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Background and ObjectivesPlasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the plasma proteome and IS risk in the population-based Cardiovascular Health Study (CHS).MethodsEligible CHS participants were free of prevalent stroke and underwent quantification of 1,298 plasma proteins using the aptamer-based SOMAScan assay platform from the 1992–1993 study visit. Multivariable Cox proportional hazards regression was used to evaluate associations between a 1-SD increase in the log2-transformed estimated plasma protein concentrations and incident IS, adjusting for demographics, IS risk factors, and estimated glomerular filtration rate. For proteins independently associated with incident IS, a secondary stratified analysis evaluated associations in subgroups defined by sex and race. Exploratory analyses evaluated plasma proteomic associations with cardioembolic and noncardioembolic IS and proteins associated with IS risk in participants with left atrial dysfunction but without atrial fibrillation.ResultsOf 2,983 eligible participants, the mean age was 74.3 (±4.8) years, 61.2% were women, and 15.4% were Black. Over a median follow-up of 12.6 years, 450 participants experienced an incident IS. N-terminal probrain natriuretic peptide (NTproBNP, adjusted HR 1.37, 95% CI 1.23–1.53,p= 2.08 × 10−08) and macrophage metalloelastase (MMP12, adjusted HR 1.30, 95% CI 1.16–1.45,p= 4.55 × 10−06) were independently associated with IS risk. These 2 associations were similar in men and women and in Black and non-Black participants. In exploratory analyses, NTproBNP was independently associated with incident cardioembolic IS, E-selectin with incident noncardioembolic IS, and secreted frizzled-related protein 1 with IS risk in participants with left atrial dysfunction.DiscussionIn a cohort of older adults, NTproBNP and MMP12 were independently associated with IS risk. We identified plasma proteomic determinants of incident cardioembolic and noncardioembolic IS and found a novel protein associated with IS risk in those with left atrial dysfunction.

BackgroundIn the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.Methods and ResultsIn the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.ConclusionThe CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

High-throughput proteomics allows researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan proteins measured in relation to 18-year incident diabetes risk in participants from the Cardiovascular Health Study (N = 2,631) and IVGTT-derived measures in participants from the HERITAGE Family Study (N = 752). We characterize 51 proteins that were associated with longitudinal diabetes risk, using their respective 39, 9, and 8 concurrent associations with insulin sensitivity index (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG). Twelve of the 51 diabetes associations appear to be novel, including β-glucuronidase, which was associated with increased diabetes risk and lower SG, suggesting an alternative pathway to insulin for glucose disposal; and plexin-B2, which also was associated with increased diabetes risk, but with lower AIRG, and not with SI, indicating a mechanism related instead to pancreatic dysfunction. Other novel protein associations included alcohol dehydrogenase-1C, fructose-bisphosphate aldolase-B, sorbitol dehydrogenase with elevated type 2 diabetes risk, and a leucine-rich repeat containing protein-15 and myocilin with decreased risk. Article Highlights Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response.

