Baseline Sex Research Articles

Multimorbidity in patients with acute heart failure across world regions and country income levels (REPORT-HF): a prospective, multicentre, global cohort study

Multimorbidity (two or more comorbidities) is common among patients with acute heart failure, but comprehensive global information on its prevalence and clinical consequences across different world regions and income levels is scarce. This study aimed to investigate the prevalence of multimorbidity and its effect on pharmacotherapy and prognosis in participants of the REPORT-HF study. REPORT-HF was a prospective, multicentre, global cohort study that enrolled adults (aged ≥18 years) admitted to hospital with a primary diagnosis of acute heart failure from 358 hospitals in 44 countries on six continents. Patients who currently or recently participated in a clinical treatment trial were excluded. Follow-up data were collected at 1-year post-discharge. The primary outcome was 1-year post-discharge mortality. All patients in the REPORT-HF cohort with full data on comorbidities were eligible for the present study. We stratified patients according to the number of comorbidities, and countries by world region and country income level. We used one-way ANOVA, χ2 test, or Mann-Whitney U test for comparisons between groups, as applicable, and Cox regression to analyse the association between multimorbidity and 1-year mortality. Between July 23, 2014, and March 24, 2017, 18 553 patients were included in the REPORT-HF study. Of these, 18 528 patients had full data on comorbidities, of whom 11 360 (61%) were men and 7168 (39%) were women. Prevalence rates of multimorbidity were lowest in southeast Asia (72%) and highest in North America (92%). Fewer patients from lower-middle-income countries had multimorbidity than patients from high-income countries (73% vs 85%, p<0·0001). With increasing comorbidity burden, patients received fewer guideline-directed heart failure medications, yet more drugs potentially causing or worsening heart failure. Having more comorbidities was associated with worse outcomes: 1-year mortality increased from 13% (no comorbidities) to 26% (five or more comorbidities). This finding was independent of common baseline risk factors, including age and sex. The population-attributable fraction of multimorbidity for mortality was higher in high-income countries than in upper-middle-income or lower-middle-income countries (for patients with five or more comorbidities: 61% vs 27% and 31%, respectively). Multimorbidity is highly prevalent among patients with acute heart failure across world regions, especially in high-income countries, and is associated with higher mortality, less prescription of guideline-directed heart failure pharmacotherapy, and increased use of potentially harmful medications. Novartis Pharma. For the Arabic, French, German, Hindi, Mandarin, Russian and Spanish translations of the abstract see Supplementary Materials section.

Sex-differences in proteasome-dependent K48-polyubiquitin signaling in the amygdala are developmentally regulated in rats

BackgroundSex differences have been observed in several brain regions for the molecular mechanisms involved in baseline (resting) and memory-related processes. The ubiquitin proteasome system (UPS) is a major protein degradation pathway in cells. Sex differences have been observed in lysine-48 (K48)-polyubiquitination, the canonical degradation mark of the UPS, both at baseline and during fear memory formation within the amygdala. Here, we investigated when, how, and why these baseline sex differences arise and whether both sexes require the K48-polyubiquitin mark for memory formation in the amygdala.MethodsWe used a combination of molecular, biochemical and proteomic approaches to examine global and protein-specific K48-polyubiquitination and DNA methylation levels at a major ubiquitin coding gene (Uba52) at baseline in the amygdala of male and female rats before and after puberty to determine if sex differences were developmentally regulated. We then used behavioral and genetic approaches to test the necessity of K48-polyubiquitination in the amygdala for fear memory formation.ResultsWe observed developmentally regulated baseline differences in Uba52 methylation and total K48-polyubiquitination, with sexual maturity altering levels specifically in female rats. K48-polyubiquitination at specific proteins changed across development in both male and female rats, but sex differences were present regardless of age. Lastly, we found that genetic inhibition of K48-polyubiquitination in the amygdala of female, but not male, rats impaired fear memory formation.ConclusionsThese results suggest that K48-polyubiquitination differentially targets proteins in the amygdala in a sex-specific manner regardless of age. However, sexual maturity is important in the developmental regulation of K48-polyubiquitination levels in female rats. Consistent with these data, K48-polyubiquitin signaling in the amygdala is selectively required to form fear memories in female rats. Together, these data indicate that sex-differences in baseline K48-polyubiquitination within the amygdala are developmentally regulated, which could have important implications for better understanding sex-differences in molecular mechanisms involved in processes relevant to anxiety-related disorders such as post-traumatic stress disorder (PTSD).

Comparison of pulse wave velocity and hypertensive response to exercise in predicting incidence of resistant hypertension

