Publications by authors named "Mitchell S V Elkind"

523 Publications

American Heart Association Precision Medicine Platform Addresses Challenges in Data Sharing.

Circ Cardiovasc Qual Outcomes 2021 Sep 14;14(9):e007949. Epub 2021 Sep 14.

Quality, Outcomes Research and Analytics, American Heart Association, Dallas, TX (L.M.S., C.R., H.A., J.L.H.).

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http://dx.doi.org/10.1161/CIRCOUTCOMES.121.007949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452247PMC
September 2021

Clinical Characteristics and Outcomes of Adults With a History of Heart Failure Hospitalized for COVID-19.

Circ Heart Fail 2021 09 14;14(9):e008354. Epub 2021 Sep 14.

Department of Medicine (P.G., E.R., M.M., J.K., R.B.D., P.M.O., J.W.W., M.M.S.), Weill Cornell Medicine, New York, NY.

Background: It is important to understand the risk for in-hospital mortality of adults hospitalized with acute coronavirus disease 2019 (COVID-19) infection with a history of heart failure (HF).

Methods: We examined patients hospitalized with COVID-19 infection from January 1, 2020 to July 22, 2020, from 88 centers across the US participating in the American Heart Association's COVID-19 Cardiovascular Disease registry. The primary exposure was history of HF and the primary outcome was in-hospital mortality. To examine the association between history of HF and in-hospital mortality, we conducted multivariable modified Poisson regression models that included sociodemographics and comorbid conditions. We also examined HF subtypes based on left ventricular ejection fraction in the prior year, when available.

Results: Among 8920 patients hospitalized with COVID-19, mean age was 61.4±17.5 years and 55.5% were men. History of HF was present in 979 (11%) patients. In-hospital mortality occurred in 31.6% of patients with history of HF, and 16.9% in patients without a history of HF. In a fully adjusted model, history of HF was associated with increased risk for in-hospital mortality (relative risk: 1.16 [95% CI, 1.03-1.30]). Among 335 patients with left ventricular ejection fraction, heart failure with reduced ejection fraction was significantly associated with in-hospital mortality in a fully adjusted model (heart failure with reduced ejection fraction relative risk: 1.40 [95% CI, 1.10-1.79]; heart failure with mid-range ejection fraction relative risk: 1.06 [95% CI, 0.65-1.73]; heart failure with preserved ejection fraction relative risk, 1.06 [95% CI, 0.84-1.33]).

Conclusions: Risk for in-hospital mortality was substantial among adults with history of HF, in large part due to age and comorbid conditions. History of heart failure with reduced ejection fraction may confer especially elevated risk. This population thus merits prioritization for the COVID-19 vaccine.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.121.008354DOI Listing
September 2021

Cardiac mechanics and incident ischemic stroke: the Cardiovascular Health Study.

Sci Rep 2021 08 30;11(1):17358. Epub 2021 Aug 30.

Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Recent evidence indicates that our understanding of the relationship between cardiac function and ischemic stroke remains incomplete. The Cardiovascular Health Study enrolled community-dwelling adults ≥ 65 years old. We included participants with speckle-tracking data from digitized baseline study echocardiograms. Exposures were left atrial reservoir strain (primary), left ventricular longitudinal strain, left ventricular early diastolic strain rate, septal e' velocity, and lateral e' velocity. The primary outcome was incident ischemic stroke. Cox proportional hazards models were adjusted for demographics, image quality, and risk factors including left ventricular ejection fraction and incident atrial fibrillation. Among 4,000 participants in our analysis, lower (worse) left atrial reservoir strain was associated with incident ischemic stroke (HR per SD absolute decrease, 1.14; 95% CI 1.04-25). All secondary exposure variables were significantly associated with the outcome. Left atrial reservoir strain was associated with cardioembolic stroke (HR per SD absolute decrease, 1.42; 95% CI 1.21-1.67) and cardioembolic stroke related to incident atrial fibrillation (HR per SD absolute decrease, 1.60; 1.32-1.95). Myocardial dysfunction that can ultimately lead to stroke may be identifiable at an early stage. This highlights opportunities to identify cerebrovascular risk earlier and improve stroke prevention via therapies for early myocardial dysfunction.
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http://dx.doi.org/10.1038/s41598-021-96702-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405795PMC
August 2021

Pre-Statistical Considerations for Harmonization of Cognitive Instruments: Harmonization of ARIC, CARDIA, CHS, FHS, MESA, and NOMAS.