ImportanceEnlarged perivascular spaces (ePVSs) have been associated with cerebral small-vessel disease (cSVD). Although their etiology may differ based on brain location, study of ePVSs has been limited to specific brain regions; therefore, their risk factors and significance remain uncertain.ObjectiveToperform a whole-brain investigation of ePVSs in a large community-based cohort.Design, Setting, and ParticipantsThis cross-sectional study analyzed data from the Atrial Fibrillation substudy of the population-based Multi-Ethnic Study of Atherosclerosis. Demographic, vascular risk, and cardiovascular disease data were collected from September 2016 to May 2018. Brain magnetic resonance imaging was performed from March 2018 to July 2019. The reported analysis was conducted between August and October 2022. A total of 1026 participants with available brain magnetic resonance imaging data and complete information on demographic characteristics and vascular risk factors were included.Main Outcomes and MeasuresEnlarged perivascular spaces were quantified using a fully automated deep learning algorithm. Quantified ePVS volumes were grouped into 6 anatomic locations: basal ganglia, thalamus, brainstem, frontoparietal, insular, and temporal regions, and were normalized for the respective regional volumes. The association of normalized regional ePVS volumes with demographic characteristics, vascular risk factors, neuroimaging indices, and prevalent cardiovascular disease was explored using generalized linear models.ResultsIn the 1026 participants, mean (SD) age was 72 (8) years; 541 (53%) of the participants were women. Basal ganglia ePVS volume was positively associated with age (β = 3.59 × 10−3; 95% CI, 2.80 × 10−3 to 4.39 × 10−3), systolic blood pressure (β = 8.35 × 10−4; 95% CI, 5.19 × 10−4 to 1.15 × 10−3), use of antihypertensives (β = 3.29 × 10−2; 95% CI, 1.92 × 10−2 to 4.67 × 10−2), and negatively associated with Black race (β = −3.34 × 10−2; 95% CI, −5.08 × 10−2 to −1.59 × 10−2). Thalamic ePVS volume was positively associated with age (β = 5.57 × 10−4; 95% CI, 2.19 × 10−4 to 8.95 × 10−4) and use of antihypertensives (β = 1.19 × 10−2; 95% CI, 6.02 × 10−3 to 1.77 × 10−2). Insular region ePVS volume was positively associated with age (β = 1.18 × 10−3; 95% CI, 7.98 × 10−4 to 1.55 × 10−3). Brainstem ePVS volume was smaller in Black than in White participants (β = −5.34 × 10−3; 95% CI, −8.26 × 10−3 to −2.41 × 10−3). Frontoparietal ePVS volume was positively associated with systolic blood pressure (β = 1.14 × 10−4; 95% CI, 3.38 × 10−5 to 1.95 × 10−4) and negatively associated with age (β = −3.38 × 10−4; 95% CI, −5.40 × 10−4 to −1.36 × 10−4). Temporal region ePVS volume was negatively associated with age (β = −1.61 × 10−2; 95% CI, −2.14 × 10−2 to −1.09 × 10−2), as well as Chinese American (β = −2.35 × 10−1; 95% CI, −3.83 × 10−1 to −8.74 × 10−2) and Hispanic ethnicities (β = −1.73 × 10−1; 95% CI, −2.96 × 10−1 to −4.99 × 10−2).Conclusions and RelevanceIn this cross-sectional study of ePVSs in the whole brain, increased ePVS burden in the basal ganglia and thalamus was a surrogate marker for underlying cSVD, highlighting the clinical importance of ePVSs in these locations.

The Life's Simple 7 (LS7) metric consists of 7 modifiable health behaviors and measures that are known health factors for cardiovascular wellness. Relatively little is known about the association of LS7 score with cardiac arrhythmias. In the setting of the Multi-Ethnic Study of Atherosclerosis, we studied the LS7 score (range 0 to 14), assessed at the 2010 to 2102 study visit, in relation to cardiac arrhythmias assessed by Zio Patch ambulatory electrocardiographic monitoring in 2016 to 2018. In participants free of clinically recognized cardiovascular disease and atrial fibrillation, we used logistic and linear regression to examine the association of total LS7 score with atrial fibrillation, supraventricular ectopy, and ventricular ectopy. In 1,329 participants in the analysis, the mean (SD) age was 67 (8) years and 48% were men. A more favorable total LS7 score was associated with fewer premature ventricular contractions (PVCs) per hour (ratio of geometric means for optimal [11 to 14] versus inadequate [0 to 7] score 0.52 [95% confidence interval 0.34 to 0.81]). After adjustment for sociodemographic characteristics, the association was attenuated (0.66 [0.43 to 1.01]). =Among the LS7 components, a more favorable body mass index was associated with less ventricular ectopy. We did not detect associations of total LS7 score with atrial arrhythmias. In conclusion, in this longitudinal study of older participants free of clinically recognized cardiovascular disease, there was little evidence of association of the LS7 cardiovascular health score with subclinical cardiac arrhythmias. However, there was a suggestion that a more favorable LS7 score was associated with fewer PVCs and specifically, that a more favorable body mass index was associated with fewer PVCs.

