Kenneth R. Butler

The Amyloidogenic V122I Transthyretin Variant in Elderly Black Americans

BACKGROUND Approximately 4% of black Americans carry a valine-to-isoleucine substitution (V122I) in the transthyretin protein, which has been associated with late-onset restrictive amyloid cardiomyopathy and increased risks of death and heart failure. METHODS We determined genotype status for the transthyretin gene (TTR) in 3856 black participants in the Atherosclerosis Risk in Communities study and assessed clinical profiles, mortality, and the risk of incident heart failure in V122I TTR variant carriers (124 participants [3%]) versus noncarriers (3732 participants). Cardiac structure and function and features suggestive of cardiac amyloidosis were assessed in participants who underwent echocardiography during visit 5 (2011 to 2013), when they were older than 65 years of age. RESULTS After 21.5 years of follow-up, we did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1382 deaths, 37%; age- and sex-stratified hazard ratio among carriers, 0.99; 95% confidence interval [CI], 0.73 to 1.36; P=0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% CI, 1.03 to 2.10; P=0.04). On echocardiography at visit 5, carriers (46 participants) had worse systolic and diastolic function, as well as a higher level of N-terminal pro-brain natriuretic peptide, than noncarriers (1194 participants), although carriers had a low prevalence (7%) of overt manifestations of amyloid cardiomyopathy. CONCLUSIONS We did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasts with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low. (Funded by the National Heart, Lung, and Blood Institute and others.).

Rationale and design of a multicenter echocardiographic study to assess the relationship between cardiac structure and function and heart failure risk in a biracial cohort of community-dwelling elderly persons: The atherosclerosis risk in communities study

Background—Heart failure is an important public health concern, particularly among persons >65 years of age. Women and blacks are critically understudied populations that carry a sizeable portion of the heart failure burden. Limited normative and prognostic data exist on measures of cardiac structure, diastolic function, and novel measures of systolic deformation in older adults living in the community. Methods and Results—The Atherosclerosis Risk in Communities (ARIC) study is a large, predominantly biracial, National Heart, Lung, and Blood Institute–sponsored epidemiological cohort study. Between 2011 and 2013, ≈6000 surviving participants, now in their seventh to ninth decade of life, are expected to return for a fifth study visit during which comprehensive 2-dimensional, Doppler, tissue Doppler, and speckle-tracking echocardiography will be performed uniformly in all cohort clinic visit participants. The following objectives will be addressed: (1) to characterize cardiac structural and functional abnormalities among the elderly and to determine how they differ by sex and race/ethnicity, (2) to determine the relationship between ventricular and vascular abnormalities, and (3) to prospectively examine the extent to which these noninvasive measures associate with incident heart failure. Conclusions—We describe the design, imaging acquisition and analysis methods, and quality assurance metrics for echocardiography in visit 5 of the ARIC cohort. A better understanding of the differences in cardiac structure and function through the spectrum of heart failure stages in elderly persons generally, and between sexes and racial/ethnic groups specifically, will deepen our understanding of the pathophysiology driving heart failure progression in these at-risk populations and may inform novel prevention or therapeutic strategies.

The Predictive Value of Left Atrial Size for Incident Ischemic Stroke and All-Cause Mortality in African Americans. The Atherosclerosis Risk in Communities (ARIC) Study

Background and Purpose— The association between left atrial (LA) size, ischemic stroke, and death has not been well established in African Americans despite their disproportionately higher rates of stroke and cardiovascular mortality compared to non-Hispanic whites. Methods— For the analysis, participants in the Jackson cohort of the Atherosclerosis Risk in Communities Study were followed from the date of the echocardiogram in cycle three to the date of the first ischemic stroke event (or death) or to December 31, 2004 if no ischemic stroke event (or death) was detected. Results— There were 1886 participants in the study population (mean age 58.9 years, 65% women). Participants in the top quintile of LA diameter indexed to height (LA diameter/height; 2.57 to 3.55 cm/m) were more likely women, hypertensive, diabetic, and obese compared to those not in the top quintile. Over a median follow-up of 9.8 years for ischemic stroke and 9.9 years for all-cause mortality, there were 106 strokes and 242 deaths. In a multivariable model adjusting for traditional clinical risk factors, the top quintile of LA diameter/height was significantly related to ischemic stroke (HR 1.7; 95% CI: 1.1, 2.7) and all-cause mortality (HR 2.0; 95% CI: 1.5, 2.7). After further adjustment for left ventricular (LV) hypertrophy and low LV ejection fraction, the top quintile remained significantly related to all-cause mortality (HR 1.8; 95% CI: 1.3, 2.5). Conclusions— In this population-based cohort of African Americans, LA size was a predictor of all-cause mortality after adjusting for traditional cardiovascular risk factors, LV hypertrophy, and low LV ejection fraction.

