included, when lifestyle modification and pharmacotherapeutic effects in prehypertensive individuals are tested to avoid exposure to risk and increase benefit.

Progression of coronary artery calcification seems to be inevitable, but predictable - results of the Heinz Nixdorf Recall (HNR) study

Aim Coronary artery calcification (CAC), as a sign of atherosclerosis, can be detected and progression quantified using computed tomography (CT). We develop a tool for predicting CAC progression. Methods and results In 3481 participants (45–74 years, 53.1% women) CAC percentiles at baseline (CACb) and after five years (CAC5y) were evaluated, demonstrating progression along gender-specific percentiles, which showed exponentially shaped age-dependence. Using quantile regression on the log-scale (log(CACb+1)) we developed a tool to individually predict CAC5y, and compared to observed CAC5y. The difference between observed and predicted CAC5y (log-scale, mean±SD) was 0.08±1.11 and 0.06±1.29 in men and women. Agreement reached a kappa-value of 0.746 (95% confidence interval: 0.732–0.760) and concordance correlation (log-scale) of 0.886 (0.879–0.893). Explained variance of observed by predicted log(CAC5y+1) was 80.1% and 72.0% in men and women, and 81.0 and 73.6% including baseline risk factors. Evaluating the tool in 1940 individuals with CACb>0 and CACb<400 at baseline, of whom 242 (12.5%) developed CAC5y>400, yielded a sensitivity of 59.5%, specificity 96.1%, (+) and (−) predictive values of 68.3% and 94.3%. A pre-defined acceptance range around predicted CAC5y contained 68.1% of observed CAC5y; only 20% were expected by chance. Age, blood pressure, lipid-lowering medication, diabetes, and smoking contributed to progression above the acceptance range in men and, excepting age, in women. Conclusion CAC nearly inevitably progresses with limited influence of cardiovascular risk factors. This allowed the development of a mathematical tool for prediction of individual CAC progression, enabling anticipation of the age when CAC thresholds of high risk are reached.

A comparison of outcomes with coronary artery calcium scanning in unselected populations: The Multi-Ethnic Study of Atherosclerosis (MESA) and Heinz Nixdorf RECALL study (HNR)

BACKGROUND The Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf RECALL (Risk factors, Evaluation of Coronary Calcium and Lifestyle Factors) study (HNR) differed in regard to informing physicians and patients of the results of their subclinical atherosclerosis. OBJECTIVE This study investigates whether the association of the presence of coronary calcium with incident nonfatal and fatal cardiovascular events is different among these 2 large, population-based observational studies. METHODS All white subjects aged 45 to 75 years, free of baseline cardiovascular disease were included (n = 2232 in MESA; n = 3119 HNR participants). We studied the association between coronary calcium and event rates at 5 years, including hard cardiac events (myocardial infarction, cardiac death, resuscitated cardiac arrest), and separately added revascularizations and strokes (fatal and nonfatal) to determine adjusted hazard ratios. RESULTS Both cohorts showed low coronary heart disease (including revascularization) rates with zero coronary calcium (1.13% and 1.16% over 5 years in MESA and HNR, respectively) and increasing significantly in both groups with Agatston score 100 to 399 (6.71% and 4.52% in MESA and HNR, respectively) and Agatston score > 400 (12.5% and 13.54% in MESA and HNR, respectively) and showing strong independent predictive values for Agatston scores of 100 to 399 and >400, despite multivariable adjustment for risk factors. Risk factor-adjusted 5-year revascularization rates were nearly identical for HNR and MESA and were generally low for both studies (1.4% [45 of 3119] for HNR and 1.9% [43 of 2232] for MESA) over 5 years. CONCLUSIONS Across 2 culturally diverse populations, Agatston score >400 is a strong predictor of events. High Agatston score did not statistically result in revascularization, and knowledge of the presence of coronary calcium did not increase revascularizations.

Coronary artery calcium score improves cardiovascular risk prediction in persons without indication for statin therapy

BACKGROUND Recent revision to the Canadian Cardiovascular Society (CCS) guidelines on cardiovascular disease (CVD) risk stratification provides expanded recommendations for statin therapy. If CVD risk in the remaining individuals can further be stratified and discriminated by additional risk assessment using coronary artery calcium (CAC) scoring is unknown. METHODS AND RESULTS In a retrospectively analyzed subgroup comprising 1934 participants from the Heinz Nixdorf Recall study, who did not meet criteria for statin therapy based on current CCS guidelines, traditional CVD risk variables and CAC were measured. Between 2000 and 2008, incident CVD events, i.e. coronary deaths, non-fatal myocardial infarction, coronary revascularization, stroke and CV death were determined. Those 43 participants who experienced 55 CVD events (5-year risk to first event: 2.2% (1.6-3.0%)) had higher CAC scores than those who did not (p<0.0001). In multiple Cox regression analysis including age, sex, total-/HDL-cholesterol ratio, and antihypertensive medication, log2(CAC+1) remained an independent predictor of CVD events (HR=1.21 (1.09-1.33), p<0.001). Measures of discrimination improved with the addition of CAC into the model: the incremental discrimination improvement was 0.0167, p=0.014. Net reclassification improvement using risk categories of 0-<3%, 3-10% and >10% was 25.1%, p=0.01, largely driven by a 32.6% correct up-classification in persons with events. Yet, only 38 (2%) of participants were identified being at high risk using CAC imaging in addition to traditional risk factor assessment. CONCLUSION Adding CAC to traditional risk assessment in persons without indication for statin therapy improves discrimination. However, reclassification to the high risk category and overall event rates seem too low to justify liberal CAC testing in all these individuals.