Marijuana use among all age groups has been increasing, including among older adults aged ≥65 years. There is a lack of epidemiologic data examining arrhythmia risk among users of marijuana. We evaluated cross-sectional associations between current and past marijuana smoking and arrhythmias among 1485 participants from the Multiethnic Study of Atherosclerosis who underwent extended ambulatory electrocardiographic monitoring with the Zio Patch XT. Outcomes included premature atrial contractions, runs of supraventricular tachycardia, premature ventricular contractions, and runs of nonsustained ventricular tachycardia (NSVT). Compared with never users, participants reporting current use of marijuana (n = 40, 3%) had more supraventricular tachycardia/day (adjusted geometric mean ratio [GMR] 1.42, 95% confidence interval [CI] 0.87 to 2.32), more premature atrial contractions/hour (GMR 1.22, 95% CI 0.72, 2.13), and more NSVT/day (GMR 1.28, 95% CI 0.95 to 1.73); although, CIs overlapped 1. Additionally, more frequent marijuana use was associated with more runs of NSVT/day (GMR 1.56, 95% CI 1.13, 2.17). In conclusion, our results suggest that current marijuana use may be associated with a greater burden of arrhythmias. There is a need for additional research, mainly using a prospective design, to clarify if marijuana use causes atrial and ventricular arrhythmias or other cardiovascular complications among older adults.

Introduction: Atrial fibrillation (AF) increases stroke risk and is associated with accelerated cognitive decline. Information is mixed about the relationship of AF and other supraventricular (SV) arrhythmias with brain changes on magnetic resonance imaging (MRI). Hypothesis: Prevalent AF and SV ectopy are associated with reduced gray matter (GM) volume and subclinical vascular brain injury. Methods: In the Multi-Ethnic Study of Atherosclerosis (MESA), participants completed Zio Patch monitoring and brain MRI. Prevalent AF was estimated from ambulatory monitoring, hospital surveillance, Medicare claims, and MESA electrocardiogram (ECG). For secondary analyses, AF was categorized into continuous - AF during 100% of monitoring - and intermittent - prevalent AF with Results: In MESA, 967 participants without a history of stroke or transient ischemic attack (TIA) completed >24 hours of ECG monitoring (median, 14.0 days) and completed brain MRI a median 17 months later. Mean (standard deviation) age was 72 (8) years; 53% were women. A total of 116 participants had prevalent AF, of whom 20 had continuous AF. Compared with no AF, prevalent AF was associated with lower WM FA (-0.22 standard deviations, 95% CI: -0.39, -0.04) and higher prevalence of CMBs (prevalence ratio: 1.46, 95% CI: 1.18, 1.80). In secondary analyses, compared with no AF, continuous but not intermittent AF was associated with lower GM volume (-18.6 mL, 95% CI: -31.4, -5.8). Rates of premature atrial contractions and runs of SV tachycardia were not significantly associated with brain MRI measures. Conclusions: In a multi-ethnic sample free of a history of stroke or TIA, prevalent AF was associated with lower WM FA, a measure of WM injury, and presence of CMBs. These results highlight the importance of AF prevention for brain health. Further analysis of subclinical infarcts is needed in this sample, and study in other settings is needed to confirm whether greater AF burden is associated with reduced GM volume.

SummaryMendelian randomization (MR) studies carried out among patients with a particular health condition should establish the genetic instrument influences the exposure in that subgroup, however this is normally investigated in the general population. Here, we investigated whether the genetic associations of four cis-acting C-reactive protein (CRP) variants differed between participants with and without three cardiometabolic conditions: obesity, type 2 diabetes, and cardiovascular disease. Associations of cis-genetic variants with CRP differed between obese and non-obese individuals. A multivariable analysis suggested strong independent associations of the gene-by-body mass index (BMI) interaction on CRP (P−8 for the CRP variants). Applying MR, we observed strong causal effect of BMI on CRP (P=2.14×10−65). In summary, our study indicates that genetic associations with CRP differ across disease sub-groups, with evidence to suggest that BMI is an effect modifier. MR studies of disease progression should report on the genetic instrument-exposure association in the disease subgroup under investigation.

