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Background Lower exercise capacity, as measured by 6-minute walk distance (6MWD), is associated with incident heart failure (HF). Among those without HF, the associations of measures of cardiac function with 6MWD are unclear, and may provide insight regarding the risk of incident HF. Objectives The purpose of this study was to understand the relationships between cardiac function and exercise capacity. Methods This study evaluated the associations of cardiac mechanics with 6MWD in the sixth examination of the Multi-Ethnic Study of Atherosclerosis. Echocardiography (2-dimensional, Doppler, and speckle-tracking) was performed at rest and after passive leg raise to evaluate functional reserve after intravascular volume challenge. Results Of 2,096 participants without HF (mean age 73 years, 48% men, 58% non-White), individuals with lower (worse) left atrial (LA) reservoir strain were older and had higher blood pressure. Lower resting LA reservoir strain (β coefficient per SD decrease: −5.0; 95% confidence interval [CI]: −8.8 to −1.3 m; p = 0.009), inability to augment LA reservoir strain after passive leg raise (β coefficient per SD decrease: −5.8; 95% CI: −9.1 to −2.5 m; p Conclusions Among individuals without HF, worse biatrial function, lack of LA functional reserve, and worse LV diastolic function were associated with reduced submaximal exercise capacity. Therapies aimed to improve these functional domains may increase exercise capacity and prevent HF.

Background and aims Elevated serum calcium and phosphorus have been associated with increased risk of cardiovascular disorders. We evaluated whether abnormal calcium and high serum phosphorus are associated cross-sectionally with echocardiographic measures of left ventricular (LV) structure and function, as doing so may provide insight into the etiology of cardiac disorders. Methods and results Included in the analysis were 5213 Atherosclerosis Risk in Communities Study (ARIC) participants who in 2011–2013 had echocardiography and serum calcium and phosphorus measurements. We evaluated the association of serum calcium (corrected for albumin) and phosphorus quintiles with measures of LV structure and function, after adjusting for other cardiovascular risk factors. Participants were on average 75.3 years old; 59.1% were female and 19.8% were African American. Mean (±SD) concentrations of calcium and phosphorus were 9.33 ± 0.38 and 3.46 ± 0.45 mg/dL, respectively. Higher calcium was associated with lower LV end-diastolic diameter (LVEDD) but greater prevalence of concentric remodeling (p-trend: 0.005 and 0.004 respectively). We observed association between high phosphorus and high septal E/e’ (p-trend: 0.02). Likewise, higher serum phosphorus was associated with higher left atrial volume index (p-trend: 0.001) and LV hypertrophy prevalence (p-trend: 0.04). Conclusions In conclusion, higher calcium was associated with more concentric remodeling but lower LVEDD, suggesting complex associations between calcium and cardiac function. Serum phosphorus was related to worse indices of LV diastolic function and LV hypertrophy, but not to LV systolic function. However, the magnitudes of association were modest, so clinical implications of these findings may be limited.

Key Points Question Is sickle cell trait associated with increased risk of myocardial infarction and coronary heart disease among African American individuals? Findings In this cohort study of 23 197 African American individuals in 5 cardiovascular epidemiologic studies, sickle cell trait was not associated with increased risk of myocardial infarction or coronary heart disease among African American individuals. Meaning In this study, sickle cell trait was not associated with increased risk of fatal and nonfatal myocardial infarction or coronary heart disease, suggesting that these disorders may not be associated with sickle cell trait–related sudden death., Importance The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT). Objective To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals. Design, Setting, and Participants This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women’s Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020. Exposures Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses. Main Outcomes and Measures Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis). Results A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47). Conclusions and Relevance In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait–related sudden death in this population., This cohort study evaluates whether African American individuals with sickle cell trait have a higher incidence of myocardial infarction or composite coronary heart disease outcomes compared with those without sickle cell trait.

Introduction: While the prognostic implications of higher pulmonary artery systolic pressure (PASP) are well established, few data exist regarding longitudinal change in pulmonary pressure in the community. We characterized longitudinal changes in PASP over ~6.5 years in late life, and identified predictors of this change. Methods: We studied 1,426 elderly participants in the prospective, community-based Atherosclerosis Risk in Communities (ARIC) study who underwent protocol echocardiography and had assessable tricuspid regurgitation spectral Doppler at 5 th (2011-2013) and 7 th (2018-2019) study visits. We used multivariable linear regression to identify clinical, echocardiographic and biomarker predictors of change in PASP. Results: Mean age was 74±5 years at Visit 5, 32% were men, 24% black, and mean PASP was 27.5±5.0 mmHg. Over a median of 6.5±3.0 years, PASP increased by 5.2±7.7 mmHg on average, with no significant differences by race (white 5.0±7.6, black 5.8±7.9; p=0.40) or sex (women 5.2±7.7, men 5.1±7.8; p=0.95). In models adjusted for heart rate and blood pressure at both visits, and for PASP, clinical and echocardiographic measures at Visit 5, independent predictors of longitudinal increase in PASP at Visit 5 were higher NT-proBNP (p=0.005), larger left atrial volume index (p=0.045), and lower forced expiratory volume at 1 second (p=0.019). Longitudinal increase in PASP was associated with concomitant increases in LAVi, E/e’ ratio, and LV mass index ( Figure ; all p Conclusions: PASP increased by 5±8 mmHg over 6.5±3.0 years in late life, with greater increases associated with higher filling pressure and worse pulmonary function. Increases in PASP are accompanied by longitudinal worsening in LV diastolic - but not systolic - measures.

Background: Aortic stenosis (AS) is a growing health problem within the aging population. We aimed to quantify longitudinal changes in aortic valve hemodynamics in late life. Methods: We studied 2,512 community-based elderly participants in the Atherosclerosis Risk in Communities (ARIC) study who underwent uniform echocardiographic imaging at study visits 5 (2011-2013) and 7 (2018-2019). Peak aortic valve (AV) velocity was assessed by continuous wave spectral Doppler from the apical 5 chamber view. Participants with heart failure or in atrial fibrillation at either echocardiographic examination were excluded. Results: Mean age at Visit 5 was 74 ± 4 years, 41% were male, 24% black, and the mean AV velocity at Visit 5 was 1.27 ± 0.28 m/s. Over median 6.6 [IQR: 6.1-7.0] years, AV velocity increased by 0.15 ± 0.32 m/s and the mean velocity at Visit 7 was 1.43 ± 0.43 m/s. Of 2,454 participants with peak AV velocity < 2.0 m/s at Visit 5, 123 (5%) developed a peak AV velocity > 2.0 m/s at Visit 7 (mean 2.45 ± 0.46 m/s). In models accounting for blood pressure and heart rate at both study visits, Visit 5 predictors of transitioning to a peak AV velocity > 2.0 m/s included age, male sex, white race, BMI, higher NT-proBNP and hs-troponin T, and greater LA volume index and E/e’ ratio ( Table ). Conclusions: Peak AV velocity increases over 6 years in late life, with ~5% developing a peak velocity > 2.0 m/s. Demographics, higher cardiac biomarkers, and worse diastolic function predict increases in peak AV velocity in late life. These data have important implications for the development of age-related aortic stenosis.

