Value of Progression of Coronary Artery Calcification for Risk Prediction of Coronary and Cardiovascular Events: Result of the HNR Study (Heinz Nixdorf Recall).

BACKGROUND: Computed tomography (CT) allows estimation of coronary artery calcium (CAC) progression. We evaluated several progression algorithms in our unselected, population-based cohort for risk prediction of coronary and cardiovascular events. METHODS: In 3281 participants (45-74 years of age), free from cardiovascular disease until the second visit, risk factors, and CTs at baseline (b) and after a mean of 5.1 years (5y) were measured. Hard coronary and cardiovascular events, and total cardiovascular events including revascularization, as well, were recorded during a follow-up time of 7.8±2.2 years after the second CT. The added predictive value of 10 CAC progression algorithms on top of risk factors including baseline CAC was evaluated by using survival analysis, C-statistics, net reclassification improvement, and integrated discrimination index. A subgroup analysis of risk in CAC categories was performed. RESULTS: We observed 85 (2.6%) hard coronary, 161 (4.9%) hard cardiovascular, and 241 (7.3%) total cardiovascular events. Absolute CAC progression was higher with versus without subsequent coronary events (median, 115 [Q1-Q3, 23-360] versus 8 [0-83], P<0.0001; similar for hard/total cardiovascular events). Some progression algorithms added to the predictive value of baseline CT and risk assessment in terms of C-statistic or integrated discrimination index, especially for total cardiovascular events. However, CAC progression did not improve models including CAC5y and 5-year risk factors. An excellent prognosis was found for 921 participants with double-zero CACb=CAC5y=0 (10-year coronary and hard/total cardiovascular risk: 1.4%, 2.0%, and 2.8%), which was for participants with incident CAC 1.8%, 3.8%, and 6.6%, respectively. When CACb progressed from 1 to 399 to CAC5y≥400, coronary and total cardiovascular risk were nearly 2-fold in comparison with subjects who remained below CAC5y=400. Participants with CACb≥400 had high rates of hard coronary and hard/total cardiovascular events (10-year risk: 12.0%, 13.5%, and 30.9%, respectively). CONCLUSIONS: CAC progression is associated with coronary and cardiovascular event rates, but adds only weakly to risk prediction. What counts is the most recent CAC value and risk factor assessment. Therefore, a repeat scan >5 years after the first scan may be of additional value, except when a double-zero CT scan is present or when the subjects are already at high risk.

The BioMonitor 2 insertable cardiac monitor: Clinical experience with a novel implantable cardiac monitor.

INTRODUCTION: Implantable loop recorders (ILR) are leadless subcutaneous devices that allow cardiac monitoring for up to 3 years and are a valuable tool in the diagnosis of arrhythmias, cryptogenic stroke and unexplained syncope. The Biotronik BioMonitor 2 is a novel, insertable ILR allowing long-term continuous monitoring with wireless telemetry options. METHODS: A single-center, prospective, observational study investigating the reliability of sensing quality and detection performance in the BioMonitor 2 ILR, as well as post-implantation patient satisfaction. R-wave amplitude was recorded immediately post implantation and 1 day post implantation, followed by extensive patient instruction. Follow-up was scheduled after 3 months, or after an event. Data from the ILR were retrieved, with documentation of all episodes, R-wave amplitude and noise burden. The anatomical position of the ILR was determined 1 day post implantation and after 3 months. A patient questionnaire was conducted after 3 months. RESULTS: 30 consecutive patients (mean age 71 ±â€¯12 years, 56% male) were analyzed. Indications for ILR implantation were: unexplained syncope (n = 24, 80%), suspected atrial fibrillation (n = 4, 13%), cryptogenic stroke (n = 1, 3%) and palpitations (n = 1, 3%). Median time from skin cut to suture was 8 min. No complications occurred. Mean R-wave amplitude at implantation was 0.84 ±â€¯0.32 mV, at day 1 post implantation 0.96 ±â€¯0.31 mV, and after a mean follow-up of 85 ±â€¯24 days 1.02 ±â€¯0.47 mV (p = 0.01). The mean noise burden was 1.4 ±â€¯2%. CONCLUSION: Implantation of the novel BioMonitor 2 ILR is fast and uncomplicated. Initial sensing values are good and improve over time.

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.).

Long-term Exposure to Particulate Matter Constituents and the Incidence of Coronary Events in 11 European Cohorts.

