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A crop breeding program started at the National Institute of Agricultural Sciences (INCA) in 1985, with the objective of obtaining some Cuban potato varieties with disease resistance, high yields and tuber quality; consequently, eight Cuban varieties were achieved. Lajera is a new variety released by the classical hybridization method, which has high yields, quality for fresh consumption and field resistance to A. solani and potato leaf roll virus (PLRV). It has been commercially recorded as a new Cuban variety, granted by the National Institute of Plant Protection from the Ministry of Agriculture of Cuba. This paper presents the main characteristics of this variety and its pedigree. [ABSTRACT FROM AUTHOR]

Context: Transitions in metabolic health status over time are strongly linked to risk for cardiovascular events, particularly among individuals with obesity. Adipokines are proteins with metabolic effects, but their role in transitions in metabolic health status over time is unknown., Objective: To evaluate the associations of adiponectin and leptin with metabolic risk transitions over time., Methods: Among 8,423 individuals who attended ARIC Visits 2 (1990-92) and 4 (1996-98), we evaluated prospective associations of Visit 2 levels of the adipokines adiponectin and leptin (per 1-SD higher) with 6-year transitions in metabolic health. Metabolic health was categorized as metabolically "healthy" (no metabolic syndrome [MetS] or diabetes), unhealthy (MetS present) without diabetes, or unhealthy with diabetes. Analyses were performed overall and stratified by obesity (body mass index [BMI] ≥30 kg/m2)., Results: At Visit 2, the mean age was 58, with 56% female and 21% Black adults. Adults with 1-SD higher adiponectin were less likely to progress from metabolically healthy to unhealthy status over 6 years (OR 0.53, 95%CI: 0.48-0.57), while those with higher leptin were more likely to progress (OR 2.22, 95%CI: 2.01-2.47). Conversely, those with 1-SD higher adiponectin were more likely to regress from metabolically unhealthy to healthy status (OR 1.58, 95% CI: 1.42-1.76), while those with higher leptin were less likely to regress (OR 0.68, 95% CI: 0.60-0.78). Similar patterns were seen across obesity strata. After adjustment for BMI, associations of adiponectin with metabolic transitions were similar, whereas associations for leptin were significantly attenuated., Conclusion: Leptin and adiponectin are differentially linked to the likelihood of worsening and improving metabolic health over time. Adipokines should be explored as targets to improve metabolic health and decrease the risk of future cardiovascular events., (© Crown copyright 2025.)

Background and Aims: Several studies reported an increased cancer risk related to lower-extremity peripheral artery disease (PAD) but had important caveats: not accounting for key confounders like smoking, follow-up <10 years, or no race-specific results. To assess the long-term independent association of PAD with cancer incidence in a bi-racial community-based cohort., Methods: We categorized 13,106 ARIC participants without cancer at baseline (mean age 54.0 [SD 5.7] years, 45.7 % male, and 26.1 % Black) into symptomatic PAD (clinical history or intermittent claudication), asymptomatic PAD (ankle-brachial index [ABI] ≤0.9), and five ABI categories (0.1-interval between 0.9 and 1.3 and > 1.3). We used cancer registries and medical records to ascertain cancer cases and ran multivariable Cox models., Results: During the median follow-up of 25.3 years, there were 4143 incident cancer cases. 25-year cumulative incidence was 37.2 % in symptomatic PAD, 32.3 % in asymptomatic PAD, and 28.0-31.0 % in the other categories. Symptomatic and asymptomatic PAD remained significantly associated with cancer incidence after adjusting for potential confounders, including smoking and diabetes (hazard ratio [HR] 1.42 [1.05-1.92] and 1.24 [1.05-1.46], respectively). When stratified by smoking status, we observed a robust association of PAD (symptomatic and asymptomatic combined) vs. no PAD with cancer risk in ever smokers (HR 1.42 [1.21-1.67]) but not in never smokers. The results were most evident for lung cancer (HR 2.16 (95 %CI 1.65-2.83) for PAD vs. no PAD within ever smokers)., Conclusions: Symptomatic and asymptomatic PAD conferred cancer risk, particularly among ever smokers and for lung cancer. Patients with PAD should receive evidence-based cancer prevention and screening., Competing Interests: Declaration of competing interest Dr. Matsushita received personal fees from Fukuda Denshi, Kowa Company, and RhythmX AI outside of the submitted work. The other authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Associations of waist circumferences (WC) and body mass index (BMI) measured once or over time, with cancer incidence were studied. WC is associated with some cancers independent of BMI. Analyses of cumulative central adiposity and cancer are lacking. We investigated associations between waist circumference-years, incorporating exposure time to WC ≥ 102 cm in men or ≥88 cm in women, and cancer, and compared this with single WC or BMI., Methods: Serial WC measurements taken over 9 years in the prospective Atherosclerosis Risk in Communities Study (ARIC) predicted yearly WC. Cox proportional hazards regression estimated hazard ratios (HRs) of cancer incidence for waist circumference-years, WC or BMI, measured in Visit 4. Harrell's C-statistic quantified metric predictive performances., Results: 10,172 participants were followed up from Visit 4 for cancer over a median 13.7 for men and 15.8 years for women. For obesity-related cancers, HRs per standard deviation waist circumference-years were 1.14 (95%CI:1.04,1.25) and 1.19 (95%CI:1.12,1.27), respectively. Differences in metric predictive performances were marginal., Discussion: This is the first study to identify positive associations between waist circumference-years and cancer. Waist circumference-years did not provide additional information on cancer risk beyond that of WC and BMI. BMI is routinely measured in clinic so it may be preferred over WC., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate The Institutional Review Boards at each study site approved the ARIC study protocol. Only participants who consented to research on chronic diseases such as cancer were included. Given the use of secondary cohort data, no ethical approval was required for the current analysis. Anonymous data was used and handled as per the data management plan and data transfer agreements [70]., (© 2024. The Author(s).)