Introduction: Older adults are at heightened risk for both kidney disease and heart failure, but there is limited data regarding the associations of kidney damage and dysfunction with incident heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fraction in late life. Hypothesis: Kidney dysfunction, as assessed by lower estimated glomerular filtration rate (eGFR), and kidney damage, as assessed by higher urine albumin-to-creatinine ratio (UACR), are each independently associated with incident HFrEF and HFpEF in late life. Methods: We studied 4,563 elderly participants in the community-based, prospective ARIC study who were free of HF at study Visit 5 (2011-2013) at which time they had UACR measured and Cystatin-C-based eGFR estimated using the CKD-EPI formula. We estimated the association of Visit 5 eGFR and UACR with post-Visit 5 incident HF overall, HFrEF, and HFpEF using multivariable Cox proportional hazards regression models adjusted for demographics, diabetes, hypertension, coronary artery disease, atrial fibrillation, body mass index, pulse pressure, and either eGFR or UACR. Results: The mean age at Visit 5 was 75±5 years, 57% were female, 21% were black. Mean Visit 5 eGFR was 67±18 mL/min per 1.73 m 2 and median UACR was 10.2 [6.2 to 21.4] mg-g. Lower eGFR and higher UACR each associated with older age, wider pulse pressure and higher prevalence of diabetes, hypertension, coronary disease and atrial fibrillation (all pFigure ). Conclusions: Lower eGFR and higher UACR are independently and additively associated with both incident HFrEF and incident HFpEF in late life.

Introduction: Diastolic dysfunction is a potent risk factor for heart failure (HF). However, there is limited data regarding longitudinal changes of diastolic function in the very old, who are at the highest risk for HF. Methods: We studied 2,559 community-based elderly participants in the prospective ARIC study who underwent protocol echocardiography, were in sinus rhythm at study Visits 5 (2011-2013) and 7 (2018-2019), and did not have an interval myocardial infarction. The primary diastolic measures were Tissue Doppler e’, E/e’ ratio, and left atrial volume index (LAVi). Results: Mean age at Visit 5 was 74±4 years, 59% were women, and 25% black. At Visit 5, mean e’ was 5.8±1.4 cm/s, E/e’ 11.8±3.6, and LAVi 24.3±6.7 ml/m 2 . Over a mean of 6.5±3.1 years, e’ decreased by 0.6±1.4 cm/s, E/e’ increased by 3.1±4.5, and LAVi increased by 1.4±7.7 ml/m 2 . Using validated ARIC-based cut-points, there was significant increase in the proportion of participants with abnormal e’ (18% at Visit 5 to 34 % at Visit 7), E/e’ (20% vs 46%), LAVi (17% vs 25%; all pFigure ). Compared to participants free of cardiovascular (CV) risk factors or CV diseases (n=237), those with CV risk factors or diseases at Visit 5 (n=2,210) demonstrated greater increases in E/e’ (2.3±3.9 vs 3.1±4.5 respectively; p=0.006) and LAVi (0.0±7.0 vs 1.5±7.7 ml/m 2 ; p=0.008) while increases in E/e’ (5.0±5.1; p2 ; p Conclusions: Diastolic function progressively worsens over 6.5 years in late life, particularly among persons with CV risk factors. Further studies are necessary to determine if risk factor prevention or control will mitigate these changes.

Introduction: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) improve prediction of incident heart failure (HF) and are cross-sectionally associated with left ventricular (LV) remodeling, but their associations with changes in cardiac structure and function are unclear. Hypothesis: Concentrations of NT-proBNP and hs-cTnT associate with 6-year change in cardiac structure in older adults. Methods: We studied 1,916 participants aged 67-88 in the ARIC Study free of overt cardiovascular disease at baseline (study Visit 5; 2011-13). We quantified the associations of baseline NT-proBNP and hs-cTnT with subsequent changes in LV structure and systolic and diastolic function assessed by echocardiography over a median of 6.6 (IQR 6.1-7.0) years using multivariable linear regression and restricted cubic spline models. Models adjusted for demographics, systolic blood pressure, heart rate, body mass index, diabetes, hypertension, kidney function, and the baseline echocardiographic value of interest at Visit 5. Results: Mean age was 75±4 years, 60% were female, 23% were black, median hs-cTnT was 9 (IQR 6-13) ng/L and NT-proBNP was 88 (50-157) ng/L at Visit 5. In adjusted models, higher hs-cTnT was modestly associated with 6-year increase in LV wall thickness (p=0.02) but not with changes in LV function. In contrast, higher NT-proBNP at Visit 5 was associated with 6-year increase in LV mass, decline in LV systolic function (ejection fraction, longitudinal and circumferential strain), and worsening of diastolic function (left atrium volume, E/e’, tricuspid regurgitation peak velocity) (all pFigure ). These associations were non-linear. Conclusions: Higher NT-proBNP, but not hs-cTnT, concentrations are associated with greater declines in LV systolic and diastolic function over ~6 years in late life.

Background Atrial fibrillation ( AF ) is associated with cognitive decline. Whether left atrial enlargement ( LAE ), a critical substrate for AF, is also associated is less well established. Therefore, we assessed the association of LAE and AF with cognitive decline in the ARIC‐NCS (Atherosclerosis Risk in Communities Neurocognitive Study). Methods and Results Participants (n=3391; mean age, 75±5 years; 59% women) underwent cognitive tests and 2‐dimensional echocardiograms at visit 5 (2011–2013) and follow‐up cognitive tests at visit 6 (2016–2017). LAE was defined as left atrium volume index ≥34 mL/m 2 . AF was ascertained using study ECG s and hospitalization discharge codes. We assessed the association of AF and LAE with (a) cognitive domain scores at visit 5 and (b) cognitive domain score changes between visit 5 and visit 6. At visit 5, compared with the reference group (without AF , normal left atrium), participants with LAE and AF had significantly lower global cognition ( Z score, −0.24; 95% CI, −0.38 to −0.10), whereas participants with AF and without LAE and participants with LAE and without AF did not have lower global cognition. In longitudinal analysis, compared with the reference group, participants with AF but without LAE had significantly greater decline in global cognition ( Z score, −0.13; 95% CI, −0.21 to −0.06). However, LAE, with or without AF, was not associated with greater cognitive decline. Conclusion Although LAE with AF was significantly associated with lower cognitive function in cross‐sectional analysis, LAE, with or without AF, was not associated with greater cognitive decline over 5 years, highlighting the importance of evaluating longitudinal cognitive function. Future studies should have longer follow‐up and evaluate left atrium function.

Purpose Based on the 2018 American College of Cardiology/American Heart Association cholesterol guidelines, the number of individuals eligible for statin therapy to reduce atherosclerotic cardiovascular disease risk has greatly expanded. Statins inhibit cholesterol biosynthesis, which can impair gonadal steroidogenesis. We evaluated the effect of statins on endogenous sex hormones in a large epidemiological study. Methods A total of 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants underwent the baseline examination. Of these, 6171 had measurements of serum sex hormones available: dehydroepiandrosterone (DHEA), SHBG, estradiol, and total and bioavailable testosterone. Multivariable linear regression models were used to assess the relationship of statin use with each sex hormone. Results A total of 345 women (17.4%) and 464 men (14.7%) were statin users (mean age, 67 years; 41% white, 29% black, 11% Chinese, and 19% Hispanic). Among the users vs nonusers of statins, the mean SHBG was 3.54 nmol/L (P < 0.01) lower in women and 3.37 nmol/L (P < 0.001) lower in men; the mean DHEA was 1.06 nmol/L (P < 0.05) lower in women and 0.70 nmol/L (P < 0.01) lower in men, after adjustment for potential confounders. With further propensity score adjustment, the mean DHEA and SHBG levels were 0.67 nmol/L (P < 0.05) and 3.49 nmol/L (P < 0.001) lower, respectively, for statin users vs nonusers. No statistically significant association was noted between estradiol, total testosterone, and bioavailable testosterone and statin use. Conclusion Statin users have lower levels of SHBG and DHEA. This is especially relevant owing to the increasing use of statin therapy.