BACKGROUND: Long-term exposure to particulate matter (PM) has been associated with increased cardiovascular morbidity and mortality but little is known about the role of the chemical composition of PM. This study examined the association of residential long-term exposure to PM components with incident coronary events. METHODS: Eleven cohorts from Finland, Sweden, Denmark, Germany, and Italy participated in this analysis. 5,157 incident coronary events were identified within 100,166 persons followed on average for 11.5 years. Long-term residential concentrations of PM < 10 µm (PM10), PM < 2.5 µm (PM2.5), and a priori selected constituents (copper, iron, nickel, potassium, silicon, sulfur, vanadium, and zinc) were estimated with land-use regression models. We used Cox proportional hazard models adjusted for a common set of confounders to estimate cohort-specific component effects with and without including PM mass, and random effects meta-analyses to pool cohort-specific results. RESULTS: A 100 ng/m³ increase in PM10 K and a 50 ng/m³ increase in PM2.5 K were associated with a 6% (hazard ratio and 95% confidence interval: 1.06 [1.01, 1.12]) and 18% (1.18 [1.06, 1.32]) increase in coronary events. Estimates for PM10 Si and PM2.5 Fe were also elevated. All other PM constituents indicated a positive association with coronary events. When additionally adjusting for PM mass, the estimates decreased except for K. CONCLUSIONS: This multicenter study of 11 European cohorts pointed to an association between long-term exposure to PM constituents and coronary events, especially for indicators of road dust.

Left ventricle size quantification using non-contrast-enhanced cardiac computed tomography--association with cardiovascular risk factors and coronary artery calcium score in the general population: The Heinz Nixdorf Recall Study.

BACKGROUND: Increased left ventricular (LV) size is associated with cardiovascular mortality and morbidity. Once non-contrast cardiac computed tomography (CT) is performed for other purposes, information of LV size is readily available. PURPOSE: To determine the association of gated CT-derived LV size with cardiovascular risk factors and coronary artery calcification (CAC) and to describe age- and gender-specific normative values in a general population cohort. MATERIAL AND METHODS: LV area was quantified from non-contrast-enhanced CT in axial, end-diastolic images at a mid-ventricular slice in participants of the population-based Heinz Nixdorf Recall Study, free of known cardiovascular disease. LV index (LVI) was calculated by the quotient of LV area and body surface area (BSA). Crude and adjusted regression analyses were used to determine the association of LVI with risk factors and CAC. RESULTS: Overall, 3926 subjects (age 59 ± 8 years, 53% women) were included in this analysis. From quantification in end-diastolic phase, men had larger LV index (2232 ± 296 mm(2)/m(2) vs. 2088 ± 251 mm(2)/m(2), both P < 0.0001). LVI was strongly correlated systolic blood pressure (men, PE [95% CI]: 22.8 [15.5-30.2] mm(2)/10 mmHg; women, 23.4 [18.1-28.6]), and antihypertensive medication (men, 45.2 [14.7-75.8] mm(2); women: 46.5 [22.7-70.2], all P < 0.005). Cholesterol levels were associated with LVI in univariate analysis, however, correlations were low (R(2) ≤ 0.04). In multivariable regression, blood pressure, antihypertensive medication and cholesterol levels, remained associated with LVI (P < 0.05). LVI was linked with CAC in unadjusted (men, increase of CAC + 1 by 13.0% [1.4-25.8] with increased LVI by 1 standard deviation of LVI, P = 0.03; women, 20.7% [10.0-32.3], P < 0.0001) and risk factor adjusted models (men, 14.6% [3.7-26.6], P = 0.007); women, 17.4% [7.8-27.8], P = 0.0002). CONCLUSION: Non-contrast cardiac CT derived LV index is associated with body size and hypertension. LVI is weakly linked with CAC-score. Further studies need to evaluate whether assessment of LV dimensions from cardiac CT helps identifying subjects with increased cardiovascular risk.

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.

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.

Coronary artery calcification, intima-media thickness, and ankle-brachial index are complementary stroke predictors.

