Sex Differences in Age of Onset of Premature Cardiovascular Disease and Subtypes: The Coronary Artery Risk Development in Young Adults Study.

Introduction: Historically, coronary heart disease (CHD) has been reported to develop about ten years earlier in males than females. However, whether this gap has narrowed in a contemporary sample and whether similar sex differences in age of onset exist for other cardiovascular disease (CVD) subtypes (stroke and heart failure [HF]) that are becoming more common is not known. Methods: Participants were enrolled in the CARDIA study between the ages of 18-30 years in 1985-1986. Sex differences in the cumulative incidence functions of premature CVD (defined as onset before 65 years), overall and for each subtype including CHD, HF, and stroke, were compared using Gray’s test. Results: Among 5115 participants (54.5% female, 51.6% Black), the mean age at study enrollment was 24.8 years (SD: 3.7). Over a median follow-up of 34.0 years (IQR 33.8, 35.7), cumulative incidence of total CVD, CHD, and HF was significantly higher in males compared with females (p<0.05 for all). For total CVD, males reached an incidence of 5% at a younger age than females (50.1 versus 57.3 years, Figure). CHD was the most frequent CVD subtype, and an incidence of 2% occurred at a younger age among males compared with females (48.3 vs. 58.5). For HF, an incidence of 1% occurred among males by age 48.4 compared with 51.7 for females. For stroke, an incidence of 2% occurred at similar ages for males and females (56.3 and 55.1 years). Cumulative incidence for CVD, CHD, HF, and stroke, respectively, by age 50, was 5.0%, 2.7%, 1.3%, and 1.3% for males and 3.0%, 1.0%, 1.0%, and 1.3% for females. In a secondary race-stratified analysis, Black males and females reached cumulative incidences of 6.3% and 4.5%, respectively, for total CVD by age 50, in comparison to 3.7% and 1.4% among White males and females. Conclusion: Males reached 5% incidence of total CVD seven years earlier than females, with the greatest difference observed in age of onset for CHD. Age of onset for HF and stroke were similar between males and females. This may inform sex-specific prevention strategies for young adults.

APOL1 renal risk variants are strongly associated with chronic kidney disease in Black adults, but reported associations with cardiovascular disease (CVD) have been conflicting. We examined associations of APOL1 with incident coronary heart disease (n=323), ischemic stroke (n=331), and the composite CVD outcome (n=500) in 10 605 Black participants of the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Primary analyses compared individuals with APOL1 high-risk genotypes to APOL1 low-risk genotypes in Cox proportional hazards models adjusted for CVD risk factors and African ancestry. APOL1 high-risk participants were younger and more likely to have albuminuria at baseline than APOL1 low-risk participants. The risk of incident stroke, coronary heart disease, or composite CVD end point did not significantly differ by APOL1 genotype status in multivariable models. The association of APOL1 genotype with incident composite CVD differed by diabetes mellitus status (Pinteraction=0.004). In those without diabetes mellitus, APOL1 high-risk genotypes associated with greater risk of incident composite CVD (hazard ratio, 1.67; 95% confidence interval, 1.12-2.47) compared with those with APOL1 low-risk genotypes in multivariable adjusted models. This latter association was driven by ischemic strokes (hazard ratio, 2.32; 95% confidence interval, 1.33-4.07), in particular, those related to small vessel disease (hazard ratio, 5.10; 95% confidence interval, 1.55-16.56). There was no statistically significant association of APOL1 genotypes with incident CVD in subjects with diabetes mellitus. The APOL1 high-risk genotype was associated with higher stroke risk in individuals without but not those with chronic kidney disease in fully adjusted models. APOL1 high-risk status is associated with CVD events in community-dwelling Black adults without diabetes mellitus.

