Browse Articles

Abstract P2131: The Association between Leisure Activities and the Risk of Cardiometabolic Multimorbidity among Older Chinese Adults

Background: Cardiometabolic multimorbidity (CMM) is becoming increasingly common in prehypertension patients and hypertension patients. Leisure activities play a vital role in preventing hypertension. However, its effect on CMM risk is unknown. Hypothesis: I hypothesized that leisure activities lower the risk of CMM among Chinese older adults. Methods: I included participants aged 65 and over from five waves (2002–2014) of the Chinese Longitudinal Healthy Longevity Survey, with follow-up until 2018. Participants diagnosed with CMM at baseline year were excluded. CMM was identified as having at least two of the four diseases: hypertension, diabetes, heart disease, or cardiovascular disease. Leisure activities were measured by the frequency (never, sometimes, and almost daily) of eight activities, including housework, fieldwork, reading books or newspapers, playing cards and/or mahjong, TV and/or radio watching, gardening, petting, and social activities. Cox proportional hazard models were used to estimate hazard ratio (HR), adjusting for demographics, lifestyles, and comorbidities. Results: Among 9,895 participants (mean age: 83.8 years; 55.3% female), 1,528 participants developed CMM during a median follow-up of 3.4 years (IQR: 3.0–6.2). Frequent participation in housework was associated with a lower risk of CMM (sometimes: HR 0.77, 95% CI 0.68–0.87; almost daily: HR 0.73, 95% CI 0.66–0.82), as was petting (sometimes: HR 0.73, 95% CI 0.63–0.86; almost every day: HR 0.68, 95% CI 0.60–0.76). In contrast, frequent TV and/or radio watching was associated with a higher risk of CMM (almost every day: HR 1.24, 95% CI 1.10–1.41). No significant associations were found between the risk of CMM and activities such as fieldwork, reading books or newspapers, playing cards and/or mahjong, gardening, or social activities. In the stratified analysis, the effect of almost daily housework and petting in reducing the risk of CMM was more pronounced among participants who frequently engage in physical exercise, while the effect of sometimes doing housework and petting was more pronounced among participants who never exercise. Conclusion: Frequent participation in housework and petting is associated with a lower risk of CMM among older Chinese adults, whereas activities such as TV and/or radio watching are linked to an increased risk. These findings underscore the importance of promoting healthy lifestyles by encouraging beneficial leisure activities in the older population.

Enhancing energy efficiency in buildings using sawdust-based insulation in hot arid climates

Brain aging shows nonlinear transitions, suggesting a midlife “critical window” for metabolic intervention

Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal “landmarks” of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain’s regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons’ energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife “critical window” for early metabolic intervention.

Abstract P3014: Night shift work and markers of cardiovascular health in workers from Spain, Denmark and Sweden: Findings from the Exposome Project for Health and Occupational Research

Objective: Night shift work disrupts normal circadian rhythms, which is hypothesized to lead to negative impacts on cardiovascular health. The underlying mechanisms remain poorly understood. We examined the associations between night shift work and cardiovascular risk factors, including blood pressure (BP), body mass index (BMI) and waist-to-hip ratio (WHR). Materials and Methods: We used data from the Exposome Project for Health and Occupational Research study (EPHOR), which included night and day shift workers from Spain, Sweden, and Denmark. We included participants with complete data on BP, BMI, and WHR. We used linear regression for the continuous outcomes and logistic regression for the binary outcomes, adjusting for relevant confounders. We conducted sex-stratified analyses, since sex may modify the relationship between night shift work exposure and cardiometabolic outcomes. Results: The analytic sample comprised 805 participants, 58% of whom were night shift workers with a mean age of 42 years (SD 11). The majority were female (87%). Compared to day workers, night shift workers had a higher BMI (β coeff. 1.10, 95%CI 0.37, 1.83), a higher odds of overweight/obesity (OR 1.39, 95%CI 1.03, 1.88), and a higher odds of moderate-high risk WHR (OR 1.39, 95%CI 1.00, 1.93). Blood pressure and the odds of hypertension were also elevated among night shift workers, but 95% CIs overlapped with the null. In the sex-stratified analyses, the point estimates were elevated among women (Table 1). Conclusion: Compared with day workers, night shift workers showed a worse cardiometabolic profile, particularly among women, indicating that cardiometabolic problems may be compounded among female night shift workers. These findings are in line with earlier research indicating that night shift work is associated with an increased cardiometabolic risk. We plan to further explore whether shift work characteristics, for example intensity of night shifts, may influence these findings.

