bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12920: Transforming Growth Factor-Beta-Dependent Pathway Induces the Cardiac Fibrosis and Remodeling in Guanylyl Cyclase/Natriuretic Peptide Receptor-A Gene-Disrupted Mice
Authors: Subramanian Umadevi , Gogulamudi Venkateswara , Kessler Isaac , Chen David , Pandey Kailash N
Published: April 2024

Introduction:
Targeted-ablation of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene (
Npr1
) in mice exhibits hypertension and provokes congestive heart failure; however, the underlying mechanisms are not well understood.

Hypothesis:
To determine whether transforming growth factor-beta 1 (TGF)-β1 receptor antagonist, GW788388 inhibits the development of cardiac fibrosis and remodeling in GC-A/NPRA gene-disrupted mice.

Methods:
The adult male (16-20 weeks)
Npr1
null mutant (
Npr1
-/-
, 0-copy), heterozygous (
Npr1
+/-
, 1-copy), and wild-type (
Npr1
+/+
, 2-copy) mice were orally administered with TGF-β1 receptor antagonist, GW788388 (2 mg/kg/day) for 28 days. The expression of cardiac fibrotic markers was analyzed using real-time PCR and Western blot. Heart weight-to-body weight (HW/BW) ratios were determined and heart functions were measured by echocardiographic analysis.

Results:
The
Npr1
-/-
mice showed markedly increased cardiac fibrosis and HW/BW ratio with increased expression of collagen-1α (3.5-fold), monocyte chemoattractant protein (4-fold), connective tissue growth factor (CTGF, 5-fold), α-smooth muscle actin (α-SMA, 4-fold), TGF-βRI (4-fold), TGF-βRII (3.5-fold) and SMAD proteins (SMAD-2, 5-fold; SMAD-3, 3-fold) compared with
Npr1
+/+
mice. The expression of phosphorylated extracellular-regulated kinase (pERK1/2) was also up-regulated in

Npr1
-/-

mice. The treatment of

Npr1
-/-

mice with GW788388 significantly prevented the development of cardiac fibrosis and down-regulated the expression of fibrotic markers and SMAD proteins compared to vehicle-treated mice. In contrast, the expression of pERK1/2 proteins was unaffected in GW7885388-treated mice excluding the involvement of non-genomic pathway. The left ventricular dimensions (systole and diastole) and fractional shortening were significantly improved in the drug-treated

Npr1
-/-

mice.

Conclusions:
The results suggest that the cardiac fibrosis, remodeling, and dysfunction in
Npr1
-/-
mice are regulated through TGF-β-mediated SMAD-dependent canonical pathway. The findings will be important for the development of new molecular therapeutic targets for the treatment of cardiac fibrosis, remodeling, and dysfunction in human patients.
Abstract 13054: Perfect 1 Year Angiographic Patency of in vivo Tissue-Engineered Vascular Grafts With an Ultra Small Diameter of 0.6 mm (MicroBiotubes) in a Rat Model
Authors: Ishii Daizo , Enmi Jun-Ichiro , Iida Hidehiro , Kurisu Kaoru , Nakayama Yasuhide
Published: April 2024

Background and Purpose:
Biotubes are autologous tubular connective tissues formed by in-body tissue architecture technology, which is a novel and practical approach in regenerative medicine. We confirmed that Microbiotubes (MBs) with diameter of 0.6 mm had high performance potential as a reliable arterial graft in acute phase of implantation in a rat model. In this study, quality and patency of MBs in chronic phase were evaluated by histological or magnetic resonance angiographic (MRA) examinations, respectively.

Method:
The mold for multiple preparing of MBs was assembled by several stainless wires covered with silicone tubes. The molds were surgically embedded into the dorsal subcutaneous pouches of rats. After 2 months, the molds were harvested with surrounding tissues and MBs were obtained by removing the molds. MBs (length, 10 mm; internal diameter, 0.6 mm) were implanted in rat femoral arteries (diameter, ca. 0.5 mm) in allogenic manner by end-to-end anastomosis without use of any anticoagulant agents. Ten patent MBs after 1-month implantation were observed by follow-up 7- Tesla MRA until 1 year after implantation.

Results:
In all follow-up periods, all MBs were patent without any observable stenoses or dilatations and a difference of signal intensity between MBs and native artery was obscure (Fig. 1). Moreover, native-like reconstructed structure of MBs’ wall was conserved histologically for 1 year.

