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Abstract Background The left ventricular (LV) force, also known as elastance, serves as a load-independent indicator of contractility and can be noninvasively assessed through echocardiography. In hypertrophic cardiomyopathy (HCM), the heightened presence of the active state of myosin heads results in an increased LV force. Purpose To assess the prognostic value of increased LV elastance at rest in patients with HCM. Methods We enrolled 1420 HCM patients (age 50±16 years, 907 males, 64%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 10 quality-controlled labs from 7 countries. TTE assessment included peak left ventricular outflow tract gradient (LVOTG), EF, and LV force (systolic blood pressure + LVOTG/LV end-systolic volume assessed with 2-D, mmHg/mL). All patients were followed up. All-cause death was the outcome measure. Results At a median follow-up of 83 months, 150 deaths occurred (Group 1). At study entry, Group 1 patients had the same ESC-Sudden cardiac death score compared to survivors (Group 2). In Group 1 compared to Group 2, TTE showed higher values of MR severity, E/e’ , left atrial volume index, estimated systolic pulmonary artery pressure, and force (see table). At multivariable Cox analysis, only age (HR =1.08, 95% CI=1.03-1.14, p=0.001) and force > median value of 5.3 mmHg/mL (HR = 2.14, 95% CI 1.53-2.99, p=0.020) were independent predictors of mortality. Ten-year survival was 95% in the pooled first (<3.8 mmHg/mL) and second (3.8-5.2 mmHg/mL) quartiles vs 80% in the pooled third (5.3-7.8 mmHg/mL) and fourth quartiles (>7.8 mmHg/mL), see figure. Conclusion HCM patients with higher values of resting LV elastance show a worse survival, highlighting the dark prognostic side of an excess of force in these patients. Table Legends E/e’, early mitral inflow to early mitral annulus motion ratio, EF, left ventricular ejection fraction, LAVI, left atrial volume index; LVOTG, left ventricular outflow tract peak gradient, MR, mitral regurgitation; MWT, maximal wall thickness, NYHA, New York Heart Association classification, RWT, relative wall thickness; SCD risk, risk score for sudden cardiac death in hypertrophic cardiomyopathy, SPAP, systolic pulmonary arterial pressure.Table.Clinical and TTE findingsFigure.Survival in the force quartiles

Abstract Background Atrial fibrillation (AF) is the most prevalent atrial tachyarrhythmia, affecting an estimated 2-4% of adults worldwide. AF is a well-recognized and treatable risk factor for stroke, but it often remains asymptomatic or subclinical, leading to underdiagnosis. This study aimed to identify distinguishing signs during exercise stress echocardiography (ESE) among patients in sinus rhythm (SR), with and without history of paroxysmal/persistent AF (PAF). Methods An international prospective cohort comprising 1035 consecutive patients was initially considered from 12 cardiology institutions. These patients were referred for clinically-driven ESE as part of the Stress Echo 2020-2030 study network. All patients underwent comprehensive ESE with the ABCDE protocol, which included assessment of B-lines, left ventricle contractile reserve (LVCR), ECG-based heart rate reserve (HRR), LV ejection fraction (EF), LV end-diastolic volume, E/e’, pulmonary artery systolic pressure estimation, tricuspid annular plane sytolic excursion (TAPSE), left atrium volume index (LAVi) and left atrium reservoir phase strain (LASr) at rest and with exercise. Results After excluding 89 patients who were in AF during the ESE, 946 patients in SR were included as the main study cohort (101 with and 845 without a history of PAF). A scoring system was then constructed using all independent variables that differentiate the two groups (those with and without history of PAF). Presence of systemic hypertension, rest LAVI>31ml/m2, rest |LASr|< 21%, stress LAVI >29 ml/m2, stress |LASr| <24%, stress E/e’ >7, ∆TAPSE <4.5 mm, HRR<1.87, and LVCR<1.6 were identified as the discriminators between patients with and without PAF. The composite score, summing all 9 items (with a total score range from 0 to 9), yielded a score of >4 as the best balance between sensitivity (87%) and specificity (60%) in predicting those with PAF. The receiver operating characteristic curve analysis of the scoring model showed an AUC of 0.79 (p-value <0.0001), Figure. Conclusion ESE evaluation can be a valuable adjunct for identifying patients in SR with history of PAF. This multifaceted approach enhances the potential for more accurate detection and clinical management of individuals in SR at risk for AF, who could be considered for aggressive monitoring programs to prevent the development of new onset AF and subsequent increase in cardiovascular risk.