BackgroundAssessing coronary artery calcium (CAC) is among AHA/ACC prevention guidelines for people at least 40 years old at intermediate risk for coronary heart disease (CHD). To study enhanced risk stratification, we investigated the predictive value of abdominal aorta calcium (AAC) relative to CAC for cardiovascular disease (CVD) and CHD events in Black and White early middle‐aged participants, initially free of overt CVD.Methods and ResultsIn the CARDIA (Coronary Artery Risk Development in Young Adults) study, a multi‐center, community‐based, longitudinal cohort study of CVD risk, the CAC and AAC scores were assessed in 3011 participants in 2010–2011 with follow‐up until 2019 for incident CVD and CHD events. Distributions and predictions, overall and by race, were computed. During the 8‐year follow‐up, 106 incident CVD events (55 were CHD) occurred. AAC scores tended to be much higher than CAC scores. AAC scores were higher in Black women than in White women. CAC predicted CVD with HR 1.77 (1.52–2.06) and similarly for AAC, while only CAC predicted CHD. After adjustment for risk factors and calcium in the other arterial bed, the association of CAC with CVD was independent of risk factors and AAC, while the association of AAC with CVD was greatly attenuated. However, AAC predicted incident CVD when CAC was 0. Prediction did not vary by race.ConclusionsAAC predicted CVD nearly as strongly as CAC and could be especially useful as a diagnostic tool when it is an incidental finding or when no CAC is found.

ImportanceCoronary artery calcium (CAC) is associated with coronary heart disease (CHD) and cardiovascular disease (CVD); however, prognostic data on CAC are limited in younger adults.ObjectiveTo determine if CAC in adults aged 32 to 46 years is associated with incident clinical CHD, CVD, and all-cause mortality during 12.5 years of follow-up.Design, Setting, and ParticipantsThe Coronary Artery Risk Development in Young Adults (CARDIA) Study is a prospective community-based study that recruited 5115 black and white participants aged 18 to 30 years from March 25, 1985, to June 7, 1986. The cohort has been under surveillance for 30 years, with CAC measured 15 (n = 3043), 20 (n = 3141), and 25 (n = 3189) years after recruitment. The mean follow-up period for incident events was 12.5 years, from the year 15 computed tomographic scan through August 31, 2014.Main Outcomes and MeasuresIncident CHD included fatal or nonfatal myocardial infarction, acute coronary syndrome without myocardial infarction, coronary revascularization, or CHD death. Incident CVD included CHD, stroke, heart failure, and peripheral arterial disease. Death included all causes. The probability of developing CAC by age 32 to 56 years was estimated using clinical risk factors measured 7 years apart between ages 18 and 38 years.ResultsAt year 15 of the study among 3043 participants (mean [SD] age, 40.3 [3.6] years; 1383 men and 1660 women), 309 individuals (10.2%) had CAC, with a geometric mean Agatston score of 21.6 (interquartile range, 17.3-26.8). Participants were followed up for 12.5 years, with 57 incident CHD events and 108 incident CVD events observed. After adjusting for demographics, risk factors, and treatments, those with any CAC experienced a 5-fold increase in CHD events (hazard ratio [HR], 5.0; 95% CI, 2.8-8.7) and 3-fold increase in CVD events (HR, 3.0; 95% CI, 1.9-4.7). Within CAC score strata of 1-19, 20-99, and 100 or more, the HRs for CHD were 2.6 (95% CI, 1.0-5.7), 5.8 (95% CI, 2.6-12.1), and 9.8 (95% CI, 4.5-20.5), respectively. A CAC score of 100 or more had an incidence of 22.4 deaths per 100 participants (HR, 3.7; 95% CI, 1.5-10.0); of the 13 deaths in participants with a CAC score of 100 or more, 10 were adjudicated as CHD events. Risk factors for CVD in early adult life identified those above the median risk for developing CAC and, if applied, in a selective CAC screening strategy could reduce the number of people screened for CAC by 50% and the number imaged needed to find 1 person with CAC from 3.5 to 2.2.Conclusions and RelevanceThe presence of CAC among individuals aged between 32 and 46 years was associated with increased risk of fatal and nonfatal CHD during 12.5 years of follow-up. A CAC score of 100 or more was associated with early death. Adults younger than 50 years with any CAC, even with very low scores, identified on a computed tomographic scan are at elevated risk of clinical CHD, CVD, and death. Selective use of screening for CAC might be considered in individuals with risk factors in early adulthood to inform discussions about primary prevention.

