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1.  ATVB Council Statement: Non-statin LDL-lowering Therapy and Cardiovascular Risk Reduction 
Pharmacologic reduction of low-density lipoprotein (LDL) cholesterol using statin drugs is foundational therapy to reduce cardiovascular disease (CVD) risk. Here we consider the place of non-statin therapies that also reduce LDL cholesterol in prevention of CVD. Among conventional non-statins, placebo-controlled randomized clinical trials showed that bile acid sequestrants, niacin and fibrates given as monotherapy each reduce CVD end points. From trials in which patients’ LDL cholesterol was already well-controlled on a statin, adding ezetimibe incrementally reduced CVD end points, while adding a fibrate or niacin showed no incremental benefit. Among emerging non-statins, monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9) added to a statin and given for up to 78 weeks showed preliminary evidence of reductions in CVD outcomes. While these promising early findings contributed to the recent approval of these agents in Europe and the US, much larger and longer duration outcomes studies are ongoing for definitive proof of CVD benefits. Other non-statin agents recently approved in the US include lomitapide and mipomersen, which both act via distinctive LDL-receptor independent mechanisms to substantially reduce LDL cholesterol in homozygous familial hypercholesterolemia. We also address some unanswered questions, including measuring alternative biochemical variables to LDL cholesterol, evidence for treating children with monitoring of subclinical atherosclerosis, and potential risks of extremely low LDL cholesterol. As evidence for benefit in CVD prevention accumulates, we anticipate that clinical practice will shift towards more assertive LDL-lowering treatment, using both statins and non-statins initiated earlier in appropriately selected patients.
doi:10.1161/ATVBAHA.115.306442
PMCID: PMC4758700  PMID: 26376908
2.  Quality Control and Reproducibility in M-mode, Two-dimensional, and Speckle Tracking Echocardiography Acquisition and Analysis: The CARDIA Study, Year-25 Examination Experience 
Echocardiography (Mount Kisco, N.Y.)  2014;32(8):1233-1240.
Introduction
Few large studies describe quality control procedures and reproducibility findings in cardiovascular ultra-sound, particularly in novel techniques such as Speckle Tracking (STE). We evaluate the echocardiography assessment performance in the CARDIA study Y25 examination (2010-2011) and report findings from a quality control and reproducibility program conducted to assess Field Center image acquisition and Reading Center (RC) accuracy.
Methods
The CARDIA Y25 examination had 3,475 echocardiograms performed in 4 US Field Centers and analyzed in a Reading Center, assessing standard echocardiography (LA dimension, aortic root, LV mass, LV end-diastolic volume [LVEDV], ejection fraction [LVEF]), and STE (2- and 4-chamber longitudinal, circumferential, and radial strains). Reproducibility was assessed using intra-class correlation coefficients (ICC), coefficients of variation (CV), and Bland-Altman plots.
Results
For standard echocardiography reproducibility, LV mass and LVEDV consistently had CV above 10% and aortic root below 6%. Intra-sonographer aortic root and LV mass had the most robust values of ICC in standard echocardiography. For STE, the number of properly tracking segments was above 80% in short-axis and 4-chamber and 58% in 2-chamber. Longitudinal strain parameters were the most robust and radial strain showed the highest variation. Comparing Field Centers with Echo RC STE readings, mean differences ranged from 0.4% to 4.1% and ICC from 0.37 to 0.66, with robust results for longitudinal strains.
Conclusion
Echocardiography image acquisition and reading processes in the CARDIA study were highly reproducible, including robust results for STE analysis. Consistent quality control may increase the reliability of echocardiography measurements in large cohort studies.
doi:10.1111/echo.12832
PMCID: PMC4426079  PMID: 25382818
Echocardiography; reproducibility; speckle tracking echocardiography; quality control
3.  DETERMINANTS OF AORTIC ROOT DILATATION AND REFERENCE VALUES AMONG YOUNG ADULTS OVER A 20-YEAR PERIOD: THE CORONARY ARTERY RISK DEVELOPMENT IN YOUNG ADULTS (CARDIA) STUDY 
Hypertension  2015;66(1):23-29.
Aortic size increases with age, but factors related to such dilatation in healthy young adult population have not been studied. We aim to evaluate changes in aortic dimensions and its principal correlates among young adults over a 20-year time period. Reference values for aortic dimensions in young adults by echocardiography are also provided.
Healthy CARDIA study participants aged 23–35 years in 1990–91 (n=3051) were included after excluding 18 individuals with significant valvular dysfunction. Aortic root diameter by M-mode echocardiography at Year-5 (43.7% men; age 30.2±3.6y) and Year-25 CARDIA exams were obtained. Univariable and multivariable analyses were performed to assess associations of aortic root diameter with clinical data at Years-5 and -25. Aortic root diameter from Year-5 was used to establish reference values of aortic root diameter in healthy young adults.
