Heart Age Research Articles

Accelerated DNA methylation age plays a role in the impact of cardiovascular risk factors on the human heart

BackgroundDNA methylation (DNAm) age acceleration (AgeAccel) and cardiac age by 12-lead advanced electrocardiography (A-ECG) are promising biomarkers of biological and cardiac aging, respectively. We aimed to explore the relationships between DNAm age and A-ECG heart age and to understand the extent to which DNAm AgeAccel relates to cardiovascular (CV) risk factors in a British birth cohort from 1946.ResultsWe studied four DNAm ages (AgeHannum, AgeHorvath, PhenoAge, and GrimAge) and their corresponding AgeAccel. Outcomes were the results from two publicly available ECG-based cardiac age scores: the Bayesian A-ECG-based heart age score of Lindow et al. 2022 and the deep neural network (DNN) ECG-based heart age score of Ribeiro et al. 2020. DNAm AgeAccel was also studied relative to results from two logistic regression-based A-ECG disease scores, one for left ventricular (LV) systolic dysfunction (LVSD), and one for LV electrical remodeling (LVER). Generalized linear models were used to explore the extent to which any associations between biological cardiometabolic risk factors (body mass index, hypertension, diabetes, high cholesterol, previous cardiovascular disease [CVD], and any CV risk factor) and the ECG-based outcomes are mediated by DNAm AgeAccel. We derived the total effects, average causal mediation effects (ACMEs), average direct effects (ADEs), and the proportion mediated [PM] with their 95% confidence intervals [CIs]. 498 participants (all 60–64 years) were included, with the youngest ECG heart age being 27 and the oldest 90. When exploring the associations between cardiometabolic risk factors and Bayesian A-ECG cardiac age, AgeAccelPheno appears to be a partial mediator, as ACME was 0.23 years [0.01, 0.52] p = 0.028 (i.e., PM≈18%) for diabetes, 0.34 [0.03, 0.74] p = 0.024 (i.e., PM≈15%) for high cholesterol, and 0.34 [0.03, 0.74] p = 0.024 (PM≈15%) for any CV risk factor. Similarly, AgeAccelGrim mediates ≈30% of the relationship between diabetes or high cholesterol and the DNN ECG-based heart age. When exploring the link between cardiometabolic risk factors and the A-ECG-based LVSD and LVER scores, it appears that AgeAccelPheno or AgeAccelGrim mediate 10–40% of these associations.ConclusionBy the age of 60, participants with accelerated DNA methylation appear to have older, weaker, and more electrically impaired hearts. We show that the harmful effects of CV risk factors on cardiac age and health, appear to be partially mediated by DNAm AgeAccelPheno and AgeAccelGrim. This highlights the need to further investigate the potential cardioprotective effects of selective DNA methyltransferases modulators.

A Real-Time Automated Machine Learning Algorithm for Predicting Mortality in Trauma Patients: Survey Says it's Ready for Prime-Time.

Though artificial intelligence ("AI") has been increasingly applied to patient care, many of these predictive models are retrospective and not readily available for real-time decision-making. This survey-based study aims to evaluate implementation of a new, validated mortality risk calculator (Parkland Trauma Index of Mortality, "PTIM") embedded in our electronic healthrecord ("EHR") that calculates hourly predictions of mortality with high sensitivity and specificity. This is a prospective, survey-based study performed at a level 1 trauma center. An anonymous survey was sent to surgical providers and regarding PTIM implementation. The PTIM score evaluates 23 variables including Glasgow Coma Score (GCS), vital signs, and laboratory data. Of the 40 completed surveys, 35 reported using PTIM in decision-making. Prior to reviewing PTIM, providers identified perceived top 3 predictors of mortality, including GCS (22/38, 58%), age (18/35, 47%), and maximum heart rate (17/35, 45%). Most providers reported the PTIM assisted their treatment decisions (27/35, 77%) and timing of operative intervention (23/35, 66%). Many providers agreed that PTIM integrated into rounds and patient assessment (22/36, 61%) and that it improved efficiency in assessing patients' potential mortality (21/36, 58%). Artificial intelligence algorithms are mostly retrospective and lag in real-time prediction of mortality. To our knowledge, this is the first real-time, automated algorithm predicting mortality in trauma patients. In this small survey-based study, we found PTIM assists in decision-making, timing of intervention, and improves accuracy in assessing mortality. Next steps include evaluating the short- and long-term impact on patient outcomes.