Abstract Background Resistant hypertension (RH) is strongly associated with occurrence of major cardiovascular events and death. Hypertensive response to exercise (HRE) and arterial stiffness estimated by peripheral pulse wave velocity (PWV) are surrogate markers of incident hypertension, whereas their role in predicting RH development remains uncertain. Purpose Explore the predictive role of PWV and HRE in incident RH. Methods A Comparison of HRE and PWV in predicting development of RH was performed in retrospective study with a cohort of 198 patients with known coronary artery disease (CAD). The patients performed two Bruce protocol stress tests (STs) between 01/2009 and 12/2022. The first ST was used to assess HRE and estimated PWV (ePWV) in predicting occurrence of apparent treatment-resistant hypertension (aTRH). ePWV was calculated using age and blood pressure, as previously described (1). HRE response was defined either as systolic BP (SBP) &amp;gt; 210 mmHg or difference between peak and baseline &amp;gt; 60mmHg for men (&amp;gt;190 mmHg or 50 mmHg in women) (2). aTRH was defined as resting SBP above 140mmHg in the last ST despite simultaneous use of ≥3 different antihypertensive agents. The average time between STs was 4±3 years. The incidence of major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, heart failure and stroke) were analyzed during the follow-up period of 10±3 years. Logistic and Cox regression models were used in time-to-event analysis. Data presented as: mean ± standard deviation; 95% confidence interval (CI) for odds ratios (OR); significance between groups p&amp;lt;0.05. Results The incidence of aTRH between STs was 15% (n=30), with 48% of them (n=14) receiving ≥4 or more antihypertensive drugs. aTRH vs non-aTRH were similar at baseline for sex (89% male, p=0.67), hypertension (HT, 62%,p=0.08), dyslipidemia (79%, p=0.86), smoke (46%, p=0.50), chronic kidney disease (13%, p=0.39), myocardial infarction (75%, p=0.39), heart failure (4.5%, p=0.40), but not for body mass index (30±3 vs 28±3 kg/m2, p=0.012) and diabetes (60.0 vs 28.6%, p=0.003) that were higher in the aTRH group. The average ePWV was 9.3±1.6 m/s (9.14±1.5 vs 10.2±1.7 m/s, non-aTRH vs aTRH p=0.001); 22.6% patients had HRE (20.4% vs 36.0%, non-aTRH vs aTRH, p=0.084). In contrast to HRE (adjusted OR=1.34, CI 0.4-4.3, p=0.62), ePWV was correlated with aTRH (adjusted OR=2.0, CI 1.1-4.1, p=0.024) after adjusting for age, comorbidities and anti-HT drugs, with an area under the ROC curve of 0.7 (CI 0.6-0.8). Both aTHR (OR=2.6, CI 1.2-5.8, p=0.017) and ePWV (adjusted OR=1.3, CI 1.2-5.8, p=0.024) were associated with MACE. Conclusion ePWV is a simple and robust marker that outperforms HRE in predicting aTRH and MACE in CAD patients. Higher ePWV values were independently associated with the incidence of aTRH. This study strengthens the importance of developing new strategies to control arterial stiffness in the treatment of RH and prevention of MACE.

Echocardiographic characterization of patients with supranormal ejection fraction: pooled core laboratory analysis of the TOPCAT and PARAGON-HF trials

Abstract Background Patients with heart failure and supranormal ejection fraction (HFsnEF) may be phenotypically distinct from those with normal or below normal left ventricular ejection fraction (LVEF), and may demonstrate different prognostic trajectories or treatment responses. Purpose To characterize clinical features, cardiac structure and function among patients with HF with preserved EF (defined as 45% ≤ LVEF ≤ 65%) and supranormal EF (defined as LVEF&amp;gt;65%). Methods Baseline clinical characteristics and key echocardiographic parameters from patients enrolled in the echocardiographic substudies of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist)-Americas and PARAGON-HF (Prospective Comparison of ARNI [angiotensin receptor–neprilysin inhibitor] with ARB [angiotensin-receptor blocker] Global Outcomes in Heart Failure with Preserved Ejection Fraction) were compared between patients with and without HFsnEF. Results Among 1,751 participants (mean age 73 years old, 51% women) in this pooled core laboratory analysis, 265 (15%) had HFsnEF. Participants in HFsnEF group were more likely to be women, and less likely to have prior myocardial infarction and atrial fibrillation (Table 1). Compared with those with LVEF ≤ 65%, those with LVEF &amp;gt; 65% had lower LV end-diastolic and end-systolic volume indices, lower LV mass index, higher LV relative wall thickness, and higher right ventricular fractional area change. LV geometry and measures of LV diastolic function were similar in both groups (Table 1). Global longitudinal strain (GLS) was abnormal (absolute GLS &amp;lt;16%) in 28% in those with HFsnEF compared with 53% in those with LVEF ≤ 65%. After adjusting for baseline LV ejection fraction and sex, and stratified by trial, abnormal GLS was associated with a higher risk of composite of first heart failure hospitalization or cardiovascular death (overall hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.23 – 1.98, P &amp;lt; 0.001), cardiovascular death (overall HR 2.06, 95% CI 1.35 – 3.13, P = 0.001), and heart failure hospitalization (overall HR 1.49, 95% CI 1.15 – 1.93, P = 0.003) in both HFsnEF and non-HFsnEF groups (P-interaction &amp;gt; 0.05 for all, Figure 1). Conclusions Among participants in the TOPCAT-Americas and PARAGON-HF trials, those with LVEF &amp;gt; 65% were predominantly women, had less LV remodeling, and had better RV function based on echocardiographic measures. Nevertheless, despite supranormal LVEF, GLS was abnormal in over a quarter of patients and remained an important predictor of adverse clinical outcomes in this cohort.Table 1Figure 1

Atrial fibrillation and electronic healthcare records in UK Biobank: Relevance of ascertainment in primary and secondary care for risk factor associations and patient outcomes