BACKGROUND AND PURPOSE: Coronary artery calcification (CAC), a marker of coronary atherosclerosis, predicts stroke in addition to established risk factors. Whether CAC's predictive value can be improved by peripheral atherosclerosis markers, namely carotid intima-media thickness (CIMT) and ankle-brachial index (ABI), was unknown. METHODS: A total of 3289 participants of the population-based Heinz Nixdorf Recall study (45-75 years; 48.8% men) without previous stroke or coronary heart disease were evaluated for incident stroke for 9.0±1.9 years. CAC, CIMT, and ABI were examined as stroke predictors. RESULTS: Eighty-four strokes occurred during follow-up. In multivariable Cox proportional hazard regressions, CAC (hazard ratio, 1.45 [95% confidence interval, 1.11-1.88] per SD increase in ln(CAC+1); SD, 2.40), CIMT (1.34 [1.08-1.66] per SD increase; SD, 0.127 mm), and ABI (1.55 [1.32-1.82] per SD decrease; SD, 0.148) were associated with stroke in addition to established risk factors. When combined with each other, ln(CAC+1)'s hazard ratio remained similar when CIMT (1.41 [1.09-1.83]) was inserted into the multivariable model, but slightly decreased when ABI (1.31 [1.01-1.72]) or CIMT and ABI (1.29 [0.99-1.68]) were included. Although CAC alone did not significantly elevate the area under the curve in Harrell's c-statistics (by 0.009; P=0.379) in addition to established risk factors, the combination of CAC and ABI increased area under the curve (by 0.029; P=0.047), as did ABI (by 0.025; P=0.038) but not CIMT (by 0.002; P=0.795) alone. The combination of CAC and ABI also resulted in significant category-free net reclassification and integrated discrimination improvement. CONCLUSIONS: CAC, CIMT, and ABI provide complementary information about stroke risk. ABI, which is distinctive in a small subpopulation, had the highest and CIMT, which is distributed across a larger range of values, had the lowest predictive value.

Left atrial size quantification using non-contrast-enhanced cardiac computed tomography - association with cardiovascular risk factors and gender-specific distribution in the general population: the Heinz Nixdorf Recall study.

BACKGROUND: Left atrial (LA) size is associated with cardiovascular mortality and morbidity. Once cardiac computed tomography (CT) is performed, information on LA size is readily available without additional contrast media or radiation exposure. PURPOSE: To determine the association of CT-derived LA area and body surface area-adjusted (BSA) LA index with cardiovascular risk factors and describe age- and gender-specific normative values in a general population cohort. MATERIAL AND METHODS: This study included 3945 participants (mean age, 59 ± 8 years; 53% women) from the community-based Heinz Nixdorf Recall Study. LA area in an axial image at the level of the mitral valve was quantified from non-contrast-enhanced electron-beam CT by manual delineations of the boundaries of the LA with exclusion of subjects with prevalent cardiovascular disease. Definition of normative values was performed in subjects without predictors of LA enlargement. RESULTS: LA quantification was feasible in all subjects. Men had larger LA size (1856 mm(2) vs. 1677 mm(2), P < 0.0001), while after adjustment for BSA, this effect was inverted (910 mm(2)/m(2) vs. 933 mm(2)/m(2) for men and women, P < 0.0001). Determinants of body size were major predictors of LA size (body mass index [BMI]: R(2) = 0.195, BSA: R(2 )= 0.216, both P < 0.0001). Blood pressure was associated with LA size (parameter-estimate [95% confidence interval] = 51.0 (4.9-57.1) mm(2)/10 mmHg for systolic, 31.4 (25.4-37.4) mm(2)/5 mmHg for diastolic blood pressure, 214.6 (186.9-242.3) mm(2) for antihypertensive medication, P < 0.0001 for all). Cholesterol levels, lipid-lowering therapy, and diabetes were associated with LA in univariable analysis, however, correlations were low (r(2 )≤ 0.026). Current smoking was associated with reduced LA size (-115.9 [-149.0 - -82.8] mm(2), P < 0.0001). In multivariable regression, BMI, blood pressure, antihypertensive medication, and smoking remained associated with LA size (P < 0.005). CONCLUSION: Non-contrast-enhanced cardiac CT enables LA quantification with body size, hypertension, and smoking status being predictors of LA size.

Impact of atherosclerotic risk factors on different ankle-brachial-index criteria--results of the Heinz Nixdorf RECALL study.