J Alzheimers Dis 2021 Aug 24. Epub 2021 Aug 24.

Cognitive Health Services Research Program, University of Michigan Medical School, Ann Arbor, MI, USA.

Background: Meta-analyses of individuals' cognitive data are increasing to investigate the biomedical, lifestyle, and sociocultural factors that influence cognitive decline and dementia risk. Pre-statistical harmonization of cognitive instruments is a critical methodological step for accurate cognitive data harmonization, yet specific approaches for this process are unclear.

Objective: To describe pre-statistical harmonization of cognitive instruments for an individual-level meta-analysis in the blood pressure and cognition (BP COG) study.

Methods: We identified cognitive instruments from six cohorts (the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Coronary Artery Risk Development in Young Adults study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study) and conducted an extensive review of each item's administration and scoring procedures, and score distributions.

Results: We included 153 cognitive instrument items from 34 instruments across the six cohorts. Of these items, 42%were common across ≥2 cohorts. 86%of common items showed differences across cohorts. We found administration, scoring, and coding differences for seemingly equivalent items. These differences corresponded to variability across cohorts in score distributions and ranges. We performed data augmentation to adjust for differences.

Conclusion: Cross-cohort administration, scoring, and procedural differences for cognitive instruments are frequent and need to be assessed to address potential impact on meta-analyses and cognitive data interpretation. Detecting and accounting for these differences is critical for accurate attributions of cognitive health across cohort studies.
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http://dx.doi.org/10.3233/JAD-210459DOI Listing
August 2021

Ethnic and Racial Variation in Intracerebral Hemorrhage Risk Factors and Risk Factor Burden.

JAMA Netw Open 2021 Aug 2;4(8):e2121921. Epub 2021 Aug 2.

Henry and Allison McCance Center for Brain Health and Center for Genomic Medicine, Massachusetts General Hospital, Boston.

Importance: Black and Hispanic individuals have an increased risk of intracerebral hemorrhage (ICH) compared with their White counterparts, but no large studies of ICH have been conducted in these disproportionately affected populations.

Objective: To examine the prevalence, odds, and population attributable risk (PAR) percentage for established and novel risk factors for ICH, stratified by ICH location and racial/ethnic group.

Design, Setting, And Participants: The Ethnic/Racial Variations of Intracerebral Hemorrhage Study was a case-control study of ICH among 3000 Black, Hispanic, and White individuals who experienced spontaneous ICH (1000 cases in each group). Recruitment was conducted between September 2009 and July 2016 at 19 US sites comprising 42 hospitals. Control participants were identified through random digit dialing and were matched to case participants by age (±5 years), sex, race/ethnicity, and geographic area. Data analyses were conducted from January 2019 to May 2020.

Main Outcomes And Measures: Case and control participants underwent a standardized interview, physical measurement for body mass index, and genotyping for the ɛ2 and ɛ4 alleles of APOE, the gene encoding apolipoprotein E. Prevalence, multivariable adjusted odds ratio (OR), and PAR percentage were calculated for each risk factor in the entire ICH population and stratified by racial/ethnic group and by lobar or nonlobar location.

Results: There were 1000 Black patients (median [interquartile range (IQR)] age, 57 [50-65] years, 425 [42.5%] women), 1000 Hispanic patients (median [IQR] age, 58 [49-69] years; 373 [37.3%] women), and 1000 White patients (median [IQR] age, 71 [59-80] years; 437 [43.7%] women). The mean (SD) age of patients with ICH was significantly lower among Black and Hispanic patients compared with White patients (eg, lobar ICH: Black, 62.2 [15.2] years; Hispanic, 62.5 [15.7] years; White, 71.0 [13.3] years). More than half of all ICH in Black and Hispanic patients was associated with treated or untreated hypertension (PAR for treated hypertension, Black patients: 53.6%; 95% CI, 46.4%-59.8%; Hispanic patients: 46.5%; 95% CI, 40.6%-51.8%; untreated hypertension, Black patients: 45.5%; 95% CI, 39.%-51.1%; Hispanic patients: 42.7%; 95% CI, 37.6%-47.3%). Lack of health insurance also had a disproportionate association with the PAR percentage for ICH in Black and Hispanic patients (Black patients: 21.7%; 95% CI, 17.5%-25.7%; Hispanic patients: 30.2%; 95% CI, 26.1%-34.1%; White patients: 5.8%; 95% CI, 3.3%-8.2%). A high sleep apnea risk score was associated with both lobar (OR, 1.68; 95% CI, 1.36-2.06) and nonlobar (OR, 1.62; 95% CI, 1.37-1.91) ICH, and high cholesterol was inversely associated only with nonlobar ICH (OR, 0.60; 95% CI, 0.52-0.70); both had no interactions with race and ethnicity. In contrast to the association between the ɛ2 and ɛ4 alleles of APOE and ICH in White individuals (eg, presence of APOE ɛ2 allele: OR, 1.84; 95% CI, 1.34-2.52), APOE alleles were not associated with lobar ICH among Black or Hispanic individuals.