Abstract P3013: Left Ventricular Diastolic to Systolic Wall Stress Ratio and Mortality Following Transcatheter Aortic Valve Replacement

Background: Most studies of left ventricular wall stress in patients with aortic stenosis (AS) focus on the end systolic (LVESWS) component with suggestion of an inverse association with adverse outcomes. LV end diastolic wall stress (LVEDWS) is less characterized and LVEDWS to LVESWS ratio, which may provide a combined measure of diastolic and systolic dysfunction and remodeling, has not been previously reported in patients with severe AS undergoing transcatheter aortic valve replacement (TAVR). Hypothesis: Higher LVEDWS to LVESWS ratio assessed by echocardiography prior to TAVR associates with greater risk of post-TAVR death. Methods: From a multicenter registry of patients with severe AS undergoing TAVR, we examined 637 participants (median age 84 years, 43% female, 95% white) who underwent pre-TAVR echocardiogram from which LVEDWS and LVESWS could be calculated from chamber dimensions, wall thicknesses, aortic valve gradient, blood pressure, and E/e’. Multivariable-adjusted Cox regression was used to examine associations between LVEDWS, LVESWS, their ratio, and the risk of post-TAVR mortality. Results: Median LVEDWS, LVESWS, and LVEDWS/LVESWS ratio were 22.1 (IQR: 16.2, 29.7) kdynes/cm2, 64.7 (IQR: 50.0, 90.7) kdynes/cm2, and 0.32 (IQR: 0.24, 0.43), respectively. Correlates of higher LVEDWS/LVESWS included: female gender, non-white race, hypertension medication use, higher natriuretic peptide and LV ejection fraction, and lower systolic and diastolic BP and hemoglobin. Over a median follow-up of 3 years post-TAVR, 262 (41%) individuals died. Higher LVEDWS tended towards greater risk of death (aHR: 1.013; 95% CI 0.999 – 1.027, p=0.071), while higher LVESWS associated with lower mortality risk (aHR: 0.993; 95% CI 0.988-0.998, p=0.008). Higher LVEDWS/LVESWS ratio associated with greater risk of death (aHR: 1.130, 95% CI 1.043-1.224, p=0.003, per 0.1 unit) (Figure), independent of age, comorbidities, LVEF, mass index, natriuretic peptide, and troponin. Conclusion: Among patients with severe aortic stenosis, higher LVEDWS to LVESWS ratio prior to TAVR associated with greater risk of post-TAVR mortality.

A general tribo-dynamic model for lubricated clearance joints in spatial multibody systems

Dynamic and context-dependent keystone species effects in kelp forests

Sea otters are an iconic keystone predator that can maintain kelp forests by preying on grazing invertebrates such as sea urchins. However, the effects of sea otters on kelp forests vary over their geographic range. Here, we analyze two 30-y datasets on kelp forest communities during the reintroduction of sea otters along the west coast of Vancouver Island, BC, Canada, and around San Nicolas Island, CA. We developed a community model to estimate species interactions as dynamic rates, varying with community state. We find evidence of a classic trophic cascade off Vancouver Island; the arrival of otters quickly led to depletion of urchins and recovery of kelp. However, this cascade was muted around San Nicolas Island, with otters, urchins, and kelp all coexisting at intermediate densities for multiple years. Our models show that this difference came from a pulse of strong otter impacts on urchins following recolonization off Vancouver Island, but not off San Nicolas Island. The mean effects of otters on urchins and urchins on kelp were not stronger in the north, indicating that interaction dynamics and not average interaction strength are key to explaining differences in community trajectories. We also find stronger multistep interaction chains in the south, arising from competitive interactions that indirectly buffered otter effects. These findings shed light on long-standing hypotheses about how interspecific interactions can alter the function of keystone species across community contexts. More broadly, we show how community change can be more accurately predicted by considering dynamic interaction strengths.