JAHA Go Red for Women Spotlight 2023

Background: Glagov identified cross-sectional enlargement and maintenance of the lumen of the coronary artery (CA) in post-mortem studies as an early feature of atherosclerotic coronary heart disease (CHD) that precedes the development of stenosis, coronary artery calcium (CAC) and plaque rupture. This structural change in the CA wall has been termed positive remodeling. We hypothesized that larger CA cross-sectional areas, consistent with positively remodeled CA, is associated with prevalent or soon-to-be incident coronary heart disease (CHD) and cardiovascular disease (CVD) events. Methods: In 2946 black and white male and female CARDIA participants aged 42-56 years, who had thin-slice (<1 mm), ECG gated, non-contrast coronary CT in 2010-2011, we measured CA cross-sectional area (CSA) in the proximal epicardial CA at 24 pre-specified locations. The mean of all measurements was calculated to provide a summary of all CA (CA CSA_all ). We performed logistic regression with medical-record adjudicated CVD prevalence (n=96) or incidence in the following 3 years (n=27) as the outcome, predicted from this estimate of positive remodeling adjusting for age, race, sex, presence of coronary artery calcium (CAC), and amount of pericardial fat as covariates. Results: CA CSA_all had a mean ± SD 21.2 ± 6.7 mm 2 . The adjusted odds ratio (OR) for having any CVD was 1.06 (95% CI 1.03-1.09, p<0.0001) per mm 2 (Table). ORs for CVD increased across quartiles of CA CSA_all . Corresponding OR for any coronary heart disease (n=66) was not significant, but was significant for stroke (n=42) and for heart failure (n=27). Further adjustment for traditional risk factors assessed in 2010-2011 did not alter these estimates substantially. Conclusion: Individuals with larger CA cross-sectional areas had increased odds of CVD, stroke, and heart failure, but not CHD, independent of CAC and pericardial fat. CA CSA_all may be an imaging biomarker of coronary positive remodeling and provide new insight into progression from subclinical to premature clinical CVD.

Introduction: Cardiovascular disease (CVD) is the leading cause of death in women and early onset of menopause before the age of 40 years has been identified as a risk enhancer for future CVD events. Quantifying the magnitude of risk for premature CVD among women with early menopause may inform and guide the intensity of sex-specific preventive strategies. Methods: We included all women in the Coronary Artery Risk Development in Young Adults (CARDIA) study who attended a follow-up exam after the age of 40 years, had available data on menopausal status, and had not experienced premature CVD before 40 years. We performed multivariable Cox proportional hazards regression to examine the relationship between early onset of menopause defined as <40 years and incident CVD (coronary heart disease, peripheral arterial disease, stroke, and heart failure) prior to the age of 65 years. We performed Cox proportional hazards models and adjusted for risk factors levels at baseline: age, race, age at menarche, years of education, smoking status, body mass index, diabetes, hypertension, and total cholesterol: high-density lipoprotein ratio. Results: Among 2136 women with mean age of 43.0 (SD 3.0), 9.1% reported premature menopause before the age of 40 years (4.5% in white and 13.9% in black women). Over a median follow-up of 14.0 (IQR 11.5, 16.9) years, 81 premature CVD events occurred. Incidence rate (95% CI) of CVD was 6.46 (2.43, 17.22) and 1.41 (0.92, 2.17) per 1,000 per person-years for white women with and without early onset menopause, respectively; 4.94 (2.66, 9.16) and 3.92 (2.94, 5.24) per 1,000 person-years for black women with and without early onset menopause (FIGURE). Conclusions: In a population-based sample, white women with early onset of menopause had a 3-fold higher rate of premature CVD events, independent of perimenopausal risk factor levels. Interventions to intensify CVD prevention in at-risk women are needed following early onset of menopause.