Background: Cardiovascular disease (CVD) and cancer frequently co-occur due to shared risk factors such as obesity, which is linked to CVD and 14 cancer types. This study explores whether CVD pathophysiologies, combined with obesity, increase cancer risk, impacting clinical management., Methods and Results: Data from the ARIC (Atherosclerosis Risk in Communities) study, spanning 28 years, were analyzed. The cohort included 5127 participants with incident CVD (myocardial infarction, stroke, heart failure, coronary heart disease), of whom 1511 developed a first primary cancer. Follow-up began at CVD diagnosis after Visit 1. Obesity was assessed using body mass index, waist circumference, and waist-to-hip ratio. Incidence rate differences between obesity groups were adjusted for age, sex, and center, whereas the obesity-cancer association was estimated using Fine-Gray regression adjusted for shared risk factors including smoking. Cancer incidence in obese individuals with CVD (body mass index: rate differences=226.6/100 000 person-years) was higher than in those with normal weight. Although obesity was not linked to overall cancer after adjusting for shared risk factors, it was nominally associated with obesity-related cancers. Specifically, women with CVD and obesity had increased obesity-related cancer risk (body mass index: hazard ratio, 1.67 [95% CI, 1.17-2.31]). No significant associations were found in men, even after excluding prostate cancer., Conclusions: This study suggests that obesity is linked to higher obesity-related cancer risk in women with incident CVD, independent of shared risk factors. Further research is needed to eliminate residual confounding, understand sex differences, and explore how CVD pathophysiologies and obesity together influence cancer risk.

Background: Immune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI-myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this "cardiomyotoxicity" are lacking., Methods: A multicenter registry collected data retrospectively from 17 countries between 2014-2023. A multivariable cox regression model (hazard-ratio(HR), [ 95% confidence-interval]) was used to determine risk factors for the primary composite outcome: severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardio-muscular symptoms, diagnostics, and treatments. Time-dependent covariates were used and missing data were imputed. A point-based prognostic risk score was derived and externally validated., Results: In 748 patients (67% male, age 23-94), 30-days incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17% respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (HR=3.60[1.93-6.72]), presence of cardio-muscular symptoms (HR=2.60 [1.58-4.28]), low QRS-voltage on presenting electrocardiogram (HR for ≤0.5mV versus >1mV=2.08[1.31-3.30]), left ventricular ejection fraction (LVEF) <50% (HR=1.78[1.22-2.60]), and incremental troponin elevation (HR=1.86 [1.44-2.39], 2.99[1.91-4.65], 4.80[2.54-9.08], for 20, 200 and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-days primary outcome incidence increased gradually from 3.9%(risk-score=0) to 81.3%(risk-score≥4). This risk-score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low risk patients who were managed with no immunosuppression resulting in no cardio-myotoxic events., Conclusions: ICI-myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low-QRS voltage, depressed LVEF, and cardio-muscular symptoms. A risk-score incorporating these features performed well., Trial Registration Number: NCT04294771 and NCT05454527.

Excess body mass index (BMI) is associated with a higher risk of at least 13 cancers, but it is usually measured at a single time point. We tested whether the overweight-years metric, which incorporates exposure time to BMI ≥25 kg/m 2 , is associated with cancer risk and compared this with a single BMI measure. We used adulthood BMI readings in the Atherosclerosis Risk in Communities (ARIC) study to derive the overweight-years metric. We calculated associations between the metric and BMI and the risk of cancers using Cox proportional hazards models. Models that either included the metric or BMI were compared using Harrell's C-statistic. We included 13,463 participants, with 3,876 first primary cancers over a mean of 19 years (SD 7) of cancer follow-up. Hazard ratios for obesity-related cancers per standard deviation overweight-years were 1.15 (95% CI: 1.05-1.25) in men and 1.14 (95% CI: 1.08-1.20) in women. The difference in the C-statistic between models that incorporated BMI, or the overweight-years metric was non-significant in men and women. Overweight-years was associated with the risk of obesity-related cancers but did not outperform a single BMI measure in association performance characteristics., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: It is unclear how metabolic syndrome (MetS) and diabetes affect Gal-3 (galectin 3) levels and the resulting implications for heart failure (HF) risk. We assessed relationships of MetS and diabetes with Gal-3, and their joint associations with incident HF., Methods and Results: We included 8445 participants without HF (mean age, 63 years; 59% men; 16% Black race) at ARIC (Atherosclerosis Risk in Communities) study visit 4 (1996-1999). We categorized participants as having MetS only, MetS with diabetes, or neither, and by quartiles of MetS severity Z score. We assessed cross-sectional associations of metabolic risk categories with high Gal-3 level (≥75th percentile) using logistic regression. We used Cox regression to evaluate combined associations of metabolic risk categories and Gal-3 quartiles with HF. In cross-sectional analyses, compared with no MetS and no diabetes, MetS only (odds ratio [OR], 1.24 [95% CI, 1.10-1.41]) and MetS with diabetes (OR, 1.59 [95% CI, 1.32-1.92]) were associated with elevated Gal-3. Over a median follow-up of 20.5 years, there were 1749 HF events. Compared with individuals with neither diabetes nor MetS and with Gal-3 in the lowest quartile, the combination of MetS with diabetes and Gal-3 ≥75th percentile was associated with a 4-fold higher HF risk (hazard ratio, 4.35 [95% CI, 3.30-5.73]). Gal-3 provided HF prognostic information above and beyond MetS, NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, and CRP (C-reactive protein) (ΔC statistic for models with versus without Gal-3: 0.003; P =0.004)., Conclusions: MetS and diabetes are associated with elevated Gal-3. The HF risk significantly increased with the combination of greater metabolic risk and higher Gal-3.