Abstract P2099: Higher Carotid IMT Related to Lower Cognitive Function in Healthy Adults: the i3C DECADE Study

Introduction: As the US population ages, the prevalence of Alzheimer’s disease and related dementias (ADRD) is expected to increase. Cardiovascular risk factors an accelerated vascular aging increase risk for ADRD. Therefore, we examined the relationship between carotid intima-media thickness (IMT) and neurocognitive function in a longitudinal study of the effect of CV risk factors on brain health. Methods: Participants had CV risk factors (BMI, BP, Lipids, high sensitivity CRP), IMT (mean R&L, common, bulb, internal) and Rowan Digital Cancellation Tests (RDCT) collected which consists of 3 tests administered on an iPAD that varied in stimulus complexity. For Letter, participants were asked to circle the letter A on a sheet of letters where there were 16 targets (the letter ‘A’) in each of the 4 quadrants of the paper, for Symbol, they were to circle a specific symbol, and for Mixed they were to alternate between A and the symbol. A Summary outcome measure was calculated for each test condition by combining correct hits, average time between correct hits, and drawing time for correct targets. Mean values for CV risk factors, IMT and RDCT were calculated; and general linear models were constructed to determine if IMT remained associated with RDCT after adjustment for demographics, age, BP, lipids, and hsCRP. Results: Forty-nine participants had data available (mean age 60.7 + 6.3 yr, 68% female, 73% white). Higher IMT was associated with reduced neurocognitive functioning (lower RDCT) independently of CV risk factors for all 3 RDCT outcomes (TABLE). Summary: In these preliminary findings among middle-aged adults, accelerated vascular aging was associated with poorer cognitive function. Additional research with a greater number of participants with replication in populations who are older, have known mild cognitive impairment, and dementia are needed to determine the utility of IMT as a biomarker for age-related neurodegenerative disease.

Abstract P3094: Digital Cardiovascular Health Promotion Among Adolescents In Nepal

The burden of cardiovascular diseases (CVDs) and the risk factors in adolescents are rising in Nepal, a low-income setting. Therefore, focusing on health education related to diet and physical activity for adolescents in their formative years is urgent. A digital medium may be an efficient way to reach this technologically oriented group. We developed a digital educational game through a collaboration between researchers in health and informatics from Nepal and Sweden and piloted the game as part of the ‘Heart-Related Intervention with Digitalization Among Young Adolescents (HRIDAYA)’ study. We found that 99% of adolescents had access to smartphones and 92% had access to the internet. The digital game was developed for android devices due to their predominance in Nepal. First, a survey was conducted among 649 adolescents to identify their digital prerequisites as well as their gaps in CVD-related knowledge, attitude, and practice. Second, the identified gaps defined the learning goals of the game, forming the foundation for an initial draft of the game concept. Third, we created a game paper prototype and tested it among 10 adolescents to explore their visual recognition and preferences. Based on the findings, we chose two levels of fidelity and tested them with 44 adolescents. We found that a higher-fidelity abstract style resulted in more positive feelings. This style was subsequently used for the final game. Fourth, the game was developed through an iterative process, which included both culturalization efforts and ensuring educational viability. Finally, the completed digital educational game ‘Happy Heart’ was played by 176 adolescents. It consisted of seven mini-games related to sugar, salt, and fat in different food items, physical activities, balanced diet, and nutrition groups. Immediate audio and video feedback kept the players motivated. Written texts in the game journal addressed knowledge gaps that could not be converted to game mechanics. In conclusion, a digital education like Happy Heart may be helpful in increasing knowledge, attitude and practice regarding CVDs among Nepalese adolescents. The development process indicated that the digital game has the potential to reach many adolescents and that they were receptive to the game. As the game is a low-cost educational effort that can easily be scaled up, it provides a promising avenue for cardiovascular health promotion in similar low-income settings.

Melatonin suppresses PD-L1 expression and exerts antitumor activity in hepatocellular carcinoma

Record of paleo water divide locations reveals intermittent divide migration and links to paleoclimate proxies

Drainage divide migration alters the geometry of drainage basins, influencing the distribution of water, erosion, sediments, and ecosystems across Earth’s surface. The rate of divide migration is governed by differences in erosion rates across the divide and is thus sensitive to spatiotemporal variations in tectonics and climate. However, established approaches for quantifying divide migration rates offer only indirect evidence for the motion of the divide and provide only migration rate averages. Consequently, transience in divide migration cannot be resolved, hindering the ability to explore environmental changes that drive the dynamics of such potential transience. Here, we study a set of datable terraces identified as markers of paleo-divide locations, which provide direct evidence for the paleo motion of the divide. The location and age of the terraces reveal intermittent divide migration at timescales of 10 4 to 10 5 y, with phases of rapid migration—at rates more than twice the average—which coincide with documented regional paleoclimate fluctuations. These findings highlight the intermittent nature of divide migration dynamics over geomorphic timescales and its potential sensitivity to climate changes, underscoring the impact of such changes on the planform evolution of drainage basins.