HEART FAILURE IN PEOPLE YOUNGER THAN 50 YEARS IS MORE COMMON IN BLACK THAN WHITE AMERICANS AND IS CLOSELY ASSOCIATED WITH POORLY TREATED AND CONTROLLED HYPERTENSION: THE CARDIA STUDY Heart failure (HF) is a major public health issue that leads to substantial morbidity and mortality in the United States. Age, hypertension, and coronary ischemia are all well-documented risk factors for HF in older adults, but less is known about the incidence, risk factors, and demographics associated with HF in younger people. The Coronary Artery Risk Development in Young Adults (CARDIA) study, a 20-year multicenter longitudinal study of black and white men and women designed to investigate the development of coronary artery disease in young adults, offered an opportunity to explore these relationships. Beginning in 1985–1986, persons 18 to 30 years of age were enrolled from 4 American cities: Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California. The cohort was well balanced with respect to self-reported race (52% black) and sex (55% women). Multiple clinical measurements, including blood pressure (BP), were obtained at baseline and after 2, 5, 7, 10, 15, and 20 years. BP was measured in standardized fashion, with hypertension defined as a BP of at least 140 ⁄90 mm Hg or use of antihypertensive medications. During both their study examinations and in yearly telephone follow-up, participants were asked about overnight hospitalizations. For each hospitalization, records were obtained and adjudicated for the presence of incident HF, defined as a hospitalization where the final diagnosis of HF was made by a treating physician and HF was treated with at least a diuretic and either digitalis or an afterload-reducing agent. Death was also reported to the study centers every 6 months, and each death was adjudicated to determine whether it was due to HF. In year 5, as part of the examination, participants underwent echocardiography. Systolic function was considered abnormal if the ejection fraction (EF) was either <40% or qualitatively described as abnormal; systolic function was considered borderline if the EF was 40% to 60%. Left ventricular hypertrophy (LVH) was defined as a left ventricular mass index at least 51 g ⁄m. Using multiple statistical tools, the CARDIA investigators compared baseline and subsequent development of risk factors in participants in whom HF did and did not develop. The CARDIA study enrolled 5115 individuals with a mean age of 25 years and a mean baseline BP around 110 ⁄70 mm Hg. The retention rate in the study was exceptionally high, with 87.5% of the original cohort completing the yearly telephone interview at year 20 and 71.8% completing the year 20 in-person examination. During the 20 years of follow-up, incident HF occurred in 27 patients (0.5%), which was more common than the incidence of myocardial infarction. Twenty-six of the 27 patients who developed incident HF were black. The cumulative incidence of HF was 1.1% in black women and 0.9% in black men, compared with 0.08% in white women and 0% in white men. From the Division of General Internal Medicine ⁄ Division of Cardiology, University of Nevada School of Medicine; Risk Reduction Center, Saint Mary’s Regional Medical Center, Reno, NV; Primary Care Service Line, Ralph H. Johnson VA Medical Center; and Division of General Internal Medicine ⁄Geriatrics, Medical University of South Carolina, Charleston, SC Address for correspondence: Michael J. Bloch, MD, Risk Reduction Center, Saint Mary’s Regional Medical Center, 645 North Arlington Street, Suite 460, Reno, NV 89503 E-mail: mbloch@aol.com

To investigate the effects of marijuana in the development of incident cardiovascular and cerebrovascular outcomes. Participants were 5113 adults aged 18 to 30 years at baseline (1985-1986) from the Coronary Artery Risk Development in Young Adults study, who were followed for more than 25 years. We estimated cumulative lifetime exposure to marijuana using repeated assessments collected at examinations every 2 to 5 years. The primary outcome was incident cardiovascular disease (CVD) through 2013. A total of 84% (n = 4286) reported a history of marijuana use. During a median 26.9 years (131 990 person-years), we identified 215 CVD events, including 62 strokes or transient ischemic attacks, 104 cases of coronary heart disease, and 50 CVD deaths. Compared with no marijuana use, cumulative lifetime and recent marijuana use showed no association with incident CVD, stroke or transient ischemic attacks, coronary heart disease, or CVD mortality. Marijuana use was not associated with CVD when stratified by age, gender, race, or family history of CVD. Neither cumulative lifetime nor recent use of marijuana is associated with the incidence of CVD in middle age.

Background: Cellular adhesion molecules (CAM) have a central role in the accumulation of circulating leukocytes at sites of vascular injury, infection and/ inflammation, and have been associated with the development of atherosclerotic plaque and coronary artery disease in mature adults. Objective: To test the hypothesis that higher overall circulating CAM levels in young adults predict cardiovascular disease (CVD) events over the next 18 years. Method: We measured several circulating CAM molecules (ICAM-1, P-selectin, E-selectin and VCAM) in the Coronary Artery Risk Development in Young Adults (CARDIA) study at exam year 7 (1992-93, black and white men and women, CVD-free, mean age 32, range 25-37 years, n=2428) and monitored incident CVD events (n=70, including coronary heart disease, stroke, and heart failure, adjudicated based on medical records) through exam year 25, mean age of 50 years. We ranked each CAM in quintiles (coded 0-4) and summed the ranks across CAMs into an index to examine the association with incident CVD with Cox regression models. Results: Unadjusted cumulative CVD event rates were 1.6% (sum of CAM quartile ranks 0-8: 22 events in 1353 participants), 2.3% (sum of ranks 9-12: 29/813), and 7.3% (sum of ranks 13-16: 19/262). In proportional hazards regression analysis adjusted for year 7 age, sex, race, clinic, education, smoking, diet, physical activity, body mass index, blood pressure, blood lipids, and blood glucose, sum of ranks 13-16 were associated with a higher risk of CVD compared to the referent (rank sum 0-8) (See Table). Conclusion: High levels of circulating CAMs at an early stage of adulthood (mean age 32, range 25-37 years) were associated with an increased risk of incident CVD events. CAMs may be an early biomarker for development of subclinical CVD, even in CVD-free young adults with low atherosclerosis burden and decades prior to the development of clinical CVD.