BACKGROUNDThe role of alcohol in the development of subclinical cardiovascular disease is unclear. We examined the association between alcohol consumption and markers of subclinical cardiac damage and wall stress.METHODSWe studied the cross-sectional and prospective associations of alcohol consumption with high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) measured at 2 time points, 6 years apart (baseline, 1990–1992; follow-up, 1996–1998), in over 11000 participants of the Atherosclerosis Risk in Communities (ARIC) Study with no history of cardiovascular disease. Alcohol consumption was categorized as follows: never, former, current: ≤1, 2–7, 8–14, and ≥15 drinks/week.RESULTSCompared to never drinkers, persons who consumed 2–7 drinks per week were less likely to have increased hs-cTnT (≥14 ng/L) at baseline (odds ratio = 0.67, 95% CI, 0.46–0.96), and had a lower risk of incident increases in hs-cTnT at follow-up (relative risk = 0.70, 95% CI, 0.49–1.00). Conversely, there was a positive association between alcohol intake and NT-proBNP concentrations at baseline. Consumption of ≥15 drinks/week was positively associated with incident increases in NT-proBNP (≥300 pg/mL) at the 6-year follow-up visit (relative risk = 2.38, 95% CI, 1.43–3.96).CONCLUSIONSIn this community-based study of middle-aged adults without a history of cardiovascular disease, moderate drinking was associated with lower concentrations of hs-cTnT, a marker of chronic subclinical myocardial damage, and positively associated with NT-proBNP, a biomarker of cardiac wall stress. Our results suggest that the cardiac effects of alcohol are complex. Cardiac biomarkers may help improve our understanding of the full cardiovascular effects of alcohol consumption.

One of the great conundrums for both oncologists and cardiologists is how to best monitor the potential and actual cardiotoxicity of doxorubicin. Pegylated-liposomal doxorubicin (PLD) has a safer cardiotoxicity profile than bolus administration of doxorubicin. Although ejection fraction (EF) is commonly performed to monitor doxorubicin-induced cardiotoxicity, evidence for its predictive utility is limited. We examined the incidence of doxorubicin-induced heart failure (HF) in patients who received a large cumulative dose of doxorubicin as PLD and its relation to EF and HF. A retrospective chart review of patients who received a large cumulative dose of PLD, sometimes after previous free doxorubicin treatment, was performed to examine the incidence of doxorubicin-induced heart failure (HF) and its relation to EF and development of HF. No definite doxorubicin-induced clinical HF was observed among 56 patients (median age 54; 15–93) who received a cumulative doxorubicin dose (free + PLD) of >450 mg/m2. Of these, 49 received >500 mg/m2, 28 > 700 mg/m2, 19 > 800 mg/m2, 14 > 1000 mg/m2, and 5 > 1400 mg/m2. The EF varied greatly over time in some patients treated with PLD in the absence of symptoms or signs of heart failure, and was not particularly useful in making decisions regarding further dosing. Pegylated-liposomal doxorubicin was associated with a low risk of doxorubicin-induced HF in a retrospective cohort of patients receiving large cumulative doses of doxorubicin and long-term follow-up. EF did not predict doxorubicin-induced cardiotoxicity in our cohort of adult patients receiving PLD. Given the lack of prognostic clarity regarding modest EF changes, regular EF monitoring may not be warranted, at least when PLD is used in adults. Modest changes in EF should probably not be used to limit a patient’s access to PLD, but may warrant cardiology consultation for long-term follow-up after completion of therapy.

Background Antibodies against human epidermal growth factor receptor 2 (HER2) affect metastatic breast cancer cells and cardiac myocytes. Guidelines recommend evaluation of cardiac ejection fraction (EF) every 3 months despite little supporting evidence for this need. We assessed the impact of EF screening on clinical practice. Patients and methods We carried out retrospective analysis of patients with HER2-positive metastatic breast cancer receiving HER2-directed therapy to assess the impact of aggressive cardiac screening on management decisions. Results Data for 128 patients were analyzed. The median number of EF screenings in the first year of therapy was 3 (range=1-8). A total of 29 patients had an asymptomatic decrease in EF. These patients had more EF screenings, more exposure to anthracyclines or left-sided radiation, were more likely to receive a cardiology consult and have an angiotensin converting enzyme inhibitor added to their therapy. Ninety patients underwent aggressive screening; this was not associated with cessation of HER2 therapy (p=0.92). Conclusion Routine EF screening did not have an impact on decisions regarding HER2 therapy in patients with metastatic breast cancer. Given the known benefit of HER2 treatment, reducing the frequency of cardiac screening may be reasonable.

Introduction Coronary artery disease (CAD) is a potent risk factor for heart failure with reduced ejection fraction (HFrEF), and is a common comorbidity in HF with preserved EF (HFpEF). However, data regarding the association of incident CAD with subsequent HFpEF independent of shared comorbidities are limited. Hypothesis Incident CAD is a risk factor for incident HFpEF independent of common shared comorbidities. Methods We evaluated 9,902 CAD-free and HF-free participants in the Atherosclerosis Risk in Communities (ARIC) cohort and followed them from 2005 to 2017. Multivariable Cox proportional hazard models were used to assess the association of incident CAD (defined as adjudicated MI or revascularization) with subsequent adjudicated hospitalization for incident HFpEF (EF ≥50%) or incident HF with mid-range or reduced EF (HFmrEF/HFrEF; EF 1 year after CAD diagnosis. Results The average age as of 2005 was 70 ± 6, 61% were female, and 26% were black. During median follow-up of 13 years, incident CAD occurred in 892 participants who subsequently experienced 71 incident HFpEF events and 86 HFmrEF/HFrEF events. Risk of both incident HFpEF and HFmrEF/HFrEF was greatest early following CAD diagnosis. Incident CAD remained predictive of both incident HFpEF (HR 1.9 [1.4 - 2.6]) and HFmrEF/HFrEF (HR 2.8 [2.0 - 3.8]) at >1 year following the CAD event, with no detected effect modification by sex or race (Figure). Similar risks for HFpEF were observed at >1 year following incident MI or following incident revascularization alone. At >1 year after incident CAD, the adjusted incidence rates of HFpEF and HFmrEF/HFrEF were similar (1.10 [95% CI 0.77 - 1.43] and 1.10 [95% CI 0.77 - 1.44] per 100 person-years respectively). Conclusions Incident CAD is an independent risk factor for subsequent incident HFpEF. At >1 year after incident CAD, incidence of HFpEF is similar to HFmrEF/HFrEF. These findings argue for an important, and potentially under-recognized, role of CAD in the development of HFpEF.

Cardiovascular disease is the leading noncancer cause of death among survivors of childhood cancer. Ejection fraction (EF) and fractional shortening (FS) are common echocardiographic measures of cardiac function, but newer imaging modalities may provide additional information about preclinical disease. This study aimed to evaluate these modalities in detection of anthracycline-induced cardiac toxicity.We compared mean radial displacement, EF, and FS among 17 adult survivors of childhood cancer exposed to ≥ 300 mg/m(2) of anthracyclines to 17 age- and sex-matched healthy controls. Survivors with a history of cardiac-directed radiation, diabetes, or heart disease were excluded.Survivors (35% male), mostly with history of treatment for a solid tumor, had a median age at diagnosis of 15 years (1-20) and 27 years (18-50) at evaluation. Median anthracycline exposure was 440 (range 300-645) mg/m(2). FS (35.5 vs. 39.6%, p 0.01) and radial displacement (5.6 vs. 6.7 mm, p = 0.02) were significantly lower in survivors compared to controls, respectively. Although the mean EF was lower in survivors versus controls (55.4 vs. 59.7%), it was not statistically significant (p = 0.057). All echocardiographic measures were inversely associated with anthracycline dose, though radial displacement was no longer significantly correlated with anthracycline dose after controlling for survival time (p = 0.07), while EF remained correlated (p = 0.003).Radial displacement, EF, and FS are lower in childhood cancer survivors compared to controls. In this study, radial displacement added no new information beyond the traditional measures, but clinical utility remains undetermined and requires further longitudinal study.