BACKGROUND: On the basis of the Heinz Nixdorf RECALL Study (HNR) we estimated the impact of classical atherosclerotic risk factors on different ankle-brachial-index (ABI) criteria. PATIENTS AND METHODS: In a subgroup of participants (n = 2586) who had normal ABI at baseline ABI measurement was repeated at a 5 years follow-up and 3 different ABIs were defined: "ABI-high" calculated from the higher pressure, "ABI-low" from the lower pressure of both foot arteries of each leg. "Pure-ABI-low" was defined by exclusion of participants with ABI-high from those with ABI-low. Mönckebergs mediacalcinosis (MC) was accepted in case of ABI-high > 1.4 in one leg. RESULTS: According to ABI-high 2 %, to ABI-low 7.8 % and pure-ABI-low 5.8 % of the participants developed peripheral arterial disease (PAD) (ABI < 0.9) and 3.6 % developed MC within the 5 years. Age did not play any role whereas female gender, diabetes mellitus and smoking were associated with an increased relative risk of pathologic ABI-high and ABI-low. Looking at the pure-ABI-low group only, female gender and smoking showed significant associations. None of the analysed risk factors except gender had an impact on the development of MC. CONCLUSIONS: Classical risk factors have different impact on incidence of PAD as defined by different ABI criteria.

The Heinz Nixdorf Recall study and its potential impact on the adoption of atherosclerosis imaging in European primary prevention guidelines.

Non-contrast-enhanced computed tomography (CT) imaging of the heart enables noninvasive quantification of coronary artery calcification (CAC), a surrogate marker of the atherosclerotic burden in the coronary artery tree. Multiple studies have underlined the ability of CAC score for individual risk stratification and, accordingly, the American Heart Association recommended cardiac CT for risk assessment in individuals with an intermediate risk of cardiovascular events as measured by Framingham Risk Score. However, limitations in transcribing risk stratification algorithms based on American cohort studies into European populations have been acknowledged in the past. Moreover, data on implications for reclassification into higher- or lower-risk groups based on CAC scores were lacking. The Heinz Nixdorf Recall (HNR) study is a population-based cohort study that investigated the ability of CAC scoring in risk prediction for major cardiovascular events above and beyond traditional cardiovascular risk factors. According to Heinz Nixdorf Recall findings, CAC can be used for reclassification, especially in those in the intermediate-risk group, to advise on lifestyle changes for the reclassified low-risk category, or to implement intensive treatments for the reclassified high-risk individuals. This article discusses the present findings of the Heinz Nixdorf Recall Study with respect to the current literature, risk stratification algorithms, and current European guidelines for risk prediction.

One-year outcome and durability of pulmonary vein isolation after prospective use of ablation index for catheter ablation in patients with persistent atrial fibrillation.

BACKGROUND: Radiofrequency (RF) catheter ablation for persistent atrial fibrillation (peAF) is associated with less favorable outcomes than for paroxysmal AF (PAF). Recent studies have shown improved clinical outcomes with use of ablation index (AI) targets for pulmonary vein isolation (PVI) in PAF. AI is a novel ablation quality marker that incorporates contact force (CF), time, and power in a weighted formula. This is a single-arm registry to investigate the 1-year efficacy of AF ablation guided by the AI in patients with peAF, and further to evaluate pulmonary vein reconduction at repeat electrophysiology study in case of recurrent AF. METHODS: In total, 55 consecutive patients (69 ± 10 years, 55% male, median time since first AF diagnosis: 31 months (Q1-Q3: 10-70)) with peAF underwent AIguided PVI using a CF surround-flow catheter. AI targets were 600 for anterior and 450 for roof/posterior/inferior antral segments. Patients were monitored for atrial tachyarrhythmia recurrence using 5-day Holter-ECG recordings at 3, 6, and 12 months. RESULTS: The median procedure time was 173 min (Q1-Q3: 152-204). The median fluoroscopy time was 4 min (Q1-Q3: 3-6) and the median fluoroscopy dose was 2.64 Gy/cm2 (Q1-Q3: 1.04-3.99). The median ablation time was 57 min (Q1-Q3: 47-63). At 12 months, 42% of the patients were in sinus rhythm. AF recurrence was seen in 58% of patients. No major complications occurred. CONCLUSIONS: RF ablation using AI in peAF is a feasible and safe technique. At 1 year, AI-guided ablation was associated with AF recurrence in 58% of the patients.

Investigation of air pollution and noise on progression of thoracic aortic calcification: results of the Heinz Nixdorf Recall Study.