Conclusions And Relevance: This study found sleep apnea as a novel risk factor for ICH. The results suggest a strong contribution from inadequately treated hypertension and lack of health insurance to the disproportionate burden and earlier onset of ICH in Black and Hispanic populations. These findings emphasize the importance of addressing modifiable risk factors and the social determinants of health to reduce health disparities.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.21921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383133PMC
August 2021

The tobacco endgame-eradicating a worsening epidemic.

Eur Heart J 2021 08;42(32):3044-3048

American Heart Association, 7272 Greenville Ave, Dallas, TX 75231, USA.

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http://dx.doi.org/10.1093/eurheartj/ehab245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380060PMC
August 2021

Determinants and Outcomes of Asymptomatic Intracranial Atherosclerotic Stenosis.

J Am Coll Cardiol 2021 Aug;78(6):562-571

Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, New York, USA.

Background: Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and confers a high risk of stroke recurrence, despite aggressive management of risk factors.

Objectives: This study identified the role of risk factors and risk of vascular events in subjects with asymptomatic ICAS for improved risk stratification.

Methods: Stroke-free participants in the NOMAS (Northern Manhattan Study) trial, prospectively followed since 1993, underwent a brain magnetic resonance angiogram from 2003 to 2008. The study rated stenosis in 11 brain arteries as: 0: no stenosis; 1: <50% or luminal irregularities; 2: 50%-69%; and 3: ≥70% stenosis or flow gap. The study ascertained vascular events during the post-magnetic resonance imaging (MRI) period. Proportional odds regression quantified the association of pre-MRI exposures, and proportional hazard adjusted models were built to identify the risk of events in the post-MRI period.

Results: The included sample included 1,211 participants from NOMAS (mean age: 71 ± 9 years; 59% women; 65% Hispanic; 45% had any stenosis). Older age (OR: 1.02 per year; 95% CI: 1.01 to 1.04), hypertension duration (OR: 1.01 per year; 95% CI: 1.00 to 1.02), higher number of glucose-lowering drugs (OR: 1.64 per each medication; 95% CI: 1.24 to 2.15), and high-density lipoprotein (OR: 0.96 per mg/dL; 95% CI: 0.92 to 0.99) were associated with ICAS. The highest event risk was noted among participants with ICAS ≥70% (5.5% annual risk of vascular events; HR: 2.1; 95% CI:1.4 to 3.2; compared with those with no ICAS).

Conclusions: ICAS is an imaging marker of established atherosclerotic disease in stroke-free subjects, and incidental diagnosis of ICAS should trigger a thorough assessment of vascular health.
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http://dx.doi.org/10.1016/j.jacc.2021.05.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352282PMC
August 2021

Misalignment between COVID-19 hotspots and clinical trial sites.

J Am Med Inform Assoc 2021 Oct;28(11):2461-2466

Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, USA.

Hundreds of interventional clinical trials have been launched in the United States to identify effective treatment strategies for combating the coronavirus disease 2019 (COVID-19) pandemic. However, to date, only a small fraction of these trials have completed enrollment, delaying the scientific investigation of COVID-19 and its treatment options. This study presents novel metrics to examine the geographic alignment between COVID-19 hotspots and interventional clinical trial sites and evaluate trial access over time during the evolving pandemic. Using temporal COVID-19 case data from USAFacts.org and trial data from ClinicalTrials.gov, U.S. counties were categorized based on their numbers of cases and trials. Our analysis suggests that alignment and access have worsened as the pandemic shifted over time. We recommend strategies and metrics to evaluate the alignment between cases and trials. Future studies are warranted to investigate the impact of the misalignment of cases and clinical trial sites on clinical trial recruitment.
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http://dx.doi.org/10.1093/jamia/ocab167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385938PMC
October 2021

Immune markers are associated with cognitive performance in a multiethnic cohort: The Northern Manhattan Study.