Lipoprotein(a) [Lp(a)] is a proatherogenic lipoprotein associated with coronary heart disease, ischemic stroke, and more recently aortic stenosis and heart failure (HF). We examined the association of Lp(a) levels with incident HF hospitalization in the Atherosclerosis Risk in Communities (ARIC) study. We also assessed the relationship between Lp(a) levels and arterial stiffness as a potential mechanism for development of HF.Lp(a) was measured in 14,154 ARIC participants without prevalent HF at ARIC visit 1 (1987-1989). The association of Lp(a) quintiles with incident HF hospitalization was assessed using Cox proportional-hazards models. Arterial stiffness parameters were stratified based on Lp(a) quintiles, and p-trend was calculated across ordered groups.At a median follow-up of 23.4 years, there were 2605 incident HF hospitalizations. Lp(a) levels were directly associated with incident HF hospitalization in models adjusted for age, race, gender, systolic blood pressure, history of hypertension, diabetes, smoking status, body mass index, heart rate, and high-density lipoprotein cholesterol (quintile 5 vs. quintile 1: hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.09-1.41; p-trend across increasing quintiles0.01), but not after excluding prevalent and incident myocardial infarction cases (HR 1.07, 95% CI 0.91-1.27; p-trend = 0.70). When adjusted for age, gender, and race, Lp(a) quintiles were not significantly associated with arterial stiffness parameters.Increased Lp(a) levels were associated with increased risk of incident HF hospitalization. After excluding prevalent and incident myocardial infarction, the association was no longer significant. Lp(a) levels were not associated with arterial stiffness parameters.

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Background: Although age-associated changes in left ventricular diastolic function are well recognized, limited data exist characterizing measures of diastolic function in older adults, including both reference ranges reflecting the older adult population and prognostically relevant values for incident heart failure (HF), as well as their associations with circulating biomarkers of HF risk. Methods: Among 5801 elderly participants in the ARIC study (Atherosclerosis Risk in Communities; age range, 67–90 years; mean age, 76±5 years; 42% male; 21% black), we determined the continuous association of diastolic measures (tissue Doppler imaging [TDI] e’, E/e’, and left atrial size) with concomitant N-terminal pro-brain natriuretic peptide and subsequent HF hospitalization or death. We also determined sex-specific 10th and 90th percentile limits for these measures using quantile regression in 401 participants free of prevalent cardiovascular disease and risk factors. Results: Each measure of diastolic function was robustly associated with N-terminal pro-brain natriuretic peptide and incident HF or death. ARIC-based reference limits for TDI e’ (4.6 and 5.2 cm/s for septal and lateral TDI e’, respectively) were substantially lower than guideline cut points (7 and 10 cm/s, respectively), whereas E/e’ and left atrial size demonstrated good agreement with guideline cut points. TDI e’ was nonlinearly associated with incident HF or death, with inflection points for risk supportive of ARIC-based limits. ARIC-based limits for diastolic function improved risk discrimination over guideline-based cut points based on the integrated discrimination improvement ( P P Conclusions: Our findings suggest that left ventricular longitudinal relaxation velocity declines as a part of healthy aging and is largely prognostically benign. The use of age-based normative values when considering an elderly population improves the risk discrimination of diastolic measures for incident HF or death.

Background: Although heart failure (HF) disproportionately affects older adults, little data exist regarding the prevalence of American College of Cardiology/American Heart Association HF stages among older individuals in the community. Additionally, the role of contemporary measures of longitudinal strain and diastolic dysfunction in defining HF stages is unclear. Methods: HF stages were classified in 6118 participants in the Atherosclerosis Risk in Communities study (67–91 years of age) at the fifth study visit as follows: A (asymptomatic with HF risk factors but no cardiac structural or functional abnormalities), B (asymptomatic with structural abnormalities, defined as left ventricular hypertrophy, dilation or dysfunction, or significant valvular disease), C1 (clinical HF without prior hospitalization), and C2 (clinical HF with earlier hospitalization). Results: Using the traditional definitions of HF stages, only 5% of examined participants were free of HF risk factors or structural heart disease (Stage 0), 52% were categorized as Stage A, 30% Stage B, 7% Stage C1, and 6% Stage C2. Worse HF stage was associated with a greater risk of incident HF hospitalization or death at a median follow-up of 608 days. Left ventricular (LV) ejection fraction was preserved in 77% and 65% in Stages C1 and C2, respectively. Incorporation of longitudinal strain and diastolic dysfunction into the Stage B definition reclassified 14% of the sample from Stage A to B and improved the net reclassification index ( P =0.028) and integrated discrimination index ( P =0.016). Abnormal LV structure, systolic function (based on LV ejection fraction and longitudinal strain), and diastolic function (based on e’, E/e’, and left atrial volume index) were each independently and additively associated with risk of incident HF hospitalization or death in Stage A and B participants. Conclusions: The majority of older adults in the community are at risk for HF (Stages A or B), appreciably more compared with previous reports in younger community-based samples. LV ejection fraction is robustly preserved in at least two-thirds of older adults with prevalent HF (Stage C), highlighting the burden of HF with preserved LV ejection fraction in the elderly. LV diastolic function and longitudinal strain provide incremental prognostic value beyond conventional measures of LV structure and LV ejection fraction in identifying persons at risk for HF hospitalization or death.

Background— This study assessed the echocardiographic predictors of sudden cardiac death (SCD) within 2 population-based cohorts. Methods and Results— Echocardiograms were obtained on 2383 participants (1993–1995) from the ARIC study (Atherosclerosis Risk in Communities; 100% black) and 5366 participants (1987–1989 and 1994–1995) from the CHS (Cardiovascular Health Study). The main outcome was physician-adjudicated SCD. We used Cox proportional-hazards models with incident coronary heart disease and heart failure as time-dependent covariates to assess the association between echocardiographic variables and SCD, adjusting for Framingham risk score variables, coronary heart disease, and renal function. Cohort-specific results were meta-analyzed. During a median follow-up of 7.3 and 13.1 years, 44 ARIC study participants and 275 CHS participants had SCD, respectively. In the meta-analyzed results, the adjusted hazard ratios (95% confidence intervals) for predictors of SCD were 3.07 (2.29–4.11) for reduced left ventricular ejection fraction; 1.85 (1.36–2.52) for mitral annular calcification; 1.64 (1.07–2.51) for mitral E/A >1.5, and 1.52 (1.14–2.02) for mitral E/A Conclusions— In addition to reduced left ventricular ejection fraction, we identified other echocardiographic-derived variables predictive for SCD that provided incremental value compared with clinical risk factors.

Background— Several cardiovascular risk factors have been associated with the risk of atrial fibrillation (AF). Limited and inconsistent evidence exists on the association of blood lipid levels and lipid-lowering medication use with AF risk. Methods and Results— We analyzed 13 969 participants (25% African American, 45% men) free of AF at baseline from the Atherosclerosis Risk in Communities study. Fasting high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), triglycerides, and total cholesterol were measured at baseline (1987–1989) and each of 3 follow-up visits. The incidence of AF was ascertained through 2007. The association of the use of statins and other lipid-lowering medications with AF was estimated in 13 044 Atherosclerosis Risk in Communities participants attending visit 2 (1990–1992), adjusting for covariates from the previous visit. During a median follow-up of 18.7 years, there were 1433 incident AF cases. Multivariable hazard ratios (HRs) and 95% CIs of AF associated with a 1-SD increase in lipid levels were as follows: HDLc, 0.97 (0.91–1.04); LDLc, 0.90 (0.85–0.96); total cholesterol, 0.89 (0.84–0.95); and triglycerides, 1.00 (0.96–1.04). Participants taking lipid-lowering medications had an adjusted HR (95% CI) of AF of 0.96 (0.82–1.13) compared with those not taking medications, whereas those taking statins had an adjusted HR of 0.91 (0.66–1.25) compared with those taking other lipid-lowering medications. Conclusions— Higher levels of LDLc and total cholesterol were associated with a lower incidence of AF. However, HDLc and triglycerides were not independently associated with AF incidence. No association was found between the use of lipid-lowering medications and incident AF.

