bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13426: Suppression of Epsin Expression Rescues Diabetes Triggered Impaired Lymphatic Function by Limiting VEGFR3 Degradation
Authors: Chen Hong
Published: April 2024

Rationale:
Impaired lymphatic circulation causes lymphedema and contributes to pathological conditions, such as diabetes. VEGF-C/VEGFR3 signaling is a crucial regulator of lymphatic development; however, whether manipulation in signaling improves lymphatic circulation under pathological conditions is unclear.

Objective:
We recently uncovered that loss of epsins in lymphatic endothelial cells (LECs) caused heightened VEGFR3 signaling and delayed lymphatic formation during development. Herein, we investigated whether elevated VEGFR3 signaling caused by epsin loss is critical for pathological lymphatic circulation in adult mice.

Methods and Results:
Using innovative near-infrared lymphatic imaging, and tail lymphedema models, we demonstrated that epsin loss accelerated recovery from diabetic secondary lymphedema. High-glucose-induced oxidative stress results in reduced VEGFR3 signaling, impaired lymphangiogenesis and delayed recovery from diabetic secondary lymphedema. The dual luciferase reporter assay system and ChIP assay showed in STZ-induced diabetic mice drove Src- and AP-1- mediated upregulation of epsin expression. Epsin deletion in primary LECs caused heightened VEGFR3 signaling and promoted
in vitro
lymphangiogenesis by preventing VEGFR3 downregulation. Mechanistically, we showed that by protecting cell surface VEGFR3 from degradation, lack of epsin rescued high-glucose-induced VEGFR3 loss, defective lymphangiogenesis
in vitro
, and ameliorated STZ-induced diabetic secondary lymphedema
in vivo
.

Conclusions:
Epsins essentially regulate lymphatic circulation through the modulation of VEGFR3 signaling. In STZ- induced diabetic mice, Src induces epsin expression via transcription factor AP-1. Epsin depletion ameliorated diabetic secondary lymphedema under hyperglycemic condition by protecting VEGFR3 from oxidative stress-induced degradation. Our findings highlight the therapeutic potential for targeted inhibition of epsins within the lymphatic endothelium as a treatment for secondary lymphedema caused by uncontrolled diabetes.

Key Words:
Epsin, VEGFR3, Lymphatics, Secondary Lymphedema, Diabetes
Abstract 13521: Cardiac Resynchronization Therapy After Prophylactic Epicardial Leads Implantation During Concomitant Cardiac Surgery: Impact on Left Ventricular Remodeling and Clinical Outcomes
Authors: Senechal Mario , Marceau Aude , Philippon François , Sarrazin Jean-François , Charbonneau Eric , Jacques Frederic , Cinq-Mars Alexandre , Dagenais François , Leroux Emilie , Voisine Pierre
Published: April 2024

Introduction:
Concomitant prophylactic epicardial leads implantation can be performed in patients with heart failure (HF) and dyssynchrony undergoing cardiac surgery, but the indication and timing of cardiac resynchronization therapy (CRT) remain controversial.

Hypothesis:
In surgical HF patients with criteria for CRT, most remain eligible for activation at distance from surgery. CRT activation can positively impact left ventricular (LV) remodeling and event-free survival.

Methods:
Forty-three patients with QRS≥120ms and EF<35% had LV epicardial leads implanted during cardiac surgery (index operation). Twenty-five of them eventually underwent CRT activation (CRT+) while 18 patients did not (CRT-). Echocardiographic data were reviewed at baseline, discharge, prior to CRT activation, and last follow-up. Re-hospitalizations for HF and cardiovascular (CV) deaths were recorded.

Results:
Clinical characteristics were similar at baseline and prior to CRT activation. At distance from the index operation (9.3±11.9 months) the majority of patients (77%) still had QRS≥120ms and EF<35%. The proportion of resynchronized patients was 25%, 50% and 75% at 1, 6 and 18 months postoperatively. CRT was associated with marked reverse LV remodeling with more pronounced reduction in LVEDV (-74±70ml vs. -14±38ml, p=0.007) and LVESV (-79±66ml vs. -25±34ml, p=0.009) and prominent increase in LVEF (+17±11% vs. +7±8%, p=0.006) at last follow-up (mean 3.5±2.1 years) compared with CRT- patients (mean 1.5±1.3 year). Including the period between index operation and CRT activation, rates per 100-patients-years of re-hospitalization for HF (16.6 vs. 1.5, p<0.0001) and the composite of re-hospitalization and death (31.5 vs. 1.5 p<0.0001) were higher in the CRT- compared to CRT+ group. Freedom from CV death was 100% at 3 years for resynchronized patients, higher than for CRT- patients (89%, 80% and 60% at 1, 2 and 3 years, respectively, p=0.002).

Conclusions:
The majority of HF patients with QRS≥120ms who undergo prophylactic implantation of epicardial leads during cardiac surgery remain eligible for CRT at distance from surgery. Delaying CRT denies them of reverse LV remodeling and results in significant increases in CV death and re-hospitalizations for HF.
Abstract 13524: Examining Variation in Interstage Mortality Rates Across the National Pediatric Cardiology Quality Improvement Collaborative: Do Lower Mortality Centers Have Lower Risk Patients?
Authors: Bates Katherine E , Pasquali Sara K , Brown David W , Manning Peter B , Uzark Karen
Published: April 2024

Introduction:
Although overall interstage mortality for infants with hypoplastic left heart syndrome has declined within the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC), variation in outcomes across centers persists. It remains unclear whether centers with lower mortality rates have lower risk interstage patients or whether differences in the type of interstage care provided may explain this variation. We examined previously established patient risk factors across NPC-QIC centers with higher and lower interstage mortality rates.