Abstract Background Electronic health data have played a pivotal role in the development and success of large-scale biobanks, and have enabled a range of epidemiological studies with wide-ranging applications[1]. Hospital admissions (HA) data are often used to identify individuals with disease, but this may result in incomplete ascertainment for conditions such as atrial fibrillation (AF), which often does not require hospitalisation. Understanding ascertainment through primary care (PC) data is essential to determine the potential benefits and drawbacks of using difference data sources for AF ascertainment. Purpose To explore potential differences between AF cases identified from PC and HA data with respect to participant characteristics, timing of ascertainment, and AF-related sequelae. Methods UK Biobank is a large prospective study with PC and HA data available in 230,000 participants[2]. Incident AF cases were defined using a combination of Read clinical codes in PC data and ICD-10 diagnostic and OPCS-4 procedural codes in HA data. Individuals were divided into 3 groups representing whether AF was defined using PC records only (PC-only), hospital admissions only (HA-only), or both (PC+HA). Descriptive statistics and multinomial regression were used to describe differences between groups in terms of ascertainment timing, risk factor associations, and post-AF stroke and death. Results During a median follow-up of 7 years, 7,142 incident AF cases were identified: 22% through PC-only (1571 new cases), 30% through HA-only, and 48% via PC+HA. In the latter group, when AF was first identified through PC (3827), there was an average lag of 1.3 years before it was identified in HA data, but a 5-year lag in the opposite direction (Figure 1). The patterns of associations for baseline age, sex, BMI, smoking, blood pressure, and composite clinical risk (CHARGE-AF[3]) suggested little evidence of systematic differences between the groups (Figure 2). However, the associations of AF with baseline diabetes, heart failure, myocardial infarction, and an AF polygenic risk score[4] suggested HA-only cases had a higher prevalence of cardiometabolic comorbities, but lower overall genetic AF risk. Moreover, HA-only AF cases had similar rates of subsequent stroke but substantially higher rates of death (73.2 per 1000 person-years) compared to the PC-only and PC+HA groups (6.6 and 23.1, respectively). Conclusion PC data identifies 28% additional AF cases than HA alone in UK Biobank, with important implications for the power of epidemiological studies. The strength of associations between risk factors and AF varies by ascertainment source, as do the rates of AF-related sequelae, suggesting that further studies comparing treatment in different groups may be warranted. Furthermore, for AF identified in HA alone, improved consistency and timeliness of routine recording of AF in PC may have important implications for management and risk of sequelae.

Clinician-created video education for patients with atrial fibrillation: a randomised clinical trial

Abstract Background Improved health literacy is associated with better health outcomes.(1) Atrial fibrillation (AF) is a complex condition and patient understanding of AF is poor.(2) There is little time during routine care to provide education on AF. Clinic waiting time provides an opportunity to deliver education that improves AF knowledge and engagement with clinical care. Purpose Assess the efficacy and feasibility of remotely-delivered clinician-created education for patients with AF. Methods Single-centre randomised clinical trial (ANZCTRN 12620000729921, registered 13/07/2020) conducted in adults over 18 years of age awaiting outpatient cardiac clinic appointments with electrocardiogram-confirmed AF, CHA²DS²VASc &amp;gt; 0 and an active electronic mailing address or mobile phone. Those with insufficient English proficiency to comprehend video content were excluded. Eligible participants were recruited remotely and randomised 1:1 to an internet-based intervention of 4 animated videos narrated by treating cardiologists totalling 15 minutes with the option to review videos weekly, or usual care. Recruiting staff, outcome assessors and those responsible for statistical analysis were blinded to treatment allocation. The primary outcome was Jessa AF Knowledge Questionnaire (JAKQ) score (a 16-item validated questionnaire consisting of general AF and anticoagulation-specific questions(2)) at 90 days post recruitment adjusted for baseline performance, AF diagnosis, educational level, age and sex. A sample size of 200, allowing for 15% attrition and a standard deviation of 18 described previously(2) was prospectively calculated to have 90% power (2-sided, type 1 error of 5%) to detect an 8.95% difference in 90-day AF knowledge. Results Between November 2020 and July 2022, 208 patients were randomised (104 intervention, 104 control). Mean (standard deviation) age was 65.0 (12) years, and 65.2% were male. Most (56.2%) had paroxysmal AF and 6.4% had first episode AF. Intervention participants were more likely to correctly answer JAKQ questions at 90 days (odds ratio [OR] 1.23 [95% confidence interval (CI) 1.01, 1.49]). Highly engaged participants were more likely to have higher JAKQ scores (OR 1.46 [95% CI 1.14, 1.88] among those who watched videos on 3 or more weeks compared to control). Video satisfaction was high (figure 2). There was no significant difference in satisfaction with care or education provided in clinic OR 1.32 [95% CI 0.71, 2.44]). Conclusions A clinician-created, low-cost, remotely-delivered educational intervention among patients with AF awaiting cardiac clinic appointments was highly acceptable and improved AF knowledge at 90 days. Increased intervention exposure correlated with higher knowledge scores. Future delivery of this intervention could investigate impact on medication adherence, AF burden, and patient-reported quality of life outcomes.Figure 1Figure 2

Effect of timely availability of TTR-stabilizing therapy on diagnosis, treatment initiation, and cardiovascular outcomes in transthyretin amyloid cardiomyopathy