Background: Among patients with heart failure (HF), fatigue is common and linked to quality of life and functional status. Fatigue is hypothesized to manifest as multiple types, with general and exertional components. Unique subtypes of fatigue in HF may require differential assessment and treatment to improve outcomes. We conducted this study to identify fatigue subtypes in persons with prevalent HF in the ARIC study (Atherosclerosis Risk in Communities) and describe the distribution of characteristics across subtypes., Methods: We performed a cross-sectional analysis of 1065 participants with prevalent HF at ARIC visit 5 (2011-2013). We measured exertional fatigue using the Modified Medical Research Council Breathlessness scale and general fatigue using the Patient Reported Outcomes Measurement Information System fatigue scale. We used latent class analysis to identify subtypes of fatigue. Number of classes was determined using model fit statistics, and classes were interpreted and assigned fatigue severity rating based on the conditional probability of endorsing survey items given class. We compared characteristics across classes using multinomial regression., Results: Overall, participants were 54% female and 38% Black with a mean age of 77. We identified 4 latent classes (fatigue subtypes): (1) high general/high exertional fatigue (18%), (2) high general/low exertional fatigue (27%), (3) moderate general/moderate exertional fatigue (20%), and (4) low/no general and exertional fatigue (35%). Female sex, Black race, lower education level, higher body mass index, increased depressive symptoms, and higher prevalence of diabetes were associated with higher levels of general and exertional fatigue., Conclusions: We identified unique subtypes of fatigue in patients with HF who have not been previously described. Within subtype, general and exertional fatigue were mostly concordant in severity, and exertional fatigue only occurred in conjunction with general fatigue, not alone. Further understanding these fatigue types and their relationships to outcomes may enhance our understanding of the symptom experience and inform prognostication and secondary prevention efforts for persons with HF., Competing Interests: Disclosures None.

Background: Cancer survivors may have elevated atherosclerotic cardiovascular disease (ASCVD) risk. Therefore, we tested how accurately the American College of Cardiology/American Heart Association 2013 pooled cohort equations (PCEs) predict 10-year ASCVD risk in cancer survivors., Objectives: To estimate the calibration and discrimination of the PCEs in cancer survivors compared to non-cancer participants in the Atherosclerosis Risk in Communities (ARIC) study., Methods: We evaluated the PCEs' performance among 1244 cancer survivors and 3849 cancer-free participants who were free of ASCVD at the start of follow-up. Each cancer survivor was incidence-density matched with up to five controls by age, race, sex, and study center. Follow-up began at the first study visit at least 1 year after the diagnosis date of the cancer survivor and finished at the ASCVD event, death, or end of follow-up. Calibration and discrimination were assessed and compared between cancer survivors and cancer-free participants., Results: Cancer survivors had higher PCE-predicted risk, at 26.1%, compared with 23.1% for cancer-free participants. There were 110 ASCVD events in cancer survivors and 332 ASCVD events in cancer-free participants. The PCEs overestimated ASCVD risk in cancer survivors and cancer-free participants by 45.6% and 47.4%, respectively, with poor discrimination in both groups (C-statistic for cancer survivors = 0.623; for cancer-free participants, C = 0.671)., Conclusions: The PCEs overestimated ASCVD risk in all participants. The performance of the PCEs was similar in cancer survivors and cancer-free participants., Implications for Cancer Survivors: Our findings suggest that ASCVD risk prediction tools tailored to survivors of adult cancers may not be needed., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The Neotropical region hosts 4225 freshwater fish species, ranking first among the world's most diverse regions for freshwater fishes. Our NEOTROPICAL FRESHWATER FISHES data set is the first to produce a large-scale Neotropical freshwater fish inventory, covering the entire Neotropical region from Mexico and the Caribbean in the north to the southern limits in Argentina, Paraguay, Chile, and Uruguay. We compiled 185,787 distribution records, with unique georeferenced coordinates, for the 4225 species, represented by occurrence and abundance data. The number of species for the most numerous orders are as follows: Characiformes (1289), Siluriformes (1384), Cichliformes (354), Cyprinodontiformes (245), and Gymnotiformes (135). The most recorded species was the characid Astyanax fasciatus (4696 records). We registered 116,802 distribution records for native species, compared to 1802 distribution records for nonnative species. The main aim of the NEOTROPICAL FRESHWATER FISHES data set was to make these occurrence and abundance data accessible for international researchers to develop ecological and macroecological studies, from local to regional scales, with focal fish species, families, or orders. We anticipate that the NEOTROPICAL FRESHWATER FISHES data set will be valuable for studies on a wide range of ecological processes, such as trophic cascades, fishery pressure, the effects of habitat loss and fragmentation, and the impacts of species invasion and climate change. There are no copyright restrictions on the data, and please cite this data paper when using the data in publications., (© 2022 The Ecological Society of America.)