Aortic root diameter at Year-25 was greater in men (33.3±3.7 vs 28.7±3.4mm, p<0.001) and in whites (30.9±4.3 vs 30.5±4.1, p=0.006). On multivariable analysis, aortic root diameter at Year-25 was positively correlated with male gender, white ethnicity, age, height, weight, 20-year gain in weight, active smoking at baseline and 20-year increase in diastolic, systolic and mean arterial pressure. A figure showing the estimated 95th percentile of aortic root diameter by age and body surface area stratified by race and gender is provided.
This study demonstrates that smoking, blood pressure, and increase in body weight are the main modifiable correlates of aortic root dilation during young adulthood. Our study also provides reference values for aortic root diameter in young adults.
doi:10.1161/HYPERTENSIONAHA.115.05156
PMCID: PMC4465858  PMID: 25941347
Ascending Aorta; Aortic Diseases; Aortic Aneurysm; Echocardiography; Epidemiology
4.  Prevalence of Eligibility Criteria for the Systolic Blood Pressure Intervention Trial in US Adults Among Excluded Groups: Age <50 Years, Diabetes Mellitus, or a History of Stroke 
Background
Adults <50 years old, with diabetes mellitus, or a history of stroke were not enrolled in the Systolic Blood Pressure Intervention Trial (SPRINT). Estimating the size and characteristics of these excluded groups who meet the other SPRINT eligibility criteria may provide information on the potential impact of providers extending the SPRINT findings to these populations.
Methods and Results
We analyzed the National Health and Nutrition Examination Survey 2003–2012 (n=25 076) to estimate the percentage and characteristics of US adults ≥20 years in 3 populations (age <50 years, diabetes mellitus, or history of stroke) excluded from SPRINT who otherwise meet the trial eligibility criteria: age ≥50 years, systolic blood pressure (SBP) 130–180 mm Hg, high cardiovascular disease risk, and not having trial exclusion criteria. Overall, 1.0% (95% CI 0.8–1.3) of US adults age <50 years, 25.4% (95% CI 23.4–27.6) with diabetes mellitus, and 19.0% (95% CI 16.0–22.4) with history of stroke met the other SPRINT eligibility criteria. Among US adults with SBP ≥130 mm Hg, other SPRINT eligibility criteria were met by 7.5% (95% CI 6.1–9.2) of those age <50 years, 32.9% (95% CI 30.5–35.4) with diabetes mellitus, and 23.0% (95% CI 19.4–27.0) with history of stroke. Among US adults meeting the other SPRINT eligibility criteria, antihypertensive medication was being taken by 31.0% (95% CI 23.9–41.3) of those <50 years, 63.0% (95% CI 58.2–67.6) with diabetes mellitus, and 68.9% (95% CI 59.4–77.1) with a history of stroke.
Conclusions
A substantial percentage of US adults with diabetes mellitus or history of stroke and a small percentage <50 years old meet the other SPRINT eligibility criteria.
doi:10.1161/JAHA.116.003547
PMCID: PMC5015392  PMID: 27405811
diabetes mellitus; high blood pressure; hypertension; stroke; systolic blood pressure; systolic blood pressure intervention trial; treatment; High Blood Pressure; Hypertension; Epidemiology
5.  Adolescent and Adult African Americans Have Similar Metabolic Dyslipidemia 
Journal of clinical lipidology  2014;9(3):368-376.
Background
African Americans (AA) have lower triglycerides (TG) and higher high density lipoprotein-cholesterol (HDL-C) than other ethnic groups yet they also have higher risk for developing diabetes mellitus despite the strong relationship of dyslipidemia with insulin resistance. No studies directly compare adolescents and adults with regard to relationships amongst dyslipidemia, C-reactive protein (hsCRP), and insulin resistance. Here we compare AA adolescents to adults with regard to the relationships of adiposity-related lipid risk markers (TG/HDL ratio and non HDL-C) with body mass index (BMI), waist circumference (WC), homeostasis model of insulin resistance (HOMA), and hsCRP.
Methods
Two cohorts of healthy AA were recruited from the same urban community. Participants in each cohort were stratified by TG/HDL ratio (based on adult tertiles) and non-HDL-C levels. BMI, WC, HOMA and hsCRP were compared in adolescents and adults in the low, middle and high lipid strata.
Results
Prevalence of TG/HDL ratio greater than 2.028 (high group) was 16% (44/283) in adolescents and 33% (161/484) in adults; prevalence of non HDL-C above 145 and 160 respectively was 8% (22/283) in adolescents and 12% (60/484) in adults. HsCRP values were lower and HOMA values were higher in adolescents (both p < 0.01). As both TG/HDL ratio and non HDL-C strata increased, BMI, WC, HOMA, and hsCRP increased in both adolescents and adults. In the high TG/HDL and non HDL-C groups, BMI and WC were similar in adolescents vs. adults (BMI 34 kg/m2 vs 32 kg/m2; WC 101 cm vs 101 cm). After adjusting for non-HDL-C and other covariates, a 2-fold increase in TG/HDL was associated with increases of 10.4% in hsCRP (95% CI: 1.1% – 20.5%) and 24.2% in HOMA (95% CI: 16.4% – 32.6%). Non-HDL-C was not significant in models having TG/HDL.