Methods:
Lower mortality NPC-QIC centers were defined as those with >25 consecutive interstage survivors, and included 7 centers. Higher mortality centers were defined as those with cumulative interstage mortality rates greater than the NPC-QIC historic baseline rate (>10%), and included 4 centers. Patient risk factors were compared between lower and higher mortality centers, accounting for within center clustering.

Results:
The 7 lower mortality centers (n=331 patients) had a lower interstage mortality rate of 2.7% compared to 13.3% in the 4 higher mortality centers (n=173 patients); p<0.0001. Post-natal diagnosis was the only risk factor less prevalent in the lower mortality centers (Figure) compared to higher mortality centers (18.4% vs. 31.8%, p=0.04). All other risk factors examined were either similar between the lower and higher mortality centers (including gestational age, anatomic diagnoses, birth weight), or more prevalent in the lower mortality centers (major syndrome- 6.9% vs. 4.0%, p=0.03; major anomalies- 7.3% vs. 4%, p=0.047).

Conclusions:
Differences in interstage mortality rates among NPC-QIC centers do not appear to be explained by a lower rate of patient risk factors in lower mortality centers. Further study is necessary to evaluate differences in interstage care practices across centers in order to identify targets for efforts to reduce variation and improve outcomes.
Abstract 13728: Poor Trunk Flexibility is Associated With Greater Progression of Age-related Arterial Stiffening: A 5-year Longitudinal Study
Authors: Gando Yuko , Yamamoto Kenta , Murakami Haruka , Kawakami Ryoko , Ohno Harumi , Sawada Susumu S , Miyatake Nobuyuki , Miyachi Motohiko
Published: April 2024

Introduction:
Low level of physical fitness, especially cardiorespiratory fitness, appear to accelerate age-related aortic stiffening. Whereas, some studies have reported that flexibility, is one of the components of physical fitness, is also associated with arterial stiffening independent of cardiorespiratory fitness in cross sectional studies. However, no longitudinal study has determined whether poor trunk flexibility might accelerate the progression of age-related aortic stiffening.

Hypothesis:
Poor trunk flexibility is associated with greater progression of age-related aortic stiffening in apparently healthy adults.

Methods:
We examined trunk flexibility and aortic stiffness progression in a 5-year follow-up study of 361 healthy men and women aged 27-73 years. Trunk flexibility was measured by a sit-and-reach test. Aortic stiffness was assessed using carotid-femoral pulse wave velocity (cfPWV) at baseline and after 5 years. To assess the effects of flexibility level on the progression of aortic stiffening, the participants were categorized into tertiles (Low, Middle, High) based on their sit-and-reach test values at baseline. ANCOVA was used to analyze the association of the annual rate of cfPWV (cm/ sec/ year) [annual ΔcfPWV = (follow-up cfPWV- baseline cfPWV) / follow-up years] across flexibility levels. Baseline age, BMI, cfPWV, brachial systolic blood pressure, cardiorespiratory fitness and sex were entered as covariates for adjustment.

Results:
The annual ΔcfPWV was significantly greater in the low (poor) flexibility group (10.95±2.49 cm/sec/year) than in the high flexibility group (2.19±2.41 cm/sec/year) (P=0.041). An inverse relationship was observed between flexibility level and the annual ΔcfPWV (P for trend = 0.042). The multiple regression analysis revealed that baseline sit and reach (β = -0.125), age (β = 0.197), cfPWV (β = - 0.432), cardiorespiratory fitness (β = -0.144), and sex (β = - 0.174) were independent correlates of ΔcfPWV. These data indicate that flexibility is associated with aortic stiffness, independent of other factors already known to be related to arterial stiffness.

Conclusions:
Poor flexibility is associated with greater progression of age-related aortic stiffening.
Abstract 13850: Achievement of Target Systolic Blood Pressure for Lowering the Risk of Major Adverse Cardiovascular Events: From the Action to Control Cardiovascular Risk in Diabetes Blood Pressure Trial
Authors: O Hartaigh Briain , Szymonifka Jackie , Okin Peter M
Published: April 2024

Background:
Prior epidemiologic studies have documented deleterious effects of more intensive systolic blood pressure (SBP) lowering in persons with diabetes mellitus (DM). Yet, whether the risk of adverse cardiovascular events might improve, as a function of achieving target SBP goals, remains to be elucidated.

Objective:
To test the efficacy of achieving target SBP less than 120 mm Hg, or below 140 mm Hg (versus those unable to achieve target SBP), for offsetting the risk of major adverse cardiovascular events (MACE).

Methods:
Data from the ACCORD BP trial were utilized, which comprised 4,732 (mean±SD age: 63±7 years; 2,258 [48%] women) persons presenting with advanced DM. Participants were randomly assigned to achieve either intensive (<120 mm Hg) or standard (<140 mm Hg) SBP control in an effort to offset the risk of MACE - defined as a composite of non-fatal myocardial infarction, non-fatal stroke, and death from cardiovascular causes.

Results:
During a median follow-up of 5.0 (interquartile range: 4.2-5.7) years, 1,939 (82%) and 2,038 (86%) persons achieved SBP targets below 120 mm Hg and 140 mm Hg in each treatment arm, respectively. In total, 208 (9%) and 237 (10%) persons belonging to the intensive and standard treatment arms experienced the composite endpoint. Multivariable Cox regression analyses revealed no significant reduction in risk of MACE for those in the intensive treatment arm, who achieved a target SBP below 120 mm Hg. Conversely, those in the standard treatment arm who achieved a target SBP of less than 140 mm Hg displayed a substantial reduction in risk of MACE (HR = 0.65, 95% CI: 0.48-0.88, P =0.005), all-cause death (HR = 0.64, 95% CI: 0.43-0.94, P =0.02), and non-fatal stroke (HR = 0.47, 95% CI: 0.26-0.87, P =0.02).