AIMS: Air pollution and noise are potential risk factors for subclinical atherosclerosis. Longitudinal analyses, especially on the interplay of these environmental factors, are scarce and inconsistent. Hence we investigated long-term traffic-related exposure to air pollution and noise with the development and progression of thoracic aortic calcification, a marker of subclinical atherosclerosis. METHODS: We used baseline (2000-2003) and follow-up (2006-2008) data from the German Heinz Nixdorf Recall cohort study, including 4814 middle-aged adults. Residence-based air pollution (PM2.5 (aerodynamic diameter ≤ 2.5 µm), PM10, nitrogen dioxide and particle number), and noise was assessed with dispersion models. Thoracic aortic calcification was quantified from non-contrast enhanced electron beam computed tomography. The presence and extent of thoracic aortic calcification progression were analysed with multiple logistic and linear regression models, respectively, adjusting for age, sex, lifestyle variables, socioeconomic status and respective co-exposure. RESULTS: We observed no association in the full study sample (n = 3155, mean age 59.1 (±7.6) years, 52.8% women). While an interquartile range in particle number and night-time noise yielded odds ratios of 1.20 (1.03, 1.40) and 1.21 (1.00, 1.46) for binary thoracic aortic calcification progression, and 0.02 (-0.01, 0.05) and 0.04 (0.00, 0.07) higher growth rates of thoracic aortic calcification in participants with baseline thoracic aortic calcification less than 10, negative findings were observed in those with baseline thoracic aortic calcification of 10 or greater. Results were similar for other pollutants and daytime noise. CONCLUSION: Our study shows no overall associations. Subgroup analyses suggest independent associations of traffic-related air pollution and noise with the development and progression of subclinical atherosclerosis in participants with no or minor thoracic aortic calcification at baseline, in contrast to negative findings in those with advanced calcification.

Air Pollution and Progression of Atherosclerosis in Different Vessel Beds-Results from a Prospective Cohort Study in the Ruhr Area, Germany.

OBJECTIVES: Due to inconsistent epidemiological evidence on health effects of air pollution on progression of atherosclerosis, we investigated several air pollutants and their effects on progression of atherosclerosis, using carotid intima media thickness (cIMT), coronary calcification (CAC), and thoracic aortic calcification (TAC). METHODS: We used baseline (2000-2003) and 5-y follow-up (2006-2008) data from the German Heinz Nixdorf Recall cohort study, including 4,814 middle-aged adults. Residence-based long-term air pollution exposure, including particulate matter (PM) with aerodynamic diameter ≤2.5µm (PM2.5), (PM10), and nitrogen dioxide (NO2) was assessed using chemistry transport and land use regression (LUR) models. cIMT was quantified as side-specific median IMT assessed from standardized ultrasound images. CAC and TAC were quantified by computed tomography using the Agatston score. Development (yes/no) and progression of atherosclerosis (change in cIMT and annual growth rate for CAC/TAC) were analyzed with logistic and linear regression models, adjusting for age, sex, lifestyle variables, socioeconomic status, and traffic noise. RESULTS: While no clear associations were observed in the full study sample (mean age 59.1 (±7.6) y; 53% female), most air pollutants were marginally associated with progression of atherosclerosis in participants with no or low baseline atherosclerotic burden. Most consistently for CAC, e.g., a 1.5 µg/m3 higher exposure to PM2.5 (LUR) yielded an estimated odds ratio of 1.19 [95% confidence interval (CI): 1.03, 1.39] for progression of CAC and an increased annual growth rate of 2% (95% CI: 1%, 4%). CONCLUSION: Our study suggests that development and progression of subclinical atherosclerosis is associated with long-term air pollution in middle-aged participants with no or minor atherosclerotic burden at baseline, while overall no consistent associations are observed. https://doi.org/10.1289/EHP7077.

Cardiovascular Risk and Atherosclerosis Progression in Hypertensive Persons Treated to Blood Pressure Targets.