Transcriptomes of aging brain, heart, muscle, and spleen from female and male African turquoise killifish

The African turquoise killifish is an emerging vertebrate model organism with great potential for aging research due to its naturally short lifespan. Thus far, turquoise killifish aging ‘omic’ studies have examined a single organ, single sex and/or evaluated samples from non-reference strains. Here, we describe a resource dataset of ribosomal RNA-depleted RNA-seq libraries generated from the brain, heart, muscle, and spleen from both sexes, as well as young and old animals, in the reference GRZ turquoise killifish strain. We provide basic quality control steps and demonstrate the utility of our dataset by performing differential gene expression and gene ontology analyses by age and sex. Importantly, we show that age has a greater impact than sex on transcriptional landscapes across probed tissues. Finally, we confirm transcription of transposable elements (TEs), which are highly abundant and increase in expression with age in brain tissue. This dataset will be a useful resource for exploring gene and TE expression as a function of both age and sex in a powerful naturally short-lived vertebrate model.

In need of age-appropriate cardiac models: Impact of cell age on extracellular matrix therapy outcomes.

Aging is the main risk factor for cardiovascular disease (CVD). As the world's population ages rapidly and CVD rates rise, there is a growing need for physiologically relevant models of aging hearts to better understand cardiac aging. Translational research relies heavily on young animal models; however, these models correspond to early ages in human life, therefore cannot fully capture the pathophysiology of age-related CVD. Here, we first investigated the transcriptomic and proteomic changes that occur with human cardiac aging. We then chronologically aged human induced pluripotent stem cell-derived cardiomyocytes (iCMs) and showed that 14-month-old iCMs exhibited a similar aging profile to the human CMs and recapitulated age-related disease hallmarks. Using aged iCMs, we studied the effect of cell age on the young extracellular matrix (ECM) therapy, an emerging approach for myocardial infarction (MI) treatment and prevention. Young ECM decreased oxidative stress, improved survival, and post-MI beating in aged iCMs. In the absence of stress, young ECM improved beating and reversed aging-associated expressions in 3-month-old iCMs while causing the opposite effect on 14-month-old iCMs. The same young ECM treatment surprisingly increased SASP and impaired beating in advanced aged iCMs. Overall, we showed that young ECM therapy had a positive effect on post-MI recovery; however, cell age was determinant in the treatment outcomes without any stress conditions. Therefore, "one-size-fits-all" approaches to ECM treatments fail, and cardiac tissue engineered models with age-matched human iCMs are valuable in translational basic research for determining the appropriate treatment, particularly for the elderly.

Proteomics and β-hydroxybutyrylation Modification Characterization in the Hearts of Naturally Senescent Mice

Aging is widely accepted as an independent risk factor for cardiovascular disease (CVD), which contributes to increasing morbidity and mortality in the elderly population. Lysine β-hydroxybutyrylation (Kbhb) is a novel post-translational modification (PTM), wherein β-hydroxybutyrate is covalently attached to lysine ε-amino groups. Recent studies have revealed that histone Kbhb contributes to tumor progression, diabetic cardiomyopathy progression, and postnatal heart development. However, no studies have yet reported a global analysis of Kbhb proteins in aging hearts or elucidated the mechanisms underlying this modification in the process. Herein, we conducted quantitative proteomics and Kbhb PTM omics to comprehensively elucidate the alterations of global proteome and Kbhb modification in the hearts of aged mice. The results revealed a decline in grip strength and cardiac diastolic function in 22-month-old aged mice compared to 3-month-old young mice. High-throughput liquid chromatogram-mass spectrometry analysis identified 1710 β-hydroxybutyrylated lysine sites in 641 proteins in the cardiac tissue of young and aged mice. Additionally, 183 Kbhb sites identified in 134 proteins exhibited significant differential modification in aged hearts (fold change (FC) > 1.5 or <1/1.5, p < 0.05). Notably, the Kbhb-modified proteins were primarily detected in energy metabolism pathways, such as fatty acid elongation, glyoxylate and dicarboxylate metabolism, tricarboxylic acid cycle, and oxidative phosphorylation. Furthermore, these Kbhb-modified proteins were predominantly localized in the mitochondria. The present study, for the first time, provides a global proteomic profile and Kbhb modification landscape of cardiomyocytes in aged hearts. These findings put forth novel possibilities for treating cardiac aging and aging-related CVDs by reversing abnormal Kbhb modifications.

SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B.

Aging is a major risk factor contributing to pathophysiological changes in the heart, yet its intrinsic mechanisms have been largely unexplored in primates. In this study, we investigated the hypertrophic and senescence phenotypes in the hearts of aged cynomolgus monkeys as well as the transcriptomic and proteomic landscapes of young and aged primate hearts. SIRT2 was identified as a key protein decreased in aged monkey hearts, and engineered SIRT2 deficiency in human pluripotent stem cell-derived cardiomyocytes recapitulated key senescence features of primate heart aging. Further investigations revealed that loss of SIRT2 in human cardiomyocytes led to the hyperacetylation of STAT3, which transcriptionally activated CDKN2B and, in turn, triggered cardiomyocyte degeneration. Intra-myocardial injection of lentiviruses expressing SIRT2 ameliorated age-related cardiac dysfunction in mice. Taken together, our study provides valuable resources for decoding primate cardiac aging and identifies the SIRT2-STAT3-CDKN2B regulatory axis as a potential therapeutic target against human cardiac aging and aging-related cardiovascular diseases.

Announcement: Call for Papers: Focus Issue on Aging and Senescence in Heart and Vascular Disease

Announcement: Call for Papers: Focus Issue on Aging and Senescence in Heart and Vascular Disease

Impact of donor-recipient age-difference in adolescent heart transplantation.

The relationship between donor age and adolescent heart transplant outcomes remains incompletely understood. We aimed to explore the effect of donor-recipient age difference on survival after adolescent heart transplantation. The United Network for Organ Sharing database was used to identify 2,855 adolescents aged 10-17 years undergoing isolated primary heart transplantation from 1/1/2000 to 12/31/2022. The primary outcome was 10-year post-transplant survival. Multivariable Cox regression identified predictors of mortality after adjusting for donor and recipient characteristics. A restricted cubic spline assessed the non-linear association between donor-recipient age-difference and the adjusted relative mortality hazard. The median donor-recipient age-difference was +3 (range -13 to +47) years, and 17.7% (n=504) of recipients had an age- difference>10 years. Recipients with an age-difference>10 years had a less favorable pre-transplant profile, including a higher incidence of priority status 1A (81.6%, n = 411 vs. 73.6%, n = 1730; p=.01). The 10-year survival rate was 54.6% (95% confidence interval (CI) 48.8- 60.4) among recipients with a donor-recipient age-difference>10 years and 66.9% (95% CI: 64.4-69.4) among those with an age-difference ≤10 years. An age-difference>10 years was an independent predictor of mortality (hazard ratio 1.43, 95% CI: 1.18-1.72, p<.001). Spline analysis demonstrated that the adjusted mortality hazard increased with increasingly positive donor-recipient age-difference and became significantly higher at an age-difference of 11 years. A donor-recipient age-difference>11 years is independently associated with higher long-term mortality after adolescent heart transplantation. This finding may help inform acceptable donor selection practice for adolescent heart transplant candidates.

Quercetin and dasatinib, two powerful senolytics in age-related cardiovascular disease.

Cellular senescence is characteristic of the development and progression of multiple age-associated diseases. Accumulation of senescent cells in the heart contributes to various age-related pathologies. Several compounds called senolytics have been designed to eliminate these cells within the tissues. In recent years, the use and study of senolytics increased, representing a promising field for finding accessible and safe therapies for cardiovascular disease (CVD) treatment. This mini-review discusses the changes in the aging heart and the participation of senescent cells in CVD, as well as the use of senolytics to prevent the progression of myocardial damage, mainly the effect of dasatinib and quercetin. In particular, the mechanisms and physiological effects of senolytics therapies in the aged heart are discussed.