Conclusion:
Achieving a standard SBP goal between 120-140 mm Hg may prove useful for lowering the burden of cardiovascular risk in persons with DM, whereas achieving a target SBP <120 mm Hg does not appear to reduce risk.
Abstract 13874: Thrombin Activatable Fibrinolysis Inhibitor Promotes Development of Chronic Thromboembolic Pulmonary Hypertension -A Possible Novel Therapeutic Target
Authors: Satoh Taijyu , Satoh Kimio , Yaoita Nobuhiro , Kikuchi Nobuhiro , Omura Junichi , Kurosawa Ryo , Sunamura Shinichiro , Nogi Masamichi , Otsuki Tomohiro , Numano Kazuhiko , Al-Mamun Md. Elias , Abdul Hai Siddique Mohammad , Tatebe Shunsuke , Aoki Tatsuo , Sugimura Koichiro , Morser John , Shimokawa Hiroaki
Published: April 2024

Background:
The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) still remains elusive.

Methods and Results:
CTEPH patients had higher plasma levels of and prevalence of SNPs of thrombin activatable fibrinolysis inhibitor (TAFI). Plasma levels of activated TAFI (aTAFI) were significantly increased in CTEPH patients (n=32) compared with controls (n=13) (8.7-fold, P<0.01). Immunostaining showed that TAFI and its linker protein thrombomodulin (TM) were strongly expressed in the distal pulmonary arteries (PA) in CTEPH patients. TAFI-deficient mice (TAFI

–/–

) exposed to hypoxia showed significantly reduced right ventricular systolic pressure (RVSP), RV hypertrophy and PA remodeling compared with controls (all P<0.05, n=10 each). In contrast, TAFI-overexpressing mice (TAFI-Tg) exposed to hypoxia showed significantly augmented RVSP, RV hypertrophy and PA remodeling compared with controls (all P<0.01, n=19 each). Importantly, systemic TAFI-Tg mice (n=19) showed a significantly reduced survival under hypoxia compared with controls (n=22) (63% vs. 95%, P<0.01). Bone marrow transplantation demonstrated that the increased plasma levels of aTAFI, but not those in the bone marrow, promoted hypoxia-induced PA thrombus formation and PH (all P<0.01, n=10 each). Interestingly, liver-specific TAFI overexpression exacerbated hypoxia-induced PH compared with controls (all P<0.01, n=12 each). Plasma levels of TAFI were increased by hypoxia and were correlated with clot lysis time and the severity of PH. Morphological analysis using 3 dimensional-CT showed multiple obstruction of PAs in TAFI-Tg mice after hypoxic exposure (P<0.01, n=10 each). Mechanistic experiments demonstrated that treatment with human TAFI (300 nM) increased permeability of PA endothelial cells and proliferation of PA smooth muscle cells compared with vehicle controls (n=10 each, both P<0.01). Finally, a PPARα agonist, WY14643, significantly reduced plasma levels of TAFI, ameliorated hypoxia-induced PH and significantly improved mortality (-70%) in TAFI-Tg mice compared with controls (P<0.01, n=12 each).

Conclusions:
TAFI promotes PA thrombus formation and the development of PH and could be a novel biomarker and therapeutic target for the disorder.
Abstract 13901: Significance of Rotor Activation Observed Outside of the Pulmonary Vein for the Maintenance of Atrial Fibrillation: Three-dimensional Analysis Using a Non-contact Mapping System
Authors: Yamabe Hiroshige , Kanazawa Hisanori , Ito Miwa , Kaneko Shozo , Kanemaru Yusuke , Kiyama Takuya , Ogawa Hisao
Published: April 2024

Background:
It has been suggested pulmonary vein (PV) acts as the driving sources of atrial fibrillation (AF). However, it is unclear whether the rotor, which is located outside the PV, also maintains the AF.

Objectives:
To define the prevalence and significance of rotor observed outside the PV in the left atrium (LA), LA activation sequence was analyzed during AF after PV isolation.

Methods:
Endocardial mapping of LA was performed in 25 AF patients (9 paroxysmal and 16 persistent AF) using a non-contact mapping system (EnSite 3000) during AF perpetuated after PV isolation. Presence of rotor activation was defined when the circular activation around the functional block line once completed its whole reentrant activation. To define the role of rotor for the maintenance of AF, the number of pivoting activation involved in the rotor activation was compared with that not involved in the rotor activation. Further, the activation time involved in the rotor activation was compared with that not involved in the rotor activation.

Results:
Rotor was identified in 14 (56%) patients (3 paroxysmal and 11 persistent AF patients). Rotor was observed at the septum (8 patients), roof (4 patients), anterior (3 patients) and posterior (1 patient), respectively. The number of rotor activation was 1.5±1.8 times/sec. Total number of pivoting activation was 9.2±6.5 times/sec. The number of pivoting activation involved in the rotor activation was significantly fewer than that not involved in the rotor activation (2.7±3.0 vs. 6.5±5.4 times/sec, p=0.0034). The activation time in which the rotor was observed in the LA occupied 18.5±21.1 % of the total recording intervals. Thus, the percentage of activation time involved in the rotor activation was significantly lower than that not involved in the rotor activation (18.5±21.1% vs. 81.5±21.1%, p<0.0001).

Conclusions:
Rotor activation was observed outside the PV in only half of AF patients. Further, most of pivoting activations were not involved in the rotor activation and the activation time involved in the rotor activation occupied a limited interval during AF. These suggest that AF after PV isolation was not maintained by the rotor, but was driven by the non-stationary random wave propagation associated with frequent pivoting activations.
Abstract 13902: Comparison of Stent Performance Between ZES and EES
Authors: Yoneda Shuichi
Published: April 2024

Introduction:
Although drug-eluting stents (DESs) have reduced restenosis, a unique issue beyond restenosis, i.e., impairment of re-endothelialization, which may delay wound healing and cause a relapse of inflammation, leading to neoathroma formation at the stented sites, in addition to lack of neointimal coverage, has arisen. Therefore, overall stent performance should be characterized by the abilities of geometric luminal gain acquisition, neointimal coverage of the stent struts, and stabilization of the underlying inflammatory neoatheroma.