Abstract Background Transthyretin-stabilization reduces cardiovascular morbidity and mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Despite increased access, regional differences in the availability of therapy continue to exist, and how these may affect diagnostic efficacy and cardiovascular outcomes is currently unknown. Objective To determine how access to and availability of tafamidis affected time-to-diagnosis, time-to-therapy, and cardiovascular outcomes in patients with ATTR-CM. Methods and Results 91 consecutive patients diagnosed with ATTR-CM between June 2019 and June 2021 were evaluated for TTR-stabilizing therapy with tafamidis. Access was regulated by an expanded access program for the initial 42 patients (early cohort; 46.2%), while insurance coverage was required for the latter 49 patients (facilitated access cohort, 53.8%) after local regulatory drug approval in April 2020. Tafamidis was started in 37 of 42 (88.1%), and 43 of 49 patients (87.8%), respectively. Baseline characteristics, e.g., age (76.3±6.4 vs. 77.3±6, p = 0.45), sex (male: 95.2% vs. 93.9%) and ATTR-CM disease stage (≤stage 2: 88.2% vs. 90.9%, p= 0.919) were comparable between both groups. Timely availability of tafamidis after April 2020 numerically reduced time from first presentation to diagnosis (median [months (IQR)]) from 6.2 (1.3;28.9) to 2.4 (0.7; 21.7) months (p = 0.196) and from presentation to therapy from 24.4 (10.7;46.8) to 11.8 (6.4; 32.4) months (p = 0.127). While RV function assessed by echocardiography significantly decreased in the early cohort between diagnosis and therapy initiation (S’ velocity 10±2.2 to 9.2±2.2 cm/s; p = 0.018; TAPSE 17.3±4.7 to 15.7±3.9, p = 0.008) it remained stable in the facilitated access cohort (S’ velocity 9.56±2.57 to 9.36±2.28 cm/s; p = 0.83; TAPSE 15.6±4.2 to 16.3±3.1, p = 0.45). After a median follow-up 42.3 and 24.9 months in the early and facilitated access cohort, respectively, timely availability of tafamidis in the facilitated access cohort was associated with a significant reduction of annual heart failure hospitalisations (treated: 0.12±0.34 vs. 0.5±1, p = 0.049; overall cohort: 0.17±0.37 vs. 0.35±0.47, p = 0.044). Overall, timely diagnosis of ATTR-CM within 12 months of first presentation was associated with a significant reduction in all-cause mortality [HR = 3.490 (95% CI 1.37 to 8.91), p = 0.009], prolonged survival without MACE [HR = 2.50 (95% CI 1.30 to 4.81), p = 0.006] or heart failure hospitalisation [HR = 2.52 (95% CI 1.24 to 5.16), p = 0.011]. Conclusions Availability of tafamidis numerically shortened time-to-diagnosis and time-to-therapy initiation in ATTR-CM patients. Timely diagnosis and initiation of therapy was associated with a reduction in all-cause mortality and heart failure hospitalisations.Door-to-diagnosis-therapyClinical outcomes

The effect of empagliflozin on ketone bodies in patients with heart failure with reduced ejection fraction (Empire HF)

Abstract Background The thrifty-substrate hypothesis suggests that Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors increase plasma levels of ketone bodies and create a salutary switch in myocardial fuel metabolism. Purpose We investigated the effect of SGLT2 inhibitor on plasma beta-hydroxybutyrate in patients with heart failure and reduced ejection fraction (HFrEF). Method This is a post hoc analysis of the Empagliflozin in Heart Failure Patients with Reduced Ejection Fraction (Empire HF) trial, an investigator-initiated, double-blind, randomized, placebo-controlled trial which enrolled 190 stable HFrEF patients with a left ventricular ejection fraction (LVEF) of ≤40%. Patients were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo. Analyses were performed in patients with complete data using a linear-mixed effect-model with log-transformed beta-hydroxybutyrate, adjusted for baseline beta-hydroxybutyrate value, age, sex, and type 2 diabetes. Results A total of 188 (99%) patients had available data. The groups were well-matched with respect to baseline characteristics. Mean age was 64 (SD, 11) years; LVEF was 29 (SD, 8) %, 13% had type 2 diabetes, New York Heart Association (NYHA) class II was found in 78%. Median plasma levels of beta-hydroxybutyrate were 0.10 (inter quartile range (IQR) 0.05–0.18) mmol/l at baseline, and 0.11(IQR 0.07–0.2) mmol/l at follow-up in the empagliflozin group. In the placebo group, baseline and at follow-up concentrations were 0.10 (0.06–0.17) mmol/l and 0.09 (0.05–0.15) mmol/l, respectively. Empagliflozin increased plasma levels of beta-hydroxybutyrate compared to placebo (adjusted between-groups treatment effect; Ratio of change 1.45 [95%confidence interval (CI); 1.12–1.87], p = 0.005 (Figure 1). The effect of empagliflozin on beta-hydroxybutyrate outcomes was consistent across multiple subgroups analyses including baseline median age, sex, N-terminal-pro B-type natriuretic peptide (NT-proBNP) cut-off 600 pg/mL, treatment with sacubitril–valsartan or beta-blockers, measured glomerular filtration rate (GFR) level, hemoglobin A1c (HbA1c) level, and concomitant type 2 diabetes (all P interaction&amp;gt;0.05). Conclusion In patients with HFrEF, predominantly without diabetes, short-term treatment with empagliflozin increased the levels of beta-hydroxybutyrate. The absolute changes were modest and the exact contribution of ketone bodies to the cardiovascular benefits of SGLT2 inhibitors requires further clarification.Figure 1Table 1

Abstract 12762: Plasma Lipidomic Signature of Peripheral Artery Disease in Young and Middle-Aged American Indian Individuals: The Strong Heart Family Study

Introduction: Dyslipidemia is an independent risk factor for peripheral artery disease (PAD). Ankle-brachial index (ABI) is a sensitive and cost-effective tool for screening and predicting PAD. The association between individual lipid species and the progression in subclinical PAD, assessed by change in ABI, remains to be determined, especially in understudied populations at high risk. Hypothesis: To identify individual molecular lipid species associated with PAD progression in American Indians, independent of traditional risk factors. Methods: Using an untargeted lipidomic method by liquid chromatography-mass spectrometry, we repeatedly measured 1,542 individual lipid species in 2,830 fasting plasma samples at two time points (2001-2003 and 2006-2009, mean 5 years apart) from 1,415 unique American Indians in the Strong Heart Family Study. Participants were free of prevalent PAD at both time points. ABI was measured in the right arm and bilateral (both left and right posterior tibial artery) using a handheld Doppler and was analyzed as a continuous variable. We first identified baseline lipid species associated with change in ABI by generalized estimating equation models, adjusting for baseline age, sex, BMI, smoking, eGFR, diabetes, hypertension, lipid-lowering medication and baseline ABI. We then examined the longitudinal association between change in lipid species and change in ABI, adjusting for same covariates plus baseline lipids. Results: Participants (63% female) were aged between 18-65 (mean 38) at baseline and 22-72 (mean 43) at follow-up. Higher baseline levels of 36 lipid species were positively (ORs: 1.01 - 3.60), whereas 16 lipid species were inversely (ORs: 0.26 - 0.98), associated with change in ABI. Longitudinal changes in 77 lipid species, largely glycerolipids, glycerophospholipids, and sphingolipids, were significantly associated with change in ABI during 5-year follow-up. Conclusions: Baseline plasma lipid species and their longitudinal changes over time are significantly associated with PAD progression beyond known risk factors. These findings shed light on the role of dyslipidemia in PAD among young and middle-aged American Indians who suffer high rates of obesity, diabetes and other cardiometabolic disorders.