Cardioprotective effect of St. Thomas’ Hospital No. 2 solution against age-related changes in aquaporin-7-deficient mice

ObjectiveThis study aimed to investigate whether St. Thomas’ Hospital No. 2 solution (STH2) is equally effective in both young and aged aquaporin-7-knockout (AQP7-KO) mice and the mechanisms by which the intra-myocardial adenosine triphosphate (ATP) content is altered during ischemia without aquaporin-7.MethodsIn study 1, isolated hearts of male wild-type (WT) and AQP7-KO mice (< 12 weeks old) were Langendorff perfused with 5-min STH2 prior to a 20-min global ischemia (GI) or 25-min GI without STH2. Similarly, in Study 2, hearts from WT and AQP7-KO mice (≥ 24 weeks old) were subjected to 2-min STH2 infusion prior to GI. In study 3, intra-myocardial ATP content was compared before (sham) and after (control or STH2) ischemia in mature WT and AQP7-KO mice.ResultsIn study 1, troponin T levels (ng/g wet weight) of WT and AQP7-KO hearts were significantly lower in the STH2 groups (75.6 ± 45.9 and 80.2 ± 52.2, respectively) than in the GI groups (934.0 ± 341.1 and 1089.3 ± 182.5, respectively). In Study 2, troponin T levels in aged WT and AQP7-KO mice were 566.5 ± 550.0 and 547.8 ± 594.3, respectively (p = 0.9561). In Study 3, ATP levels (μmol/g protein) in the sham, control, and STH2 AQP7-KO mice groups were 4.45, 2.57, and 3.37, respectively(p = 0.0005).ConclusionsThe present study revealed the cardio-protective efficacy of STH2 in an experimental model of isolated AQP7-KO young and aged murine hearts. Further, STH2 preserved intra-myocardial ATP during ischemia with Krebs–Henseleit buffer perfusion in the Langendorff setting.

Cardiac Aging Is Promoted by Pseudohypoxia Increasing p300-Induced Glycolysis.

Heart failure is typical in the elderly. Metabolic remodeling of cardiomyocytes underlies inexorable deterioration of cardiac function with aging: glycolysis increases at the expense of oxidative phosphorylation, causing an energy deficit contributing to impaired contractility. Better understanding of the mechanisms of this metabolic switching could be critical for reversing the condition. To investigate the role of 3 histone modifications (H3K27ac, H3K27me3, and H3K4me1) in the metabolic remodeling occurring in the aging heart, we cross-compared epigenomic, transcriptomic, and metabolomic data from mice of different ages. In addition, the role of the transcriptional coactivator p300 (E1A-associated binding protein p300)/CBP (CREB binding protein) in cardiac aging was investigated using a specific inhibitor of this histone acetyltransferase enzyme. We report a set of species-conserved enhancers associated with transcriptional changes underlying age-related metabolic remodeling in cardiomyocytes. Activation of the enhancer region of Hk2-a key glycolysis pathway gene-was fostered in old age-onset mouse heart by pseudohypoxia, wherein hypoxia-related genes are expressed under normal O2 levels, via increased activity of P300/CBP. Pharmacological inhibition of this transcriptional coactivator before the onset of cardiac aging led to a more aerobic, less glycolytic, metabolic state, improved heart contractility, and overall blunting of cardiac decline. Taken together, our results suggest how epigenetic dysregulation of glycolysis pathway enhancers could potentially be targeted to treat heart failure in the elderly.

The link between obesity and aging - insights into cardiac energy metabolism

Obesity and aging are well-established risk factors for a range of diseases, including cardiovascular diseases and type 2 diabetes. Given the escalating prevalence of obesity, the aging population, and the subsequent increase in cardiovascular diseases, it is crucial to investigate the underlying mechanisms involved. Both aging and obesity have profound effects on the energy metabolism through various mechanisms, including metabolic inflexibility, altered substrate utilization for energy production, deregulated nutrient sensing, and mitochondrial dysfunction. In this review, we aim to present and discuss the hypothesis that obesity, due to its similarity in changes observed in the aging heart, may accelerate the process of cardiac aging and exacerbate the clinical outcomes of elderly individuals with obesity.

Age, sex, endurance capacity, and chronic heart failure affect central and peripheral factors of oxygen uptake measured by non-invasive and continuous technologies: support of pioneer work using invasive or non-continuous measures.