Hypothesis:
Our hypothesis is that stent performance would be different between 2 second generation DESs, zotarolimus-eluting stent (ZES) and everolimus-eluting stent (EES).

Methods:
We compared stent performance among ZES, EES and bare metal stent (BMS) using optical coherence tomography (OCT) and coronary angioscope (CA). For 37 stented coronary lesions (EES; 16 lesions, ZES; 10 lesions and BMS; 11 lesions) in 20 patients, we observed stented sites by the OCT at 6-12 months after stent placement and measured neointimal area at the site of minimal lumen area and ratio of uncovered stent strut to the whole struts. Also by the CA, neointimal coverage was observed, and neointimal color was simultaneously observed. From the CA findings, the grades of neointimal coverage and yellow color were classified into 0 to 3.

Results:
The neointimal area (mm
2
) was 1.30±1.12 in the EES lesions, 2.74±1.17 in the ZES lesions (P<0.05 vs EES), and 3.76±1.01 in the BMS lesions (P<0.001 vs EES, P=0.07 vs ZES). The OCT-based uncovered ratio was 26.9% in the EES lesions, 2.1% in the ZES lesions (P<0.01 vs EES), and 1.2% in the BMS lesions (P<0.001 vs EES, P=0.9 vs ZES). Stent coverage grade by the CA findings was 0.44±0.53 in the EES lesions, 2.00±1.00 in the ZES lesions (P<0.001 vs EES), and 2.33±0.82 in the BMS lesions (P<0.01 vs EES, P=0.5 vs ZES). The yellow grade was 1.67±0.50 in the EES lesions, 0.29±0.48 in the ZES lesions (P<0.001 vs EES), and 0.17±0.41 in the BMS lesions (P<0.001 vs EES, P=0.7 vs ZES).

Conclusions:
ZES might be better than BMS in terms of neointimal thickening, and better than EES in terms of neointimal coverage as well as stabilization of inflammatory neoatheroma. ZES may have superior stent performance, compared to EES.
Abstract 13909: Predicting Factors for Chronic Phase Ventricular Tachycardia in Cardiac Sarcoidosis Under Corticosteroid Therapy
Authors: Fujiishi Tamami , Fukaya Hidehira , Niwano Shinichi , Nakamura Hironori , Igarashi Tazuru , Ishizue Naruya , Nabeta Takeru , Yoshizawa Tomoharu , Oikawa Jun , Ishii Shunsuke , Kishihara Jun , Satoh Akira , Murakami Masami , Ako Junya
Published: April 2024

Background:
Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Ventricular tachycardia (VT) is frequently observed in cardiac sarcoidosis (CS), which can be sometimes fatal. Corticosteroid therapy is effective for suppression of the lethal arrhythmias with CS, however, the lethal ventricular arrhythmia still occurs even in chronic phase under corticosteroids therapy. In the present study, we retrospectively evaluated the predictors for chronic phase VT in the patients with CS with corticosteroid therapy.

Methods:
The study population consisted of 37 consecutive patients diagnosed with CS. Corticosteroid therapy was indicated in all patients with a mean follow-up period of 59.9 ± 42.2 months. To exclude the events during unstable acute phase of the therapy, we focused on the occurrence of VT at least 3 months after the initiation of corticosteroids therapy as chronic phase events. Various clinical parameters including echocardiographic parameters, 12-lead electrocardiogram (ECG) and findings of laboratory data at 6, 12 and 24 months after the initiation of corticosteroid therapy, were obtained and compared between patients with and without chronic phase VT (VT and non-VT group). To adjust for the baseline diversity, all data were evaluated as change from baseline data, e.g., ▹QRS calculated by subtracting the baseline QRS duration from the QRS data at each month.

Results:
Out of the 37 patients, 7 exhibited VT in the chronic phase (19%). In the echocardiographic parameters, VT group showed larger ▹left ventricular end-diastolic diameter (LVDd) in 6 months (5.7±1.5 vs. -1.7±5.3 mm, p=0.028) and 24 months (4.5±1.0 vs. -0.8±7.2 mm, p=0.009) compared with those in the non-VT group (n=30), but there was no significant difference in ▹ejection fraction (EF). In the 12-lead ECG parameters, VT group showed longer ▹QRS in 6 months (30.0±19.8 vs. -6.1±11.2 ms, p=0.001) compared with those in the non-VT group. There were no significant differences in findings of laboratory data including the changes of brain natriuretic peptide (BNP) and angiotensin-converting enzyme (ACE) between 2 groups.

Conclusions:
Serial changes in echocardiographic parameters and QRS duration may predict chronic phase VT in CS after corticosteroid therapy.
Abstract 13999: Elevated Asleep Blood Pressure is Associated With All-cause and Cardiovascular Mortality in Heart Failure With Preserved Left Ventricular Ejection Fraction (HFpEF) -From Nara-HF Study
Authors: Ueda Tomoya , Nakada Yasuki , Kawata Hiroyuki , Kawakami Rika , Okura Hiroyuki , Saito Yoshihiko
Published: April 2024

Introduction:
Abnormal circadian blood pressure (BP) rhythms are one of the risks of cardiovascular diseases and death. However, circadian BP rhythms in heart failure (HF) patients are unclear. Therefore, we examined the relationship between circadian BP rhythms for survival in HF patient. Moreover, we valued the difference of circadian BP rhythms between HF with preserved left ventricular ejection fraction (HFpEF) and HF with reduced left ventricular ejection fraction (HFrEF).

Methods:
Of 810 consecutive patients with acute decompensated HF emergently admitted to our hospital, we studied 228 HF patients performed ambulatory blood pressure monitoring (ABPM) at discharge. We examined the relationship between circadian BP rhythms and survival in HFpEF and HFrEF. Kaplan-Meier survival analysis and Cox proportional hazard model were performed to assess outcomes.