Abstract P1164: Sex Differences in Cardiovascular Risk Factors among Cardiac Rehabilitation Participants

Introduction: Cardiac rehabilitation (CR) programs collect cardiovascular health measures related to AHA core component recommendations for patient care and American Association of Cardiovascular and Pulmonary Rehabilitation certification. In secondary data analysis, we investigated sex differences in cardiovascular risk factors. Hypothesis: Cardiovascular risk factors will be different by sex. Methods: We obtained certification data [BMI, smoking status (Never, Former, Current), and Patient Health Questionnaire (PHQ9) score] as well as Generalized Anxiety Disorder (GAD7) score and diet (Picture Your Plate) score for CR participants in 2023 from our hospital associated outpatient CR program. Since data did not have a normal or log-normal distribution, categorical analyses were completed. BMI (kg/m 2 ) was categorized into Ideal (<25), Intermediate (25 to <30), Poor (≥30). PHQ9 and GAD7 were categorized as No, Minimal, or >Minimal Symptoms. Diet score categories were based upon published thresholds: Ideal (>60), Intermediate (51-60), Poor (<51). Descriptive statistics and standardized differences were computed. Results: Of the 202 CR participants, 29% were female, 31% were <65 years old, 86% were White, and 25% had a qualifying event of NSTEMI. Heart failure was higher in females (17%) than males (10%). On average, participants completed 31(SD:5.5) sessions. The majority (60% to 99%) of participants with data at program entry and exit did not switch categories regardless of measurement. There were similar proportions of males and females with stable ideal (25% vs 21%) or intermediate (37% vs 36%) BMI; however, a higher proportion of females (36%) had stable poor BMI than males (27%) (Table 1). Higher proportions of males had no symptoms (PHQ9: 22%, GAD7: 48%) than females (9%, 28%) pre-CR (Table 2). Among those with pre-/post-CR PHQ9 (25% missing), we observed improvement in a higher proportion of females (38%) than males (30%). Although 13% of pre-CR diet scores were missing, we observed higher proportions of females with ideal and intermediate (64%, 30%) diet scores than males (58%, 25%) (Table 3). One participant quit smoking post-CR. Except BMI and smoking, missing data was a limitation of post-CR analyses. Conclusions: Females gained greater mental health benefit from CR participation than males. Although exercise prescriptions are personalized, investigating the effect of sex-specific educational content is warranted given the differences we observed.

Abstract P3089: Predicting Reductions In Hemoglobin A1c From Large Dietary Datasets Using Artificial Intelligence Pipeline With Interpretable Encoder-Decoder Deep Neural Networks

Introduction: Artificial intelligence algorithms can help understand and predict the complex interactions between dietary intake and health outcomes, especially from large datasets. Precision nutrition leverages machine learning techniques to analyze such patterns, but the methods and uses need deeper examination. Objective: Demonstrate the viability of fully unsupervised training of a β-Variational Autoencoder (β-VAE, a fully unsupervised and robust framework for capturing latent features from high-dimensional data) to predict improved hemoglobin A1c from complex population-level dietary data. Methods: Our β-VAE neural network architecture (Figure 1) was trained using 10 cycles of cross-sectional datasets from the US National Health and Nutrition Examination Survey from 1999 to 2018. Dietary data were collected with 24-hour recalls. A cumulative 102,957 participants and 5885 food/nutrient items were aggregated into 547 interpretable latent variables. Results: The trained network performance was evaluated through an aggregated multi-participant study case (n=1000) that explored the relationship between the target hemoglobin A1c change percentage and associated potential changes in participants' diet. Among the top five dietary changes required to achieve a 20% reduction in the latent space value corresponding to hemoglobin A1c were increasing coffee/tea and seafood intake and decreasing sweets, pizza, and salt intake (Figure 1). Conclusion: The prediction model showed a reasonable alignment with dietary recommendations despite being trained in a fully unsupervised way. β-VAE may be a first-in-class, efficient, and interpretable framework to analyze complex population-level dietary data for precision nutrition research.