It is known that maximum oxygen uptake depends on age, sex, endurance capacity, and chronic heart failure. However, due to the required invasive or often applied non-continuous approaches, less is known on underlying central and peripheral factors. Thus, this study aimed to investigate the effects of age, sex, endurance capacity, and chronic heart failure on non-invasively and continuously measured central and peripheral factors of oxygen uptake. 15 male children (11 ± 1 years), 15 male (24 ± 3 years) and 14 female recreationally active adults (23 ± 2 years), 12 male highly trained endurance athletes (24 ± 3 years), and 10 male elders (59 ± 6 years) and 10 chronic heart failure patients (62 ± 7 years) were tested during a cardiopulmonary exercise test on a cycling ergometer until exhaustion for: blood pressure, heart rate, stroke volume, cardiac output, cardiac power output, vastus lateralis muscle oxygen saturation, and (calculated) arterio-venous oxygen difference. For the non-invasive and continuous measurement of stroke volume and muscle oxygen saturation, bioreactance analysis and near-infrared spectroscopy were used, respectively. A two-factor repeated measure ANOVA and partial eta-squared effect sizes () were applied for statistical analyses at rest, 80, and 100% of oxygen uptake. For the age effect, there were statistically significant group differences for all factors (p ≤ .033; ). Concerning sex, there were group differences for all factors (p ≤ .010; ), except diastolic blood pressure and heart rate (p ≥ .698; ). For the effect of endurance capacity, there were no group differences for any of the factors (p ≥ .065; ). Regarding chronic heart failure, there were group differences for the heart rate and arterio-venous oxygen difference (p ≤ .037; ). Age, sex, endurance capacity, and chronic heart failure affect central and peripheral factors of oxygen uptake measured by non-invasive and continuous technologies. Since most of our findings support pioneer work using invasive or non-continuous measures, the validity of our applied technologies is indirectly confirmed. Our outcomes allow direct comparison between different groups serving as reference data and framework for subsequent studies in sport science and medicine aiming to optimise diagnostics and interventions in athletes and patients.

Endoplasmic reticulum stress and alterations of peroxiredoxins in aged hearts

Aging-related cardiovascular disease is influenced by multiple factors, with oxidative stress being a key contributor. Aging-induced endoplasmic reticulum (ER) stress exacerbates oxidative stress by impairing mitochondrial function. Furthermore, a decline in antioxidants, including peroxiredoxins (PRDXs), augments the oxidative stress during aging. To explore if ER stress leads to PRDX degradation during aging, young adult (3 mo.) and aged (24 mo.) male mice were studied. Treatment with 4-phenylbutyrate (4-PBA) was used to alleviate ER stress in young adult and aged mice. Aged hearts showed elevated oxidative stress levels compared to young hearts. However, treatment with 4-PBA to attenuate ER stress reduced oxidative stress in aged hearts, indicating that ER stress contributes to increased oxidative stress in aging. Moreover, aging resulted in reduced levels of peroxiredoxin 3 (PRDX3) in mitochondria and peroxiredoxin 4 (PRDX4) in myocardium. While 4-PBA treatment improved PRDX3 content in aged hearts, it did not restore PRDX4 content in aged mice. These findings suggest that ER stress not only leads to mitochondrial dysfunction and increased oxidant stress but also impairs a vital antioxidant defense through decreased PRDX3 content. Additionally, the results suggest that PRDX4 may contribute an upstream role in inducing ER stress during aging.

Announcement: Call for Papers: Focus Issue on Aging and Senescence in Heart and Vascular Disease

Announcement: Call for Papers: Focus Issue on Aging and Senescence in Heart and Vascular Disease

Survival After Cardiac Transplantation in Adults With Single-Ventricle Congenital Heart Disease