Abstract 16764: Changes in Triglyceride Levels During Omega-3 Fatty Acid Supplementation, and Incident Cardiovascular Events: Secondary Analysis From the OMEMI Trial

Background: Elevated triglyceride levels are associated with increased cardiovascular risk. Omega-3 polyunsaturated fatty acids (n-3PUFA) are known to reduce triglyceride levels, but whether changes in triglycerides mediate any cardiovascular effects of n-3PUFA, remains unclear. Methods: In the randomized controlled OMEMI trial, 1014 elderly (70-82 years) patients with a recent acute myocardial infarction (AMI) were treated with 1.8 g/day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) or placebo (corn oil) for two years, and followed for the primary outcome of MACE (AMI, coronary revascularization, stroke, heart failure hospitalization or all-cause death). Relative changes in triglycerides from baseline to 3 months (n=920, 91%), were associated with incident MACE (N=175) using landmark Cox regression models. Results: The median (Q1-Q3) baseline triglyceride concentration was 97 (74-135) mg/dL, and higher levels were associated with higher BMI, diabetes and heart failure, in multivariable models. After 3 months of treatment, triglycerides decreased by median -10% and 0% in the n-3PUFA and placebo groups, respectively, followed by relatively stable levels at 12 and 24 months ( Figure ). Greater triglyceride reductions at 3-months were associated with a lower risk of MACE in the n-3PUFA group (HR 1.98 [95%CI 1.23-3.17] per doubling, p=0.004; Figure ), and this persisted after adjusting for baseline triglycerides, age, sex, BMI and comorbidities (HR 2.34 [1.37-3.98], p=0.002). Changes in triglycerides did not associate with MACE in the placebo group (HR 1.13 [0.63-2.02], p=0.68). Conclusion: Treatment with 1.8 g/day of EPA/DHA modestly reduced triglyceride levels and greater on-treatment triglyceride-reductions were associated with a lower risk of MACE. Although the overall OMEMI-trial was neutral, these findings suggest that n-3PUFA-related triglyceride changes may play a role with respect to cardiovascular outcomes.

Abstract 12837: Studies of Suboptimal Low Density Lipoprotein Reduction Following Lipid Lowering Therapy on Cardiovascular Outcomes in Patients With Acute Coronary Syndrome

Introduction: Current guidelines advocate achieving a fixed LDL-C target and attaining a more than half reduction of LDL-C levels. As the heterogeneity of response to lipid lowering therapy, effective LDL-C reduction is not achieved even in patients achieved a fixed LDL-C target. Aims: This study ought to investigate the clinical impact of suboptimal LDL-C reduction following lipid lowering therapy on cardiovascular outcomes in patients with acute coronary syndrome. Methods: A total of 561 consecutive ACS patients undergone PCI with measurement of LDL-C levels at the index of admission and 12 months after PCI were enrolled in the study. Based on the current guidelines, &lt;50% LDL-C reduction within 12 months were defined as suboptimal LDL-C reduction. The relationship between the suboptimal LDL-C reduction and cardiovascular events including the composite of cardiac death, myocardial infarction, target vessel reperfusion, and stent thrombosis was evaluated. Results: In the current study, under the use of lipid-lowering therapies (statin: 84.1 %; high intensity statin: 18.9 %, ezetimibe: 24.8 % and PCSK9 inhibitor: 1.2 %), 24.6 % of study population exhibited LDL-C &lt;1.4 mmol/L at 12 month after the index of PCI and 24.2 % achieved more than half reduction of LDL-C within 12 months. There were no significant differences in cardiovascular events between 2 groups according to LDL-C &lt; 1.4 mmol/L (23.2 % - 17.4 %, P = 0.15), whereas the MACEs were higher in the suboptimal reduction group than the optimal reduction group (24.9 % - 11.8 %, P= 0.007). Of note, even in patients with LDL-C &lt;1.4 mmol/L, the MACEs were highly observed in the suboptimal reduction group than the optimal reduction group (25.0 % - 12.4 %, P= 0.04). Multivariate analysis adjusting baseline LDL-C, HbA1c, sex and age revealed that suboptimal LDL-C reduction was an independent predictor of cardiovascular outcomes (HR: 0.7, 95% CI: 0.49-0.90). Conclusions: In addition to a fixed LDL-C target, more than half reduction of LDL-C following lipid lowering therapy is another relevant potential to reduce cardiovascular outcomes in patients with ACS.