Conclusions
Elevated TG/HDL ratio is associated with similar inflammation and metabolic risk relationships in adolescent and adult African-Americans.
doi:10.1016/j.jacl.2014.11.010
PMCID: PMC4468785  PMID: 26073396
triglycerides; HDL cholesterol; obesity; inflammation; insulin resistance; risk factors
6.  Association of the Degree of Adiposity and Duration of Obesity with Measures of Cardiac Structure and Function: The CARDIA Study 
Obesity (Silver Spring, Md.)  2014;22(11):2434-2440.
OBJECTIVE
Examine whether there are independent influences of a greater degree of adiposity and longer duration of obesity on cardiac structure and function.
METHODS
Participants of CARDIA were 18-30 years when they underwent a baseline examination in 1985-86. Seven follow-up examinations were conducted every 2-5 years.
RESULTS
Among 2,547 participants who underwent an echocardiogram at the year 25 examination and were not obese at baseline, 34.4% and 35.5% were overall (BMI ≥30 kg/m2) and abdominally obese (waist circumference: men: >102 cm; women: >88 cm) at year 25, respectively. A greater degree of overall and abdominal adiposity at year 25 were each associated with a greater left ventricular (LV) mass (p<0.001), LV volume (p<0.001), LV mass-to-volume ratio (p<0.001), left atrial dimension (p<0.001), and ejection fraction (p<0.05) after adjustment for duration of obesity and other risk factors. In contrast, a longer duration of overall obesity was associated with a greater LV mass (p=0.003) and a trend for a lower ejection fraction (p=0.07).
CONCLUSIONS
A greater degree of adiposity is strongly associated with concentric LV remodeling in midlife, while the cumulative effects of a longer duration of overall obesity during young adulthood contribute to concentric remodeling predominantly by increasing LV mass.
doi:10.1002/oby.20865
PMCID: PMC4224979  PMID: 25124342
cardiovascular risk; obesity; heart; echocardiography
7.  Fibroblast Growth Factor-23 in Obese, Normotensive Adolescents is Associated with Adverse Cardiac Structure 
The Journal of pediatrics  2014;165(4):738-743.e1.
Objectives
Fibroblast growth factor-23 (FGF23) is a biomarker for cardiovascular (CV) disease. Obesity may promote FGF23 production in the absence of chronic kidney disease (CKD). We sought to determine among normotensive African American adolescents, whether FGF23 levels are higher in obese compared with normal weight African American adolescents; and to determine the relationship of FGF23 with markers of cardiac structure and insulin resistance.
Study design
Cross-sectional data were obtained from a cohort of 130 normotensive, African American adolescents aged 13-18 years old without CKD; 74 were obese; 56 were normal weight. Plasma C-terminal FGF23, fasting glucose and insulin, and hsCRP were measured; participants underwent M-mode echocardiography.
Results
FGF23 was skewed and approximately normally distributed after natural log transformation (logFGF23). FGF23 levels were higher in obese versus normal weight participants (geometric mean 43 vs. 23 RU/mL, p<0.01). FGF23 values were significantly higher in participants with eccentric or concentric cardiac hypertrophy compared with those without hypertrophy (p<0.01). LogFGF23 directly correlated with BMI, BMI z-score, waist circumference, fasting insulin levels, and HOMA scores. Regression models adjusted for age, sex, and hsCRP suggest that each 10% increase in FGF23 is associated with 1.31 unit increase in LVM (p<0.01), 0.29 unit increase in LVMI (p<0.01), and 0.01 unit increase in left atrial dimension indexed to height (p=0.02).
Conclusions
In this sample of obese African American adolescents, FGF23 blood levels were associated with abnormal cardiac structure. We postulate that FGF23 may be an early marker of cardiac injury in obese but otherwise healthy African American adolescents.
doi:10.1016/j.jpeds.2014.06.027
PMCID: PMC4177448  PMID: 25063724
obesity; left ventricular mass; FGF23; adolescence; African American
8.  Association of Obesity in Early Adulthood and Middle Age with Incipient Left Ventricular Dysfunction and Structural Remodeling: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
JACC. Heart failure  2014;2(5):500-508.
Objectives
We investigated the relationship of body mass index (BMI) and its 25-year change to left ventricular (LV) structure and function.
Background
Longstanding obesity may be associated with clinical cardiac dysfunction and heart failure. Whether obesity relates to cardiac dysfunction during young adulthood and middle age has not been investigated.