ObjectivesFetal growth restriction (FGR) is commonly associated with placental dysfunction, increasing perinatal morbidity and mortality. Visualizing placental vessels in utero would be advantageous for identifying functional FGR cause and determining proper management strategies. We aimed to utilize high‐sensitivity ultrasound microvessel imaging (HUMI) for quantifying placental vessel density (VD) in pregnancies diagnosed with FGR.MethodsThis pilot case–control study enrolled subjects in the third trimester with a diagnosis of FGR (n = 40) and gestational age‐matched controls with normal fetal growth (n = 20) at a 2:1 ratio, respectively. The Verasonics Vantage ultrasound system was used to perform HUMI on each participant at one timepoint. Scanning involved randomized singular value decomposition‐based clutter filtering to identify the villous tree, followed by step‐by‐step scanning to acquire 3‐dimensional‐like data. Mean VD was calculated from three ultrasound measurements per subject. Additional clinical and pathology data were also collected and compared.ResultsSixteen participants were utilized to establish the scanning protocol and 2 met exclusion criteria at delivery. Thus, VD was successfully measured on 42 pregnancies scanned at 35 weeks 5 days on average. In FGR (n = 24), placental VD was significantly reduced compared to controls (P < .01). VD measures were as good at predicting FGR as systolic/diastolic (S/D) ratios (area under the curve 0.86 versus 0.80). In a smaller cohort, VD in placentas with a diagnosis of inflammatory villitis (n = 10) by histology showed an increase in VD compared to those without inflammation (P = .01). Low VD was correlated with increased S/D ratios (P = .03).ConclusionsHUMI is useful for identifying altered placental vascularization in utero for FGR. VD may be a valuable indicator for placental health and could lead to improved risk stratification methods considering underlying biology.

Key Points The rat arteriovenous fistula (AVF) model exhibits marked upregulation of p16 Ink4a and p21 Cip1 and multiple markers of senescence. Fisetin, an established vasoprotective senolytic agent, when administered for 3 weeks, increases AVF blood flow and AVF outward remodeling. Heme is shown to be a novel prosenescence metabolite, and when chronically administered, it decreases AVF blood flow. Background Maturational failure of dialysis arteriovenous fistulas (AVFs) not uncommonly occurs and is of considerable and timely importance. Our prior studies demonstrate that senescence, a phenotypic process that promotes vascular and other diseases, occurs in the murine AVF. In this study, we examined whether senescence also occurs in the rat AVF model and the effect of compounds that inhibit or accelerate senescence. Methods The rat AVF was created in the femoral vessels by an end vein-side artery anastomosis. In the AVF, we assessed the expression of critical drivers of senescence, specifically, the cell cycle inhibitors p16 Ink4a and p21 Cip1 , and such indices of a senescence phenotype as senescence-associated β -galactosidase (SA- β -gal) activity, SA- β -gal staining, and a senescence-associated secretory phenotype. We examined the effects of compounds that retard or accelerate senescence on AVF blood flow. Results The AVF evinced upregulation of p16 Ink4a and p21 Cip1 when assessed 3 days after AVF creation. The AVF also demonstrated increased SA- β -gal activity in the artery and vein; staining for SA- β -gal in the AVF artery, anastomosis, and vein; and a prominent senescence-associated secretory phenotype. Fisetin, an established senolytic that is protective in other models of vascular injury, when administered for 3 weeks, increased AVF blood flow and outward remodeling. Hemin, when administered for 3 weeks, decreased AVF blood flow. We demonstrate that hemin is a novel inducer of a senescence phenotype in endothelial cells, as reflected by several senescence indices. However, when administered relatively acutely (for 5 days), hemin increased AVF blood flow by heme oxygenase–dependent mechanisms because the latter was entirely prevented by a competitive inhibitor of heme oxygenase activity. Conclusions The rat AVF exhibits senescence within 3 days of its creation. Chronic administration of a senolytic compound (fisetin) increases AVF blood flow, whereas chronic administration of a prosenescence compound (hemin) decreases AVF blood flow.