Food insecurity is associated with prevalent cardiovascular disease (CVD), but studies have been limited to cross-sectional data. To study whether food insecurity is associated with incident CVD and to determine whether this association varies by sex, education, or race. This prospective cohort study was conducted among US adults without preexisting CVD participating in the CARDIA (Coronary Artery Risk Development in Young Adults) study from 2000 to August 31, 2020. Data analysis was conducted from December 2022 to April 2024. Food insecurity, defined as endorsing limitations in household food variety and/or food quantity, assessed in the period 2000-2001. The primary outcome was CVD events, consisting of fatal and nonfatal coronary heart disease, heart failure, stroke, transient ischemic attack, or peripheral arterial disease, identified annually through August 31, 2020. Of 3616 total participating adults, mean (SD) age was 40.1 (3.6) years, and 2027 participants (56%) were female. Of 3616 participants, 1696 (47%) self-reported Black race and 529 participants (15%) had food insecurity at baseline. Individuals with food insecurity were more likely to self-identify as Black and report lower educational attainment. The mean (SD) follow-up period was 18.8 (3.4) years, during which 255 CVD events occurred: 57 events (11%) in food-insecure participants and 198 events (6%) in food-secure participants over the study period. After adjusting for age, sex, and field center, food insecurity was associated with incident CVD (adjusted hazard ratio [aHR], 1.90; 95% CI, 1.41-2.56). The association persisted (aHR, 1.47; 95% CI, 1.08-2.01) after further adjustment for the socioeconomic factors of education, marital status, and usual source of medical care. In this prospective cohort study among participants in the CARDIA study, food insecurity was associated with incident CVD even after adjustment for socioeconomic factors, suggesting that food insecurity may be an important social deprivation measure in clinical assessment of CVD risk. Whether interventions to reduce food insecurity programs can potentially alleviate CVD should be further studied.

Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease (CVD). Most observational studies on the association between LDL-C and CVD have focused on LDL-C level at a single time point (usually in middle or older age), and few studies have characterized long-term exposures to LDL-C and their role in CVD risk. To evaluate the associations of cumulative exposure to LDL-C, time-weighted average (TWA) LDL-C, and the LDL-C slope change during young adulthood and middle age with incident CVD later in life. This cohort study analyzed pooled data from 4 prospective cohort studies in the US (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Framingham Heart Study Offspring Cohort, and Multi-Ethnic Study of Atherosclerosis). Participants were included if they had 2 or more LDL-C measures that were at least 2 years apart between ages 18 and 60 years, with at least 1 of the LDL-C measures occurring during middle age at 40 to 60 years. Data from 1971 to 2017 were collected and analyzed from September 25, 2020, to January 10, 2021. Cumulative exposure to LDL-C, TWA LDL-C, and LDL-C slope from age 18 to 60 years. Incident coronary heart disease (CHD), ischemic stroke, and heart failure (HF). A total of 18 288 participants were included in this study. These participants had a mean (SD) age of 56.4 (3.7) years and consisted of 10 309 women (56.4%). During a median follow-up of 16 years, 1165 CHD, 599 ischemic stroke, and 1145 HF events occurred. In multivariable Cox proportional hazards regression models that adjusted for the most recent LDL-C level measured during middle age and for other CVD risk factors, the hazard ratios for CHD were as follows: 1.57 (95% CI, 1.10-2.23; P for trend = .01) for cumulative LDL-C level, 1.69 (95% CI, 1.23-2.31; P for trend <.001) for TWA LDL-C level, and 0.88 (95% CI, 0.69-1.12; P for trend = .28) for LDL-C slope. No association was found between any of the LDL-C variables and ischemic stroke or HF. This cohort study showed that cumulative LDL-C and TWA LDL-C during young adulthood and middle age were associated with the risk of incident CHD, independent of midlife LDL-C level. These findings suggest that past levels of LDL-C may inform strategies for primary prevention of CHD and that maintaining optimal LDL-C levels at an earlier age may reduce the lifetime risk of developing atherosclerotic CVD.