Conclusion:
It was unprecedented result that there was no occluded case in chronic phase and MBs preserved high quality and patency for a long-term period. We are convinced that MBs could be useful grafts for ultramicrosurgery, such as a replantation of severed fingers or a reconstruction of lymphatic vesssels, in the not too distant future.
Abstract 13147: Obstructive Sleep Apnea Associates With Elevated Leukocytes and Markers of Inflammation in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Geovanini Glaucylara R , Jenny Nancy S , Wang Rui , Shea Steven J , Kaufman Joel D , Allison Matthew , Punjabi Naresh M , Tracy Russell , Libby Peter , Redline Susan
Published: April 2024

Introduction:
Obstructive sleep apnea (OSA) is associated with incident cardiovascular disease (CVD), which may reflect dysregulation of pathways leading to atherosclerosis. Inflammation and adaptive immunity participate in the pathogenesis of atherosclerosis, and may be influenced by OSA-related stresses. No prior community-based study has examined the associations of OSA with both leukocytes and serum inflammatory markers.

Hypothesis:
Biomarkers of inflammation are associated with OSA severity in a community-based cohort. We particularly focused on White Blood Cell (WBC), which has not been well-studied in association with OSA. Since OSA has been associated more strongly with CVD in middle-age vs. old age, we explored potential age modification.

Methods:
We analyzed data from MESA participants who underwent polysomnography in conjunction with Exam 5 (2010-13) and had available biomarkers from that exam. The primary analysis (n=1344) modeled WBC count and Cystatin-C as outcomes (available for largest subset, n=1344), with log Apnea Hypopnea Index (AHI) as the exposure. Secondary analysis evaluated high-sensitivity C-reactive protein (hsCRP), fibrinogen, D-dimer, and intercellular-adhesion molecule-1 (ICAM-1) (n=228) as outcomes, and considered dichotomized OSA as absent (AHI <5) or present (AHI ≥5) as the exposure.

Results:
The primary sample (n=1344) had a mean age 68.5 ±9 y, and was 47% male; 14% of individuals had severe OSA (AHI ≥30). Increasing AHI associated with male sex, body mass index (BMI), and a higher prevalence of diabetes (DM) and hypertension (HTN). After adjusting for age, sex, race, smoking, BMI, DM, HTN, and statins, AHI associated significantly with WBC (beta=0.017; p=0.034). Associations tended to be stronger in those age <65 y (beta=0.031; p=0.011). However, the p for interaction was not significant. A fully adjusted model also showed elevated hsCRP in those with OSA (AHI ≥5) (beta=0.357; p=0.011). Associations with Cystatin-C, D-dimer, and ICAM-1 did not attain significance after adjustments.

Conclusions:
Elevation of WBC count and hsCRP in individuals with OSA suggests heightened inflammation and innate immunity as a novel mechanism that links OSA with increased cardiovascular risk.
Abstract 13157: Relationship Between Body Mass Index and Mortality in the African-American Heart Failure Trial
Authors: Oluleye Oludamilola , Baxi Khyati , Rector Thomas , Ngo Phuong , Miller Alan , Anand Inder S
Published: April 2024

Introduction:
In patients with heart failure and reduced ejection fraction (HFrEF), increasing body mass index (BMI) is not associated with worsening prognosis, termed the obesity paradox. Although this phenomenon has been studied extensively, data on the African-American population are limited. The aim of this study was to examine the relationship between BMI and all-cause mortality in African Americans with HFrEF.

Methods and Results:
The African-American Heart Failure Trial (A-HeFT) database was utilized to conduct a retrospective analysis. In A-HeFT, 1050 self-identified black patients with BMI range of 15.7 to 69.4 kg/m
2
(median 30.3 kg/m
2
) were followed for a median of 15 months, with 86 deaths. BMI was modeled as a curvilinear continuous variable using restricted cubic splines. Unadjusted Cox regression analysis of the relationship between BMI and all-cause mortality revealed a significant (p = 0.001)
inverse
relationship, with an increase in mortality risk below the median BMI of approximately 30 kg/m
2
(HR> 1.0) without an upward trend in mortality risk above a BMI > 30 kg/m
2
(Figure1). Adjustment for other variables including age, sex, comorbidities, and clinical assessments did not reveal an increase in HR above the median BMI.