Atrial fibrillation (AF) is one of the most clinically diagnosed cardiac disturbances but little is known about its risk factors. Previous epidemiological studies have reported on the association between diabetes mellitus (DM) and subsequent risk of AF with inconsistent results. The aim of this study was to conduct a meta-analysis of published studies to reliably determine the direction and magnitude of any association between DM and AF. A systematic review and meta-analysis was conducted. PUBMED and EMBASE were searched to identify prospective cohort and case-control studies that had reported on the association between DM and other measures of glucose homeostasis with incident AF by April 2010. Studies conducted in primarily high-risk populations and participants in randomized controlled trials were excluded. Seven prospective cohort studies and four case-control studies with information on 108,703 cases of AF among 1,686,097 individuals contributed to this analysis. The summary estimate indicated that individuals with DM had an approximate 40% greater risk of AF compared with unaffected individuals: RR 1.39 (95% Confidence Intervals: 1.10 – 1.75; p for heterogeneity

Opinion statement Survivors of hematopoietic stem cell transplant (HSCT) are at significant risk for cardiac disease and cardiac complications. While there may be cardiac complications during the acute period of HSCT, long-term survivors remain at risk for cardiovascular disease at a rate at least fourfold higher than the general population. Aggressive screening for cardiac risk factors such as diabetes, hypertension, and arrhythmias is warranted pretransplant. For those with risk factors, particularly a history of cardiovascular disease or atrial fibrillation, cardiology consultation is warranted in the pretransplantation period. Aggressive screening for cardiac risk factors such as diabetes, hypertension, and hyperlipidemia is warranted in HSCT survivors as well; early and aggressive treatment of left ventricular dysfunction is warranted. Collaboration between hematology/oncology and cardiology through a cardio-oncology clinic is an optimal way to help manage these patients.

Tako-tsubo syndrome appears to be an apparently reversible form of the cardiomyopathy, but little is known about the long term risk even with normalization of ventricular function. The incidence of ventricular arrhythmias after resolution of cardiomyopathy is not known. We present a unique case of tako-tsubo syndrome in a 71-year-old woman who developed symptomatic ventricular arrhythmias after complete resolution of cardiomyopathy.

Background: The new 2013 ACC/AHA cholesterol guidelines recommend statin therapy to reduce atherosclerotic cardiovascular disease. Statins inhibit cholesterol biosynthesis which may impair gonadal steroidogenesis. Higher levels of estradiol (E2) and lower levels of sex hormone binding globulin (SHBG) are associated with greater central obesity, metabolic syndrome and diabetes in both men and postmenopausal women. There is however limited information regarding the impact of statins on endogenous sex hormones in large population studies. Methods: We included 3163 men and 1977 women from the baseline examination of the MESA study who had measurement of serum sex hormones: total and bioavailable testosterone (T), E2, dehydroepiandrosterone (DHEA) and SHBG, and excluded those on hormone replacement therapy and non-statin lipid medications. Results: Of the 5140 individuals examined, statin users (n=812) were 67 + 9 years old, 57% males, 41% Whites, 29% Blacks, 11% Chinese and 19% Hispanics. After adjustment for age, gender and race, total cholesterol, HDL-c and BMI, compared to non-users of statins, statin users had significantly lower SHBG by 4.5 nmol/L (95% CI; -6.1, -2.9) and DHEAS by 0.9 nmol/L (95% CI; -1.4, -0.4). No significant gender interaction with statin was seen. No association was noted between statin use and E2, total and bioavailable T. Conclusion: Statin use is associated inversely with serum SHBG and DHEA levels. This is particularly interesting in light of the association of statin use and diabetes, raising the possibility of mediation by endogenous hormones.

OBJECTIVE Gestational diabetes mellitus (GDM) predicts incident cardiovascular disease (CVD). However, mechanisms linking GDM to CVD beyond intervening incident diabetes are not well understood. We examined the relation of GDM with echocardiographic parameters of left ventricular (LV) structure and function, which are important predictors of future CVD risk. RESEARCH DESIGN AND METHODS We studied 609 women (43% black) from the Coronary Artery Risk Development in Young Adults (CARDIA) study who delivered one or more births during follow-up and had echocardiograms in 1990–1991 (mean age 28.8 years) and 2010–2011. RESULTS During the 20-year follow-up, 965 births were reported, with GDM developing in 64 women (10.5%). In linear regression models adjusted for sociodemographic factors, BMI, physical activity, parity, smoking, use of oral contraceptives, alcohol intake, family history of coronary heart disease, systolic blood pressure, and lipid levels, women with GDM had impaired longitudinal peak strain (−15.0 vs. −15.7%, P = 0.025), circumferential peak strain (−14.8 vs. −15.6%, P = 0.028), lateral e′ wave velocity (11.0 vs. 11.8 cm/s, P = 0.012), and septal e′ wave velocity (8.6 vs. 9.3 cm/s, P = 0.015) in 2010–2011 and a greater 20-year increase in LV mass indexed to body surface area (14.3 vs. 6.0 g/m2, P = 0.006) compared with women with non-GDM pregnancies. Further adjustment for incident type 2 diabetes after pregnancy did not attenuate these associations. CONCLUSIONS Pregnancy complicated by GDM is independently associated with increased LV mass and impaired LV relaxation and systolic function. Implementation of postpartum cardiovascular health interventions in women with a history of GDM may offer an additional opportunity to reduce future CVD risk.

Background Natriuretic peptides promote natriuresis, diuresis, and vasodilation. Experimental deficiency of natriuretic peptides leads to hypertension ( HTN ) and cardiac hypertrophy, conditions more common among African Americans. Hospital‐based studies suggest that African Americans may have reduced circulating natriuretic peptides, as compared to Caucasians, but definitive data from community‐based cohorts are lacking. Methods and Results We examined plasma N‐terminal pro B‐type natriuretic peptide ( NT pro BNP ) levels according to race in 9137 Atherosclerosis Risk in Communities ( ARIC ) Study participants (22% African American) without prevalent cardiovascular disease at visit 4 (1996–1998). Multivariable linear and logistic regression analyses were performed adjusting for clinical covariates. Among African Americans, percent European ancestry was determined from genetic ancestry informative markers and then examined in relation to NT pro BNP levels in multivariable linear regression analysis. NT pro BNP levels were significantly lower in African Americans (median, 43 pg/ mL ; interquartile range [ IQR ], 18, 88) than Caucasians (median, 68 pg/ mL ; IQR , 36, 124; P NT pro BNP levels were 40% lower (95% confidence interval [ CI ], −43, −36) in African Americans, compared to Caucasians, which was consistent across subgroups of age, gender, HTN , diabetes, insulin resistance, and obesity. African‐American race was also significantly associated with having nondetectable NT pro BNP (adjusted OR , 5.74; 95% CI , 4.22, 7.80). In multivariable analyses in African Americans, a 10% increase in genetic European ancestry was associated with a 7% (95% CI , 1, 13) increase in adjusted log NT proBNP. Conclusions African Americans have lower levels of plasma NT pro BNP than Caucasians, which may be partially owing to genetic variation. Low natriuretic peptide levels in African Americans may contribute to the greater risk for HTN and its sequalae in this population.