Objectives: In young adults, which blood pressure (BP) patterns, determined over multiple clinic visits, are most associated with future risk for cardiovascular disease (CVD) and all-cause mortality remains unclear. We determined BP patterns during young adulthood most associated with CVD events and all-cause mortality by middle age. BP patterns included average systolic BP (SBP)/diastolic BP (DBP) levels, cumulative exposure to SBP/DBP, visit-to-visit SBP/DBP variability, and average annual change in SBP/DBP. Methods: We analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, which enrolled 5115 adults aged 18-30 years from 1985-1986, with up to 30 years of follow-up (through 2015). BP patterns were evaluated with measurements at Year 0 [baseline], and 2, 5, 7, and 10 years following baseline. We estimated visit-to-visit BP variability as variability independent of the mean (VIM). Average annual change of BP from the Year 0 to Year 10 exams was calculated using linear regression. Cox proportional hazards models were used to assess the associations between BP patterns and adjudicated CVD events (coronary heart disease, stroke, heart failure, and other vascular disease) and all-cause mortality. Results: At Year 10, the mean±standard deviation (SD) age of the 3,394 participants was 35.1±3.6 years, 46% were African American, 56% were female, and only 3% were taking antihypertensive medication. Cumulative exposure to SBP and average SBP levels were highly correlated (Pearson’s correlation = 0.94). Over a median follow-up of 19.2 years, 162 CVD events and 181 deaths occurred. Average SBP and DBP levels and VIM of SBP were associated with increased CVD risk (see table), with no interaction by race or sex (each p&gt;0.4). Only VIM of SBP was associated with all-cause mortality. Conclusions: Among young adults, the assessment of visit-to-visit SBP variability in addition to average SBP and DBP levels can help identify young adults who have an increased CVD risk and all-cause mortality by middle age.

Association of Incident Cardiovascular Disease With Time Course and Cumulative Exposure to Multiple Risk Factors

Left ventricular (LV) ejection fraction (LVEF) is an extensively utilized marker of LV function that is often interpreted without recourse to alterations in LV geometry and hypertrophy. LV global function index (LVGFI) is a novel marker that incorporates LV structure in the assessment of LV cardiac performance. We evaluated the prognostic utility of LVGFI from young adulthood into middle age for incident heart failure (HF) and cardiovascular disease (CVD) in comparison to LVEF. Included were 4107 CARDIA participants with echocardiograms in Year-5 (1990-1991). LVGFI was defined as LV stroke volume/LV global volume*100, where LV global volume was the sum of the LV mean cavity volume ((LV end-diastolic volume + LV end-systolic volume)/2) and myocardial volume (LV mass/density). Adjusted Cox proportional hazard models were utilized to predict incident HF and CVD outcomes. Mean age of participants was 29.8 ± 3.7 years, 55% female, and 48.7% black. Higher body mass index [beta coefficient (B) = -0.11 standard error (SE) = 0.02, P < 0.001], higher blood pressure (B = -0.04, SE = 0.01, P < 0.01), smoking (B = -0.82, SE = 0.22, P < 0.001), male sex (P < 0.001), and black race (P < 0.001) were associated with worse LVGFI. A total of 207 incident CVD events were observed over the course of 98035 person-years at risk. Higher LVGFI was associated with HF, hazard ratio (HR) = 0.70, 95% confidence interval (CI) (0.54-0.91), hard CVD HR = 0.83, 95% CI (0.71-0.96), and all CVD HR = 0.83, 95% CI (0.72-0.96). For HF outcomes, Harrell's C-statistic for LVGFI (0.80) was greater than LVEF (0.66). LVGFI is a strong, independent predictor of incident HF and CVD that provides incremental prognostic value compared with LVEF. Male sex, black race, obesity, hypertension, and smoking are associated with worse LVGFI in the early adult lifespan.