CPX-351 Versus FLAG-IDA with or without Venetoclax in Previously Untreated and Relapsed or Refractory Acute Myeloid Leukemia

1. Introduction A recent randomized comparison of liposomal daunorubicin and cytarabine (CPX-351) did not improve response rates or overall survival compared with FLAG-IDA in newly diagnosed acute myeloid leukemia (AML) - although subgroup analyses appeared to show some benefit with CPX-351. The real-world outcomes of these cohorts are unknown. Additionally, there is little data on the relative outcomes of these cohorts in the relapsed or refractory (RR) setting. We aimed to explore the efficacy of CPX-351 and FLAG-IDA with or without venetoclax in newly diagnosed and RR AML outside of clinical trials. 2. Methods We analyzed 142 patients from the Project ERIS database with newly diagnosed or relapsed or refractory (RR) AML treated with CPX-351 or FLAG-IDA from January 1, 2013 to April 18, 2023 at VCU Massey Comprehensive Cancer Center. We recorded baseline patient-related and disease characteristics, including age, ECOG, Charlson comorbidity index (CCI) scores, molecular profiling and ELN 2022 cytogenetic risk, dates of regimen initiation, and survival. We used the D'Agostino &amp; Pearson method for normality testing and the t-test or Mann-Whitney (as applicable) tests for between-group comparisons. Categorical comparisons used Fischer's exact test. We applied the Bonferroni correction if multiple comparisons were made. The Wilson-Brown method was used for 95% confidence intervals. We analyzed survival by the Kaplan-Meier method with significance determined by the log-rank test. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. 3. Results First, we analyzed 43 (30.3%) patients with newly diagnosed AML fit for intensive chemotherapy: 33 (76.7%) received CPX-351 and 10 (23.3%) received FLAG-IDA. In the FLAG-IDA cohort, three (30.0%) patients received concurrent venetoclax. There were no significant differences in baseline characteristics, including age, sex, race, or CCI scores, shown in Table A. However, patients in the CPX-351 cohort had significantly worse ECOG performance status compared with the FLAG-IDA cohort (median, 1 vs 0, p = 0.007). There were no significant differences in the proportion of patients that had ELN 2022 adverse risk cytogenetics between the CPX-351 and FLAG-IDA cohorts (65.6% vs 55.6%, p = 0.701). The composite complete response rate (CRc; CR + CRi + CRh) was 53.6% (95% CI: 35.8-70.5) in the CPX-351 cohort and 62.5% (95% CI: 30.6-86.3) for FLAG-IDA (p = 0.709). The rate of MRD negativity was 33.3% for CPX-351 (95% CI: 5.9-70.0) and 50.0% (95% CI: 2.6-97.4) for FLAG-IDA. A similar proportion of patients proceeded to allogeneic stem cell transplant (alloSCT; 39.4% vs 40.0%, p &amp;gt; 0.999). There was no significant difference in the median overall survival in patients treated with CPX-351 or FLAG-IDA (16.1 m. vs 11.4 m., p = 0.129, Figure B). Next, we analyzed 96 (90.7%) patients that received FLAG-IDA and ten (9.3%) that received CPX-351 for RR AML in any subsequent line; three (2.1%) patients in the overall cohort received either CPX-351 or FLAG-IDA in the first-line setting, then crossed over to the other arm at disease progression. Sixteen (16.7%) patients received venetoclax with FLAG-IDA. There were no significant baseline differences between cohorts, as shown in Table A. The CRc for CPX-351 was 33.3% (95% CI, 5.9-70.0) compared with 47.7% (95% CI, 37.6-58.0, p = 0.681) for FLAG-IDA. The rate of MRD negativity was 50.0% (95% CI, 2.6-97.4) for CPX-351 and 66.7% for FLAG-IDA (95% CI, 39.1-86.2, p &amp;gt; 0.999). There was no significant difference in the median overall survival in patients treated with CPX-351 or FLAG-IDA (12.7 m. vs 14.5 m., p = 0.561). 4. Discussion There was no significant difference in the rates of CRc, MRD negativity, or overall survival in patients that received CPX-351 or FLAG-IDA with or without venetoclax in the first-line setting or at the time of disease progression. Both approaches appear to be viable in carefully selected cohorts of patients. A comprehensive toxicity analysis and exploratory molecular subgroup analysis are ongoing.

50 Effects of Cerebrovascular Risk Factors and Alzheimer’s Disease Pathology on Executive Function and Memory Changes: Analysis of the National Alzheimer’s Coordinating Center Cohort

Objective:A common assumption in clinical neuropsychology is that cerebrovascular risk is adversely associated with executive function, while Alzheimer’s disease (AD) primarily targets episodic memory. The goal of the present study was to determine the cross-sectional and longitudinal validity of these assumptions using validated markers of cerebrovascular and AD burden.Participants and Methods:19271 longitudinally-followed participants from the National Alzheimer Coordinating Center (NACC) database (Mean age= 72.25; SD age= 10.42; 58% women; 51.6% CDR= 0, 33.7% CDR= 0.5, 14.7% CDR&gt; 1) were included. Cognitive outcomes were a composite memory score and an executive function composite score (UDS3-EF; Staffaroni et al., 2020). Baseline presence of cerebrovascular disease was indexed by the presence of moderate to severe white matter hyperintensities or lacunar infarct on brain MRI (yes/no), while baseline AD pathology was indexed by the presence of a positive amyloid PET scan or elevated CSF AD biomarkers (yes/no). We used linear mixed effect models to assess the effects of baseline cerebrovascular disease, baseline AD pathology, and their interactions with time in study (years post baseline) controlling for baseline age, sex, education, and baseline MoCA score.Results:Baseline cerebrovascular disease was significantly associated with a lower intercept on executive functioning (between-person effect) (p &lt; -0.001, 95% CI -0.37, -0.14) but not memory, while presence of AD biomarkers was associated with a lower memory intercept (p &lt; -0.001, 95% CI -0.52, -0.39) but not executive function. However, only presence of AD pathology at baseline was associated with faster longitudinal decline on both memory and executive functioning over time. Baseline cerebrovascular disease did not independently relate to rate of cognitive decline.Conclusions:Consistent with widely held assumptions, our between-person analyses showed that MRI evidence of cerebrovascular disease was associated with worse executive functioning but not memory, while biomarker evidence of AD pathology was associated with worse memory but not executive function. Longitudinally, however, AD is the primary driver of decline in both executive and memory function. These results extend our understanding of how pathology impacts cognition in aging cohorts and highlight the importance of using longitudinal models.