Conclusion:
Consistent with the obesity paradox, the mortality risk increased with decreasing BMI and did not increase when the BMI exceeded the definition of obesity. Until the mechanisms of the obesity paradox are better understood, these results question whether weight reduction would be beneficial in the African American population with HFrEF.
Abstract 13160: Low-intensity Pulsed Ultrasound Enhances Angiogenesis and Ameliorates Contractile Cardiac Function in Pressure-Overloaded Hearts in Mice
Authors: Ogata Tsuyoshi , Ito Kenta , Shindo Tomohiko , Hatanaka Kazuaki , Eguchi Kumiko , Kurosawa Ryo , Kagaya Yuta , Shimokawa Hiroaki
Published: April 2024

Introduction:
Chronic pressure overload causes relative ischemia with resultant left ventricular (LV) dysfunction. Because the number of patients with chronic heart failure of ischemic origin is increasing worldwide, development of novel therapeutic strategies for those patients are needed. We have previously demonstrated that low-intensity pulsed ultrasound (LIPUS) improves myocardial ischemia in a pig model of chronic myocardial ischemia through enhanced myocardial angiogenesis. We also have recently reported that the LIPUS ameliorates post-MI LV remodeling in a mouse model of acute myocardial infarction (AMI). In the present study, we thus examined whether LIPUS also ameliorates contractile cardiac function in pressure-overloaded hearts in mice.

Methods and Results:
Chronic LV pressure overload was induced with transverse aortic constriction (TAC) in mice. The heart was treated with either placebo or LIPUS three times in the first week after TAC and was subsequently repeated once a week for 8 weeks. At 8 weeks, LV fractional shortening (LVFS) was significantly depressed in the placebo group, which was significantly ameliorated in the LIPUS group (36.2±3.8 vs. 30.4±0.5%, P<0.05). Capillary density in the LV was significantly higher in the LIPUS group than in placebo group (4229±455 vs. 3243±143 /mm
2
, P<0.05). Perivascular fibrosis was attenuated in the LIPUS group compared with the placebo group (P<0.05). The mRNA expression of BNP and Collagen III (Iα) was lower in the LIPUS group than in the placebo group (both P<0.05). Western blot analysis revealed that VEGF, eNOS and Hif-1α were significantly up-regulated in the LIPUS group (all P<0.05 vs. placebo). Akt was also significantly activated in the LIPUS group (P<0.05 vs. placebo). No adverse effect related to LIPUS therapy was noted.

Conclusions:
These results indicate that the LIPUS therapy ameliorates contractile cardiac function in pressure overload-induced cardiac dysfunction, for which enhanced myocardial angiogenesis may be involved. Thus, the LIPUS therapy may be a promising, non-invasive therapeutic strategy for the treatment of cardiac dysfunction due to pressure overload.
Abstract 13238: Association of Worsening Arterial Stiffness With the Progression of Stage A/B Heart Failure
Authors: Aisu Hiroe , Saito Makoto , Inaba Shinji , Morofuji Toru , Takahashi Kayo , Sumimoto Takumi , Okura Takafumi , Higaki Jitsuo
Published: April 2024

Introduction:
Several studies have suggested that an enhanced and deteriorating arterial stiffness is associated with an increase in left ventricular (LV) afterload and LV diastolic dysfunction, which may contribute to heart failure (HF) progression. We sought to investigate the independent and incremental role of worsening arterial stiffness in new-onset HF in patients with preclinical HF.

Methods:
We retrospectively studied 456 consecutive asymptomatic patients with HF risk factors (hypertension, obesity, type 2 diabetes mellitus, atrial fibrillation, and ischemic heart disease) who underwent paired applanation tonometry examinations (median interval of 2.4 years) during 2006-2011. Brachial ankle pulse wave velocity (baPWV) was measured as a surrogate marker of arterial stiffness. Patients were followed up for admission for new-onset HF over a median duration of 4.9 years after the second examination.