Results:
During a mean follow-up of 27.9 months, there were 80 deaths from all causes, including 36 deaths from cardiovascular causes. The pattern of circadian BP rhythms was similar between HFpEF and HFrEF. In HFpEF patients, Kaplan-Meier analysis showed that all-cause and cardiovascular death were significantly higher in patients with the pattern of elevated asleep BP (EABP), in which sleep BP exceeded awake BP (log-rank P=0.0298 and P=0.0195, respectively). In a multivariate analysis, EABP pattern was an independent predictor for all-cause and cardiovascular death (HR 2.57; 95% CI 1.09-6.13; P=0.0310 and HR 10.66; 95% CI 1.91-93.9; P=0.0063, respectively) after adjusted by age, hemoglobin and brain natriuretic peptide. However, these findings were not observed in HFrEF.

Conclusions:
EABP pattern was associated with increasing risk for adverse outcome in HFpEF patients, but not in HFrEF patients. Although further studies are necessary to elucidate the mechanism, we should pay attention to EABP pattern in HFpEF.
Abstract 14002: Randomized Comparison of Once-daily Fixed Combination versus Free-drug Combination of Three Antihypertensive Agents
Authors: Marazzi Giuseppe , Pelliccia Francesco , Campolongo Giuseppe , Cacciotti Luca , Poggi Sara , Tanzilli Alessandra , Di Iorio Martina , Rosano Giuseppe
Published: April 2024

Background:
A 3 drug combination strategy is often needed to achieve blood pressure (BP) targets. However, the optimal strategy of drug administration remains unknown.

The aim
of this study was to compare the efficacy and safety of once-daily fixed (ODF) combination versus free-drug combination of 3 antihypertensive agents.

Methods:
The ONE&ONLY Trial was a randomized, prospective, multicenter trial. A total of 731 hypertensive patients (pts) treated with the combination of perindopril plus indapamide or amlodipine were screened initially. The 305 pts who did not meet the BP targets after 4 weeks were randomized to ODF combination of perindopril 10 mg + indapamide 2.5 mg + amlodipine 5 or 10 mg (N=154, fixed group) versus free-drug combination of the 3 antihypertensive agents (N=151, free group). Primary end-points were the differences in clinic BP between the 2 groups after 12 weeks. Secondary end-points included intragroup differences in clinic BP during the study period and achievement of BP targets at week 12. Safety and compliance were also assessed during the trial.

Results:
Baseline characteristics were similar among the treatment groups. At 12-weeks, the fixed group had lower systolic BP (SBP) (125±12 vs 129±11 mm Hg, p=0.002) and similar diastolic BP (DBP) (82±9 vs 84±7 mm Hg, p=0.082) compared to the free group. With respect to baseline measures, changes in BP with fixed combination were statistically significant for systolic (-18.9± 11.2 mm Hg, p<0.01), and diastolic values (-6.3±5.7 mm Hg, p<0.01). On free combination, changes vs. baseline in SBP and DBP, conversely, were of borderline significance. BP targets at week 12 were more commonly reached with fixed than free combination (89% [137 of 154] and 80% [121 of 151], respectively, p=0.048). Safety was not significantly different between the 2 groups. Conversely, compliance was significantly greater in the fixed-group vs the free-group (94% [144 of 154] and 85% [129 of 151], respectively, p=0.034).

Conclusion:
This randomized trial shows in a large population of hypertensive pts that ODF combination of perindopril, indapamide, and amlodipine is as effective and safe as free combination of the 3 drugs, although is associated with a significantly greater compliance. ClinicalTrials.gov ID: NCT02710539
Abstract 16592: A Next-Generation Artificial Intelligence-Based Integrated Genetic-Epigenetic Prediction of 5-Year Risk for Coronary Heart Disease
Authors: Dogan Meeshanthini V , Simons Ronald L , Beach Steven , Lendasse Amaury , Philibert Robert A
Published: April 2024

Coronary heart disease (CHD) is a leading cause of death in the US. CHD associated morbidity and mortality can be reduced if those at risk can be identified well in advance, to put in place prevention interventions prior to an acute coronary event. Limitations of current approaches call for additional efforts to improve risk predictions. We recently developed a Precision Medicine tool capable of predicting 5-year risk, that can also guide personalized prevention interventions and monitor changes in risk over time. It was developed using an application of AI, machine learning, in the Framingham Heart Study to mine integrated genetic-epigenetic biosignatures that capture the complex interplay between our genome and the environment in conferring risk for CHD. The training and test sets consisted of 1180 (19/695 females and 23/485 males developed symptomatic CHD within 5-years) and 524 (8/293 females and 12/231 males developed symptomatic CHD within 5-years) individuals, respectively, of Northern European ancestry. Non-linear data mining and modeling techniques were employed on the training set to identify prediction signatures from genome-wide SNP and DNA methylation (DNAm) data. We identified 14 DNAm and 10 SNPs from the training set (training bootstrap average sensitivity and specificity of 0.61 and 0.71, respectively) that predicted the 5-year risk in the test set with a sensitivity and specificity of 0.60 and 0.69, respectively. Performance was compared to that of the Framingham Risk Score (FRS) and the ASCVD Risk Estimator. The sensitivity and specificity in the test set were 0.05 and 0.99 for FRS, and 0.38 and 0.85 for ASCVD. Even with a small number of incident cases, our tool performed with superior sensitivity, which is vital because, while a false positive would result in additional testing, a false negative can be detrimental. Unlike genetics, because DNAm is dynamic, it can be mapped to actionable risk factors to guide personalized interventions and over time, re-assess risk and continuously monitor heart health. We demonstrate translational feasibility of this tool via next-gen digital PCR assays. Additional efforts are ongoing to optimize, validate and extend our tool to further improve performance in larger, more ethnically diverse cohorts.
Abstract 16598: Carnosine Synthetase Overexpression in Skeletal Muscle Promotes Functional Recovery of Ischemic Limb
Authors: Conklin Daniel , Guo Luping , Bhatnagar Aruni , Baba Shahid P
Published: April 2024