Abstract Disclosure: D. Segura Torres: None. K. Raygoza: None. M. Garcia: None. J.P. Brito: None. M.E. McDonnell: None. M. Corrigan: None. C.R. McCartney: None. R. Dhaliwal: None. N.M. Singh Ospina: None. Clinical practice guidelines (CPG) improve healthcare quality by guiding decision making. Recent trends in CPG development emphasize incorporating race/ethnicity terms and health equity considerations. However, the appropriateness of how race/ethnicity is utilized remains uncertain. Objective This study seeks to evaluate the use of race/ethnicity in published Endocrine Society (ES) CPG and elucidate the context in which race and ethnicity terms are used. Methods: We identified 30 active clinical practice guidelines from ES up to January 2023. Two reviewers independently and in duplicate: a) located statements addressing race/ethnicity using an electronic search with 24 keywords, b) determined the statements' location within guidelines, and c) classified them based on content using frameworks by Cerdena and Gilliam. Disagreements were resolved by consensus. Exclusions were made for statements not addressing race and ethnicity terms in the appropriate context (e.g., “minority” of the panel disagreed), as well as for those in references or duplicates. Results: We reviewed 30 clinical practice guidelines, with 19 of them containing statements related to race or ethnicity. After applying exclusion criteria, we identified a final analytic sample of 114 statements. The majority of these statements were found in the body of the clinical guidelines (79%), followed by the evidence-to-decision framework (14%), and clinical recommendations (7%).The predominant classification were statements in which there was biologization of race/ethnicity 55% (n=63). Discussions on racial/ethnic disparities accounted for 23% (n=26) of the statements, with 31% (n=8) of these including explicit considerations of social context. Additionally, there were descriptions of race-specific treatment or diagnosis/screening in 14% (n=16) and 9% (n=10) of the statements, respectively.Less commonly statements of race/ethnicity reflected the consideration of ancestry as a code for race/ethnicity (n=7, 6%), identified ancestry as a risk factor for disease (n=19, 6%), highlighted racial/ethnic groups as understudied n=6, 5%), normalized findings to the majority group (White centeredness) (n=7, 6%), and other categories (7%). None of the statements employed race/ethnicity terms to emphasize cultural humility or the value of inclusivity in guideline committees. Conclusion: We systematically analyzed how race and ethnicity terms are used in ES CPGs. Our findings align with prior assessments made in non-ES CPG, highlighting the prevalent biologization of race and ethnicity constructs. Addressing this trend and incorporating socio-structural context considerations could bolster the impact of clinical guidelines in promoting health equity. Presentation: 6/1/2024

SummaryDespite the clinical and molecular heterogeneity of follicular lymphoma (FL), there remains a lack of biomarker‐directed therapeutic approaches in routine clinical practice, with the notable exception of the EZH2 inhibitor tazemetostat in EZH2‐mutant FL. Here we examined whether gene mutation status predicts response to clinical mTOR inhibitors (mTORi) in FL, by performing targeted mutational profiling of biopsies from 21 relapsed/refractory FL patients treated with mTORi everolimus or temsirolimus within clinical trials. We observed an enrichment of mutations within the catalytic histone acetyltransferase (HAT) domain of CREBBP in mTORi‐responders, and describe distinct transcriptional characteristics and co‐occurring mutations of FL harbouring these mutations; reinforcing the growing appreciation of CREBBPHAT mutation as a key biological determinant and its promise as a therapeutic biomarker in FL.