Stability analysis of existing tunnels under dynamic loads during excavation of new tunnels

Mechanical ventilation energy analysis: Recruitment focuses injurious power in the ventilated lung

The progression of acute respiratory distress syndrome (ARDS) from its onset due to disease or trauma to either recovery or death is poorly understood. Currently, there are no generally accepted treatments aside from supportive care using mechanical ventilation. However, this can lead to ventilator-induced lung injury (VILI), which contributes to a 30 to 40% mortality rate. In this study, we develop and demonstrate a technique to quantify forms of energy transport and dissipation during mechanical ventilation to directly evaluate their relationship to VILI. A porcine ARDS model was used, with ventilation parameters independently controlling lung overdistension and alveolar/airway recruitment/derecruitment (RD). Hourly measurements of airflow, tracheal and esophageal pressures, respiratory system impedance, and oxygen transport were taken for six hours following lung injury to track energy transfer and lung function. The final degree of injury was assessed histologically. Total and dissipated energies were quantified from lung pressure–volume relationships and subdivided into contributions from airflow, tissue viscoelasticity, and RD. Only RD correlated with physiologic recovery. Despite accounting for a very small fraction (2 to 5%) of the total energy dissipation, RD is damaging because it occurs quickly over a very small area. We estimate power intensity of RD energy dissipation to be 100 W/m 2 , equivalent to 10% of the Sun’s luminance at the Earth’s surface. Minimizing repetitive RD events may thus be crucial for mitigating VILI.

Abstract MP71: Smoking and Biological Aging Acceleration Measured by Midlife Proteomic Aging Clocks: Insights from the Multi-Ethnic Study of Atherosclerosis (MESA)

Background: Biological age may provide unique health insights beyond chronological age. Proteomic aging clocks (PACs) assess a person’s biological age, and a positive deviation of biological age from chronological age is known as age acceleration. Smoking has been associated with greater risk of age-related diseases and conditions. It is also associated with age acceleration in previous studies that assessed biological age using DNA methylation-based epigenetic clocks; however, this association has not been investigated using PACs. Methods: A total of 5,762 participants free of CVD from the Multi-Ethnic Study of Atherosclerosis (MESA) had over 7,000 plasma proteins measured using an aptamer-based proteomic profiling platform at exam 1 (2000-2002). Two previously published midlife PACs (ARIC and Lehallier) were calculated from available proteins in MESA, and we calculated age acceleration for each PAC as residuals after regressing PAC on chronological age. We used linear regression to assess the association of self-reported smoking (status, pack-years, and secondhand smoke exposure) with age acceleration measured using both PACs, adjusting for demographics and other potential confounders. Results: The analytic sample was 52% female with a mean age of 62 years (range 45-84) and a race/ethnicity breakdown of 39% White, 12% Chinese, 26% Black, and 23% Hispanic. For smoking, 13% were current smokers, 49% had a total pack-years > 0, and 37% of never smokers had exposure to secondhand smoke. The age acceleration median was -0.15 years using the ARIC midlife PAC and -0.13 years using the Lehallier midlife PAC ( Table ). Smoking status and secondhand smoke exposure in non-smokers were not associated with age acceleration measured by either PAC. Pack-years in ever smokers was positively associated with age acceleration after adjustment for demographics only (model 1). Additional adjustment slightly attenuated the association between pack-years and age acceleration (model 2). Conclusion: Further research is needed to examine the effect of smoking on age acceleration measured by other PACs and determine how these associations compare to those between smoking and epigenetic aging clocks.

Abstract P3176: Burden of Stroke Attributable to Air Pollution in India and its Trend from 1990-2021: A cross State Comparative Assessment

Background: Stroke is a leading cause of mortality and disability worldwide, with environmental factors such as air pollution increasingly recognized as significant contributors. This study aims to evaluate the burden of stroke attributable to air pollution in India over a 31-year period. Methods: We conducted a retrospective analysis using burden of disease study 2021 from 1990 to 2021. The study focused on particulate matter (PM2.5 and PM10) as primary pollutants. The population attributable fraction (PAF) of stroke due to air pollution was calculated using risk estimates from contemporary studies, adjusted for demographic changes. Results: Over the three-decade period, the total recorded deaths attributable to air pollution-induced strokes amounted to 8,533,316, with an average of 7,983 deaths per year. The total Disability-Adjusted Life Years (DALYs) accrued due to strokes were over 204 million, averaging around 205,890 DALYs annually. Additionally, the total Years of Life Lost (YLLs) summed up to about 14,836,982, with a mean annual YLL of 192,675. Maharashtra reported the highest burden with 56,407 deaths, around 654,246 DALYs, and 611,353 YLLs due to stroke, indicating it as the state most affected by air pollution-related stroke incidents. In contrast, Sikkim reported the lowest stroke burden, with the smallest numbers across all measures: 109 deaths, 1,436 DALYs, and 1,250 YLLs. Males experienced a slightly higher stroke burden due to air pollution with 168,709 deaths and about 4,040,735 Years of Life Lost (YLLs). Females had about 148,785 deaths and approximately 3,377,256 YLLs. The 65-69 years age group had the highest number of deaths at 51,944 and over 1.26 million YLLs. This was closely followed by the 70-74 years age group, with about 54,945 deaths and over 1.10 million YLLs. Conclusion: Our findings underscore the critical need for stringent air quality control measures and public health strategies to mitigate the impact of air pollution on stroke incidence in India. Younger age groups, particularly below 25 years, show significantly lower numbers, indicating that air pollution primarily impacts the elderly in terms of stroke burden. Addressing this environmental risk factor is crucial for reducing the future burden of stroke and improving public health outcomes.