Background: Diabetes exerts adverse effects on the heart, and a longer diabetes duration is associated with greater heart failure risk. We studied diabetes duration and subclinical myocardial injury, as reflected by high-sensitivity cardiac troponin (hs-cTnT)., Methods: We analyzed 9052 participants without heart failure or coronary heart disease (mean age 63 years, 58% female, 21% Black, 15% with diabetes) at The Atherosclerosis Risk in Communities Study (ARIC) Visit 4 (1996 to 1998). Diabetes duration was calculated based on diabetes status at Visits 1 (1987 to 1989) through 4, or using self-reported age of diabetes diagnosis prior to Visit 1. We used multinomial logistic regression to determine the association of diabetes duration with increased (≥14 ng/L) or detectable (≥6 ng/L) Visit 4 hs-cTnT, relative to undetectable hs-cTnT, adjusted for demographics and cardiovascular risk factors., Results: The prevalence of increased Visit 4 hs-cTnT was higher in persons with longer diabetes duration, from 12% for those with diabetes 0 to <5 years up to 31% among those with diabetes for ≥15 years (P for trend <0.0001). New onset diabetes at Visit 4 was associated with 1.92× higher relative risk (95% CI, 1.27-2.91) of increased hs-cTnT than no diabetes. Longer diabetes duration was associated with greater myocardial injury, with duration ≥15 years associated with 9.29× higher risk (95% CI, 5.65-15.29) for increased hs-cTnT and 2.07× (95% CI, 1.24-3.16) for detectable hs-cTnT, compared to no diabetes., Conclusions: Longer diabetes duration is strongly associated with subclinical myocardial injury. Interventional studies are needed to assess whether the prevention and delay of diabetes onset can mitigate early myocardial damage., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: More than 80% of adult patients diagnosed with cancer survive long term. Long-term complications of cancer and its therapies may increase the risk of cardiovascular disease (CVD), but prospective studies using adjudicated cancer and CVD events are lacking., Objectives: The aim of this study was to assess the risk of CVD in cancer survivors in a prospective community-based study., Methods: We included 12,414 ARIC (Atherosclerosis Risk In Communities) study participants. Cancer diagnoses were ascertained via linkage with state registries supplemented with medical records. Incident CVD outcomes were coronary heart disease (CHD), heart failure (HF), stroke, and a composite of these. We used multivariable Poisson and Cox regressions to estimate the association of cancer with incident CVD., Results: Mean age was 54 years, 55% were female, and 25% were Black. A total of 3,250 participants (25%) had incident cancer over a median 13.6 years of follow-up. Age-adjusted incidence rates of CVD (per 1,000 person-years) were 23.1 (95% CI: 24.7-29.1) for cancer survivors and 12.0 (95% CI: 11.5-12.4) for subjects without cancer. After adjustment for cardiovascular risk factors, cancer survivors had significantly higher risks of CVD (HR: 1.37; 95% CI: 1.26-1.50), HF (HR: 1.52; 95% CI: 1.38-1.68), and stroke (HR: 1.22; 95% CI: 1.03-1.44), but not CHD (HR: 1.11; 95% CI: 0.97-1.28). Breast, lung, colorectal, and hematologic/lymphatic cancers, but not prostate cancer, were significantly associated with CVD risk., Conclusions: Compared with persons without cancer, adult cancer survivors have significantly higher risk of CVD, especially HF, independent of traditional cardiovascular risk factors. There is an unmet need to define strategies for CVD prevention in this high-risk population., Competing Interests: Funding Support and Author Disclosures The ARIC study has been supported with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health (NIH), and the Department of Health and Human Services under contract numbers 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005. Studies on cancer in the ARIC study are also supported by the National Cancer Institute (grant U01CA164975). This research was additionally supported by a Cancer Center Support Grant from the National Cancer Institute (grant P30 CA006973). Ms Daya was supported by NIH/NHLBI grant T32HL007024. Dr Selvin was supported by NIH/National Institute of Diabetes and Digestive and Kidney Diseases grants K24 HL152440 and R01 DK089174. Dr Ndumele was supported by NIH/NHLBI grant R01 HL146907 and American Heart Association grant 20SFRN35120152. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The influence of diabetes on progression from preclinical heart failure (HF) stages to overt HF is poorly understood., Objectives: The purpose of this study was to characterize the influence of diabetes on the progression from preclinical HF stages (A or B based on the 2021 Universal Definition) to overt HF., Methods: We included 4,774 adults with preclinical HF (stage A [n = 1,551] or B [n = 3,223]) who attended the ARIC (Atherosclerosis Risk In Communities) study Visit 5 (2011-2013). Within each stage (A or B), we assessed the associations of diabetes and glycemic control (hemoglobin A 1C [HbA 1C ] <7% vs ≥7%) with progression to HF, and of cross-categories of HF stages (A vs B), diabetes, and glycemic control with incident HF., Results: Among the participants (mean age 75.4 years, 58% women, 20% Black), there were 470 HF events during 8.6 years of follow-up. Stage B participants with HbA 1C  ≥7% experienced clinical HF at a younger age than those with controlled diabetes or without diabetes (mean age 80 years vs 83 years vs 82 years; P < 0.001). HbA 1C  ≥7% was more strongly associated with HF in stage B (HR: 1.83; 95% CI: 1.33-2.51) compared with stage A (HR: 1.52; 95% CI: 0.53-4.38). In cross-categories of preclinical HF stage and HbA 1C , participants with stage B and HbA 1C  ≥7% had increased risk of HF progression compared with stage A without diabetes (HR: 7.56; 95% CI: 4.68-12.20)., Conclusions: Among older adults with preclinical HF stages, uncontrolled diabetes was associated with substantial risk of HF progression. Our results suggest that targeting diabetes early in the HF process is critical., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I). Dr Echouffo-Tcheugui was supported by NIH/NHLBI grant K23 HL153774. Dr Ndumele was supported by NIH grant R01HL146907. Dr Shah was supported by NIH/NHLBI grants R01HL135008, R01HL143224, R01HL150342, R01HL148218, and K24HL152008; has received research support not related to this study from Novartis and Philips Ultrasound; and has received consulting fees from Philips Ultrasound and Edwards Lifesciences. Dr Selvin was supported by NIH/NHLBI grant K24 HL152440 and NIH/NIDDK grant R01DK089174; and has received payments from Wolters Kluwer for chapters and laboratory monographs in UpToDate on measurements of glycemic control and screening tests for type 2 diabetes. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background Laboratory data suggest obesity is linked to myocardial inflammation and fibrosis, but clinical data are limited. We aimed to examine the association of obesity with galectin-3, a biomarker of cardiac inflammation and fibrosis, and the related implications for heart failure (HF) risk. Methods and Results We evaluated 8687 participants (mean age 63 years; 21% Black) at ARIC (Atherosclerosis Risk in Communities) Visit 4 (1996-1998) who were free of heart disease. We used adjusted logistic regression to estimate the association of body mass index (BMI) categories with elevated galectin-3 (≥75th sex-specific percentile) overall and across demographic subgroups, with tests for interaction. We used Cox proportional hazards models to assess the combined associations of galectin-3 and BMI with incident HF (through December 31, 2019). Higher BMI was associated with higher odds of elevated galectin-3 (odds ratio [OR], 2.32; 95% CI, 1.88-2.86) for severe obesity ([BMI ≥35 kg/m 2 ] versus normal weight [BMI 18.5-<25 kg/m 2 ]). There were stronger associations of BMI with elevated galectin-3 among women versus men and White versus Black participants (both P -for-interaction <0.05). Elevated galectin-3 was similarly associated with incident HF among people with and without obesity (HR, 1.49; 95% CI, 1.18-1.88; and HR, 1.71; 95% CI, 1.38-2.11, respectively). People with severe obesity and elevated galectin-3 had >4-fold higher risk of HF (HR, 4.19; 95% CI, 2.98-5.88) than those with normal weight and galectin-3 <25th percentile. Conclusions Obesity is strongly associated with elevated galectin-3. Additionally, the combination of obesity and elevated galectin-3 is associated with marked HF risk, underscoring the importance of elucidating pathways linking obesity with cardiac inflammation and fibrosis.