This study sought to investigate the relationship between myocardial perfusion and N-terminal pro-brain natriuretic peptide (NT-proBNP) in asymptomatic individuals without overt coronary artery disease. NT-proBNP is a cardiac neurohormone secreted from the ventricles in response to ventricular volume expansion and pressure overload, and may also be elevated in the setting of reduced myocardial perfusion. We hypothesized that reduced myocardial perfusion reserve (MPR) would be associated with elevated NT-proBNP in individuals free of overt cardiovascular disease. MPR was measured by cardiac magnetic resonance, before and after adenosine infusion, in 184 MESA participants (mean age 60 ± 10.4, 58% white, 42% Hispanic, 44% female) without overt cardiovascular disease. MPR was modeled as hyperemic myocardial blood flow (MBF) adjusted for resting MBF. A linear regression analysis, adjusted for demographics, established cardiovascular risk factors, left ventricular mass, coronary calcium score, body mass index and medications, was used to determine the association between MPR and NT-proBNP. Individuals with low hyperemic MBF were more likely to be older, male, diabetic, have higher blood pressure and higher coronary artery calcium score. Mean hyperemic MBF was 3.04 ± 0.829 ml/min/g. MPR was inversely associated with NT-proBNP levels. In a fully adjusted model, every one standard deviation decrement in MPR was associated with a 21 % increment in NT-proBNP (p=0.04). In conclusion, MPR is inversely associated with NT-proBNP level in this cross sectional study of asymptomatic individuals free of overt coronary artery disease, suggesting that higher NT-proBNP levels may reflect subclinical myocardial microvascular dysfunction.

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 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.

e14016 Background: The use of doxorubicin (D) is limited by cardiotoxicity. Cumulative dose is an important risk factor for D-induced heart failure (D-HF). Retrospective studies found a ~7.5% incidence of clinical HF at a cumulative dose of 550 mg/m2, and prospective trials have found even higher rates. The administration of D by continuous intravenous infusion (CIVI) has less cardiotoxicity than when given by bolus administration. Pegylated-liposomal doxorubicin (PLD) has a longer half-life in blood, and may have lower cardiotoxicity. Limiting D use based on ejection fraction (EF) is commonly performed. Despite the wide use of EF to monitor D-HF, evidence for its utility to predict D-HF is limited, and monitoring adds cost. There is even less information regarding large cumulative doses of PLD and its effect on D-HF and EF. We examined the incidence of D-HF in patients who received a large cumulative dose of D as PLD, and its relation to EF and HF. Methods: A retrospective chart review of patients who received a large cumulative dose of PLD, sometimes following previous free D, was performed. Results: Definite clinical D-HF was not observed in 53 patients who received a cumulative D dose (free + PLD) of > 450 mg/m2, 46 of whom received > 500 mg/m2, 26 > 700 mg/m2, 14 > 1000 mg/m2, and 5 > 1400 mg/m2. The EF varied greatly over time in some patients in the absence of symptoms or signs of HF and was not a reliable predictor of the development of heart failure. Conclusions: The findings provide further evidence for the low risk of D-HF with PLD. Although this study is subject to the usual limits of a retrospective study, the doses received and long-term follow-up are noteworthy. While the determination of EF is commonly used to monitor D cardiotoxicity, it has many limitations. Serial monitoring of EF during treatment may not be helpful, at least in the case of PLD and CIVI-D in adults. Indeed, given the lack of prognostic clarity regarding modest EF changes, regular measurement of EF may sometimes inappropriately limit patient access to this useful drug. These findings may not apply to children or other liposomal formulations, such as non-pegylated formulations.

Introduction: Most cases of sudden cardiac death (SCD) in the general population occur primarily among persons who do not have any prior history of clinical heart disease. Hypothesis: After evaluating a comprehensive panel of traditional and novel cardiovascular risk factors in two, large, racially diverse, population-based cohorts, we sought to develop a predictive model of SCD among US adults without a history of cardiovascular disease. Methods: We evaluated a series of 26 demographic, clinical, laboratory and electrocardiographic measures in participants who were free of baseline cardiovascular disease in the Atherosclerosis Risk in Communities (ARIC) Study (n=13,677) and the Cardiovascular Health Study (CHS) (n=3,650). Results: After a median follow-up of approximately 13 years, there were a combined total of 318 adjudicated SCD events for analysis. The following 11 risk factors were significant risk factors for SCD after meta-analyzing the findings from each cohort: age (per 5 years; HR 1.32, 95% CI [1.17 - 1.49]), male sex (HR 2.23; 1.70 - 2.93]), African American race (HR 1.62, 1.19 - 2.20), current smoking (HR 2.19, 1.65 - 2.92), low physical activity (HR 1.42, 1.09 - 1.85), hypertension (HR 1.82, 1.37 - 2.42), diabetes (HR 2.49, 1.86 - 3.34), low serum albumin (per 0.3 g/dL decrease; HR 1.38, 1.20 - 1.59), low HDL ( Conclusions: A prediction model including demographic, clinical, laboratory, and electrocardiographic variables provided accurate information on the future SCD risk in middle-aged and elderly populations.

To examine the association of body mass index (BMI), waist circumference (WC) and waist hip ratio (WHR) with sudden cardiac death (SCD) in community dwelling individuals.Data from a multicentre, prospective, cohort study of 14 941 men and women (African American, and white), aged 45-64 years, participating in the Atherosclerosis Risk in Communities study was analysed. Obesity measures were assessed at baseline (1987-1989). SCD was adjudicated by a committee.At enrolment mean±SD age of the participants was 54±6 years (55% female; 26% African American). During 12.6±2.5 years of follow-up, 253 SCD occurred (incidence rate 1.34/100 person-years). The association between obesity and SCD differed by smoking status (interaction p≤0.01). In models adjusting for age, sex, race, study centre and education level, SCD risk was positively associated (p0.001) with BMI, WC and WHR in non-smokers, but not in smokers. WHR was more strongly associated with SCD in non-smokers than was BMI or WC (HR per SD increment (95% CI) 2.00 (1.65 to 2.42); 1.34 (1.15 to 1.56) and 1.49 (1.28 to 1.74), respectively). After adjustment for potential mediators (hypertension, diabetes, lipid profile, prevalent coronary heart disease, heart failure, and LV hypertrophy), non-smokers in the highest WHR category (0.95 in women;1.01 in men) had double the risk of SCD (HR 2.03, 95% CI 1.19 to 3.46; incidence rate 1.43/1000 person-years) versus those with normal WHR.General obesity is associated with increased risk of SCD in middle-aged, non-smoking individuals, mediated by traditional cardiovascular risk factors. Central obesity, however, is independently associated with SCD by pathways that remain to be elucidated.

Background Several studies have examined the link between atrial fibrillation (AF) and various echocardiographic measures of cardiac structure and function in whites and other racial groups but not in blacks. Exploring AF risk factors in blacks is important given that the lower incidence of AF in this racial group despite higher risk factors, is not completely explained. Methods We examined the association of echocardiographic measures with AF incidence in 2283 blacks (64.5% women, mean age 58.8 years) free of diagnosed AF and enrolled in the Jackson cohort of Atherosclerosis Risk in Communities (ARIC) study, a prospective study of cardiovascular disease. Echocardiography was performed in 1993–1995, and incident AF was determined by electrocardiograms at a follow-up study exam, hospitalization discharge codes and death certificates through the end of 2009. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals for AF associated with the echocardiographic measures, adjusting for age, sex, and known AF risk factors. Results During an average follow-up of 13.5 years, 191 (8.4%) individuals developed AF. Left ventricular (LV) internal diameter 2-D (diastole) and percent fractional shortening of LV diameter displayed a U-shaped relationship with risk of AF, while left atrial diameter displayed a J-shaped nonlinear association. LV mass index was associated positively with AF. E/A ratio 1.5 and ejection fraction (EF

Objectives We investigate how early adult and 20-year changes in modifiable cardiovascular risk factors (MRF) predict left atrial dimension (LAD) at age 43–55 years. Methods The Coronary Artery Risk Development in Young Adults (CARDIA) study enrolled black and white adults (1985–1986). We included 2903 participants with echocardiography and MRF assessment in follow-up years 5 and 25. At years 5 and 25, LAD was assessed by M-mode echocardiography, then indexed to body surface area (BSA) or height. Blood pressure (BP), body mass index (BMI), heart rate (HR), smoking, alcohol use, diabetes and physical activity were defined as MRF. Associations of MRF with LAD were assessed using multivariable regression adjusted for age, ethnicity, gender and year-5 left atrial (LA) size. Results The participants were 30±4 years; 55% white; 44% men. LAD and LAD/height were modest but significantly higher over the follow-up period, but LAD/BSA decreased slightly. Increased baseline and 20-year changes in BP were related to enlargement of LAD and indices. Higher baseline and changes in BMI were also related to higher LAD and LAD/height, but the opposite direction was found for LAD/BSA. Increase in baseline HR was related to lower LAD but not LAD indices, when only baseline covariates were included in the model. However, baseline and 20-year changes in HR were significantly associated to LA size. Conclusions In a biracial cohort of young adults, the most robust predictors for LA enlargement over a 20-year follow-up period were higher BP and BMI. However, an inverse direction was found for the relationship between BMI and LAD/BSA. HR showed an inverse relation to LA size.