Background: Air pollution contributes to cardiovascular morbidity, including heart failure. Exposure to pollutants has been associated with hypertension and inflammation, which contribute to cardiac remodeling. Few studies have investigated long-term air pollution concentrations and measures of cardiac structure, and no large longitudinal analyses have investigated this association. Hypothesis: Long-term air pollution concentrations are associated with magnetic resonance imaging-derived measures of left ventricular structure and function. Methods: In the Multi-Ethnic Study of Atherosclerosis (MESA), we investigated cross-sectional and longitudinal associations between modeled fine particulate matter (PM2.5), oxides of nitrogen (NOX) and ozone (O3) concentrations and left ventricular mass index (LVMI), mass to volume ratio, ejection fraction, and circumferential strain by cardiac magnetic resonance imaging (CMR) at two time points roughly 10 years apart. Multivariable linear regression was used to estimate the association between pollutants and both cross-sectional and longitudinal CMR measures. Results: At MESA Exam 1 (2000-2002), 4,825 participants in our cross-sectional analysis sample had a mean age of 61 years (standard deviation: 10), 53% were women, 40% were white, 13% were Chinese-American, 25% were African-American, and 21% were Hispanic. At Exam 1, Higher concentrations of PM2.5 and NOX in the year prior to Exam 1 were associated with higher LVMI at Exam 1 (1.6% per 5ug/m3 higher PM2.5, 95% CI: 0.3, 2.9; 1.8% per 40 parts per billion [ppb] NOX, 95% CI: 0.3, 3.3) and higher O3 was associated with lower LVMI (-3.5% per 10ppb, 95% CI: -6.0, -1.0). In longitudinal analyses, higher NOX was associated with a worsening of LV circumferential strain (-0.87% per 40ppb, 95% CI: -1.69, -0.05). Conclusions: Our study offers mixed evidence of a cross-sectional association between higher PM2.5 and NOx concentrations and greater LVMI. We also found associations between greater O3 concentration and lower cross-sectional LVMI, though this association may be confounded by other pollutants. These findings suggest a role for NOX, PM2.5, and O3 in cardiac remodeling. Additional work is needed to clarify that role and better understand the biological underpinnings of these associations.

Introduction: Cardiovascular risk factors are associated with cognitive decline and dementia. Brain magnetic resonance imaging (MRI) provides sensitive measurement of cerebral atrophy and small vessel disease, reflecting multiple pathologies leading to dementia. However, large brain MRI studies include primarily white participants. We investigated associations in the diverse Multi-Ethnic Study of Atherosclerosis (MESA). Hypothesis: Cardiovascular and sociodemographic risk factors are associated with brain morphology and white matter injury in a racially and ethnically diverse population. Methods: In MESA, brain MRI was performed in 2018-2019 with automated measurement of total brain volume, gray and white matter (GM, WM) volume, and measures of WM injury including WM lesion volume, WM fractional anisotropy, and WM apparent diffusion coefficient. In cross-sectional analyses, we assessed the association of race/ethnicity with MRI measures, with and without adjustment for cardiovascular risk factors, education, and socioeconomic status. In a multivariable model, we assessed the association of cardiovascular risk factors with brain MRI measures. All analyses of volumes, including WM lesion volume, were adjusted for total intracranial volume. Results: MRI data were complete in 1,051 participants; 40% were white, 15% Chinese-American, 25% African-American, and 20% Hispanic. Mean (standard deviation, SD) age was 73 (8) years and 53% of participants were women. Adjusted for age and sex, African-American participants had slightly greater total brain and WM volume than white participants. Adjusted for age and sex, African-American participants had on average more WM injury than whites as measured by higher WM lesion volume (46.7% higher, 95% CI: 19.9, 79.4%) and lower fractional anisotropy (-0.20 SD, 95% CI: -0.34, -0.05); these associations were attenuated after additional adjustment for cardiovascular risk factors and socioeconomic status (24.3% higher WM lesion volume, 95% CI: 0.0, 54.3; -0.06 SD fractional anisotropy, 95% CI: -0.22, 0.09). Conversely, all non-white race/ethnic groups had slightly less WM injury than white participants as estimated by apparent diffusion coefficient. Overall, greater age, diabetes, current smoking, high systolic blood pressure, and treated hypertension were strongly associated with more WM injury; in addition, age and diabetes were strongly associated with lower brain volumes. Conclusions: We found little evidence of differences in measures of brain atrophy and WM injury by race/ethnicity after adjustment for cardiovascular risk factors and socioeconomic status. Findings of differences by race/ethnicity in apparent diffusion coefficient are intriguing and need further investigation. Consistent with previous studies, age, diabetes, current smoking and hypertension were strongly and consistently associated with WM injury.