Leptinemia and its association with stroke and coronary heart disease in the Jackson Heart Study

Background  To examine the association of increased plasma leptin concentration with prevalent stroke and coronary heart disease (CHD) and to examine the genetic contributions of leptin to this association in the Jackson Heart Study cohort.

Reducing the Blood Pressure-Related Burden of Cardiovascular Disease: Impact of Achievable Improvements in Blood Pressure Prevention and Control.

Background US blood pressure reduction policies are largely restricted to hypertensive populations and associated benefits are often estimated based on unrealistic interventions. Methods and Results We used multivariable linear regression to estimate incidence rate differences contrasting the impact of 2 pragmatic hypothetical interventions to reduce coronary heart disease, stroke, and heart failure (HF) incidence: (1) a population‐wide intervention that reduced systolic blood pressure by 1 mm Hg and (2) targeted interventions that reduced the prevalence of unaware, untreated, or uncontrolled blood pressure above goal (per Eighth Joint National Committee treatment thresholds) by 10%. In the Atherosclerosis Risk in Communities Study (n=15 744; 45 to 64 years at baseline, 1987–1989), incident coronary heart disease and stroke were adjudicated by physician panels. Incident HF was defined as the first hospitalization with discharge diagnosis code of “428.” A 10% proportional reduction in unaware, untreated, or uncontrolled blood pressure above goal resulted in ≈4.61, 3.55, and 11.01 fewer HF events per 100 000 person‐years in African Americans, and 3.77, 1.63, and 4.44 fewer HF events per 100 000 person‐years, respectively, in whites. In contrast, a 1 mm Hg population‐wide systolic blood pressure reduction was associated with 20.3 and 13.3 fewer HF events per 100 000 person‐years in African Americans and whites, respectively. Estimated event reductions for coronary heart disease and stroke were smaller than for HF, but followed a similar pattern for both population‐wide and targeted interventions. Conclusions Modest population‐wide shifts in systolic blood pressure could have a substantial impact on cardiovascular disease incidence and should be developed in parallel with interventions targeting populations with blood pressure above goal.

Echocardiographic Left Ventricular Mass Index Predicts Incident Stroke in African Americans Atherosclerosis Risk in Communities (ARIC) Study

Background and Purpose— Despite theories that link stroke to left ventricular mass, few large, population-based studies have examined the predictive value of echocardiographically derived left ventricular mass index (LVMI) to incident stroke in African Americans. Methods— Participants in the Jackson cohort of the Atherosclerotic Risk in Communities study have had extensive baseline evaluations, have undergone echocardiography during the third examination (1993–1995), and have been followed up for incident cardiovascular disease including ischemic stroke. Results— The study population consisted of 1792 participants, of whom 639 (35.7%) were men and the mean±SD age was 58.8±5.7 years. Compared with those without ischemic stroke, those with ischemic stroke had a higher frequency of hypertension (85.6% vs 58.7%) and diabetes (46.9% vs 21.0%). Left ventricular hypertrophy was more prevalent in those with stroke (62.2% vs 38.6%). During a median follow-up of 8.8 years, 98 incident strokes occurred (6.5 per 1000 person-years). LVMI was independently associated with stroke after adjusting for age, sex, hypertension, systolic blood pressure, smoking, diabetes, total to HDL cholesterol ratio, body mass index, and low left ventricular ejection fraction (adjusted hazard ratio per 10 g/m2.7 increment of LVMI=1.15; 95% CI, 1.02 to 1.28). The relation remained statistically significant after adding left atrial size and mitral annular calcification to the multivariable model. Conclusions— In this large, population-based African American cohort, we found that echocardiographic LVMI was an independent predictor of incident ischemic stroke even after taking into account traditional clinical risk factors.

Relationship between alcohol consumption and cardiac structure and function in the elderly: the Atherosclerosis Risk In Communities Study.