Methods
The Coronary Artery Risk Development in Young Adults (CARDIA) enrolled white and black adults aged 18-30 years in 1985-86 (Year-0). At the Year-25, cardiac function was assessed by conventional echocardiography, tissue Doppler imaging (TDI), and speckle tracking echocardiography (STE). Twenty-five year change in BMI (classified as Low:<27 Kg/m2 and High:≥27 Kg/m2) was categorized into four groups (Low-Low, High-Low, Low-High, and High-High). Multiple linear regression was used to quantify the association between categorical changes in BMI (Low-Low as reference) with LV structural and functional parameters obtained in middle age, adjusting for baseline and 25-year change in risk factors.
Results
The mean BMI was 24.4 kg/m2 in 3,265 participants included at Year-0. Change in BMI adjusted for risk factors was directly associated with incipient myocardial systolic dysfunction assessed by STE (High-High:β-coefficient=0.67; Low-High:β-coefficient=0.35 for longitudinal peak-systolic strain) and diastolic dysfunction assessed by TDI (High-High:β-coefficient=-074; Low-High:β-coefficient=-0.45 for e′) and STE (High-High:β-coefficient= -0.06 for circumferential early-diastolic strain rate). Greater BMI was also significantly associated with increased LV mass/height (High-High:β-coefficient=26.11; Low-High:β-coefficient=11.87).
Conclusions
Longstanding obesity from young adulthood to middle age is associated with impaired LV systolic and diastolic function assessed by conventional echocardiography, TDI, and STE in a large bi-racial cohort of adults aged 43-55 years.
doi:10.1016/j.jchf.2014.03.001
PMCID: PMC4194150  PMID: 25194290
echocardiography; speckle tracking echocardiography; tissue Doppler imaging; obesity; risk factors; left ventricular function; left ventricular remodeling
9.  Early Progressive Dilated Cardiomyopathy in a Family with Becker Muscular Dystrophy Related to a Novel Frameshift Mutation in the Dystrophin Gene Exon 27 
Journal of human genetics  2014;60(3):151-155.
We report a family in which two male siblings with Becker muscular dystrophy (BMD) developed severe dilated cardiomyopathy (DCM) and progressive heart failure (HF) at age 11; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device (LVAD) implantation at the same age. Genetic analysis of one sibling showed a novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAins GG), in which 7 base pairs are deleted and two are inserted. While this predicts an amino acid substitution and premature termination (p.Thr1260Argfs*8), muscle biopsy dystrophin immunostaining instead indicates that the mutation is more likely to alter splicing. Despite relatively preserved skeletal muscular performance, both siblings developed progressive heart failure secondary to early onset DCM. In addition, their 7 year old nephew with delayed gross motor development, mild proximal muscle weakness, and markedly elevated serum creatine kinase (CK) level (> 13,000 IU/L) at 16 months was recently demonstrated to have the familial DMD mutation. Here we report a novel genotype of BMD with early onset DCM and progressive lethal heart failure during early adolescence.
doi:10.1038/jhg.2014.112
PMCID: PMC4374993  PMID: 25537791
Becker muscular dystrophy (BMD); Dilated cardiomyopathy (DCM); Dystrophin; Frameshift mutation; Alternative splicing
10.  Left atrial dimension and traditional cardiovascular risk factors predict 20-year clinical cardiovascular events in young healthy adults: the CARDIA study 
Aims
We investigated whether the addition of left atrial (LA) size determined by echocardiography improves cardiovascular risk prediction in young adults over and above the clinically established Framingham 10-year global CV risk score (FRS).
Methods and results
We included white and black CARDIA participants who had echocardiograms in Year-5 examination (1990–91). The combined endpoint after 20 years was incident fatal or non-fatal cardiovascular disease: myocardial infarction, heart failure, cerebrovascular disease, peripheral artery disease, and atrial fibrillation/flutter. Echocardiography-derived M-mode LA diameter (LAD; n = 4082; 149 events) and 2D four-chamber LA area (LAA; n = 2412; 77 events) were then indexed by height or body surface area (BSA). We used Cox regression, areas under the receiver operating characteristic curves (AUC), and net reclassification improvement (NRI) to assess the prediction power of LA size when added to calculated FRS or FRS covariates. The LAD and LAA cohorts had similar characteristics; mean LAD/height was 2.1 ± 0.3 mm/m and LAA/height 9.3 ± 2.0 mm2/m. After indexing by height and adjusting for FRS covariates, hazard ratios were 1.31 (95% CI 1.12, 1.60) and 1.43 (95% CI 1.13, 1.80) for LAD and LAA, respectively; AUC was 0.77 for LAD and 0.78 for LAA. When LAD and LAA were indexed to BSA, the results were similar but slightly inferior. Both LAD and LAA showed modest reclassification ability, with non-significant NRIs.
Conclusion
LA size measurements independently predict clinical outcomes. However, it only improves discrimination over clinical parameters modestly without altering risk classification. Indexing LA size by height is at least as robust as by BSA. Further research is needed to assess subgroups of young adults who may benefit from LA size information in risk stratification.
doi:10.1093/ehjci/jeu018
PMCID: PMC4215562  PMID: 24534011
Left atrial size; Cardiovascular events; Echocardiography; Young adults
11.  Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment 
European Heart Journal  2015;36(36):2425-2437.
Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FH children. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol (LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testing. Childhood is the optimal period for discrimination between FH and non-FH using LDL-C screening. An LDL-C ≥5 mmol/L (190 mg/dL), or an LDL-C ≥4 mmol/L (160 mg/dL) with family history of premature CHD and/or high baseline cholesterol in one parent, make the phenotypic diagnosis. If a parent has a genetic defect, the LDL-C cut-off for the child is ≥3.5 mmol/L (130 mg/dL). We recommend cascade screening of families using a combined phenotypic and genotypic strategy. In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. A healthy lifestyle and statin treatment (from age 8 to 10 years) are the cornerstones of management of heterozygous FH. Target LDL-C is <3.5 mmol/L (130 mg/dL) if >10 years, or ideally 50% reduction from baseline if 8–10 years, especially with very high LDL-C, elevated lipoprotein(a), a family history of premature CHD or other cardiovascular risk factors, balanced against the long-term risk of treatment side effects. Identifying FH early and optimally lowering LDL-C over the lifespan reduces cumulative LDL-C burden and offers health and socioeconomic benefits. To drive policy change for timely detection and management, we call for further studies in the young. Increased awareness, early identification, and optimal treatment from childhood are critical to adding decades of healthy life for children and adolescents with FH.
doi:10.1093/eurheartj/ehv157
PMCID: PMC4576143  PMID: 26009596
Familial hypercholesterolaemia; Children; Adolescents; LDL cholesterol; Diagnosis; Treatment; Statin; Ezetimibe; PCSK9 inhibitor; Consensus statement
12.  Obesity Associated Inflammation in African American Adolescents and Adults 
C-Reactive Protein (CRP) is related to adiposity, metabolic risk, and predicts events in adults.
Objective
To determine if relationships between adiposity and CRP have similar magnitudes in adolescents as adults.
Methods
Healthy African Americans (484 adults and 282 adolescents) were recruited from similar environments. In both cohorts measurements included anthropometrics, blood pressure (BP), metabolic risk factors and inflammatory markers. After stratification by high sensitivity CRP (hsCRP: ≤1, 1-≤3, >3 mg/dl), adults and adolescents were compared with regard to body mass index (kg/m2; BMI), waist circumference (cm; WC), BP, and other risk factors. hsCRP was regressed on BMI and WC with covariates including cohort, age, sex, BP, insulin resistance, smoking, alcohol, and other biomarkers. Interaction terms and a subset of the covariates were subject to a supervised variable selection procedure for a final model. Skewed variables were log-transformed and summarized by geometric means (GMs) with first and third quartiles [Q1, Q3].
Results
Among adolescents (16.3%) and adults (34.1%) having high hsCRP (> 3 mg/dl), BMI was distributed similarly (GM=36.4 [32.7, 43.1] and GM=34.7 [28.8, 40.8], respectively) as was WC (GM=104.2 [93.0, 119.0] and GM=104.9 [93.0, 117.2], respectively). In an adjusted regression model, for a given BMI, elevated WC was associated with elevated hsCRP (p=0.02). While elevated BMI was significantly associated with elevated hsCRP, the relationship was stronger among adolescents (interaction p=0.04).
Conclusion
These findings demonstrate that in African Americans obesity is associated with inflammation and adverse changes in metabolic parameters among both adolescents and young adults.
doi:10.1097/MAJ.0b013e31829555f0
PMCID: PMC3781178  PMID: 23698155
Obesity; CRP; Inflammation; Adolescents; African Americans
13.  Framingham Score and LV Mass predict Events in Young Adults: CARDIA Study 
International journal of cardiology  2014;172(2):350-355.
Background
Framingham risk score (FRS) underestimates risk in young adults. LV mass (LVM) relates to cardiovascular disease (CVD), with unclear value in youth. In a young biracial cohort, we investigate how FRS predicts CVD over 20 years and the incremental value of LVM. We also explore the predictive ability of different cut-points for hypertrophy.
Methods
We assessed FRS and echocardiography-derived LVM (indexed by BSA or height2.7) from 3980 African-American and white CARDIA participants (1990-1991); and followed over 20 years for a combined endpoint: cardiovascular death; nonfatal myocardial infarction, heart failure, cerebrovascular disease, and peripheral artery disease. We assessed the predictive ability of FRS for CVD and also calibration, discrimination, and net reclassification improvement for adding LVM to FRS.
Results
Mean age was 30±4 years, 46% males, and 52% white. Event incidence (n = 118) across FRS groups was, respectively, 1.3%, 5.4%, and 23.1% (p<0.001); and was 1.4%, 1.3%, 3.7%, and 5.4% (p<0.001) across quartiles of LVM (cut-points 117g, 144g, and 176g). LVM predicted CVD independently of FRS, with the best performance in normal weight participants. Adding LVM to FRS modestly increased discrimination and had a statistically significant reclassification. The 85th percentile (≥116 g/m2 for men; ≥96 g/m2 for women) showed event prediction more robust than currently recommended cut-points for hypertrophy.