Background High levels of supraventricular ectopy are associated with greater risk of atrial fibrillation, stroke, and death. Little information is available about differences by race/ethnicity in the extent of supraventricular ectopy, or about whether high levels of supraventricular ectopy are associated with impaired left atrial (LA) function and LA enlargement. Methods and Results In the MESA (Multi‐Ethnic Study of Atherosclerosis), 1148 participants (47% men; mean age, 67 years) had cardiovascular magnetic resonance imaging in 2010 to 2012, followed by 14‐day ambulatory electrocardiographic monitoring in 2016 to 2018. We analyzed participant characteristics and cardiovascular magnetic resonance measures of LA function and structure in relation to average count of premature atrial contractions (PACs) per hour and average number of runs per day of supraventricular tachycardia. In adjusted regression analyses, older age, male sex, White race, elevated NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), and a history of clinically detected atrial fibrillation were associated with more PACs/hour. Chinese and Hispanic participants had on average fewer PACs/hour than White participants (Chinese participants, 31% less [95% CI, 8%–49%]; Hispanic participants, 38% less [95% CI, 19%–52%]). Greater LA total emptying fraction was associated with fewer PACs/hour (per SD, 16% fewer PACs/hour [95% CI, 7%–25% fewer PACs/hour]). Larger LA minimum volume was associated with more PACs/hour (per SD, 7% more PACs/hour [95% CI, 2%–13% more PACs/hour]). Associations of LA volumes with runs of supraventricular tachycardia/day were similar in direction but were weaker. Conclusions Impaired LA function and LA enlargement were associated with more PACs/hour on extended ambulatory electrocardiographic monitoring. Measurement of supraventricular ectopy may provide information about the extent of atrial myopathy.

Background: African Americans are consistently found to have a lower prevalence of clinically detected atrial fibrillation (AF) than whites, despite a higher prevalence of major AF risk factors and higher risk of ischemic stroke. Long-term ambulatory ECG monitors provide the opportunity for unbiased AF detection. We determined differences by race/ethnicity in the prevalence of clinically detected AF and in the proportion with monitor-detected AF. Methods: We conducted a cross-sectional analysis in the MESA (Multi-Ethnic Study of Atherosclerosis), a community-based cohort study that enrolled 6814 Americans free of clinically recognized cardiovascular disease in 2000 to 2002. At the 2016 to 2018 examination, 1556 individuals participated in an ancillary study involving ambulatory ECG monitoring and had follow-up for clinically detected AF since cohort entry. Results: Among 1556 participants, 41% were white, 25% African American, 21% Hispanic, and 14% Chinese; 51% were women; and the mean age was 74 years. The prevalence of clinically detected AF after 14.4 years’ follow-up was 11.3% in whites, 6.6% in African Americans, 7.8% in Hispanics, and 9.9% in Chinese and was significantly lower in African Americans than in whites, in both unadjusted and risk factor-adjusted analyses (adjusted rate difference, −6.6% [95% CI, −10.1% to −3.1%]; P P >0.5). Conclusions: The prevalence of clinically detected AF was substantially lower in African American than in white participants, without or with adjustment for AF risk factors. However, unbiased AF detection by ambulatory monitoring in the same individuals revealed little difference in the proportion with AF by race/ethnicity. These findings provide support for the hypothesis of differential detection by race/ethnicity in the clinical recognition of AF, which may have important implications for stroke prevention.

Objective To determine whether greater pericardial fat volume would be associated with increased risk of incident atrial fibrillation (AF). Methods In the Multi-Ethnic Study of Atherosclerosis and Jackson Heart Study, pericardial fat volume was quantified by computed tomography. Incident AF was identified from discharge diagnosis codes, study electrocardiograms, and Medicare claims. Results Among 7,991 participants, 40% were African American, 32% white, 18% Hispanic, and 10% Chinese American; mean age was 62 years; 55% were women. During an average of 10.0 years of follow-up in the Multi-Ethnic Study of Atherosclerosis and 4.5 years in the Jackson Heart Study, 756 incident AF cases were identified. After adjustment for age, sex, study, race/ethnicity, height, glucose status, systolic blood pressure, treated hypertension, and BMI, greater pericardial fat volume was associated with higher AF risk in Hispanics (hazard ratio 1.24 per SD, 95% confidence interval 1.05-1.46) but not overall (hazard ratio 1.06, 95% confidence interval 0.97-1.15). In mediation analysis, pericardial fat volume partially mediated the association of BMI with incident AF in Hispanics. Conclusions After adjustment for BMI, greater pericardial fat volume was associated with incident AF in Hispanics but not overall. Additional research is needed on the mechanisms by which pericardial fat volume is related to increased AF risk and possible differences by race/ethnicity.