Background—Excessive alcohol consumption is associated with cardiomyopathy, but the influence of moderate alcohol use on cardiac structure and function is largely unknown. Methods and Results—We studied 4466 participants from visit 5 of the Atherosclerosis Risk in Communities (ARIC) study (76±5 years and 60% women) who underwent transthoracic echocardiography, excluding former drinkers and those with significant valvular disease. Participants were classified into 4 categories based on self-reported alcohol intake: nondrinkers, drinkers of ⩽7, ≥7 to 14, and ≥14 drinks per week. We related alcohol intake to measures of cardiac structure and function, stratified by sex, and fully adjusted for covariates. In both genders, increasing alcohol intake was associated with larger left ventricular diastolic and systolic diameters and larger left atrial diameter (P<0.05). In men, increasing alcohol intake was associated with greater left ventricular mass (8.2±3.8 g per consumption category; P=0.029) and higher E/E′ ratio (0.82±0.33 per consumption category; P=0.014). In women, increasing alcohol intake was associated with lower left ventricular ejection fraction (−1.9±0.6% per consumption category; P=0.002) and a tendency for worse left ventricular global longitudinal strain (0.45±0.25% per consumption category; P=0.07). Conclusions—In an elderly community-based population, increasing alcohol intake is associated with subtle alterations in cardiac structure and function, with women appearing more susceptible than men to the cardiotoxic effects of alcohol.