BackgroundWithout large-scale analyses of adults with single-ventricle congenital heart disease (CHD) undergoing heart transplantation, little evidence exists to guide listing practices and patient counseling. ObjectivesThis study aims to evaluate survival after heart transplantation in adults with single and biventricular CHD and compare it to that of non-CHD transplant recipients. MethodsIn this 15-year (2005-2020) retrospective analysis, outcome-blinded investigators used probability-linkage to merge the National (Nationwide) Inpatient Sample and Organ Procurement and Transplantation Network data sets. ResultsOf 382 adult (≥18 years of age) heart transplant recipients with CHD, 185 (48%) had single-ventricle physiology. Compared to biventricular CHD, single-ventricle patients showed significantly reduced survival at 1 (80% vs 91%; HR: 2.50; 95% CI: 1.40-4.49; P = 0.002) and 10 years (54% vs 71%; HR: 2.10; 95% CI: 1.38-3.18; P < 0.001). Among patients who survived the first post-transplantation year, biventricular CHD patients exhibited similar 10-year survival as single-ventricle patients, except for those with hypoplastic left heart syndrome (79% vs 71%; HR: 1.58; 95% CI: 0.85-2.92; P = 0.15). Additionally, biventricular CHD transplant recipients showed significantly better 10-year conditional survival compared to their non-CHD counterparts (79% vs 68%; HR: 0.73; 95% CI: 0.59-0.90; P = 0.003). ConclusionsAmong adult CHD transplant recipients, single-ventricle physiology correlated with higher short-term mortality. However, 10-year conditional survival was similar for biventricular and most single-ventricle CHD patients, and notably better for biventricular CHD patients compared to non-CHD heart transplant recipients. These findings have significant implications towards patient selection and listing strategies, easing concerns related to heart transplantation in adults with CHD and destigmatizing most subtypes of single-ventricle CHD.

Cardioprotective effect of naringin against the ischemia/reperfusion injury of aged rats.

Aging is known as a main risk factor in the development of cardiovascular diseases. Naringin (NRG) is a flavonoid compound derived from citrus fruits. It possesses a wide spectrum of pharmacological properties, including antioxidant anti-inflammatory, and cardioprotective. This investigation aimed to assess the cardioprotective effect of NRG against the ischemia/reperfusion (I/R) injury in aged rats. In this study, D-galactose (D-GAL) at the dose of 150 mg/kg/day for 8 weeks was used to induce aging in rats. Rats were orally gavaged with NRG (40 or 100 mg/kg/day), in co-treatment with D-GAL, for 8 weeks. The Langendorff isolated heart was used to evaluate the effect of NRG on I/R injury in aged rats. NRG treatment diminished myocardial hypertrophy and maximum contracture level in aged animals. During the pre-ischemic phase, reduced heart rate was normalized by NRG. The effects of D-GAL on the left ventricular end diastolic pressure (LVDP), the rate pressure product (RPP), and the minimum and maximum rate of left ventricular pressure (±dp/dt) improved by NRG treatment in the perfusion period. NRG also enhanced post-ischemic recovery of cardiac functional parameters (± dp/dt, and RPP) in isolated hearts. An increase in serum levels of the lactate dehydrogenase (LDH), the creatine kinase-MB (CK-MB), and the tumor necrosis factor-alpha (TNF-α) were reversed by NRG in aged rats. It also normalized the D-GAL-decreased the superoxide dismutase (SOD) activity in the heart tissue. NRG treatment alleviated cardiac injury in aged hearts under conditions of I/R. NRG may improve aging-induced cardiac dysfunction through anti-oxidative and anti-inflammatory mechanisms.

Prognosis, characteristics, and provision of care for patients with the unspecified heart failure electronic health record phenotype: a population-based linked cohort study of 95262 individuals

Whether the accuracy of the phenotype ascribed to patients in electronic health records (EHRs) is associated with variation in prognosis and care provision is unknown. We investigated this for heart failure (HF, characterised as HF with preserved ejection fraction [HFpEF], HF with reduced ejection fraction [HFrEF] and unspecified HF). We included individuals aged 16 years and older with a new diagnosis of HF between January 2, 1998 and February 28, 2022 from linked primary and secondary care records in the Clinical Practice Research Datalink in England. We investigated the provision of guideline-recommended diagnostic investigations and pharmacological treatments. The primary outcome was a composite of HF hospitalisation or all-cause death, and secondary outcomes were time to HF hospitalisation, all-cause death and death from cardiovascular causes. We used Kaplan-Meier curves and log rank tests to compare survival across HF phenotypes and adjusted for potential confounders in Cox proportional hazards regression analyses. Of a cohort of 95,262 individuals, 1271 (1.3%) were recorded as having HFpEF, 10,793 (11.3%) as HFrEF and 83,198 (87.3%) as unspecified HF. Individuals recorded as unspecified HF were older with a higher prevalence of dementia. Unspecified HF, compared to patients with a recorded HF phenotype, were less likely to receive specialist assessment, echocardiography or natriuretic peptide testing in the peri-diagnostic period, or receive angiotensin-converting enzyme inhibitors, beta blockers or mineralocorticoid receptor antagonists up to 12 months after diagnosis (risk ratios compared to HFrEF, 0.64, 95% CI 0.63-0.64; 0.59, 0.58-0.60; 0.57, 0.55-0.59; respectively) and had significantly worse outcomes (adjusted hazard ratios compared to HFrEF, HF hospitalisation and death 1.66, 95% CI 1.59-1.74; all-cause mortality 2.00, 1.90-2.10; cardiovascular death 1.77, 1.65-1.90). Our findings suggested that absence of specification of HF phenotype in routine EHRs is inversely associated with clinical investigations, treatments and survival, representing an actionable target to mitigate prognostic and health resource burden. Japan Research Foundation for Healthy Aging and British Heart Foundation.