Carnosine synthetase (ATPGD1) is an ATP grasp enzyme that catalyzes formation of histidyl dipeptides such as carnosine (β-alanine-histidine) and anserine (β-alanine-methyl histidine). These dipeptides are food constituents found in a high concentration in the skeletal muscle (10-20 mM) that have the abilities to chelate metals, scavenge lipid peroxidation products and buffer intracellular pH. These dipeptides are regarded as protective against injury and stress. Despite this knowledge, whether carnosine regulates angiogenesis is unknown. To assess this potential, a model of hindlimb ischemia (HLI) was surgically induced by femoral artery and vein ligation in the C57BL/6J (wild type, WT) mice provided drinking water without or with carnosine (1g/L) for 21 days post-surgery. C57BL/6J WT mice subjected to HLI and supplemented with carnosine had increased skeletal muscle expression of the dipeptide/histidine transporter (PHT1), carnosine transport, improved blood flow recovery, re-vascularization and regeneration of myocytes in the ischemic limb compared with mice without carnosine. To support that elevated skeletal muscle carnosine was beneficial in HLI, transgenic mice overexpressing ATPGD1 in the skeletal muscle were constructed. Transgenic (α-HSA-ATPGD1TG) mice had ~2-2.5-fold increase in carnosine (WT: 2.71±0.54
vs
7.40±0.54 nmoles/mg protein α-HSA-ATPGD1TG;
p
<0.05) and anserine levels (WT: 3.65±1.12
vs
8.04±0.23 nmoles/mg protein α-HSA-ATPGD1TG
p
<0.05) in the skeletal muscle than WT mice. At 2 and 3 weeks post-HLI surgery, α-HSA-ATPGD1TG mice had significantly improved blood flow recovery compared with the WT mice (2 weeks: α-HSA-ATPGD1TG: 59±3%
vs
45±3% WT;
p
<0.05; 3 weeks: α-HSA-ATPGD1TG: 65±4%
vs
46±2% WT;
p
<0.05). Because faster recovery of blood flow in the carnosine-supplemented mice was accompanied with increased expression of hypoxia inducible factor (HIF-1α) and vascular endothelial factor (VEGF) in the ischemic limb, we further investigated the mechanistic connection. Skeletal muscle myoblasts C2C12 cells pretreated with octyl-D-carnosine and subjected to 1 h of hypoxia, replacing oxygen with 95% N
2
and 5% CO
2
, had enhanced HIF-1α translocation, VEGF mRNA and secretion compared with untreated hypoxic and normoxic cells. Collectively, our results demonstrate that carnosine improves ischemia-stimulated angiogenesis potentially by stabilizing HIF1-α and promoting VEGF formation suggesting that carnosine may be a useful therapy in critical limb ischemia.
Abstract 16629: Empagliflozin Directly Stimulates PGC-1α-Dependent Mitochondrial Biogenesis in Cardiac Cells; A Potential Mechanism Associated With Its Cardiovascular Benefits
Authors: Andres Allen M , Song Yang , Gottlieb Roberta A , Mentzer Robert M
Published: April 2024

Empagliflozin (EMP) is a member of the gliflozin class of drugs used to treat type 2 diabetes mellitus (T2DM). These drugs inhibit the sodium glucose co-transporter 2 (SGLT-2) and facilitate glucose disposal via the kidneys. There is considerable interest in the growing evidence that select anti-diabetic drugs such as empagliflozin may have a cardioprotective effect independent of glycemic control manifested as a reduction in the risk of developing a major adverse cardiovascular event (MACE). The mechanism(s) underlying this effect are unknown. To test the hypothesis that the beneficial cardiac effects of EMP may be mediated by enhancing mitochondrial turnover, specifically enhanced mitophagy and mitochondrial biogenesis, we treated 5 day differentiated H9C2 rat ventricular cardiomyocytes with 100nM EMP for 24h. As shown below, we found that EMP increases several markers of mitochondrial mass assessed by western blot. Seahorse respirometry confirmed that this translates to increased basal and maximal respiratory capacity of the cardiomyocyte. Moreover, these findings were associated with increased translocation of PGC-1α to the nucleus suggesting that EMP-mediated mitochondrial biogenesis is PGC-1α-dependent. To determine if increased mitochondrial biogenesis was SGLT-2 receptor mediated we interrogated the protein expression in our differentiated H9C2 cardiomyocytes and in several tissues of the mouse. We detected protein expression in our differentiated H9C2 cardiomyocytes and in mouse heart, liver, adipose, kidney, lung, and spleen. Whether EMP-mediated stimulation of mitochondrial biogenesis is related to SGLT-2 receptor inhibition, or if this process is linked to its ability to improve cardiac function has yet to be determined. Our findings suggest however that a possible mechanism underlying the reduction in MACE associated with EMP treatment may be due in part to its effect on mitochondrial turnover.
Abstract 16637: Left Ventricular Mass Predicts Response to Cardiac Resynchronization Therapy in Men but Not Women
Authors: Ward Chad C , Ayinde Hakeem , Adams Casey , Adeola Oluwaseun , Zubairu Josiah , Dezorzi Christopher , Hopson James , Sigurdsson Gardar , Giudici Michael
Published: April 2024

Introduction:
The effect of left ventricular mass (LVM) on response to cardiac resynchronization therapy (CRT) is not well known.

Hypothesis:
We hypothesize that baseline LVM would be positively associated with improved CRT outcomes.