The association of adolescent fitness with cardiometabolic diseases in late adulthood: A 45-year longitudinal study.

The aim of this study was to examine the associations of adolescent cardiorespiratory fitness (CRF), muscular fitness (MF), and speed-agility fitness (SA) with middle-aged cardiometabolic disease risk and explore sex differences. This 45-year prospective cohort study examined the associations between objectively measured fitness at adolescence (12-19 years) and physician-ascertained diabetes mellitus, elevated blood pressure (BP), and coronary heart disease reported either in early (37-44 years) or late (57-64 years) middle age, and self-measurement of waist circumference (WC) in late middle age. Fitness measurements for healthy adolescents in baseline included CRF (1.5 km [girls] and 2 km [boys] run), MF (standing broad jump, sit-ups, pull-ups [boys], and flexed-arm hang [girls]), and SA (50 m dash and 4 × 10 m shuttle run). Logistic regression and general linear models were adjusted for baseline age, sex, and body mass index (BMI), involving data from baseline and at least one follow-up measurement (N up to 1358, 47% males). Adolescent CRF was inversely, and regardless of adiposity, associated with middle age accumulated burden of cardiometabolic conditions in the whole sample (N = 562, ß = -0.10, 95% confidence intervals [CI] [-0.18, -0.03], p = 0.006), and elevated BP in females (N = 256, OR = 0.71, 95% CI [0.51, 0.91]). Overall, we observed stronger associations in females than in males. An inverse association of adolescent MF and SA with middle-aged WC was observed, but it did not show as consistent associations as with CRF. In this study, adolescent fitness, particularly CRF, was inversely associated with the burden of cardiometabolic conditions up to 45 years. Promotion of fitness in youth may be beneficial in preventing adulthood cardiometabolic diseases.

Association between periodontal diseases and chronic obstructive pulmonary disease: Evidence from sequential cross-sectional and prospective cohort studies based on UK Biobank.

To investigate the association between periodontal diseases, airflow limitation and incident chronic obstructive pulmonary disease (COPD) in a large-scale prospective UK Biobank cohort. Our approach comprised a cross-sectional study and a prospective cohort. Periodontal diseases were determined based on the participants' self-reported dental symptoms, including painful gums, bleeding gums and loose teeth. Logistic regression and Cox proportional hazards models were used to evaluate the association of periodontal diseases with airflow limitation and incident COPD in the cross-sectional study and the prospective cohort, respectively. The cross-sectional study involved 495,610 participants. Multivariable analysis found that periodontal diseases were significantly associated with airflow limitation (odds ratio = 1.036, 95% confidence interval [CI]: 1.015-1.059). The cohort study included 379,266 participants with a median follow-up period of 12.68 years. An elevated risk of incident COPD was associated with the presence of periodontal diseases (hazard ratio: 1.248, 95% CI: 1.174-1.326). The effect was consistent among subgroups, including baseline age (≤65 or >65 years), sex, smoking status and diabetes mellitus. Periodontal diseases are associated with airflow limitation and elevated COPD incidence. Maintaining good periodontal health in patients with chronic bronchitis and emphysema may help prevent the onset of COPD.

Persistence of Autism Spectrum Disorder From Early Childhood Through School Age

While the prevalence of autism spectrum disorder (ASD) continues to increase and early diagnosis is emphasized, there is limited information on outcomes for children diagnosed with ASD in early childhood using contemporary diagnostic criteria. To determine the frequency with which children who are clinically diagnosed with ASD at 12 to 36 months of age continue to meet diagnostic criteria for ASD at 5 to 7 years of age and to evaluate whether baseline child-specific and demographic characteristics and receipt of interventions are associated with ASD persistence. In this natural history cohort study, children who received a clinical ASD diagnosis at 12 to 36 months of age underwent a research diagnostic assessment at 5 to 7 years of age. Research assessments occurred from August 14, 2018, to January 8, 2022. Children received community-based interventions, and parents provided details about interventions received. The main outcome was persistence of ASD diagnosis based on current functioning. An experienced research psychologist assigned an ASD diagnosis (present or absent) according to criteria from the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) after the research assessment. The research assessment included administration of the Autism Diagnostic Observation Schedule-2, Autism Diagnostic Interview-Research, and a cognitive measure. Of the 213 participants diagnosed with ASD at initial clinical assessment (mean [SD] age, 24.6 [3.9] months; 177 boys [83.1%]), 79 (37.1%) did not continue to meet diagnostic criteria for ASD (nonpersistent ASD) at research assessment (mean [SD] age, 74.3 [7.1] months). All children with nonpersistent ASD had IQ of at least 70, while there was a bimodal distribution of IQ for those with persistent ASD (46 with IQ <70 and 88 with IQ ≥70). All children received some interventions, and 201 (94.4%) received ASD-specific intervention, mostly applied behavioral analysis. In a multilevel logistic regression model, the only variables associated with increased odds of being in the nonpersistent ASD group at 6 years of age were higher baseline adaptive skills (b coefficient = -0.287 [SE, 0.108]) and female sex (b = 0.239 [SE, 0.064]). The findings of this cohort study suggest that among toddlers diagnosed with ASD, baseline adaptive function and sex may be associated with persistence of ASD.