Background It is unknown whether atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. This association was examined in 2 population-based cohorts. Methods In the Atherosclerosis Risk in Communities (ARIC) Study, we analyzed data from 15 439 participants (baseline age, 45-64 years; 55.2% women; and 26.6% black) from baseline (1987-1989) through December 31, 2001. In the Cardiovascular Health Study (CHS), we analyzed data from 5479 participants (baseline age, ≥65 years; 58.2% women; and 15.4% black) from baseline (first cohort, 1989-1990; second cohort, 1992-1993) through December 31, 2006. The main outcome was physician-adjudicated SCD, defined as death from a sudden, pulseless condition presumed to be due to a ventricular tachyarrhythmia. The secondary outcome was non-SCD (NSCD), defined as coronary heart disease death not meeting SCD criteria. We used Cox proportional hazards models to assess the association between AF and SCD/NSCD, adjusting for baseline demographic and cardiovascular risk factors. Results In the ARIC Study, 894 AF, 269 SCD, and 233 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 2.89 per 1000 person-years (with AF) and 1.30 per 1000 person-years (without AF). The multivariable hazard ratios (HRs) (95% CIs) of AF for SCD and NSCD were 3.26 (2.17-4.91) and 2.43 (1.60-3.71), respectively. In the CHS, 1458 AF, 292 SCD, and 581 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 12.00 per 1000 person-years (with AF) and 3.82 per 1000 person-years (without AF). The multivariable HRs (95% CIs) of AF for SCD and NSCD were 2.14 (1.60-2.87) and 3.10 (2.58-3.72), respectively. The meta-analyzed HRs (95% CIs) of AF for SCD and NSCD were 2.47 (1.95-3.13) and 2.98 (2.52-3.53), respectively. Conclusions Incident AF is associated with an increased risk of SCD and NSCD in the general population. Additional research to identify predictors of SCD in patients with AF is warranted.

Background The incidence of and mortality from coronary heart disease (CHD) is significantly higher among African Americans (AAs) compared to Whites, even after adjusting for traditional CHD risk factors. Studies suggests that the unexplained excess risk might be the result of genetic modifiers associated with African ancestry conferring a higher risk of CHD. One such gene variant is the sickle cell mutation. The heterozygous state, or sickle cell trait (SCT), with a prevalence of 8 - 12% among AAs, was previously deemed clinically benign; however, recent evidence indicates that SCT is associated with increased risk of chronic kidney disease venous thromboembolism and sudden death following exertion. Individuals with SCT have higher circulating levels of C-reactive protein, fibrinogen, prothrombin fragment 1.2 and D-dimer. We hypothesized that AAs with SCT have a higher risk for myocardial infarction (MI) and coronary heart disease (CHD) than AAs who are homozygous for wild-type hemoglobin. Methods We obtained genotype and phenotype data from the Women's Health Initiative (WHI) REasonsfor Geographic and Racial Differences in Stroke (REGARDS), Multi-Ethnic Study of Atherosclerosis (MESA), Jackson Heart Study (JHS) and Atherosclerosis Risk In Communities (ARIC) cohorts. The outcomes were incident MI or CHD. Incident MI was defined as adjudicated non-fatal or fatal MI, while incident CHD was defined as 1) adjudicated non-fatal MI, 2) fatal MI, 3) documented coronary revascularization procedures or 4) non-MI CHD death. SCT status was determined by either direct genotyping or imputation for rs334 using the 1000Genome reference panel. Homozygous individuals and those with a prior history of CHD were excluded. Individuals with incident “micro MI”, only defined in REGARDS, were also excluded from the analysis. Analysis was performed separately in each cohort using a Cox proportional hazard models to estimate the hazard ratio (HR) for incident MI or CHD comparing SCT carriers to non-carriers. Models in each cohort were adjusted for age, sex, study site or region of residence, hypertension or systolic blood pressure, diabetes, serum LDL or HDL or total cholesterol, and population stratification (using principal components of global ancestry). The results from each cohorts were then meta-analyzed using a random effect model due to significant heterogeneity between studies (I2 = 39.1%, p = 0.02 for MI meta-analysis and I2 = 56%, p = 0.01 for CHD meta-analysis). Results A total of 20,053 African American men and women were included in the combined sample; 1503 with SCT (7.5% prevalence). Average ages in years at baseline were: 65.0±6.0 in WHI (N = 2248), 62.0 ± 9.2 in REGARDS (N = 10573); 62.2±10.2 in MESA (N = 1556); 50.0 ± 11.9 in JHS (N = 2133); and 54.0 ± 6.0 in ARIC (N = 3543). There were no statistically significant differences in the distribution of traditional cardiovascular risk factors by SCT status within cohorts, except that atrial fibrillation was more prevalent among REGARDS participants with SCT compared to those without SCT (9.9% vs. 7.8%, p = 0.03). The crude incidence rate of MI per 1000 person years in those with SCT compared to those without SCT was: 4.0 vs. 5.2 in WHI; 5.7 vs. 5.0 in REGARDS; 5.8 vs 4.3 in MESA, 2.0 vs 2.1 in JHS; and 4.1 vs 5.9 in ARIC. For CHD, the crude incidence rate was: 5.8 vs. 7.2 in WHI, 8.9 vs. 7.4 in REGARDS; 15.4 vs. 6.4 in MESA; 3.4 vs. 3.4 in JHS; and 10.5 vs. 9.5 in ARIC. The HR (95% CI) for MI was: 0.96 (0.49 - 1.89) in WHI; 1.27 (0.8 - 2.0) in REGARDS; 1.84 (0.74 - 4.60) in MESA; 1.24 (0.28 - 5.44) in JHS; and 0.68 (0.42 - 1.10) in ARIC. And that for CHD was: 1.05 (0.63 - 1.74) in WHI; 1.49 (1.01 - 2.18) in REGARDS; 2.82 (1.48 - 5.38) in MESA; 1.45 (0.50 - 4.19) in JHS; and 1.10 (0.80 - 1.50) in ARIC. Meta-analysis showed that, while SCT status was not significantly associated with incident MI (1.10 [0.73 - 1.64]), it was significantly associated with incident CHD (1.42 [1.02 - 1.98] Figures 1a and 1b). Conclusions This study showed a significant association between SCT and incident CHD, but not MI. Our conclusion is limited by the significant heterogeneity that existed between studies. Since SCT status was not associated with MI, but was associated with CHD, further work is needed to confirm these findings, determine which CHD component(s) explain the observed association and elucidate the possible mechanism(s) involved. Disclosures No relevant conflicts of interest to declare.

e12074Background: Monoclonal antibodies directed against the HER2 receptor are effective in HER2 positive metastatic breast cancer. HER2 (ErbB2) receptors are present on cardiac myocytes and inhibition can lead to cardiomyopathy. Guidelines recommend evaluation of EF every 3 months due to potential cardiac dysfunction, despite little data to support this recommendation. Additionally, if there is a decrease in EF during treatment defined as a drop in EF > 10% or EF < 50%, consideration of holding therapy is recommended despite the known clinical benefit of this treatment. In this study, the impact of frequent EF screening on clinical practice was evaluated. Methods: We conducted a retrospective analysis of women with metastatic breast that received HER2 directed therapy between 2011 through 2015 to evaluate local trends in EF screening. The primary objectives were to determine whether aggressive screening defined as ≥ 3 echocardiograms (echos) or MUGAs impacted treatment strategies. Results: 147 HER2 posit...