Aims: Heart failure is an increasingly recognized later stage manifestation of arrhythmogenic right ventricular cardiomyopathy (ARVC) that can require heart transplantation (HT) to appropriately treat. We aimed to study contemporary ARVC HT outcomes in a national registry., Methods and Results: The United Network for Organ Sharing registry was queried for HT recipients from 1/1994 through 2/2020. ARVC patients were compared with non-ARVC dilated, restrictive, and hypertrophic cardiomyopathy HT patients (HT for ischaemic and valvular disease was excluded from analysis). Post-HT survival was assessed using Kaplan-Meier estimates. A total of 189 of 252 (75%) waitlisted ARVC patients (median age 48 years, 65% male) underwent HT, representing 0.3% of the total 65 559 HT during the study time period. Annual frequency of HT for ARVC increased significantly over time. ARVC patients had less diabetes (5% vs. 17%, P < 0.001), less cigarette use (15% vs. 23%, P < 0.001), lower pulmonary artery and pulmonary capillary wedge pressures, and lower cardiac output than the 33 659 non-ARVC patients (P < 0.001). Ventricular assist device use was significantly lower in ARVC patients (8% vs. 32%, P < 0.001); 1 and 5 year post-HT survival was 97% and 93% for ARVC vs. 95% and 82% for non-ARVC HT recipients (P < 0.001). On adjusted multivariable Cox regression, ARVC had decreased risk of post-HT death compared with non-ARVC aetiologies (hazard ratio 0.48, 95% confidence interval 0.28-0.82, P = 0.008). Patients with ARVC also had lower risk of death or graft failure than non-ARVC patients (hazard ratio 0.51, 95% confidence interval 0.32-0.81, P = 0.004)., Conclusions: In the largest series of HT in ARVC, we found that HT is increasingly performed in ARVC, with higher survival compared with other cardiomyopathy aetiologies. The right ventricular predominant pathophysiology may require unique considerations for heart failure management, including HT., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Angiotensin receptor-neprilysin inhibitors (ARNIs) greatly benefit functional capacity and longevity in heart failure with reduced ejection fraction (HFrEF). Angiotensin receptor-neprilysin inhibitors remain underutilized and unstudied, however, in left ventricular assist device (LVAD) recipients, in spite of their underlying HFrEF. In this case series, we studied the feasibility and short-term efficacy of ARNI utilization in 21 LVAD patients. Angiotensin receptor-neprilysin inhibitor initiation was successful in most, resulting in significant consolidation of blood pressure (BP) medical management and marked improvements in both functional capacity and diuretic requirements. Angiotensin receptor-neprilysin inhibitors are safe, feasible, and within a short timeframe benefit BP and heart failure control in LVAD recipients., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

Objectives: This study assessed the association of diabetes duration with incident heart failure (HF)., Background: Diabetes increases HF risk. However, the independent effect of diabetes duration on incident HF is unknown., Methods: We included 9,734 participants (mean age 63 years, 58% women, 22% Black) at ARIC (Atherosclerosis Risk In Communities) Visit 4 (1996-1998) without HF or coronary heart disease. We calculated diabetes duration at Visit 4 (baseline), utilizing diabetes status at the first 4 ARIC visits spaced 3 years apart, and self-reported diagnosis date for those with diabetes diagnosed before Visit 1. We used Cox regression to estimate associations of diabetes duration with incident HF, accounting for intercurrent coronary heart disease and other risk factors. We performed analyses stratified by age (<65 years or ≥65 years), race, sex, and glycemic control (hemoglobin A 1C [HbA 1C ] consistently <7%, vs HbA 1C  ≥7%), with tests for interaction., Results: Over 22.5 years of follow-up, there were 1,968 HF events. Compared to those without diabetes, HF risk rose with longer diabetes duration, with the highest risk among those with ≥15 y diabetes duration (HR: 2.82; 95% CI: 2.25-3.63). Each 5-year increase in diabetes duration was associated with a 17% (95% CI: 11-22) relative increase in HF risk. Similar results were observed across HF subtypes. The HF and diabetes duration associations were stronger among those aged <65 years, those with HbA 1C  ≥7%, those with a body mass index ≥30 kg/m 2 , women, and Blacks (all P interactions <0.05)., Conclusions: Delaying diabetes onset may augment HF prevention efforts, and therapies to improve HF outcomes might target those with long diabetes duration., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), and Department of Health and Human Services, under Contract nos. HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr Tcheugui was supported by National Institutes of Health (NIH)/NHLBI grant K23 HL153774. Dr Hamo was supported by NIH/NHLBI grant number T32 HL007024. Dr Selvin was supported by NIH/National Institute of Diabetes and Digestive and Kidney Diseases grants K24 HL152440 and R01DK089174, and American Heart Association grant 20SFRN35120152. Dr Ndumele was supported by NIH grant R01HL146907 and American Heart Association grant 20SFRN35120152. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background Greater physical activity (PA) is associated with lower heart failure (HF) risk. However, it is unclear whether this inverse association exists across all subgroups at high risk for HF, particularly among those with preexisting atherosclerotic cardiovascular disease. Methods and Results We followed 13 810 ARIC (Atherosclerosis Risk in Communities) study participants (mean age 55 years, 54% women, 26% black) without HF at baseline (visit 1; 1987-1989). PA was assessed using a modified Baecke questionnaire and categorized according to American Heart Association guidelines: recommended, intermediate, or poor. We constructed Cox models to estimate associations between PA categories and incident HF within each high-risk subgroup at baseline, with tests for interaction. We performed additional analyses modeling incident coronary heart disease as a time-varying covariate. Over a median of 26 years of follow-up, there were 2994 HF events. Compared with poor PA, recommended PA was associated with lower HF risk among participants with hypertension, obesity, diabetes mellitus, and metabolic syndrome (all P <0.01), but not among those with prevalent atherosclerotic cardiovascular disease (coronary heart disease, stroke, or peripheral arterial disease) (hazard ratio, 0.91; 95% CI, 0.74-1.13 [ P interaction=0.02]). Recommended PA was associated with lower risk of incident coronary heart disease (hazard ratio, 0.79; 95% CI, 0.72-0.86), but not with lower HF risk in those with interim coronary heart disease events (hazard ratio, 0.90; 95% CI, 0.78-1.04 [ P interaction=0.04]). Conclusions PA was associated with decreased HF risk in patients with hypertension, obesity, diabetes mellitus, and metabolic syndrome. Despite a myriad of benefits in patients with atherosclerotic cardiovascular disease, PA may have weaker associations with HF prevention after ischemic disease is established.