Muscle transcriptome profiles in elite male ultra-endurance athletes acclimated to a high-carbohydrate versus low-carbohydrate diet

Direct observation of cholesterol monohydrate crystallization

Cholesterol crystallization is integral to the pathology of diseases such as atherosclerosis and gallstones, yet the relevant mechanisms of crystal growth have remained elusive. Here, we use a variety of in situ techniques to examine cholesterol monohydrate crystallization over multiple length scales. In this study, we first identified a biomimetic solvent to generate triclinic monohydrate crystals, while avoiding the formation of nonphysiological solvates and enabling crystallization at rates where the dynamics of surface growth could be captured in real time. Using a binary mixture of water and isopropanol, with the latter serving as a surrogate for lipids in physiological environments, we show that cholesterol monohydrate crystals grow classically by the nucleation and spreading of crystal layers. Time-resolved imaging confirms that layers are generated by dislocations and monomers incorporate into advancing steps after diffusion along the crystal surface and not directly from the solution. In situ atomic force microscopy (AFM) and microfluidics measurements concertedly reveal abundant macrosteps, which engender a self-inhibition mechanism that reduces the rate of crystal growth. This finding stands in contrast to numerous other systems, in which classical mechanisms lead to unhindered growth by spreading of single layers.

Abstract MP75: Novel Heart Failure Stages Incorporating Cardiorespiratory Fitness are Differentially Associated with Heart Failure Risk in the Community

Background: Heart failure (HF) progresses through stages as depicted by the AHA/ACC/HFSA guidelines. These stages advance from the presence of risk factors (stage A), to asymptomatic structural heart disease, elevated filling pressures, or abnormal biomarkers (stage B), to clinical HF (stage C). However, even among individuals classified as having the highest pre-clinical risk (stage B), the majority do not progress to clinical HF. This highlights the need to identify new risk factors to refine preclinical HF phenotypes. Impaired cardiorespiratory fitness (CRF) is a powerful predictor of HF risk but is not currently considered in HF staging. Accordingly, we hypothesized that HF substages incorporating CRF would be differentially associated with HF risk. Methods: We investigated Framingham Heart Study participants with submaximal exercise testing (up to Bruce protocol stage 2) at a routine exam. CRF was estimated based on stage 2 heart rate, weight, age, sex, treadmill grade, and velocity using the equation from Loe, et al. Due to the importance of HR for determining estimated CRF, we excluded individuals on atrioventricular nodal blocking agents. We evaluated the association of HF substages (categorized by CRF above vs. below sex-specific median) with incident HF using Cox models adjusted for age and sex. Results: Our sample included 1683 individuals, 55% women, mean age 58±8 yrs, with estimated CRF 35±3mL/kg/min in women and 40±4mL/kg/min in men. A total of 522 individuals (31%) were classified as having no HF risk factors (“healthy”; stage H), 693 (41%) as stage A, and 468 (28%) as stage B. Over a median follow up of 20 years, 99 incident HF events occurred. HF incidence was highest in individuals categorized as stage B with lower than median CRF (B2, Figure 1A). Stage B participants with estimated CRF above the median did not have a significantly higher risk of HF compared to stage H participants, but those with stage B and low CRF had an over 2.5-fold higher risk of HF (hazard ratio [HR] 2.75, 95% CI 1.50-5.07, P<0.01; Figure 1B). Among stage B participants, every 1-SD higher CRF was associated with lower HF risk (HR 0.57, 95% CI 0.43-0.76, P<0.001). We did not observe an association of CRF with incident HF among individuals categorized as stage A. Conclusion: Incorporating CRF into HF staging criteria may improve risk assessment and facilitate precision targeting of preventive therapies, especially among individuals classified as stage B HF.