Brain Behav Immun 2021 10 25;97:186-192. Epub 2021 Jul 25.

Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.

Objective: To determine whether immune protein panels add significant information to correlates of cognition.

Background: Immune mechanisms in vascular cognitive aging are incompletely characterized.

Design/methods: A subsample of the prospective Northern Manhattan Study underwent detailed neuropsychological testing. Cognitive scores were converted into Z-scores and categorized into four domains (memory, language, processing speed, and executive function) based on factor analysis. Blood samples were analyzed using a 60-plex immunoassay. We used least absolute shrinkage and selection operator (LASSO) procedures to select markers and their interactions independently associated with cognitive scores. Linear regression models assessed cross-sectional associations of known correlates of cognition with cognitive scores, and assessed model fit before and after addition of LASSO-selected immune markers.

Results: Among 1179 participants (mean age 70 ± 8.9 years, 60% women, 68% Hispanic), inclusion of LASSO-selected immune markers improved model fit above age, education, and other risk factors (p for likelihood ratio test < 0.005 for all domains). C-C Motif Chemokine Ligand 11 (CCL 11, eotaxin), C-X-C Motif Chemokine Ligand 9 (CXCL9), hepatocyte growth factor (HGF), and serpin E1 (plasminogen activator inhibitor-1) were associated with each of the domains and with overall cognitive function. Immune marker effects were comparable to conventional risk factors: for executive function, each standard deviation (SD) increase in CCL11 was associated with an effect equivalent to aging three years; for memory, HGF had twice the effect of aging.

Conclusions: Immune markers associate with cognitive function in a multi-ethnic cohort. Further work is needed to validate these findings and determine optimal treatment targets.
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http://dx.doi.org/10.1016/j.bbi.2021.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453105PMC
October 2021

Clinician Well-Being: Addressing Global Needs for Improvements in the Health Care Field A Joint Opinion From the American College of Cardiology, American Heart Association, European Society of Cardiology, and the World Heart Federation.

J Am Coll Cardiol 2021 Aug 13;78(7):752-756. Epub 2021 Jul 13.

President, American College of Cardiology, Washington, DC, USA; Division of Cardiology, Department of Internal Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

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http://dx.doi.org/10.1016/j.jacc.2021.04.043DOI Listing
August 2021

Clinician Well-Being-addressing global needs for improvements in the health care field: a joint opinion from the American College of Cardiology, American Heart Association, European Society of Cardiology, World Heart Federation.

Eur Heart J 2021 08;42(33):3122-3126

President, American College of Cardiology; Division of Cardiology, Department of Internal Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

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http://dx.doi.org/10.1093/eurheartj/ehab346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408661PMC
August 2021

Launching a New Collaborative Journal: Stroke: Vascular and Interventional Neurology.

Stroke 2021 Jul 28;52(7):2200-2202. Epub 2021 Jun 28.

Department of Neurology, Miller School of Medicine, University of Miami, FL (R.L.S.).

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http://dx.doi.org/10.1161/STROKEAHA.121.035500DOI Listing
July 2021

Use of the HAVOC Score to Identify Patients at Highest Risk of Developing Atrial Fibrillation.

Cardiology 2021 22;146(5):633-640. Epub 2021 Jun 22.

Columbia University Medical Center, New York, New York, USA.

Background: Recent studies using insertable cardiac monitors (ICMs) show a high incidence of atrial fibrillation (AF). Further identifying subsets of patients who could benefit most from ICMs is desirable. We evaluated whether the HAVOC risk score which predicts AF in patients with cryptogenic stroke also predicts AF detection by ICMs in those without recent stroke.

Methods: Participants were included from the prospective, industry-sponsored REVEAL AF study assessing AF incidence in patients with CHADS2 scores ≥3 or =2 with 1 or more additional AF risk factors, who had ICM data and were not receiving anti-arrhythmic drugs. Ischemic stroke occurring less than 1 year prior to enrollment or documented AF were exclusion criteria. AF was defined as an adjudicated ICM-detected episode ≥6 min in duration. HAVOC scores were calculated by assigning 4 points for congestive heart failure, 2 points for each of hypertension, age ≥75 years, valvular disease, and coronary artery disease, and 1 point for each of peripheral vascular disease and obesity (body mass index >30). Scores classified risk as low (0-4), intermediate (5-9), or high (10-14); corresponding AF detection rates were compared using the log-rank test. AF incidence rates in patients with and without a history of remote stroke at baseline were also compared.