We report the first case of a patient with a durable left ventricular assist device admitted with cardiogenic shock and managed with biventricular Impella support as a successful bridge to heart transplantation. ( Level of Difficulty: Advanced. )., (© 2020 The Authors.)

Background Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized by high arrhythmic burden and progressive heart failure, which can prompt referral for heart transplantation. Cardiopulmonary exercise testing (CPET) has an established role in risk stratification for advanced heart failure therapies, but has not been described in ARVC/D. This study sought to determine the safety and prognostic utility of CPET in patients with ARVC/D. Methods and Results Using the Johns Hopkins ARVC/D Registry, we examined patients with ARVC/D undergoing CPET. Baseline characteristics and transplant-free survival were compared on the basis of peak oxygen consumption (pVO2) (≤14 or >14 mL/kg per minute) and ventilatory efficiency (Ve/VCO 2 slope ≤34 or >34). Thirty-eight patients underwent 50 CPETs. There were no sustained arrhythmic events. Twenty-nine patients achieved a maximal test. Patients with pVO2 ≤14 mL/kg per minute were more often men ( P =0.042) compared with patients with pVO2 >14 mL/kg per minute. Patients with Ve/VCO 2 slope >34 tended to have more moderate/severe right ventricular dilation (7/9 [78%] versus 10/26 [38%]; P =0.060) and clinical heart failure (8/9 [89%] versus 13/26 [50%]; P =0.056) compared with patients with Ve/VCO 2 slope ≤34. Patients who underwent heart transplantation were more likely to have clinical heart failure (10/10 [100%] versus 13/28 [46%]; P =0.003). Patients with Ve/VCO 2 slope >34 had worse transplant-free survival compared with patients with Ve/VCO 2 slope ≤34 (n=35; hazard ratio, 6.57 [95% CI, 1.28-33.72]; log-rank P =0.010), whereas transplant-free survival was similar on the basis of pVO2 groups (n=29; hazard ratio, 3.38 [95% CI, 0.75-15.19]; log-rank P =0.092). Conclusions CPET is safe to perform in patients with ARVC/D. Ve/VCO 2 slope may be used for risk stratification and guide referral for heart transplantation in ARVC/D.

Cancer survivors might have an excess risk of cardiovascular disease (CVD) resulting from toxicities of cancer therapies and a high burden of CVD risk factors. We sought to evaluate the association of cancer survivorship with subclinical myocardial damage, as assessed by elevated high-sensitivity cardiac troponin T (hs-cTnT) test results. We included 3,512 participants of the Atherosclerosis Risk in Communities Study who attended visit 5 (2011-2013) and were free of CVD (coronary heart disease, heart failure, or stroke). We used multivariate logistic regression to evaluate the cross-sectional associations of survivorship from any, non-sex-related, and sex-related cancers (e.g., breast, prostate) with elevated hs-cTnT (≥14 ng/L). Of 3,512 participants (mean age, 76 years; 62% women; 21% black), 19% were cancer survivors. Cancer survivors had significantly higher odds of elevated hs-cTnT (OR = 1.26, 95% CI: 1.03, 1.53). Results were similar for survivors of non-sex-related and colorectal cancers, but there was no association between survivorship from breast and prostate cancers and elevated hs-cTnT. Results were similar after additional adjustments for CVD risk factors. Survivors of some cancers might be more likely to have elevated hs-cTnT than persons without prior cancer. The excess burden of subclinical myocardial damage in this population might not be fully explained by traditional CVD risk factors., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Physical activity (PA) is inversely associated with risk of heart failure and cardiovascular disease (CVD), whereas increased left ventricular (LV) mass and mass to volume (m:v) ratio are unfavorable CVD risk factors. We assessed whether changes in leisure time PA were associated with longitudinal changes in cardiac structure in a community-based population., Methods: We included 2779 Multi-Ethnic Study of Atherosclerosis participants, free of baseline CVD, who had available data on PA and cardiac magnetic resonance imaging at examinations 1 (2000-2002) and 5 (2010-2012). Physical activity was measured by a Typical Week PA Survey and converted to MET-minutes per week of moderate+vigorous activity. We used linear mixed effect models to estimate the associations of baseline and change in PA with baseline and change in cardiac structure, adjusting for CVD risk factors and body size., Results: At baseline, the mean age was 59 yr, 53% were women, and 58% of nonwhite race/ethnicity. During average 10-yr follow-up, and after accounting for baseline PA levels, the highest quintiles of PA increase were significantly associated with increases in LV mass (2.3 g; 95% confidence interval [CI], 0.4-4.2), LV end-diastolic volume (4.7 mL; 95% CI, 2.4-7.0), and stroke volume (3.3 mL; 95% CI, 1.6-5.1), but lower M:V ratio (-2.9; 95% CI, -5.0 to -0.8) compared with the lowest quintiles. Increasing exercise PA was associated with increases in LV diameter and reductions in M:V ratio, whereas occupational PA was associated with increases in m:v ratio. Increasing PA over 10 yr was also associated with greater risk of eccentric dilated LV hypertrophy at examination 5., Conclusions: After accounting for baseline PA, greater positive changes in leisure-time PA levels were associated with a more eccentric-type of LV remodeling pattern over 10 yr. The clinical implications of such findings remain to be determined.