Methods:
We retrospectively studied 343 consecutive patients who received CRT at our institution between 2008 and 2014. LVM was measured by echocardiography using the truncated ellipsoid method. Primary outcome was all-cause mortality. Secondary outcomes were (1) change in left ventricular ejection fraction (LVEF) by > 5% at 6-12 months and (2) change in QRSd within 3 months.

Results:
There were 241 males and 102 females. Mean age at CRT implant was 63.6 ± 11.9 years. LVM was 366 ± 367g. Ischemic cardiomyopathy and left bundle branch block (LBBB) were present in 57% and 67% respectively. Fifty three percent of the study cohort had NYHA class III or IV at the time of implant. Death occurred in 36% of patients at a median follow up of 2.2 years. LVEF improved by > 5% in 65% of patients at 6-12 months while QRSd decreased by a mean of 6.7 ± 27.8 ms within 3 months. The relationship between LVM and CRT response appeared to be strongly sex-specific. Higher LVM was associated with reduced mortality in men when LVM was used as a continuous and categorical variable dichotomized at the 75th percentile ([OR 0.999 (0.998-1.0000; p=0.068)] and [OR 0.47 (0.23-1.00; p=0.05)] respectively). There was no association in women (p=0.826). Higher LVM predicted improvement in LVEF in men [OR 0.99898 (0.9983-0.9997; p=0.005)] but not in women (p=0.324). Men with higher LVM experienced greater reduction in QRSd [OR 1.0015 (1.0006-1.0024; p=0.001)]. Again, there was no association in women (p=0.322). The relationship between LVM and change in both LVEF and QRSd remained significant and sex-specific after adjusting for age, LBBB, ischemic cardiomyopathy and atrial fibrillation (OR 0.99904, p=0.039 and OR 1.001, p=0.028 respectively in men).

Conclusions:
Left ventricular mass is an independent predictor of CRT outcomes in men but not in women. In males, greater left ventricular mass predicted improvement in LVEF as well as reduction in QRSd. This remained significant after adjusting for age, LBBB, ischemic cardiomyopathy, and atrial fibrillation.
Abstract 16717: Cardiovascular Risk Profile of a Young Adult Population Assisted on a Primary Family Health Care Unit Located in Rio De Janeiro - A Pilot Project of LapARC Cohort Study
Authors: Azevedo Rafael B , Andrade Letícia Z , Oliveira Marcelle G , Campos Thiago O , Miguel Isadora S , Assunção Juliana B , Carvalho Jaquline A , Costa Raquel M , Barbosa Yan B , Ganem Gustavo d , Carvalho Lais A , Ramos Maria Eduarda A , Ramalho Rafaela d , Pereira Lucas L , Crivellari Humberto M , Pedrosa Bruna , Pereira Aline S , Angelim Abraão I , Franco Ana Luisa B , Silva Carolina S , Muxfeldt Elizabeth S
Published: April 2024

Methods:
This cross-sectional population study enrolled young adults between 20-50 years old, registered in a primary family healthcare unit located in the center of Rio de Janeiro, Brazil. The pilot study has already evaluated 23% of the local population. A database is being developed at the entrance of each participant into the cohort including sociodemographic characteristics, anthropometric measurements, and traditional cardiovascular (CV) risk factors. Furthermore, Office Blood Pressure (BP) was measured in 2 different occasions and the mean value was registered. Also, all subjects were submitted to a standard protocol, including a thorough clinical examination, a laboratory evaluation (lipid and glycemic profile and renal function) and electrocardiogram (EKG).

Results:
A total of 411 subjects were evaluated [162 (40%) males, mean age: 38 ± 8 years]. The most common CV risk factor was physical inactivity (45%), followed by obesity (25%) and dyslipidemia (19%). The prevalence of hypertension was 23%. Hypertensives were more frequently male, with a high prevalence of obesity and diabetes, and increased Sokolow’s index in the EKG. Moreover, a total of 23 (5%) subjects were diagnosed with impaired glucose tolerance and 18 (4%) with Diabetes Mellitus (DM), considering those with a previous diagnosis and the ones with serum glucose higher than 126mg/dL. The diabetic patients were older, with a higher prevalence of obesity, hypertension and dyslipidemia. A total of 147 (32%) presented dyslipidemia and only 15 (3%) are undergoing pharmacological intervention. The prevalence of metabolic syndrome was 21%. In relation to renal function, there are only 2 patients with Chronic Kidney Disease (CKD) stage 3 and no patients presented moderately increased albuminuria. Median UAER was 4.01 [IQL 2.75-5.92] and there is no difference between genders. Additionally, only 29% of participants did not present CV risk factors while 31% presented 2 to 5 CV risk factors.

Conclusions:
This young and apparently healthy population presented a high prevalence of modifiable (obesity and physical inactivity) and controllable (hypertension and dyslipidemia) CV risk factors, pointing to the importance of early CV risk stratification. Thus, effective prevention measures can be planned and implemented to decrease the probability of this population to develop a CV disease in the future.
Abstract 16728: Cigarette Smoke Impairs the Anti-Oxidative Response by Reducing Heme Levels and Inducing Bach1
Authors: Almedawar Mohamad M , Brux Melanie , Brunssen Coy , Morawietz Henning
Published: April 2024

Introduction:
Cigarette smoke is a major risk factor of cardiovascular diseases. Heme regulates the activity of enzymes and transcription factors including Bach1. Bach1 competes with Nrf2 transcriptional activity and inhibits the expression of anti-oxidative enzymes. However, the molecular mechanism of Bach1 activation and its impact on the anti-oxidative response after exposure to cigarette smoke is not clear.

Hypothesis:
We aim to understand the mechanism through which cigarette smoke impairs the anti-oxidative response.