Arterial hypertension promotes atherosclerosis and cardiovascular events. We evaluated how cardiovascular risk and atherosclerosis progression are associated with blood pressure, antihypertensive treatment, and treatment efficacy. In 3555 participants of the population-based Heinz Nixdorf Recall study without previous cardiovascular disease (mean±SD; age, 58.9±7.6 years, 46.9% men), we analyzed associations of baseline antihypertensive treatment efficacy (normotension without antihypertensives, normotension with antihypertensives, hypertension without antihypertensives, hypertension with antihypertensives, based on 140/90 mmHg cutoffs) with incident coronary artery calcification (CAC) and CAC progression during 5-year-follow-up and with incident cardiovascular events during 13.5-year-follow-up. We further evaluated associations of incident arterial hypertension and efficacy of new antihypertensive treatment at the 5-year-follow-up with subsequent cardiovascular events. At baseline, 1706 participants had normotension without antihypertensives, 553 normotension with antihypertensives, 786 hypertension without antihypertensives, and 510 hypertension with antihypertensives. Six hundred forty-seven participants experienced rapid CAC progression. One hundred seven, 132, and 249 had incident stroke, coronary event, and cardiovascular event, respectively. Compared with normotensives without antihypertensives, normotensives with antihypertensives had an elevated stroke (hazard ratio, 2.33 [95% CI, 1.19-4.55]), coronary (2.04 [95% CI, 1.20-3.45]), and cardiovascular (2.23 [95% CI, 1.48-3.36]) risk, and increased baseline CAC, but not increased CAC progression. Participants without hypertension at baseline, who were newly hypertensive but achieved normotension with antihypertensives at the 5-year-follow-up, again exhibited elevated stroke (4.80 [95% CI, 1.38-16.70]) and cardiovascular (2.99 [95% CI, 1.25-7.16]) risk, whereas coronary risk was less elevated (2.24 [95% CI, 0.70-7.18]). Normotensives with antihypertensives have an elevated cardiovascular risk. They are characterized by elevated baseline CAC but show no signs of increased CAC progression.

Association of progressive thoracic aortic calcification with future cardiovascular events and all-cause mortality: ability to improve risk prediction? Results of the Heinz Nixdorf Recall (HNR) study.

AIMS: Thoracic aortic calcification (TAC) is measured by computed tomography (CT). We investigated the association of TAC-progression with incident cardiovascular (CV) events and all-cause mortality in a population-based cohort and to determine its predictive value for these endpoints. METHODS AND RESULTS: In 3080 participants (45-74 years, 53.6% women), risk factors and TAC via CT were measured at baseline and at a second examination after 5.1 ± 0.3 years. Hard coronary, hard CV events as well as CV events including revascularization and all-cause mortality were recorded during a follow-up time of 7.8 ± 2.2 years after the second CT scan. Cox regression analysis determined the association of TAC-progression with observed endpoints. The predictive value of TAC-progression was assessed using Harrell's C index. We observed 81 hard coronary, 154 hard CV, 231 CV events including revascularization, and 266 deaths. In the crude analysis, event rates increased continuously with the level of TAC-change over 5 years for all endpoints. After adjustment, the significant association of TAC-progression with hard CV events [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.05-1.57] and all-cause mortality (HR 1.34, 95% CI 1.14-1.58) persisted, per one standard deviation increase in TAC-progression (log(TAC + 1)). Regarding aortic segments separately, HRs were consistently higher for descending thoracic aorta. When adding TAC (baseline and progression) to the model containing classical risk factors and coronary artery calcification (CAC), Harrell's C indices did not increase for any of the observed endpoints. CONCLUSION: TAC-progression is associated with incident hard CV events and all-cause mortality but fails to improve event prediction over CAC.

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.

Initial experience of percutaneous left atrial appendage closure using the LAmbre device for thromboembolic prevention.

AIMS: Stroke due to atrial fibrillation has been associated with a high risk of disability and mortality. Percutaneous left atrial appendage (LAA) closure has been established as an alternative strategy for stroke prevention in patients not eligible for oral anticoagulation. The LAmbre is a novel occluder, specifically designed for LAA closure adaptive to various LAA anatomies. The aim of this study was to demonstrate feasibility and initial experience in a nonprescreened patient cohort for LAA occlusion using the novel LAmbre occluder. METHODS: The device was implanted in 11 patients with nonvalvular atrial fibrillation. Follow-up included transesophageal echocardiography and an outpatient visit at 6 weeks and 6 months after implantation. RESULTS: All devices were implanted successfully. Device sizes ranged from 16/22 to 22/34 mm. Patients' mean CHA2DS2-VASc and HAS-BLED scores were 3.3 ±â€Š1.0 and 3.2 ±â€Š1.0, respectively. Two out of 11 patients had previously been rejected for Watchman occluder implantation by reasons of too small LAA. At 6 weeks and 6 months, there were no deaths, strokes, systemic thromboembolism or severe bleeding complications. There was no device-related thrombus or pericardial effusion seen with transesophageal echocardiography. In one out of 11 patients, a minimal peridevice flow (less than 5 mm) was present at 6-week follow-up. CONCLUSION: The LAmbre occluder is a novel LAA-closure device with features that provide many options for LAA-closure to physicians, particularly in patients with challenging anatomies. From our initial experience, implantation is associated with a good success rate and clinical outcome.