BACKGROUND –: Patch electrocardiographic (ECG) monitors permit extended noninvasive ambulatory monitoring. To guide use of these devices, information is needed about their performance. We sought to determine in a large general population sample the acceptability of patch ECG monitors, the yield of arrhythmia detection, and the consistency of findings in participants monitored twice. METHODS –: In the Multi-Ethnic Study of Atherosclerosis, 1122 participants completed one or two monitoring episodes using the Zio Patch XT, a single-channel ECG patch monitor capable of recording for 14 days. Recordings were analyzed for atrial fibrillation (AF), atrial flutter, atrioventricular block, pauses, and supraventricular and ventricular ectopy. RESULTS –: The mean(SD) age at the time of monitoring was 75(8) years, 52% were men, and 15% had a prior history of clinically-recognized AF/flutter. The median monitoring duration was 13.8 days. Among 804 participants with no prior clinical history of AF/flutter and at least 12 days of monitoring on a single device, AF/flutter was detected in 32 (4.0%); in 38% of these, AF/flutter was first detected during days 3 through 12 of monitoring. In participants monitored twice, findings from the two devices showed excellent agreement for supraventricular and ventricular ectopic beats per hour, but only fair agreement for high-grade atrioventricular block and pauses of greater than 3 seconds duration. CONCLUSIONS –: In a general population of older individuals, new diagnoses of AF/flutter were made in 4.0% of participants without a prior history. A single monitoring episode accurately estimated rates of supraventricular and ventricular ectopy.

Background QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. Methods and Results We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. Conclusions Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.

Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11794 CRC cases and 14190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E-05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89-0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P heterogeneity = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn's-like reaction but not tumors without such immune infiltrate (P heterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P heterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn's-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.

The KRAS oncogene influences angiogenesis, metastasis and chemoresistance in colorectal cancers (CRCs), and these processes are all enhanced in hypoxic conditions. To define functional activities of mutant KRAS in a hypoxic microenvironment, we first performed cDNA microarray experiments in isogenic DKs5 and DKO3 colon cancer cell lines that differ only by their expression of mutant KRAS (K-ras(D13)). Adrenomedullin (ADM) was identified as one of the most significantly upregulated genes in DKs5 cells that express the KRAS oncogene in hypoxia (3.2-fold, p = 1.47 × 10(-5)). Ectopic expression of mutant KRAS (K-ras(V12)) in Caco-2 cells (K-ras(WT)) induced ADM, whereas selective knockdown of mutant KRAS alleles (K-ras(D13) or K-ras(V12)) in HCT116, DLD1 and SW480 colon cancer cells suppressed the expression of ADM in hypoxia. Knockdown of ADM in colon tumor xenografts blocked angiogenesis and stimulated apoptosis, resulting in tumor suppression. Furthermore, ADM also regulated colon cancer cell invasion in vitro. Among 56 patients with CRC, significantly higher expression levels of ADM were observed in samples harboring a KRAS mutation. Collectively, ADM is a new target of oncogenic KRAS in the setting of hypoxia. This observation suggests that therapeutic targets may differ depending upon the specific tumor microenvironment.