Conclusion
In a biracial cohort of young adults, FRS and LVM are helpful independent predictors of CVD. LVM can modestly improve discrimination and reclassify participants beyond FRS. Currently recommended cut-points for hypertrophy may be too high for young adults.
doi:10.1016/j.ijcard.2014.01.003
PMCID: PMC4068332  PMID: 24507735
young adults; cardiovascular risk; left ventricular hypertrophy; echocardiography
14.  Race–Ethnic and Sex Differences in Left Ventricular Structure and Function: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Background
We investigated race–ethnic and sex‐specific relationships of left ventricular (LV) structure and LV function in African American and white men and women at 43 to 55 years of age.
Methods and Results
The Coronary Artery Risk Development in Young Adults (CARDIA) Study enrolled African American and white adults, age 18 to 30 years, from 4 US field centers in 1985–1986 (Year‐0) who have been followed prospectively. We included participants with echocardiographic assessment at the Year‐25 examination (n=3320; 44% men, 46% African American). The end points of LV structure and function were assessed using conventional echocardiography and speckle‐tracking echocardiography. In the multivariable models, we used, in addition to race–ethnic and gender terms, demographic (age, physical activity, and educational level) and cardiovascular risk variables (body mass index, systolic blood pressure, diastolic blood pressure, heart rate, presence of diabetes, use of antihypertensive medications, number of cigarettes/day) at Year‐0 and ‐25 examinations as independent predictors of echocardiographic outcomes at the Year‐25 examination (LV end‐diastolic volume [LVEDV]/height, LV end‐systolic volume [LVESV]/height, LV mass [LVM]/height, and LVM/LVEDV ratio for LV structural indices; LV ejection fraction [LVEF], Ell, and Ecc for systolic indices; and early diastolic and atrial ratio, mitral annulus early peak velocity, ratio of mitral early peak velocity/mitral annulus early peak velocity; ratio, left atrial volume/height, longitudinal peak early diastolic strain rate, and circumferential peak early diastolic strain rate for diastolic indices). Compared with women, African American and white men had greater LV volume and LV mass (P<0.05). For LV systolic function, African American men had the lowest LVEF as well as longitudinal (Ell) and circumferential (Ecc) strain indices among the 4 sex/race–ethnic groups (P<0.05). For LV diastolic function, African American men and women had larger left atrial volumes; African American men had the lowest values of Ell and Ecc for diastolic strain rate (P<0.05). These race/sex differences in LV structure and LV function persisted after adjustment.
Conclusions
African American men have greater LV size and lower LV systolic and diastolic function compared to African American women and to white men and women. The reasons for these racial‐ethnic differences are partially but not completely explained by established cardiovascular risk factors.
doi:10.1161/JAHA.114.001264
PMCID: PMC4392424  PMID: 25770024
echocardiography; left ventricular function; left ventricular mass; speckle‐tracking echocardiography
15.  Relation of Left Ventricular Mass at Age 23 to 35 years to Global Left Ventricular Systolic Function 20 Years Later (From the Coronary Artery Risk Development in Young Adults Study) 
The American journal of cardiology  2013;113(2):377-383.
Left ventricular (LV) mass and LV ejection fraction (EF) are major independent predictors of future cardiovascular disease. The association of LV mass with future LVEF in younger populations has not been studied. We investigated the relation of LV mass index (LVMI) at age 23 to 35 years to LV function after 20 years of follow-up in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. CARDIA is a longitudinal study that enrolled young adults in 1985–1986. We included participants with echocardiographic examinations at both years-5 and -25. LVMI and LVEF were assessed using M-mode echocardiography at year-5 and using both M-mode and 2-dimensional images at year-25. Statistical analytic models assessed the correlation between LVMI and LV functional parameters both cross-sectionally and longitudinally. A total of 2,339 participants were included. The mean LVEF at year-25 was 62%. Although there was no cross-sectional correlation between LVMI and LVEF at year-5, there was a small, but statistically significant negative correlation between LVMI at year-5 and LVEF 20 years later (r = −0.10, p < 0.0001); this inverse association persisted for LVMI in the multivariable model. High LVMI was an independent predictor of systolic dysfunction (LVEF < 50%) 20 years later (odds ratio 1.46, p = 0.0018). In conclusion, we have shown that LVMI in young adulthood in association with chronic risk exposure impacts systolic function in middle age; the antecedents of heart failure may occur at younger ages than previously thought.
doi:10.1016/j.amjcard.2013.08.052
PMCID: PMC3901209  PMID: 24176073
left ventricular mass; left ventricular ejection fraction; echocardiography; left ventricular remodeling
16.  Longitudinal Determinants of Left Ventricular Mass and Geometry: The CARDIA Study 
Circulation. Cardiovascular imaging  2013;6(5):10.1161/CIRCIMAGING.112.000450.