Results: Among 391 participants, the mean age was 71.5 ± 9.8 years and 186 (47.6%) were women. In total, 130 (33.2%) developed AF over 18 months. Stratification by HAVOC risk score was: 95 (24%) low, 241 (62%) intermediate, and 55 (14%) high. At 18 months, AF incidence in patients with low HAVOC scores (19.5%) was lower than in those with intermediate (32.1%) or high (34.2%) scores. AF incidence was similar among those with (n = 78) versus without (n = 313) remote stroke (27.3% vs. 29.8%; median time from stroke to ICM insertion was 4.2 [2.2-8.2] years).

Conclusions: The HAVOC risk score identified a subset of individuals at greatest risk of developing AF, while AF incidence rates were similar among those with and without remote stroke. The use of the HAVOC score could help identify those at greatest likelihood of manifesting AF during long-term monitoring.
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http://dx.doi.org/10.1159/000517827DOI Listing
June 2021

Systemic Arterial Correlates of Cervical Carotid Artery Tortuosity : The Northern Manhattan Study.

Clin Neuroradiol 2021 Jun 16. Epub 2021 Jun 16.

Department of Neurology, Columbia University, New York, NY, USA.

Introduction: The association between cervical internal carotid artery (cICA) tortuosity and atherosclerosis is a matter of debate. Additionally, some genetic syndromes characterized by connective tissue remodeling are associated with arterial tortuosity, raising the possibility that cICA tortuosity may not only be atherosclerotic. In this study, we hypothesized that cICA tortuosity is not associated with imaging biomarkers of atherosclerosis.

Methods: The Northern Manhattan Study (NOMAS) was a prospective, multiethnic cohort of stroke-free individuals who underwent brain MRA, carotid ultrasound and transthoracic echocardiogram from 2003-2008. The cICA tortuosity was scored in each carotid as 0 = no tortuosity, 1 = tortuosity <90°, 2 = tortuosity ≥90°. A summary cICA tortuosity score (possible range 0-4) was created by adding up the tortuosity score from each carotid. Participants were assessed for atherosclerotic markers by using B‑mode carotid sonography and transthoracic echocardiography.

Results: Of 558 participants 178 (31.9%) had any cervical ICA tortuosity (tortuosity score >0). The cICA tortuosity score was higher in women and was associated with diastolic and systolic blood pressures and height (all P < 0.05). In models adjusted for demographics and risk factors, only the association with diastolic blood pressure remained significant (β = 0.002, P = 0.02). Similarly, cICA tortuosity was associated with larger aortic root diameter (B = 1.03 ± 0.36, P = 0.004) but not with other markers of carotid or aortic atherosclerosis.

Conclusion: Cervical ICA tortuosity is associated with a higher diastolic blood pressure and larger aortic root diameter but not with other measures of atherosclerosis. Determining the risks of vascular events associated with this non-atherosclerotic phenotype may help for a better risk stratification for individuals with cICA tortuosity.
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http://dx.doi.org/10.1007/s00062-021-01044-yDOI Listing
June 2021

Intracerebral Hemorrhage in Patients With COVID-19: An Analysis From the COVID-19 Cardiovascular Disease Registry.

Stroke 2021 07 4;52(7):e321-e323. Epub 2021 Jun 4.

Department of Neurology, Yale School of Medicine, New Haven, CT (A.C.L., L.H.S., G.J.F., K.N.S.).

[Figure: see text].
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http://dx.doi.org/10.1161/STROKEAHA.121.034215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238884PMC
July 2021

Systolic Blood Pressure and Cognition in the Elderly: The Northern Manhattan Study.

J Alzheimers Dis 2021 ;82(2):689-699

Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA.

Background: Increasing evidence suggests that hypertension is a risk factor for cognitive impairment and dementia. The relationship between blood pressure and cognition in a racially and ethnically diverse population remains unclear.

Objective: To study association of blood pressure with cognition cross-sectionally and longitudinally in the elderly.

Methods: Participants are stroke-free individuals from the racially and ethnically diverse Northern Manhattan Study (NOMAS) (n = 1215). General linear models are constructed to examine blood pressure in relation to cognition cross-sectionally and longitudinally at a five-year follow-up.