Introduction: Obesity is associated with higher risk of incident AF, but the underlying mechanisms are not well understood. Increased pericardial fat deposition may lead to atrial fibrosis and renin-angiotensin system activation due to free diffusion of cytokines into the thin atrial wall, promoting AF development. Little is known about the association of pericardial fat volume with incident AF. Hypothesis: We assessed the hypothesis that greater pericardial fat volume is associated with higher AF risk in MESA and JHS, overall and in four race/ethnic groups. Methods: Pericardial fat volume was measured on chest CT scans (performed 2000-02 in MESA, 2007-09 in JHS) in 18 2.5-mm slices, from 1.5 cm above to 3.0 cm below the superior extent of the left main coronary artery, using Volume Analysis software (GE Healthcare, Waukesha, WI). Data were combined across the 2 studies. Participants with prevalent AF before the scan were excluded. Incident AF was identified by hospital discharge diagnosis codes for AF or atrial flutter, by study ECG at a follow-up visit, or, for those enrolled in fee-for-service Medicare, by an inpatient or outpatient claim with an AF diagnosis in any position. We used Cox regression to estimate adjusted hazard ratios for incident AF. Results: A total of 8056 participants (6681 in MESA; 1375 in JHS) had pericardial fat volume measured and were followed for clinical events. Among MESA participants, 1855 were AA, 2568 white, 1470 Hispanic, and 788 Chinese; all JHS participants were AA. In the combined data, the average age was 62 years; 55% were women. Greater pericardial fat volume was associated with male sex, older age, white or Hispanic race/ethnicity, greater BMI and systolic blood pressure (SBP), treated hypertension (HTN), impaired fasting glucose, and diabetes mellitus. Despite more obesity, AA participants had on average the lowest pericardial fat volume. During an average of 9 years of follow-up in MESA and 4 years in JHS, a total of 614 cases of incident AF were identified. Whites had the highest unadjusted AF incidence and AA the lowest. In all 4 race/ethnic groups, pericardial fat volume was positively associated with unadjusted AF incidence. After adjustment for age, sex, race/ethnicity, and study, greater pericardial fat volume was associated with higher risk of incident AF (HR=1.17 per SD pericardial fat volume [41 ml], 95% CI 1.09-1.26). After further adjustment for BMI, height, diabetes, SBP, and treated HTN, the association was attenuated (HR 1.06 per SD, 95% CI 0.97-1.16). Associations did not differ in subgroups defined by sex, race/ethnicity, or study. Conclusion: Greater deposition of fat in the pericardium is associated with higher AF incidence and higher adjusted risk of incident AF. Much of this association appears to be related to obesity, diabetes, and HTN. Lower average pericardial fat volume may explain in part the observed lower AF incidence in AA than in whites.

The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis.This study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association study to identify risk factors in other regions of the genome. A total of 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies.Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (P=0.002), but not variants in CYP2C8 (P=0.073) or UGTs (P=0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (odds ratio: 1.89; 95% confidence interval: 1.40-2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (P0.001). The genome-wide association study identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (P=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (odds ratio: 0.48; 95% confidence interval: 0.36-0.63).We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.

Oncogene-induced senescence (OIS), a tumor-suppressive mechanism that is induced by the replicative and metabolic stress of oncogene activation, is a key barrier in the development of BRAF V600E colon cancer. Inhibition of this mechanism has been observed through epigenetic changes observed in sporadic serrated polyps, as well as through the germline mutations associated with those who develop serrated polyposis. We hypothesize that upregulated autocrine factors exist that are specific to the serrated pathway and also promote bypass of oncogene-induced senescence. To identify such autocrine factors, we integrate analyses of microarrays of sessile serrated polyps and two large colon cancer cohorts, the Cancer Genome Atlas (TCGA; n = 153), and French national Cartes d'Identité des Tumeurs (CIT) program (n = 462), with enhanced gene annotation through natural language processing techniques of the existing medical corpus. We reproducibly associate higher expression of the ligand–receptor axis of TFF2 and CXCR4 with BRAF V600E-mutant colon cancer (P = 3.0 × 10−3 and 0.077, respectively for TCGA; P = 3.0 × 10−8 and 5.1 × 10−7 for CIT). Given well-described oncogenic roles of TFF2 and CXCR4 in colon cancer, and availability of CXCR4 inhibitors for other clinical indications, this ligand–receptor axis may represent an actionable target for prevention and treatment of this molecular subtype of colorectal cancer. Cancer Prev Res; 8(7); 614–9. ©2015 AACR.