3051 Background: Clonal hematopoiesis (CH), characterized by the presence of somatic mutations in blood cells, can be found in cancer-related genes when sequencing tumor tissue or plasma samples. Inability to distinguish somatic, tumor-derived mutations from CHm can lead to inaccurate treatment decisions. In this prospective study, we confirmed potential CHm in solid tumors by sequencing and analysis of paired matched normal (PMN) specimens. Methods: We prospectively enrolled 56 patients diagnosed with advanced cancer, including lung (16), colorectal (13), breast (10), gastric (7), ovarian (2), pancreatic (2), liver (2), cervix (1), uterine (1), fallopian tube (1), and perihilar bile duct (1). Targeted next-generation sequencing using a 523 gene panel was performed on paired formalin-fixed paraffin-embedded (FFPE) and circulating tumor DNA (ctDNA) samples. Additionally, whole exome sequencing was performed on PMN buffy coat samples. Analysis of all three specimens was performed to classify somatic mutations as tumor-derived or CHm. Results: We identified 21 potential CHm within the FFPE and ctDNA samples of 13 patients (23.2% of the cohort) with lung (7), breast (2), liver (2), colorectal (1), and gastric (1) cancers. CHm were further confirmed when present in buffy coat samples. The VAF of CHm in FFPE and ctDNA samples exhibited a wide range, spanning from 0.85% to 38.4%, with 7 of those identified at <2% VAF. For these same aberrations, VAF in buffy coat samples ranged from 1.6% to 48%, with seven mutations exhibiting VAF levels <5%. Four of these CHm were classified as oncogenic or likely oncogenic. Four CHm, including an oncogenic TP53 mutation, were identified in the oldest patient (75 years old, lung cancer), while an oncogenic DNMT3A mutation was detected in the youngest patient (42 years old, breast cancer). Both had a 30-year history of smoking. Conclusions: Our findings identified somatic CHm in a substantial subset (23.2%) of solid tumors, with four identified as oncogenic or likely oncogenic mutations. The broad spectrum of VAFs for CHm suggests that using VAF as a cut-off to exclude likely CHm may be unreliable. The low VAF CHm found in matched normal specimens indicates low-pass sequencing may not detect critical CHm, even in paired analysis. The diverse age range of patients with CHm (42 to 75 years old) suggests that CHm are not restricted to older populations, and that additional factors, such as smoking history, may play a role. These findings underscore the importance of incorporating routine PMN buffy coat sequencing into clinical practice, to identify somatic CHm that can impact personalized cancer treatment strategies.

Abstract Background Hypercontractile phenotype (HP) of the left ventricle (LV) is an actionable therapeutic target in patients with chronic coronary syndromes (CCS) or heart failure (HF), but its clinical recognition remains difficult. Objectives To assess the clinical variables associated with the HP. Methods In a prospective, observational, multicenter study, we recruited 5,122 patients (age 65 ± 11 years, 2974 males, 58%) with CCS and/or HF with preserved ejection fraction (EF). Systolic blood pressure (SBP) was measured. We assessed wall motion score index (WMSI), LV end-diastolic volume (EDV), end-systolic volume (ESV), EF, force (SBP/ESV), stroke volume (SV), arterial elastance (SBP/SV), and ventricular-arterial coupling (VAC, as SV/ESV). Univariable and multivariable logistic regression analysis assessed independent factors associated with the highest force sextile. Results For all the studied patients, force was 4.51 ± 2.11 mmHg/ml, with the highest sextile (Group 6) > 6.36 mmHg/ml. By multivariable logistic regression model, the highest sextile of force was associated with age > 65 years (OR 1.62, 95% CI 1.36–1.93, p < 0.001), hypertension (OR 1.76, 95% CI 1.40–2.21, p < 0.001), female sex (OR 4.52, 95% CI 3.77–5.42, p < 0.001), absence of beta-blocker therapy (OR 1.41, 95% CI 1.16–1.68), rest SBP ≥ 160 mmHg (OR 2.81, 95% CI 2.21–3.56, p < 0.001), high heart rate (OR 2.08, 95% CI 1.61–2.67, p < 0.001), and absence of prior myocardial infarction (OR 1.34, 95% CI 1.07–1.68, p = 0.012). Patients in the highest sextile of force showed lower values of WMSI, SV, EDV, and ESV, and higher values of arterial elastance and VAC. Conclusions HP of the LV with high force was clinically associated with advanced age, female sex, high resting SBP, and the absence of 𝛽-blocker therapy. By transthoracic echocardiography, HP was associated with a small heart with reduced EDV, reduced SV despite high EF, and higher arterial elastance.