Percutaneous closure of the left atrial appendage in patients with diabetes mellitus.

BACKGROUND: Left atrial appendage closure is a preventive treatment of atrial fibrillation-related thrombo-embolism. Patients with diabetes mellitus have increased risk for a negative outcome in percutaneous cardiac interventions. We assessed whether percutaneous left atrial appendage closure is safe and effective in patients with diabetes mellitus. METHODS: We included 78 patients (mean age of 74.4 ± 8.3 years) with indication for left atrial appendage closure in an open-label observational single-centre study. RESULTS: Patients with diabetes mellitus ( n = 31) were at higher thrombo-embolic and bleeding risk (CHA2DS2-VASc: 4.5 ± 0.9, HAS-BLED: 4.7 ± 0.7) compared to patients without diabetes mellitus ( n = 47, CHA2DS2-VASc: 3.5 ± 1.0, HAS-BLED: 4.1 ± 0.8; p < 0.001 for both). Pre- and periprocedural risk was elevated in patients with diabetes mellitus (Euro II-Score: 6.6 ± 3.7 vs 3.9 ± 1.9, p < 0.01; Society of Thoracic Surgeons (STS)-Score: 4.0 ± 2.5 vs 2.6 ± 1.2, p < 0.01). Procedural success was similar. Periprocedural major adverse cardiac and cerebrovascular events occurred in one patient from the control group (2.1%), whereas patients with diabetes mellitus had no events ( p = 0.672). Follow-up of 6 months revealed no bleeding complication in both groups. No stroke occurred in follow-up, and left atrial appendage flow velocity reduction (55.6 ± 38.6 vs 51.4 ± 19.1 cm/s, p = 0.474) and rate of postinterventional leakage in the left atrial appendage were comparable (0% vs 2.1%, p = 0.672). CONCLUSION: Despite patients with diabetes mellitus are high-risk patients, the outcome of percutaneous left atrial appendage closure is similar to patients without diabetes mellitus.

Aortic Calcification Onset and Progression: Association With the Development of Coronary Atherosclerosis.

BACKGROUND: Thoracic aortic calcification (TAC) and coronary artery calcification (CAC) are markers of subclinical atherosclerosis and are associated with incident major cardiovascular events. We investigated major determinants for incidence and progression of TAC and the association between TAC and CAC incidence and progression. METHODS AND RESULTS: In a population-based cohort study, 3270 participants (aged 45-74 years, 53.1% women) received cardiac computed tomography at baseline and after a mean follow-up of 5.1±0.3 years for quantification of calcification of the ascending (ATAC) and descending thoracic aorta (DTAC) and CAC. Multivariable relative risk regression analysis was used to investigate associations of cardiovascular risk factors with incident TAC, of baseline TAC with incident CAC, and of baseline CAC with incident TAC. Of 1243 participants with baseline TAC of 0, 517 (41.6%) revealed incident TAC after 5 years. Incidence of descending TAC was higher (34.5%) than ascending TAC (23.3%). Incident TAC after 5 years was associated with age (relative risk 1.26 [95% CI 1.21-1.33], per 5 years), blood pressure (relative risk 1.06 [95% CI 1.03-1.10], per 10 mm Hg), low-density lipoprotein cholesterol (relative risk 1.08 [95% CI 1.04-1.12], per 20 mg/dL), and smoking (relative risk 1.28 [95% CI 1.07-1.53]). Among the 1185 participants without CAC at baseline, the risk of developing CAC was 28.3% when baseline TAC was present compared with 22.2% among those without baseline TAC (excess risk 6.1% [95% CI 1.2-11.0%]). The point estimate of excess risk for incident CAC was higher for ascending TAC (10.8% [95% CI 4.8-16.7%]) and low for descending TAC (1.8% [95% CI -3.2% to 6.7%]). Excess risk for developing ascending and descending TAC with present baseline CAC was 16.4% (95% CI 12.7-20.0%) and 15.6% (95% CI 10.8-20.4%), respectively. CONCLUSION: TAC and CAC share similar major determinants for incident calcification. Participants with TAC, especially ascending TAC, are at elevated risk for development of CAC.