Small brain lesions and incident stroke and mortality: A cohort study

Context Subclinical brain infarctions are typically defined as lesions 3 mm or larger on imaging in patients without a history of stroke. The clinical significance of lesions smaller than 3 mm is unknown. Contribution This prospective longitudinal study involved 2892 adults living in 2 U.S. communities who had brain magnetic resonance imaging (MRI) at baseline. Hospitalizations for nonfatal and fatal strokes were ascertained yearly during follow-up (average, 14.5 years). Caution One quarter of patients declined to have brain MRI. Implication Very small brain lesions were associated with an increased risk for stroke and death. The risks were greater if lesions 3 mm or larger were also present. Subclinical brain infarctions (SBIs) are usually defined as lesions larger than 3 mm on brain imaging (1, 2) in persons with no history of clinical stroke. Both SBIs and white matter hyperintensities (WMHs) have been associated with increased risk for stroke and death, primarily in older persons (314). Brain structural abnormalities may be objective markers of stroke risk, yet lesions smaller than 3 mm are typically ignored in clinical and research settings because of potential misclassification of presumed nonvascular lesions (such as VirchowRobin spaces) as vascular lesions and a lack of data on associations with outcomes. However, even very small lesions may be mediated through vascular processes, such as infarctions, leukoaraiosis, and endothelial dysfunction (1518). The STRIVE (Standards for Reporting Vascular Changes on Neuroimaging) consortium recently included small lesions, including potential perivascular spaces, as a possible form of cerebral small vessel disease (18). The relationship between lesions smaller than 3 mm and important clinical outcomes is unknown. If even very small lesions (<3 mm) are associated with stroke and mortality, they may enable early identification of at-risk persons in whom targeted preventive measures may be warranted. Members of ethnic minority groups, including non-Hispanic black persons, are more likely than white persons to have strokes, strokes at earlier ages, and stroke-related disability and death (19, 20). Yet, most studies of brain structural abnormalities and stroke risk have been in older and primarily white populations (5, 6, 10, 13, 14, 21). Increased stroke risk associated with brain vascular lesions has been observed in the younger Framingham Offspring cohort (6), as have increased stroke and mortality in a middle-aged to older Japanese population (4), but studies are limited in middle-aged persons and minority groups, including black persons. Identifying early markers of at-risk persons could significantly affect the public health burden of cerebrovascular disease in all ethnic groups, given associations with cognitive decline and dementia, gait impairment, and stroke (13, 2226). The purpose of this study was to examine the associations of incident stroke, stroke-related mortality, and all-cause mortality with the presence of lesions smaller than 3 mm, lesions 3 mm or larger, lesions of both sizes, and WMHs in a middle-aged biracial population. Methods Population The ARIC (Atherosclerosis Risk in Communities) study cohort has been described previously (27). Participants aged 55 years or older from Forsyth County, North Carolina, and Jackson, Mississippi, were invited to undergo brain magnetic resonance imaging (MRI) at ARIC visit 3 (1993 to 1995; n= 2892). Of these, 103 were ineligible for safety reasons, 654 declined, 122 did not initially decline but did not undergo MRI, 73 attempted but did not complete MRI, and 6 completed MRI forms but had no data (Appendix Figure 1). Participants who had MRI were older (62 vs. 58 years) but were otherwise similar to those who did not have MRI (Appendix Table 1). We obtained MRI data on 1934 participants and excluded 46 with prevalent strokes and 4 who reported nonwhite, nonblack ethnicity, leaving 1884 for this analysis. Institutional review boards approved study protocols, and all participants provided informed consent. Appendix Figure 1. Study flow diagram. ARIC = Atherosclerosis Risk in Communities; MRI = magnetic resonance imaging. Appendix Table 1. Comparison of Visit 3 Characteristics Among Participants Without and With MRI at the Forsyth County and Jackson ARIC Sites and Those Included in the Current Study* Brain Imaging Protocols for brain MRI have been described in detail and were identical to those used in the CHS (Cardiovascular Health Study) (28, 29). Briefly, 5-mm contiguous axial T1-, T2-, and proton densityweighted images of the whole brain were obtained using 1.5-Tesla scanners. Subclinical brain infarctions were defined by shape, absence of mass effect, and hyperintensity to gray matter on proton densityweighted and T2-weighted images, in contrast to perivascular spaces, which show intensity similar to that of cerebrospinal fluid as well as typical locations and morphology (30). Subclinical brain infarctions within deep cerebral white matter were also required to be hypointense on T1-weighted images. The maximal right-to-left and anterior-to-posterior lesion dimensions were recorded with an electronic cursor. The superior-to-inferior dimension was reported as the number of 5-mm axial sections on which the lesion appeared. Lesions smaller than 3 mm on right-to-left or anterior-to-posterior measurements were recorded as less than 3 mm (28, 31). Images were double-read independently by 2 neuroradiologists, and discrepant cases were adjudicated by consensus among 3 or more readers. We included cortical and noncortical lesions. Lacunes were defined as 3- to 20-mm noncortical lesions in the basal ganglia, brainstem, thalamus, internal capsule, or cerebral white matter. Nonlacunar lesions were defined as 3- to 20-mm lesions outside these areas or lesions larger than 20 mm in any area on right-to-left or anterior-to-posterior measurements. The number of lesions smaller than 3 mm was recorded as 0, 1 to 2, or more than 2, and the number of lesions 3 mm or larger was recorded as 0, 1, or 2 or more (up to 5) (28, 31). Periventricular and subcortical WMHs were graded on a scale of 0 (no white matter signal abnormalities) to 9 (extensive confluent white matter involvement), based on pattern matching to a set of reference standards (29, 32). Incident Stroke and Mortality Ascertainment and Criteria Adjudicated nonfatal and fatal clinical strokes requiring hospitalization were identified through yearly telephone interviews and surveillance methods that also included hospital record reviews and medical chart abstraction (33). Deaths were identified through contacts with next of kin, hospital records, state death records, and the National Death Index. Stroke-related deaths were adjudicated by expert stroke reviewers. Follow-up was complete through 2010. Stroke was defined according to the National Survey of Stroke criteria and required evidence of sudden or rapid onset of neurologic symptoms that persisted for more than 24 hours or led to death with no other apparent cause, such as trauma, tumor, infection, or anticoagulation (7, 33, 34). Of patients hospitalized for stroke, 99% had diagnostic computed tomography (CT) or MRI (7). Ischemic stroke was defined as symptoms plus acute infarction or absence of hemorrhage on imaging. Hemorrhagic stroke met one of the following criteria: CT or MRI with intraparenchymal hematoma; demonstration at autopsy or surgery; or at least 1 major or 2 minor neurologic deficits, bloody spinal fluid on lumbar puncture, no CT or MRI with or without cerebral angiography demonstrating an avascular mass effect, and no evidence of aneurysm or arteriovenous malformation (7, 21, 33). Covariates All covariates were measured at ARIC visit 3 when the MRI was conducted. Body mass index was calculated in kilograms per square meter. Hypertension was defined as systolic blood pressure of at least 140 mmHg, diastolic blood pressure of at least 90 mmHg, or use of antihypertensive medication in the previous 2 weeks. Diabetes mellitus was defined as a fasting blood glucose level of at least 7 mmol/L (126 mg/dL), a nonfasting blood glucose level greater than 11.1 mmol/L (200 mg/dL), antidiabetic medication use in the previous 2 weeks, or a physician diagnosis of diabetes. Standardized questionnaires were used to ascertain medical history, smoking, and alcohol consumption. Smoking and alcohol use were categorized as never, former, or current. Educational attainment was categorized as less than 12 years, 12 to 16 years, or more than 16 years. Additional covariates from the Framingham stroke risk factors were not included because of reductions in the sample size and low prevalence (for example, <1% [n= 4] for atrial fibrillation and 4% [n= 78] for left ventricular hypertrophy). Statistical Analysis We examined associations between participant characteristics and lesion size (no lesions, <3 mm only, 3 mm only, and both sizes) by using Fisher exact tests, KruskalWallis tests, and multinomial regression to estimate relative risk ratios (RRRs). Cumulative incidence curves show incidence of stroke and stroke-related mortality over time by lesion type and WMHs (standardized curves are provided in Appendix Figure 2). Cox proportional hazards models were used to estimate hazard ratios (HRs) for associations of MRI predictors with adjudicated event outcomes (incident stroke, stroke subtype, all-cause mortality, and stroke-related mortality). We used a single model to examine the associations of presence of no lesions versus very small lesions only (<3 mm) versus larger lesions only (3 mm) versus lesions of both sizes. We then examined the presence and number of very small lesions (doseresponse effects) in separate models (for example, associations of presence of very small lesions regardless of presence of larger ones) to preserve cell sizes when examining numbers of lesions. Presence of larger lesions, lacunar and nonlacunar inf