The aim of the study was to determine whether young women with polycystic ovary syndrome (PCOS) have evidence of early structural changes in echocardiographic parameters as a measurement of cardiovascular risk.We investigated the association of PCOS and echocardiographic parameters in 984 black and white women in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort followed prospectively for 20 yr. Women ages 34-46 (Year 16) completed questionnaires recalling symptoms of oligomenorrhea and hirsutism in their 20s and 30s. Serum androgens were obtained at Year 2. Women in their 20s and 30s were classified into four mutually exclusive groups: 1) PCOS; 2) isolated oligomenorrhea (IO); 3) isolated hyperandrogenism (IH); and 4) reference group. Outcome measures were defined as echocardiography data from Year 5. We used multivariable linear regression models to evaluate the association of PCOS and its components with left ventricular (LV) mass index, left atrial (LA) diameter, LV ejection fraction (LVEF), and mitral inflow early wave to late wave ratio.Among 984 participants, 42 women (4.3%) were classified as PCOS, 67 (6.8%) as IO, and 178 (18.0%) as IH. In multivariable linear regression analyses, women with PCOS had a 3.14 g/m(2.7) (95% confidence interval, 0.48-5.81) higher LV mass index compared to the reference group (approximately 10% higher). PCOS women also had a 0.11 cm/m (95% confidence interval, 0.02-0.19) larger LA diameter, after adjustment for age and race.PCOS, but not IO or IH, is associated with a higher LV mass index and larger LA diameter in young women, suggestive of early adverse cardiac remodeling. Additional longitudinal studies are needed to evaluate whether this difference persists over time.

We read with great interest the recent article by Lopez et al,1 in Circulation Arrhythmia and Electrophysiology , on roles of blood lipid levels asnd lipid-lowering therapy for the incidence of atrial fibrillation. Their conclusion that higher levels of total cholesterol and low-density lipoprotein (LDL) cholesterol are associated with a lower incidence of atrial fibrillation is consistent with the results of our previous study indicating the existence of “cholesterol paradox” in atrial fibrillation.2,3 …

Carditis can complicate Lyme disease in an estimated

Background— Atrial fibrillation (AF) is an important risk factor for stroke and overall mortality, but information about the preventable burden of AF is lacking. The aim of this study was to determine what proportion of the burden of AF in blacks and whites could theoretically be avoided by the maintenance of an optimal risk profile. Methods and Results— This study included 14 598 middle-aged Atherosclerosis Risk in Communities (ARIC) Study cohort members. Previously established AF risk factors, namely high blood pressure, elevated body mass index, diabetes mellitus, cigarette smoking, and prior cardiac disease, were categorized into optimal, borderline, and elevated levels. On the basis of their risk factor levels, individuals were classified into 1 of these 3 groups. The population-attributable fraction of AF resulting from having a nonoptimal risk profile was estimated separately for black and white men and women. During a mean follow-up of 17.1 years, 1520 cases of incident AF were identified. The age-adjusted incidence rates were highest in white men and lowest in black women (7.45 and 3.67 per 1000 person-years, respectively). The overall prevalence of an optimal risk profile was 5.4% but varied according to race and gender: 10% in white women versus 1.6% in black men. Overall, 56.5% of AF cases could be explained by having ≥1 borderline or elevated risk factors, of which elevated blood pressure was the most important contributor. Conclusion— As with other forms of cardiovascular disease, more than half of the AF burden is potentially avoidable through the optimization of cardiovascular risk factors levels.

Background Many people may underappreciate the role of lifestyle in avoiding heart failure. We estimated whether greater adherence in middle age to American Heart Association's Life's Simple 7 guidelines—on smoking, body mass, physical activity, diet, cholesterol, blood pressure, and glucose—is associated with lower lifetime risk of heart failure and greater preservation of cardiac structure and function in old age. Methods We studied the population-based Atherosclerosis Risk in Communities Study cohort of 13,462 adults ages 45-64 years in 1987-1989. From the 1987-1989 risk factor measurements, we created a Life's Simple 7 score (range 0-14, giving 2 points for ideal, 1 point for intermediate, and 0 points for poor components). We identified 2218 incident heart failure events using surveillance of hospital discharge and death codes through 2011. In addition, in 4855 participants free of clinical cardiovascular disease in 2011-2013, we performed echocardiography from which we quantified left ventricular hypertrophy and diastolic dysfunction. Results One in four participants (25.5%) developed heart failure through age 85 years. Yet, this lifetime heart failure risk was 14.4% for those with a middle-age Life's Simple 7 score of 10-14 (optimal), 26.8% for a score of 5-9 (average), and 48.6% for a score of 0-4 (inadequate). Among those with no clinical cardiovascular event, the prevalence of left ventricular hypertrophy in late life was approximately 40% as common, and diastolic dysfunction was approximately 60% as common, among those with an optimal middle-age Life's Simple 7 score, compared with an inadequate score. Conclusions Greater achievement of American Heart Association's Life's Simple 7 in middle age is associated with a lower lifetime occurrence of heart failure and greater preservation of cardiac structure and function.

Amiodarone is an antiarrhythmic frequently used in the treatment of atrial fibrillation (AF). Isolated reports have suggested that use of amiodarone may cause acute pancreatitis.1–3 This potential adverse effect of amiodarone has not been explored in large studies. We assessed whether use of amiodarone or other antiarrhythmics indicated for AF management is associated with developing acute pancreatitis in a large US population.

Hematopoietic cell transplantation (HCT) is a potential cure for certain hematologic malignancies. However, because of risks of complications and mortality, this treatment option is limited to patients with minimal comorbidities. We performed a retrospective cohort study evaluating the impact of pre-HCT systolic dysfunction on outcomes. We identified 49 subjects with systolic dysfunction, defined as left ventricular ejection fraction (LVEF) < 50% and 49 controls (matched by age, gender, conditioning regimen, and HCT donor number; all with LVEF ≥ 50%) undergoing HCT at the University of Minnesota between 2002 and 2012. Treatment complications, use of beta-blockers and angiotensin-converting enzyme inhibitors, and overall survival (OS) after HCT out to 24 months were analyzed. The median LVEF was 45% (range, 27.5% to 49%) for the study group and 60% (range, 50% to 69%) for controls. The majority of patients in both groups (81.6%) received reduced-intensity conditioning (RIC). Treatment-related mortality (TRM) at day 100 was identical, with a cumulative incidence of 14% in the study (95% confidence interval [CI], 5% to 24%) versus 14% in controls (95% CI, 5% to 24%) (P = .89). Two-year OS was similar in the study group (53%; 95% CI, 38% to 66%) versus controls (61%; 95% CI, 46% to 73%) (P = .34). LVEF ≥ 43% was associated with improved OS at 1 year (hazard ratio [HR], .36; 95% CI, .15 to .87; P = .02). There was no significant difference in the incidence of non–life-threatening cardiac complications (12.2% in cases versus 8.2% in controls, P = .50) or serious (life-threatening or fatal) cardiac complications (4.1% in cases versus 2.0% in controls, P = .56). Pre-existing coronary artery disease was associated with increased TRM at 100 days (HR, 4.35; 95% CI, 1.24 to 15.32; P = .02). Cardiac medication use had no effect on TRM. Our study demonstrates that patients with asymptomatic borderline systolic dysfunction can safely undergo HCT with RIC. Coronary artery disease remains a risk factor for increased TRM. Patients with borderline systolic dysfunction can safely undergo HCT, but may need particular vigilance for potential hemodynamic or ischemic cardiac complications.