Background & Aims Little is known about the genetic factors that contribute to the development of sessile serrated adenomas (SSAs). SSAs contain somatic mutations in BRAF or KRAS early in development. However, evidence from humans and mouse models indicates that these mutations result in oncogene-induced senescence (OIS) of intestinal crypt cells. Progression to serrated neoplasia requires cells to escape OIS via inactivation of tumor suppressor pathways. We investigated whether subjects with multiple SSAs carry germline loss-of-function mutations (nonsense and splice site) in genes that regulate OIS: the p16-Rb and ATM-ATR DNA damage response pathways. Methods Through a bioinformatic analysis of the literature, we identified a set of genes that function at the main nodes of the p16-Rb and ATM-ATR DNA damage response pathways. We performed whole-exome sequencing of 20 unrelated subjects with multiple SSAs; most had features of serrated polyposis. We compared sequences with those from 4300 subjects matched for ethnicity (controls). We also used an integrative genomics approach to identify additional genes involved in senescence mechanisms. Results We identified mutations in genes that regulate senescence ( ATM , PIF1 , TELO2 , XAF1 , and RBL1 ) in 5 of 20 subjects with multiple SSAs (odds ratio, 3.0; 95% confidence interval, 0.9–8.9; P = .04). In 2 subjects, we found nonsense mutations in RNF43 , indicating that it is also associated with multiple serrated polyps (odds ratio, 460; 95% confidence interval, 23.1–16,384; P = 6.8 × 10 −5 ). In knockdown experiments with pancreatic duct cells exposed to UV light, RNF43 appeared to function as a regulator of ATM-ATR DNA damage response. Conclusions We associated germline loss-of-function variants in genes that regulate senescence pathways with the development of multiple SSAs. We identified RNF43 as a regulator of the DNA damage response and associated nonsense variants in this gene with a high risk of developing SSAs.

The factors underlying the development of interval colon cancers are not well defined and are likely heterogeneous. We sought to determine whether there are distinct molecular properties associated with interval colon cancers. Colon cancers diagnosed within 5 years of a complete and well-prepped colonoscopic examination were identified over a 7-year period at a single institution. The clinical and pathological features of the tumors were defined. Analysis of DNA mismatch repair (MMR) and genotyping of a panel of oncogenes associated with colon cancer were performed. Forty-two interval colon cancers were diagnosed at an average age of 70 years. 69 % of tumors were located in the right colon. 41 % of tumors exhibited DNA microsatellite instability (MSI). Loss of staining of DNA MMR proteins by immunohistochemistry (IHC) was confirmed in 82 % of the MSI-positive tumors. Among tumors with abnormal MSI and IHC, 54 % exhibited somatic methylation of the MLH1 promoter, but the remaining 43 % exhibited molecular features indicative of underlying Lynch syndrome (LS). The frequency of somatic mutations in the KRAS, BRAF, NRAS, and PIK3CA oncogenes was similar between interval cancer cases and controls. Interval colon cancers are not distinguished by the activation of the KRAS, NRAS, BRAF, or PIK3CA oncogenic pathways. However, MSI pathway defects are present in a significant proportion of interval colon cancers. Underlying LS may explain nearly half of these MSI-positive cases, and the remaining cases appear to represent sporadic serrated pathway tumors.

The KRAS oncogene influences angiogenesis, metastasis and chemoresistance in colorectal cancers (CRCs), and these processes are all enhanced in hypoxic conditions. To define functional activities of mutant KRAS in a hypoxic microenvironment, we first performed cDNA microarray experiments in isogenic DKs5 and DKO3 colon cancer cell lines that differ only by their expression of mutant KRAS (K-ras(D13)). Adrenomedullin (ADM) was identified as one of the most significantly upregulated genes in DKs5 cells that express the KRAS oncogene in hypoxia (3.2-fold, p = 1.47 × 10(-5)). Ectopic expression of mutant KRAS (K-ras(V12)) in Caco-2 cells (K-ras(WT)) induced ADM, whereas selective knockdown of mutant KRAS alleles (K-ras(D13) or K-ras(V12)) in HCT116, DLD1 and SW480 colon cancer cells suppressed the expression of ADM in hypoxia. Knockdown of ADM in colon tumor xenografts blocked angiogenesis and stimulated apoptosis, resulting in tumor suppression. Furthermore, ADM also regulated colon cancer cell invasion in vitro. Among 56 patients with CRC, significantly higher expression levels of ADM were observed in samples harboring a KRAS mutation. Collectively, ADM is a new target of oncogenic KRAS in the setting of hypoxia. This observation suggests that therapeutic targets may differ depending upon the specific tumor microenvironment.

The key to the diagnosis of pheochromocytoma is a high index of suspicion on the part of the clinician. Confirmation of the diagnosis and localization of the tumor have been rendered relatively straightforward by advances in biochemistry, nuclear medicine, and radiology. Close cooperation and team effort between a physician, anesthetist, and surgeon possessing expertise in this field will ensure optimal preoperative, operative, and postoperative care, particularly for the small group of patients seriously ill with “acute” catecholamine excess.

A study was made to quantify the consitency of preferences for simple geometric forms, in this case the isosceles triangle.