Methods:
Primary human umbilical vein endothelial cells (HUVEC) were exposed to a cigarette smoke extract (CSE) (3 mg/ml nicotine) under static and unidirectional shear stress conditions. Shear stress was induced using the ibidi pump system and cone-and-plate viscometer. Llevels of reduced glutathione (GSH) were measured using the fluorescent probe o-phthalaldehyde. Heme levels were measured after oxalic acid extraction. Gene and miR expression was quantified by RT-qPCR. Immunofluorescence imaging was performed on fixed HUVEC. MiR-125b overexpression was achieved by transfecting mimics. Inhibition of Bach1 was done using siRNA transfection. Apoptosis was assessed using the caspase 3/7 assay. Human umbilical veins as an
ex vivo
model were exposed to CSE under static conditions.

Results:
Exposure to CSE induced the expression of
BACH1
(1.90±0.18; p<0.05) and reduced total heme levels (0.30±0.04; p<0.001) in HUVEC. It also reduced miR-125b expression in HUVEC (0.39±0.09; p<0.001) and umbilical veins (0.72±0.12; p<0.05), whereas the expression of miR-125b target AhR repressor (
AHRR
) increased (14.93±4.08; p<0.05). Inhibiting
BACH1
rescued miR-125b expression (1.02±0.45; p>0.05) and reduced
AHRR
expression (0.66±0.12; P<0.05). Acute exposure to CSE led to a high oxidative stress load. This observation was supported by a 2-fold reduction in glutathione levels, an increase in nuclear:cytosolic ratio of the upstream transcription factor Nrf2 (1.33±0.05; p<0.01) and an increase in expression of anti-oxidative
HMOX1
(18.18±1.8; p<0.001) and
NQO1
(16.12±1.99; p<0.001). CSE-induced apoptosis (1.23±0.04; p<0.001) was reversible by pre-conditioning with 1 mM N-acetyl cysteine (0.99±0.02; p>0.05) or overexpression of miR-125b (0.99±0.07; p>0.05).

Conclusions:
These results show that cigarette smoke-induced Bach1 impairs the anti-oxidative response through inhibiting miR-125b in the human endothelium. Reduced heme levels could be involved in the upregulation of Bach1 activity.
Abstract 16796: Persistent Anemia Associates Long-Term Higher Mortality in Patients After Percutaneous Coronary Intervention
Authors: Funamizu Takehiro , Iwata Hiroshi , Doi Shinichiro , Endo Hirohisa , Wada Hideki , Dohi Tomotaka , Kasai Takatoshi , Okazaki Shinya , Miyauchi Katsumi , Daida Hiroyuki
Published: April 2024

Introduction:
Anemia is known to be associated with mortality in patients after percutaneous coronary intervention (PCI). However, the impact of temporal change in anemia on prognosis is not fully elucidated.

Methods:
We prospectively enrolled consecutive 4589 patients undergoing PCI from January 2000 to December 2016. Among them, patients, whose hemoglobin (Hb) level at PCI procedure (baseline) and follow-up coronary angiography (CAG, 6-12 months after PCI), were subjected to the study (n=1832). Patients were divided into 4 groups based on baseline and follow-up Hb level, such as anemia (-) to (-) (n=1122), anemia (-) to (+) (n=171), anemia (+) to (-) (n=159) and anemia (+) to (+) (n=380). Median follow-up period was 5.8±3.7 years.

Results:
Kaplan-Meier analysis showed that patients with persistent anemia, who had anemia at both baseline PCI and follow-up coronary angiogram (anemia (+) to (+)), had highest mortality rate, while survival rate in patients with recovered anemia (anemia (+) to (-)) was similar in patients without baseline anemia (anemia (-) to (-)) (p=0.01, anemia (+) to (+) vs. anemia (+) to (-)) (Figure). Adjusted Cox proportional hazard analysis showed that persistent anemia was an independent risk for all-cause mortality (Hazard-Ratio: 1.81, 95% confidential interval: 1.35-2.47, p=0.001).

Conclusions:
Persistent anemia, continuous anemia at PCI and 6-12 months later, is strongly associated with higher all-cause mortality.
Abstract 16797: Long-Term Incidence of Clinically Important Aortic Stenosis Among Community-Dwelling Older Adults: The Cardiovascular Health Study
Authors: Owens David S , Massera Daniele , Bartz Traci , Biggs Mary Lou , Gottdiener John S , Kizer Jorge R
Published: April 2024

Background:
Subclinical aortic valve calcification is common among older adults, but the incidence and prevalence of clinically significant aortic stenosis (AS) in the general population is not well characterized. We leveraged the Cardiovascular Health Study (CHS), a population-based investigation of older adults with up to 25 years of follow up, to study AS at an epidemiologic level.

Methods:
We used a case capture methodology involving ICD-9 diagnosis and procedure codes and CHS echo data to ascertain probable or definite cases of AS at baseline and during longitudinal follow up. Using targeted procedure- and diagnosis-code screening, review of CHF hospitalizations and CHS echo data, along with systematic review of longitudinal hospital records, we identified CHS subjects who developed at least moderate AS, had AS-related hospitalizations, or had AS-related valve interventions.

Results:
There were 5888 participants in CHS (mean age 72.9, 42% male). Of these, 958 were identified for review based on screening methods. Among those with an echo at baseline (1989-1990 for the first cohort and 1994-1995 for the second cohort) and without AS at that time, there were 275 (4.7%) incident probable or definite cases of moderate or greater AS and 169 (2.9%) incident probable or definite cases of severe AS. The median time to moderate or greater AS was 11.3 (range 0.3-24.9) years following baseline echo. Among these subjects, 248 (90%) had an AS-related hospitalization, while only 98 (36%) underwent an aortic valve procedure in this largely pre-TAVR era. Sensitivity analyses were performed, showing that clinically significant AS among the non-reviewed subjects was uncommon (<1%).

Conclusions:
To our knowledge, this is the first study to evaluate the long-term incidence of clinical AS in the general elderly U.S. population. Starting at age 65, moderate to severe AS affects about 1 in 20 individuals late in life, and is associated with high rate of morbidity leading to hospitalization.