Results: We found a cross-sectional association of systolic blood pressure (SBP) with word fluency/semantic memory, executive function, and processing speed/visual motor integration (VMI) function. This association was independent of demographics, vascular risk factors, white matter hyperintensity volume (WMHV), and carotid intima-media thickness (cIMT). The cross-sectional association of SBP with processing speed/VMI and executive function was attenuated after adjusting anti-hypertension medications in the models. Baseline SBP was associated with the change of processing speed/VMI function after adjusting vascular risk factors, WMHV, and cIMT at a 5-year follow-up. This longitudinal association was not found after adjusting anti-hypertension medications in the models. Further analyses revealed that individuals with category SBP from < 120 mmHg to≥140 mmHg had a linear decline in processing speed/VMI function at a 5-year follow-up.

Conclusion: We show that SBP is negatively associated with cognition cross-sectionally and longitudinally in the elderly. Anti-hypertension treatment eliminates the negative association of SBP with processing speed/VMI function longitudinally. Our findings support the treatment of stage 1 systolic hypertension in the elderly.
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http://dx.doi.org/10.3233/JAD-210252DOI Listing
September 2021

The Tobacco Endgame: Eradicating a Worsening Epidemic A Joint Opinion From the American Heart Association, World Heart Federation, American College of Cardiology, and the European Society of Cardiology.

J Am Coll Cardiol 2021 07 26;78(1):77-81. Epub 2021 May 26.

President, American Heart Association, Dallas, Texas, USA; Departments of Neurology and Epidemiology, Columbia University, New York, New York, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jacc.2021.04.005DOI Listing
July 2021

Silent Myocardial Infarction and Subsequent Ischemic Stroke in the Cardiovascular Health Study.

Neurology 2021 08 24;97(5):e436-e443. Epub 2021 May 24.

From the Clinical and Translational Neuroscience Unit (A.E.M., H.K.), Feil Family Brain and Mind Research Institute (A.E.M., H.K.), and Departments of Neurology (A.E.M., H.K.) and Medicine (P.M.O., M.M.S.), Weill Cornell Medical College, New York, NY; Department of Biostatistics (T.M.B.), Cardiovascular Health Research Unit (B.M.P.), and Departments of Medicine (B.M.P.), Epidemiology (B.M.P., W.T.L.), Health Services (B.M.P.), and Neurology (W.T.L.), University of Washington, Seattle; Epidemiological Cardiology Research Center (E.Z.S.), Wake Forest University School of Medicine, Winston-Salem, NC; Department of Epidemiology (V.H.), School of Public Health, University of Alabama at Birmingham; Kaiser Permanente Washington Health Research Institute (B.M.P.), Seattle; and Department of Neurology, Vagelos College of Physicians and Surgeons (M.S.V.E.), and Department of Epidemiology (M.S.V.E.), Mailman School of Public Health, Columbia University, New York, NY.

Objective: To test the hypothesis that silent myocardial infarction (MI) is a risk factor for ischemic stroke, we evaluated the association between silent MI and subsequent ischemic stroke in the Cardiovascular Health Study.

Methods: The Cardiovascular Health Study prospectively enrolled community-dwelling individuals ≥65 years of age. We included participants without prevalent stroke or baseline evidence of MI. Our exposures were silent and clinically apparent, overt MI. Silent MI was defined as new evidence of Q-wave MI, without clinical symptoms of MI, on ECGs performed during annual study visits from 1989 to 1999. The primary outcome was incident ischemic stroke. Secondary outcomes were ischemic stroke subtypes: nonlacunar, lacunar, and other/unknown. Cox proportional hazards analysis was used to model the association between time-varying MI status (silent, overt, or no MI) and stroke after adjustment for baseline demographics and vascular risk factors.

Results: Among 4,224 participants, 362 (8.6%) had an incident silent MI, 421 (10.0%) an incident overt MI, and 377 (8.9%) an incident ischemic stroke during a median follow-up of 9.8 years. After adjustment for demographics and comorbidities, silent MI was independently associated with subsequent ischemic stroke (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.03-2.21). Overt MI was associated with ischemic stroke both in the short term (HR, 80; 95% CI, 53-119) and long term (HR, 1.60; 95% CI, 1.04-2.44). In secondary analyses, the association between silent MI and stroke was limited to nonlacunar ischemic stroke (HR, 2.40; 95% CI, 1.36-4.22).