Background: This study assessed the independent associations between participation in self-reported sport and exercise activities and incident cardiovascular disease (CVD)., Methods: Data were from 13,204 participants in the Atherosclerosis Risk in Communities Study cohort (1987-2015). Baseline sport and exercise activities were assessed via the modified Baecke questionnaire. Incident CVD included coronary heart disease, heart failure, or stroke. Multivariable-adjusted Cox proportional hazard models assessed the association of participation in specific sport and exercise activities at enrollment with risk of CVD., Results: During a median follow-up time of 25.2 years, 30% of the analytic sample (n = 3966) was diagnosed with incident CVD. In fully adjusted models, participation in racquet sports (hazard ratio [HR] 0.75; 95% confidence interval [CI], 0.61-0.93), aerobics (HR 0.75; 95% CI, 0.63-0.88), running (HR 0.68; 95% CI, 0.54-0.85), and walking (HR 0.89; 95% CI, 0.83-0.95) was significantly associated with a lower risk of CVD. There were no significant associations for bicycling, softball/baseball, gymnastics, swimming, basketball, calisthenics exercises, golfing with cart, golfing with walking, bowling, or weight training., Conclusions: Participation in specific sport and exercises may substantially reduce the risk for CVD.

Cardiovascular toxicities associated with immune checkpoint inhibitors (ICIs) have been reported in case series but have been underappreciated due to their recent emergence, difficulties in diagnosis and non-specific clinical manifestations. ICIs are antibodies that block negative regulators of the T cell immune response, including cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and PD-1 ligand (PD-L1). While ICIs have introduced a significant mortality benefit in several cancer types, the augmented immune response has led to a range of immune-related toxicities, including cardiovascular toxicity. ICI-associated myocarditis often presents with arrhythmias, may co-exist with myositis and myasthenia gravis, can be severe, and portends a poor prognosis. In addition, pericardial disease, vasculitis, including temporal arteritis, and non-inflammatory heart failure, have been recently described as immune-related toxicities from ICI. This narrative review describes the epidemiology, diagnosis, pathophysiology, and treatment of cardiovascular toxicities of ICI therapy, highlighting recent developments in the field in the past year., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Higher physical activity (PA) is associated with lower heart failure (HF) risk; however, the effect of changes in PA on HF risk is unknown., Methods: We evaluated 11 351 ARIC study (Atherosclerosis Risk in Communities) participants (mean age 60 years) who attended visit 3 (1993-1995) and did not have a history of cardiovascular disease. Exercise PA was assessed using a modified Baecke questionnaire and categorized according to American Heart Association guidelines as recommended, intermediate, or poor. We used Cox regression models to characterize the association of 6-year changes in PA between the first (1987-1989) and third ARIC visits and HF risk., Results: During a median of 19 years of follow-up, 1750 HF events occurred. Compared with those with poor activity at both visits, the lowest HF risk was seen for those with persistently recommended activity (hazard ratio, 0.69; 95% confidence interval, 0.60-0.80). However, those whose PA increased from poor to recommended also had reduced HF risk (hazard ratio, 0.77; 95% confidence interval 0.63-0.93). Among participants with poor baseline activity, each 1 SD higher PA at 6 years (512.5 METS*minutes/week, corresponding to ≈30 minutes of brisk walking 4 times per week) was associated with significantly lower future HF risk (hazard ratio, 0.89, 95% confidence interval, 0.82-0.96)., Conclusions: Although maintaining recommended activity levels is associated with the lowest HF risk, initiating and increasing PA, even in late middle age, are also linked to lower HF risk. Augmenting PA may be an important component of strategies to prevent HF., (© 2018 American Heart Association, Inc.)