Abstract P3199: Role Of Acetylation In Regulating Mitochondrial Dysfunction In The Aged Heart

Cardiac mitochondrial dysfunction is a critical contributor to the pathogenesis of aging. Cardiac muscle is an extremely high energy demanding tissue, necessitating properly functioning mitochondria to meet this demand for contractile function. As such, complete control of mitochondrial function is indispensable to maintain cardiac efficiency. Lysine acetylation is a post-translational modification of proteins that has been shown to regulate several metabolic and biochemical processes in the mitochondria. The goal of this study is to understand the role of mitochondrial lysine acetylation in regulating mitochondrial processes in the aged heart. We observed an increased propensity towards a pro-acetylation profile resulting in increased acetylation of several cardiac mitochondrial proteins involved in metabolism, redox milieu and electron transport chain complexes in aging which was attenuated in our cardiac GCN5L1 knockout old animal. Based upon these findings, we hypothesize that mitochondrial acetyltransferase GCN5L1 has a critical role in regulating the function of mitochondrial proteins in the aged heart. Using immunoprecipitation assay, we observed an age-associated increase in acetylation of several key fatty acid oxidation and glucose oxidation proteins. This increased acetylation correlated with decreased activity of several fatty acid oxidation proteins, including short- and long-chain acyl-CoA dehydrogenase. Several mitochondrial proteins involved in mitochondrial fatty acid import and electron transport chain complexes were hyperacetylated in aging. These proteins largely exhibited increased acetylation levels in response to age that was attenuated by cardiac-specific GCN5L1 knockout. Lastly, we observed an age-associated increase in GCN5L1-mediated acetylation of the antioxidant enzyme manganese superoxide dismutase (SOD2) at lysine site K122. Acetylation of SOD2 at the K122 site has been shown to inhibit SOD2 activity. Based upon our findings, we conclude that age-associated increases in GCN5L1 expression results in derangements in cardiac fuel substrate utilization, electron transport chain complex function, and mediation of reactive oxygen species-associated damage.

Abstract P3118: Gender Differences In The Efficacy Of A Mobile-based Self-management Program For Patients With Heart Failure

Background: This study was to develop a mobile application (App) program, presenting educational materials and giving interactive feed-backs on self-management for heart failure patients and to evaluate the gender differences in the efficacy of the program. Methods: We developed a mobile App program for heart failure patients’ self-management, which included comprehensive educational materials and daily record logs for the patients. Also, it took into account the mobile use characteristics and convenience of aged heart failure patients, as well as active and instant interactions and feedback via group chat among the patients and healthcare providers. Regarding the experimental study, we employed a randomized controlled trial to evaluate the effects of the program in 66 heart failure patients. The intervention group was guided to use the mobile App program in their daily life at home for 3 months. Results: Male patients in the experimental group exhibited significantly decreased waist circumference and improved NYHA functional class than the control group after 3 months. As for female patients in the experimental group, they showed significantly improved NYHA functional class, depressive symptoms, and quality of life than the control group after 3 months. Conclusion: This mobile App program showed effective improvements in heart failure patients' symptom classes for both men and women. Also, it showed that women had overall higher positive outcomes in psychosocial aspects, such as depressive symptoms and quality of life than men. Future study is needed to develop self-management programs considering gender differences and also to understand their effectiveness according to gender.