Conclusion: In a community-based sample, we found an association between silent MI and ischemic stroke.
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http://dx.doi.org/10.1212/WNL.0000000000012249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356380PMC
August 2021

Mechanisms of Ischemic Stroke in Patients with Cancer: A Prospective Study.

Ann Neurol 2021 07 3;90(1):159-169. Epub 2021 Jun 3.

Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.

Objective: The objective of this study was to examine the pathophysiology of ischemic stroke with cancer.

Methods: We conducted a prospective cross-sectional study from 2016 to 2020 at 2 hospitals. We enrolled 3 groups of 50 adult participants each. The main group included patients with active solid tumor cancer and acute ischemic stroke. The control groups included patients with acute ischemic stroke only or active cancer only. The patients with stroke-only and patients with cancer-only were matched to the patients with cancer-plus-stroke by age, sex, and cancer type, if applicable. The outcomes were prespecified hematological biomarkers and transcranial Doppler microemboli detection. Hematological biomarkers included markers of coagulation (D-dimer and thrombin-antithrombin), platelet function (P-selectin), and endothelial integrity (thrombomodulin, soluble intercellular adhesion molecule-1 [sICAM-1], and soluble vascular cell adhesion molecule-1 [sVCAM-1]). Hematological biomarkers were compared between groups using the Kruskal-Wallis and Wilcoxon Rank-Sum tests. In multivariable linear regression models, we adjusted for race, number of stroke risk factors, smoking, stroke severity, and antithrombotic use. Transcranial Doppler microemboli presence was compared between groups using chi-square tests.

Results: Levels of all study biomarkers were different between groups. In univariate between-group comparisons, patients with cancer-plus-stroke had higher levels of D-dimer, sICAM-1, sVCAM-1, and thrombomodulin than both control groups; higher levels of thrombin-antithrombin than patients with cancer-only; and higher levels of P-selectin than patients with stroke-only. Findings were similar in multivariable analyses. Transcranial Doppler microemboli were detected in 32% of patients with cancer-plus-stroke, 16% of patients with stroke-only, and 6% of patients with cancer-only (p = 0.005).

Interpretation: Patients with cancer-related stroke have higher markers of coagulation, platelet, and endothelial dysfunction, and more circulating microemboli, than matched controls. ANN NEUROL 2021;90:159-169.
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http://dx.doi.org/10.1002/ana.26129DOI Listing
July 2021

Frequency of cardiac arrhythmias in older adults: Findings from the Subclinical Atrial Fibrillation and Risk of Ischemic Stroke (SAFARIS) study.

Int J Cardiol 2021 08 6;337:64-70. Epub 2021 May 6.

Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States of America. Electronic address:

Background: Prolonged monitoring of cardiac rhythm has been used to screen for subclinical atrial fibrillation (AF); little is known about other arrhythmias in the general population, especially in the elderly, who are at higher risk of arrhythmias.

Methods: We evaluated the frequency of arrhythmias in the tri-ethnic (white, Black, Hispanic), community-based Subclinical Atrial Fibrillation and Risk of Ischemic Stroke (SAFARIS) study using a patch-based recorder for up to 14 days in 527 participants free of AF, congestive heart failure (CHF) or history of stroke. Differences according to gender, age, ethnicity and presence of hypertension, diabetes and pertinent ECG and echocardiographic variables were examined.

Results: Mean age was 77.2 ± 6.8 years (37.2% men, 62.8% women). AF was present in 10 participants (1.9%), only 2 of them symptomatic. Supraventricular tachycardia (SVT) and ventricular tachycardia (VT) episodes were observed in 84.4% and 25.0% but only 13.5% and 10.6% of participants reported symptoms, respectively. Severe bradycardia (<40 bpm) was present in 12.5%. Sinus pauses and high-degree atrioventricular blocks were infrequent (2.1% and 1.5%, respectively). Most arrhythmias were more frequent in participants > 75 years; ventricular arrhythmias and severe bradycardia were more common in men. Whites had significantly more episodes of AF than Hispanics, SVT than Blacks and VT ≥ 10 beats than Hispanics and Blacks. Hypertensives had more episodes of severe bradycardia. LV hypertrophy or LVEF <55% were associated with more frequent ventricular and supraventricular arrhythmias.