Background
The purpose of this study was to identify determinants of 20 year change in left ventricular (LV) mass (LVM) and LV geometry in black and white young adults in the CARDIA Study.
Methods and Results
We studied 2426 black and white men and women (54.7% Caucasian) aged 43-55 years with cardiovascular (CV) risk factor data and echocardiograms from CARDIA year 5 and 25 examinations. In regression models, year 25 LVM or relative wall thickness was the dependent variable and with year 5 echo values, age, gender, race, body mass index (BMI), change in BMI, mean arterial blood pressure, change in mean blood pressure, heart rate (HR), change in HR, tobacco use, presence of diabetes, alcohol use, and physical activity score as independent variables. LVM and relative wall thickness increased while prevalence of normal geometry declined from 84.2% to 69.7%. Significant determinants of year 25 LVM/m2.7 were year 5 LVM, year 5 and change in BMI, year 5 and change in mean arterial pressure, year 5 and change in HR, baseline diabetes, and year 5 tobacco and/or alcohol use (overall r2 = 0.40). Significant determinants of year 25 relative LV wall thickness were year 5 value, black race, change in BMI, year 5 and change in mean arterial pressure, starting smoking, and year 5 diabetes. (overall r2 = 0.11).
Conclusions
Prevalence of abnormal LV hypertrophy and geometry increased from young adulthood to middle age. Both young adult CV risk traits and change in these traits predicted change in LV mass/geometry.
doi:10.1161/CIRCIMAGING.112.000450
PMCID: PMC3873157  PMID: 23922005
echocardiography; left ventricular mass; blood pressure; obesity; risk assessment
17.  Better Population Health Through Behavior Change in Adults A Call to Action 
Circulation  2013;128(19):2169-2176.
doi:10.1161/01.cir.0000435173.25936.e1
PMCID: PMC4074536  PMID: 24100544
AHA Scientific Statements; behavior; population health; prevention
18.  Associations Between a Parental History of Premature Cardiovascular Disease and Coronary Calcium and Carotid Intima-Media Thickness: The Coronary Artery Risk Development In Young Adults (CARDIA) Study 
Background
It is unclear if associations between a parental history of premature CVD (pCVD) and subclinical atherosclerosis are attenuated by adjustment for long-term risk factors levels through middle adulthood.
Design
Prospective community-based cohort study
Methods
CARDIA participants who attended the year 20 exam (N=2283, mean age 45 years) were grouped by pCVD status: maternal only, paternal only, any parental, and no parental history (referent). We used separate logistic regression models, adjusted for average risk factor levels over 20 years' follow-up to assess associations of parental pCVD and subclinical atherosclerosis in offspring.
Results
White participants with any parental history of pCVD had a higher odds of CAC>0 than participants with no parental history (OR 1.55; 95% CI, 1.01-2.37). This was largely driven by the association of a paternal history of pCVD with CAC>0 (OR 2.15; 95% CI, 1.42-3.23), which was minimally attenuated by multivariable adjustment (OR 2.09; 95% CI, 1.31-3.32). Similarly, adjusted associations between parental pCVD and IMT > 90%tile were observed in white participants with a paternal history of pCVD (OR=1.93; 95% CI, 1.10-3.39) and any parental history pCVD (OR 1.67; 95% CI, 1.02-2.74). No significant associations between a parental history of pCVD and the odds of subclinical atherosclerosis were observed in black participants.
Conclusions
Parental pCVD is independently associated with early development of subclinical atherosclerosis; these associations may be race-specific for participants in their 5th decade of life.
doi:10.1177/2047487312462801
PMCID: PMC3779512  PMID: 23027592
Family History of Premature Cardiovascular Disease; Coronary Artery Calcium; Carotid Intima-Media Thickness
19.  Association of early adult modifiable cardiovascular risk factors with left atrial size over a 20-year follow-up period: the CARDIA study 
BMJ Open  2014;4(1):e004001.
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.
doi:10.1136/bmjopen-2013-004001
PMCID: PMC3902509  PMID: 24384901
Cardiology; Epidemiology
20.  High Risk Blood Pressure and Obesity Increase the Risk for Left Ventricular Hypertrophy in African-American Adolescents 
The Journal of pediatrics  2012;162(1):94-100.
Objective
To examine the relative effects of high blood pressure (BP) and obesity on left ventricular mass (LVM) among African-American adolescents; and if metabolic or inflammatory factors contribute to LVM.
Study design
Using a 2×2 design, AA adolescents, were stratified by body mass index (BMI) percentile (BMI <95th %=non-obese; ≥95th %=obese) and average BP (normal <120/80 mm Hg; high BP ≥120/80). Glucose, insulin, insulin resistance, lipids, and inflammatory cytokines were measured. From echocardiography measures of LVM, calculated LVM index (LVMI) ≥95th % defined left ventricular hypertrophy (LVH).