The impact of COVID-19 lockdowns on the body mass index of people living with obesity: A UK retrospective cohort study using the UK Clinical Practice Research Datalink

BackgroundRestrictions implemented by governments during the coronavirus disease 2019 (COVID-19) pandemic affected people’s eating habits and physical activity. We investigated the effect of COVID-19 lockdowns and restrictions on body mass index (BMI) and weight in a UK population, according to BMI class, sex, age and ethnicity. MethodsThis retrospective observational cohort study used the Clinical Practice Research Datalink AURUM database. Baseline spanned from 22 March 2017–22 March 2020, and the follow-up lockdown period was from 23 March 2020 (start of the lockdown in the UK) to 13 March 2021. The descriptive analysis included individuals with ≥ 1 valid BMI/weight measurements during both the baseline and follow-up periods, while the model-based analysis comprised individuals with ≥ 1 valid measurement(s) during baseline. Results were stratified by baseline BMI category, sex, age and ethnicity. ResultsIn the descriptive analysis (n = 273,529), most individuals did not change BMI category post-lockdown (66.4–83.3%). A greater proportion of women (12.6%) than men (9.5%) moved up BMI categories post-lockdown. Compared with older groups, a higher proportion of individuals < 45 years old increased post-lockdown BMI category. The model-based analysis (n = 938,150) revealed consistent trends, where changes in body weight and BMI trajectories pre- and post-lockdown were observed for women and for individuals < 45 years. ConclusionDuring COVID-19 restrictions, women and young individuals were more likely than other groups to increase BMI category and weight post-lockdown.

Sex Differences in Recovery Capital Gains Post-Incarceration

Background People with substance use disorders are highly prevalent in the carceral system. Recovery capital (RC) is the resources available to an individual to initiate or maintain substance use cessation. Sex differences have been identified in RC during both active substance use and recovery in the general population, however, less is known about these sex differences in the post-incarceration population. Methods Participants (n = 136) were those with an opioid or stimulant use disorder with past year involvement with the Iowa criminal justice system (USA), who completed the Assessment of Recovery Capital (ARC) twice over a six-month cohort study. Participants were involved in an addiction clinic that utilized active case management. Analysis of covariance evaluated changes in ARC during the study. Separate models compared total ARC and individual ARC domains, with sex as the independent variable of interest. Model means were generated for interpretation based on sex, comparing baseline and study endpoint ARC scores. Results There were no baseline sex differences in total ARC. ARC increased significantly for the group, however, males showed disproportionate growth. Females ended the study with a mean ARC of 37.8 (SD= 9.3) and males finished at 41.6 (SD= 9.3), which was a significant difference (p = 0.044); this significant difference was driven by ARC subdomains of ‘Psychological Health’ and ‘Physical Health.’ Conclusions People post-incarceration are at high risk for return to substance use. Treatment that is informed by sex-based differences may have the potential to decrease the differing rates of growth in RC between sexes.

The association of food insecurity on body mass index change in a pediatric weight management intervention.

Childhood obesity is a critical public health concern. One potential determinant to obesity that is less understood is food insecurity. To examine the association of food security status on body mass index (BMI) change in a Pediatric Weight Management Intervention (PWMI) consistent with national treatment recommendations. This analysis included 201 participants from the Healthy Weight Clinic (HWC). Using linear mixed models, we compared BMI and %BMIp95 change per year between the food insecure group and food secure group, adjusting for baseline BMI, age and sex, and SNAP enrolment. In fully adjusted models, children in households with food insecurity had a 0.50 (0.26-0.74) kg/m2 BMI increase per year and a 2.10 (1.02-3.19) %BMIp95 increase per year compared to households that were food secure. When comparing the BMI effect of the HWC between the food insecure group and food secure group, those experiencing food insecurity in the HWC had an increase in BMI compared to those with food security. These findings suggest that food insecurity may reduce the effectiveness of PWMIs consistent with national recommendations; however, more studies should be conducted to better understand this relationship.

Steroid Response Following Dropless Cataract Surgery Using Subconjunctival Triamcinolone.

To assess the rates of postoperative steroid response following dropless cataract surgery using a subconjunctival depot of triamcinolone versus conventional cataract surgery using topical prednisolone. We reviewed consecutive cataract surgery cases performed by a single surgeon to determine the likelihood of steroid response, defined as intraocular pressure (IOP) 50% above baseline or IOP > 24 mmHg postoperatively, excluding the first 72 hours. Logistic regression models were performed including baseline characteristics as exposures in the model and steroid response as the outcome. Main outcome measures were the proportion of eyes developing steroid response, risk factors for developing steroid response, and duration of steroid response. Of the 150 dropless and 218 conventional cases, 26 eyes developed steroid response (15 dropless and 11 conventional cases [10% vs 5%, P=0.096]). Risk factors for steroid response included dropless surgery (OR=2.43, 95% CI=1.03-6.02], P=0.046) and prior diagnosis of glaucoma (OR=7.18, 95% CI=2.66-19.22], P<0.001). Baseline IOP, age, sex, race, and axial length did not increase risk for steroid response. Of the eyes with steroid response, more dropless cases had an IOP elevation ≥30 days (9/15 eyes vs 1/11 eyes; P=0.008), including one patient with refractory IOP elevation in the dropless group who required urgent bilateral trabeculectomy for IOP control. Dropless cataract surgery increases the risk of prolonged steroid response postoperatively. Patients with glaucoma have an increased risk of steroid response and may not be good candidates for dropless cataract surgery with subconjunctival triamcinolone.