Conclusions: Prolonged cardiac rhythm monitoring revealed moderate frequency of AF, but higher than expected frequencies of AF-predisposing arrhythmias. Ventricular arrhythmias were relatively frequent, whereas severe bradyarrhythmias were infrequent.
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http://dx.doi.org/10.1016/j.ijcard.2021.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243841PMC
August 2021

Risk of stroke and myocardial infarction after influenza-like illness in New York State.

BMC Public Health 2021 05 5;21(1):864. Epub 2021 May 5.

Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA.

Background: Influenza may be associated with increased stroke and myocardial infarction (MI) risk. We hypothesized that risk of stroke and MI after influenza-like illness (ILI) would be higher in patients in New York State. We additionally assessed whether this relationship differed across a series of sociodemographic factors.

Methods: A case-crossover analysis of the 2012-2014 New York Statewide Planning and Research Cooperative System (SPARCS) was used to estimate odds of ischemic stroke and MI after ILI. Each patient's case window (the time period preceding event) was compared to their control windows (same dates from the previous 2 years) in conditional logistic regression models used to estimate odds ratios and 95% confidence intervals (OR, 95% CI). We varied the case windows from 15 to 365 days preceding event as compared to control windows constructed using the same dates from the previous 2 years. Analyses were stratified by sex, race, and urban-rural status based on residential zip code.

Results: A total of 33,742 patients were identified as having ischemic stroke and 53,094 had MI. ILI events in the 15 days prior were associated with a 39% increase in odds of ischemic stroke (95% CI 1.09-1.77), increasing to an almost 70% increase in odds when looking at ILI events over the last year (95% CI 1.56, 1.83). In contrast, the effect of ILI hospitalization on MI was strongest in the 15 days prior (OR = 1.24, 95% CI 1.06-1.44). The risk of ischemic stroke after ILI was higher among individuals living in rural areas in the 90 days prior to stroke and among men in the year prior to event. In contrast, the association between ILI and MI varied only across race with whites having significantly higher ILI associated MI.

Conclusion: This study highlights risk period differences for acute cardiovascular events after ILI, indicating possible differences in mechanism behind the risk of stroke after ILI compared to the risk of MI. High risk populations for stroke after ILI include men and people living in rural areas, while whites are at high risk for MI after ILI. Future studies are needed to identify ways to mitigate these risks.
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http://dx.doi.org/10.1186/s12889-021-10916-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097921PMC
May 2021

Medical Records-Based Genetic Studies of the Complement System.

J Am Soc Nephrol 2021 08 3;32(8):2031-2047. Epub 2021 May 3.

Division of Nephrology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York

Background: Genetic variants in complement genes have been associated with a wide range of human disease states, but well-powered genetic association studies of complement activation have not been performed in large multiethnic cohorts.

Methods: We performed medical records-based genome-wide and phenome-wide association studies for plasma C3 and C4 levels among participants of the Electronic Medical Records and Genomics (eMERGE) network.

Results: In a GWAS for C3 levels in 3949 individuals, we detected two genome-wide significant loci: chr.1q31.3 (CFH locus; rs3753396-A; =0.20; 95% CI, 0.14 to 0.25; =1.52x10) and chr.19p13.3 (C3 locus; rs11569470-G; =0.19; 95% CI, 0.13 to 0.24; =1.29x10). These two loci explained approximately 2% of variance in C3 levels. GWAS for C4 levels involved 3998 individuals and revealed a genome-wide significant locus at chr.6p21.32 (C4 locus; rs3135353-C; =0.40; 95% CI, 0.34 to 0.45; =4.58x10). This locus explained approximately 13% of variance in C4 levels. The multiallelic copy number variant analysis defined two structural genomic C4 variants with large effect on blood C4 levels: C4-BS (=-0.36; 95% CI, -0.42 to -0.30; =2.98x10) and C4-AL-BS (=0.25; 95% CI, 0.21 to 0.29; =8.11x10). Overall, C4 levels were strongly correlated with copy numbers of C4A and C4B genes. In comprehensive phenome-wide association studies involving 102,138 eMERGE participants, we cataloged a full spectrum of autoimmune, cardiometabolic, and kidney diseases genetically related to systemic complement activation.

Conclusions: We discovered genetic determinants of plasma C3 and C4 levels using eMERGE genomic data linked to electronic medical records. Genetic variants regulating C3 and C4 levels have large effects and multiple clinical correlations across the spectrum of complement-related diseases in humans.
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http://dx.doi.org/10.1681/ASN.2020091371DOI Listing
August 2021
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