Cardiovascular Dysfunction and Frailty Among Older Adults in the Community: The ARIC Study

Background The contribution of cardiovascular dysfunction to frailty in older adults is uncertain. This study aimed to define the relationship between frailty and cardiovascular structure and function, and determine whether these associations are independent of coexisting abnormalities in other organ systems. Methods We studied 3,991 older adults (mean age 75.6±5.0 years; 59% female) from the Atherosclerosis Risk in Communities (ARIC) Study in whom the following six organ systems were uniformly assessed: cardiac (by echocardiography), vascular (by ankle-brachial-index and pulse-wave-velocity), pulmonary (by spirometry), renal (by estimated glomerular filtration rate), hematologic (by hemoglobin), and adipose (by body mass index and bioimpedance). Frailty was defined by the presence of ≥3 of the following: low strength, low energy, slowed motor performance, low physical activity, or unintentional weight loss. Results Two hundred eleven (5.3%) participants were frail. In multivariable analyses adjusted for demographics, diabetes, hypertension, and measures of other organ system function, frailty was independently and additively associated with left ventricular hypertrophy (odds ratio [OR] = 1.72; 95% confidence interval [CI] = 1.30-2.40), reduced global longitudinal strain (reflecting systolic function; OR = 1.68; 95% CI = 1.16-2.44), and greater left atrial volume index (reflecting diastolic function; OR = 1.60; 95% CI = 1.13-2.27), which together demonstrated the greatest association with frailty (OR = 2.10; 95% CI = 1.57-2.82) of the systems studied. Lower magnitude associations were observed for vascular and pulmonary abnormalities, anemia, and impaired renal function. Cardiovascular abnormalities remained associated with frailty after excluding participants with prevalent cardiovascular disease. Conclusions Abnormalities of cardiac structure and function are independently associated with frailty, and together show the greatest association with frailty among the organ systems studied.

Psychometric Evaluation of the Interpersonal Support Evaluation List–Short Form in the ARIC Study Cohort

The impact of social support on health outcomes is well documented. The current study evaluated a short form of the Interpersonal Support Evaluation List (ISEL-SF) administered to 14,257 participants in the Atherosclerosis Risk in Communities study. Using confirmatory factor analysis, we attempted to replicate the subscale structure of the full-scale version. Additional analyses were conducted to examine the relationship of ISEL scores to key demographic variables, as well as the relationship with the Lubben Social Support Scale. We replicated the existing full-scale ISEL subscale structure in this short version. In addition, subscale scores were found to differ across gender, race, level of educational attainment, and marital status, although the magnitude of the various effects was modest. Correlations with another established measure of social support provide convergent validity for this abbreviated instrument. Results suggest this brief measure of perceived social support is a psychometrically valid instrument. An evaluation of its clinical utility is warranted.