The impact of lifestyle-related factors on temporal decreases in high-sensitivity cardiac troponin T (hs-cTnT), possibly reflecting reversal of subclinical myocardial damage, has not been evaluated in a community-based setting. We measured hs-cTnT twice, 6 years apart, in 9,256 participants from the Atherosclerosis Risk in Communities (ARIC) Study who were free from baseline cardiovascular disease. We used Poisson and multinomial regression to evaluate the associations of cigarette smoking, alcohol consumption, body mass index, healthy diet score, physical activity, and Life's Simple 7 (LS7) score (a composite measure of lifestyle-related health factors) with 6-year decreases in hs-cTnT. Of the 3,017 patients with detectable baseline hs-cTnT (≥5 ng/L), 2,418 (80%) remained detectable, whereas 599 (20%) had undetectable levels (<5 ng/L) at the 6-year follow-up visit. Patients with a body mass index of <30 kg/m 2 , adherence to American Heart Association's physical activity guidelines, and average or optimal LS7 scores were more likely to improve from a detectable to an undetectable hs-cTnT level during follow-up. There was a robust association between optimal LS7 score and temporal hs-cTnT reduction (relative risk 1.64, 95% confidence interval 1.11 to 2.42, for baseline ≥5 ng/L and for follow-up <5 ng/L). A greater duration of exposure to average or optimal LS7 score was also associated with increased likelihood of temporal hs-cTnT reduction (p-trend <0.001). In conclusion, we found that lifestyle factors and the LS7 score were associated with reversal of subclinical myocardial damage. In conclusion, our results support the growing evidence that hs-cTnT levels change in response to lifestyle modifications and hs-cTnT may serve as a useful dynamic surrogate for monitoring cardiovascular risk., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: This study sought to evaluate the association of physical activity with chronic myocardial damage, assessed by elevated high-sensitivity cardiac troponin T (hs-cTnT), in individuals with and without obesity., Background: Physical activity is associated with reduced risk of heart failure (HF), particularly among obese people. The role of chronic myocardial damage in this association is uncertain., Methods: We studied 9,427 participants in the Atherosclerosis Risk in Communities Study without cardiovascular disease, with body mass index >18.5 kg/m 2 . Physical activity was categorized per American Heart Association guidelines as recommended, intermediate, or poor. We evaluated cross-sectional associations of physical activity and obesity with elevated hs-cTnT (≥14 ng/l). In prospective analyses, we quantified the association of elevated hs-cTnT with HF risk within cross-categories of baseline physical activity and obesity., Results: People with poor physical activity were more likely to have elevated hs-cTnT than those with recommended levels (odds ratio [OR]: 1.39; 95% confidence interval [CI]: 1.15 to 1.68). In cross-categories of physical activity and obesity, using the non-obese/recommended activity group as the reference, individuals with obesity and poor activity were most likely to have elevated hs-cTnT (OR: 2.46; 95% CI: 1.91 to 3.19), whereas the obese/recommended activity group had a weaker association (OR: 1.68; 95% CI: 1.28 to 2.21; p < 0.001 for interaction between physical activity and obesity). In prospective analyses, elevated hs-cTnT was strongly associated (p < 0.001) with incident HF in all obesity/physical activity cross-categories (p > 0.20 for interaction)., Conclusions: Physical activity is inversely associated with chronic subclinical myocardial damage. Physical activity might lessen the association between obesity and subclinical myocardial damage, which could represent a mechanism by which physical activity reduces HF risk., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Context: Physical activity (PA) is associated with 25-hydroxyvitamin D [25(OH)D] levels. Both are associated with atherosclerotic cardiovascular disease (ASCVD), but their joint association with ASCVD risk is unknown., Objective: To examine the relationship between PA and 25(OH)D, and assess effect modification of 25(OH)D and PA with ASCVD., Design: Cross-sectional and prospective study., Setting: Community-dwelling cohort., Participants: A total of 10,342 participants free of ASCVD, with moderate- to vigorous-intensity PA assessed (1987 to 1989) and categorized per American Heart Association (AHA) guidelines (recommended, intermediate, or poor)., Main Outcome Measures: Serum 25(OH)D levels (1990 to 1992) and ASCVD events (i.e., incident myocardial infarction, fatal coronary disease, or stroke) through 2013., Results: Participants had mean age of 54 years, and were 57% women, 21% black, 30% 25(OH)D deficient [<20 ng/mL (<50 nmol/L)], and <40% meeting AHA-recommended PA. PA was linearly associated with 25(OH)D levels in whites. Whites meeting recommended PA were 37% less likely to have 25(OH)D deficiency [relative risk, 0.63 (95% confidence interval [CI], 0.56, 0.71)]; there was no significant association in blacks. Over 19.3 years of follow-up, 1800 incident ASCVD events occurred. Recommended PA was associated with reduced ASCVD risk [hazard ratio [HR], 0.78 (95% CI, 0.65, 0.93) and 0.76 (95% CI, 0.62, 0.93)] among participants with intermediate [20 to <30 ng/mL (50 to <75 nmol/L)] and optimal [≥30 ng/mL (≥75 nmol/L)] 25(OH)D, respectively, but not among those with deficient 25(OH)D (P for interaction = 0.04)., Conclusion: PA is linearly associated with higher 25(OH)D levels in whites. PA and 25(OH)D may have synergistic beneficial effects on ASCVD risk., (Copyright © 2017 by the Endocrine Society)

Background: The effects of some atherosclerotic cardiovascular disease (ASCVD) risk factors vary according to whether an individual has a family history (FHx) of premature coronary heart disease (CHD). Physical activity (PA) is associated with reduced risk of ASCVD, but whether this association varies by FHx status is not well established., Methods and Results: We evaluated 9996 participants free of ASCVD at baseline. FHx of premature CHD was defined as CHD occurring in a father before age 55 or mother before age 60. PA, assessed by a Baecke questionnaire, was converted into minutes/week of moderate or vigorous exercise and categorized per American Heart Association guidelines as recommended, intermediate, or poor. Incident ASCVD was defined as incident myocardial infarction, fatal CHD, or stroke. Multivariable-adjusted Cox hazard models were used. The mean age was 54±6 years, 56% were women, and 21% of black race. Participants with and without a FHx of premature CHD reported similar levels of PA at baseline (423 versus 409 metabolic equivalents of task×min/week, respectively, P=0.852), and ≈40% of both groups met American Heart Association recommended PA levels. Over a mean follow-up of 20.9 years, there were 1723 incident ASCVD events. Compared to those with poor PA adherence to American Heart Association guidelines, participants who reported PA at recommended levels had significantly lower risk of incident ASCVD after adjustment for demographics and lifestyle factors (hazard ratio 0.84, 95% CI 0.74-0.94), but this association was not modified by FHx status (P-interaction=0.680)., Conclusions: PA was associated with a reduced risk of ASCVD among individuals with and without a FHx of premature CHD., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Rationale: Molecular phenotyping of chronic obstructive pulmonary disease (COPD) has been impeded in part by the difficulty in obtaining lung tissue samples from individuals with impaired lung function., Objectives: We sought to determine whether COPD-associated processes are reflected in gene expression profiles of bronchial airway epithelial cells obtained by bronchoscopy., Methods: Gene expression profiling of bronchial brushings obtained from 238 current and former smokers with and without COPD was performed using Affymetrix Human Gene 1.0 ST Arrays., Measurements and Main Results: We identified 98 genes whose expression levels were associated with COPD status, FEV1% predicted, and FEV1/FVC. In silico analysis identified activating transcription factor 4 (ATF4) as a potential transcriptional regulator of genes with COPD-associated airway expression, and ATF4 overexpression in airway epithelial cells in vitro recapitulates COPD-associated gene expression changes. Genes with COPD-associated expression in the bronchial airway epithelium had similarly altered expression profiles in prior studies performed on small-airway epithelium and lung parenchyma, suggesting that transcriptomic alterations in the bronchial airway epithelium reflect molecular events found at more distal sites of disease activity. Many of the airway COPD-associated gene expression changes revert toward baseline after therapy with the inhaled corticosteroid fluticasone in independent cohorts., Conclusions: Our findings demonstrate a molecular field of injury throughout the bronchial airway of active and former smokers with COPD that may be driven in part by ATF4 and is modifiable with therapy. Bronchial airway epithelium may ultimately serve as a relatively accessible tissue in which to measure biomarkers of disease activity for guiding clinical management of COPD.