Results
Data included 301 adolescents (48% female), mean age 16.2 years, 51% obese, and 29% high BP. LVMI was highest among adolescents with both obesity and high BP. The multiplicative interaction of obesity and high BP on LVH was not significant (OR= 2.35, p=0.20) but the independent additive associations of obesity and high BP with log-odds of LVH were significant; obesity OR = 3.26, p<0.001; high BP OR = 2.92, p<0.001. Metabolic and inflammatory risk factors were associated with obesity, but had no independent association with LVMI. Compared with those with average systolic BP <75th %, adolescents with systolic BP from the 75th to 90th % had higher LVMI (33.2 vs 38.7 gm/m2.7, p<0.001) and greater LVH (18% vs 43%, p<0.001), independent of obesity.
Conclusions
Prevalence of LVH is highest among AA adolescents with average BP ≥120/80 mm Hg and obesity. There also is an independent association of LVMI with BP, beginning at the 75th systolic BP percentile.
doi:10.1016/j.jpeds.2012.06.009
PMCID: PMC3480988  PMID: 22817908
Adolescents; Blood Pressure; Obesity; Cardiac Hypertrophy; Minority Children
21.  Integrated wall stress: a new methodological approach to assess ventricular workload and myocardial contractile reserve 
Background
Wall stress is a useful concept to understand the progression of ventricular remodeling. We measured cumulative LV wall stress throughout the cardiac cycle over unit time and tested whether this “integrated wall stress (IWS)” would provide a reliable marker of total ventricular workload.
Methods and results
We applied IWS to mice after experimental myocardial infarction (MI) and sham-operated mice, both at rest and under dobutamine stimulation. Small infarcts were created so as not to cause subsequent overt hemodynamic decompensation. IWS was calculated over one minute through simultaneous measurement of LV internal diameter and wall thickness by echocardiography and LV pressure by LV catheterization. At rest, the MI group showed concentric LV hypertrophy pattern with preserved LV cavity size, LV systolic function, and IWS comparable with the sham group. Dobutamine stimulation induced a dose-dependent increase in IWS in MI mice, but not in sham mice; MI mice mainly increased heart rate, whereas sham mice increased LV systolic and diastolic function. IWS showed good correlation with a product of peak-systolic wall stress and heart rate. We postulate that this increase in IWS in post-MI mice represents limited myocardial contractile reserve.
Conclusion
We hereby propose that IWS provides a useful estimate of total ventricular workload in the mouse model and that increased IWS indicates limited LV myocardial contractile reserve.
doi:10.1186/1479-5876-11-183
PMCID: PMC3750700  PMID: 23919327
Wall stress; Ventricular workload; Myocardial contractile reserve; Ventricular remodeling
23.  LVM Assessed by Echocardiography and Cardiac Magnetic Resonance, Cardiovascular Outcomes, and Medical Practice 
JACC. Cardiovascular imaging  2012;5(8):837-848.
We investigate three important areas related to the clinical use of LVM (LVM): accuracy of assessments by echocardiography and cardiac magnetic resonance (CMR), the ability to predict cardiovascular outcomes, and the comparative value of different indexing methods. The recommended formula for echocardiographic estimation of LVM uses linear measurements and is based on the assumption of the left ventricle as a prolate ellipsoid of revolution. CMR permits a modeling of the left ventricle free of cardiac geometric assumptions or acoustic window dependency, showing better accuracy and reproducibility. However, echocardiography has lower cost, easier availability, and better tolerability. From the Medline database, 26 longitudinal echocardiographic studies and 5 CMR studies, investigating LVM or LV hypertrophy as predictors of death or major cardiovascular outcomes, were identified. LVM and LV hypertrophy were reliable cardiovascular risk predictors using both modalities. However, no study directly compared the methods for the ability to predict events, agreement in hypertrophy classification, or performance in cardiovascular risk reclassification. Indexing LVM to BSA was the earliest normalization process used, but it seems to underestimate the prevalence of hypertrophy in obese and overweight subjects. Dividing LVM by height to 1.7 or 2.7 as allometric powers are the most promising normalization methods in terms of practicality and usefulness from a clinical ans scientific standpoints for scaling myocardial mass to body size. The measurement of LVM, calculation of LVMi, and classification for LVH should be standardized by scientific societies across measurement techniques and adopted by clinicians in risk stratification and therapeutic decision.
doi:10.1016/j.jcmg.2012.06.003
PMCID: PMC3501209  PMID: 22897998
LVM; LVH; cardiovascular events; cardiac magnetic resonance; echocardiography
25.  Childhood Obesity and Blood Pressure: Back to the Future? 
Hypertension  2011;58(5):754-755.
doi:10.1161/HYPERTENSIONAHA.111.180430
PMCID: PMC3287055  PMID: 21968756

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