Results:
HF was observed in 30 patients (7%). The change in baPWV (ΔbaPWV) was significantly associated with hospitalization for new-onset HF, independent of and incremental to comorbidities, renal dysfunction, left ventricular (LV) dysfunction, and baPWV at baseline (Per 10% increase, Hazard ratio, 1.23-1.42). Even in patients with an LV ejection fraction of ≥40%, ΔbaPWV was significantly associated with the primary outcome after similar adjustments. When the patients were divided into groups based on the optimal cutoff value of ≥15% ΔbaPWV and the generally accepted external cutoff value of ≥1750 cm/s for baseline baPWV, the Kaplan-Meier estimates of the time of hospitalization for new-onset HF showed that a higher rate of HF was associated with higher baPWV at baseline and higher ΔbaPWV (Figure).

Conclusions:
In patients with stage A/B HF, the deterioration of arterial stiffness was associated with hospitalization for new-onset HF, independent of and incremental with the clinical LV function and increased stiffness parameters at baseline.
Abstract 13388: Autonomic Balance And Mental Stress-induced Myocardial Ischemia
Authors: Alkhoder Ayman , Hammadah Muhammad , Shah Amit , Al Mheid Ibhar , Wilmot Kobina , Ramadan Ronnie , Obideen Malik , Abdelhadi Naser , Isakadze Nino , Awad Mosaab , Ibeanu Ijeoma , Kelli Heval M , Levantsevych Oleksiy , Kutner Michael , Shallenberger Lucy H , Murrah Nancy , Pearce Brad , Bremner Douglas , Vaccarino Viola , Quyyumi Arshed A
Published: April 2024

Introduction:
Although mental stress-induced myocardial ischemia (MSIMI) has been linked to adverse cardiovascular outcomes, its underlying mechanisms remain to be elucidated. We assessed whether autonomic dysfunction was important in precipitating MSIMI with the hypothesis that autonomic function, estimated using heart rate variability (HRV), will be associated with MSIMI.

Methods:
We examined autonomic function at rest in 168 patients with CAD using the ANSAR method (ANX 3.0, ANSAR Inc. Philadelphia, PA). Sympathetic and parasympathetic tone were assessed using low (LFa) and respiratory (RFa) frequency HRV that was adjusted for respiration using continuous wavelet transform. Sympathovagal balance was calculated as the ratio of LFa/RFa. Patients underwent 99mTc sestamibi myocardial perfusion imaging during both mental stress testing using a public speaking task, and, as a control condition, with conventional (pharmacologic or exercise) stress testing. Ischemia was defined as a new or worsening impairment in myocardial perfusion within each myocardial segment using a 17-segment model.

Results:
In our population, (age 63 ± 9 years, 70% men), 11% developed MSIMI and 28% developed conventional stress-induced myocardial ischemia (CSIMI). Patients with MSIMI had higher sympathetic tone and increased sympathovagal balance [median (IQR) LFa of 1.1 (0.4-8.2) vs 0.6 (0.3-1.1) bpm2, p=0.017 and LFa/RFa of 1.7 (0.8-3.6) vs 1.0 (0.6-2.0), p=0.02] but not parasympathetic activity [RFa of 0.8 (0.3-2.9) vs 0.5 (0.2-1.3) bpm2, p=0.29] compared to those without MSIMI. Patients with increased LFa/RFa ratio had significantly higher risk of MSIMI [3rd vs 1st tertile OR(95%CI) of 4.4 (1.1 - 17), p=0.03], that remained significant after adjustment for CAD risk factors, beta blockers, rate pressure product and CSIMI. No correlation was found between LFa, RFa or LFa/RFa HRV and CSIMI.

Conclusion:
Increased resting sympathovagal balance is associated with increased risk of MSIMI but not CSIMI. This suggests that chronic autonomic imbalance with increased symptathetic tone may be an important factor in the pathogenesis of MSIMI, and may have implications on potential therapies.
Abstract 13828: Real World Bleeding Risks in Non-valvular Atrial Fibrillation Patients With Heart Failure: Contemporary EHR Results Among Prescribed Apixaban, Dabigatran, Rivaroxaban and Warfarin
Authors: Lin Iris , Horblyuk Ruslan , Mardekian Jack , Park Sang Hee , Kamble Shital , Hamilton Melissa , Abdulsattar Younos , Petkun William , Menzin Joseph , Lip Gregory Y
Published: April 2024

Introduction:
With the availability of four non-Vitamin K antagonist oral anticoagulants (NOACs) for patients with non-valvular atrial fibrillation (NVAF), insights into how these medications perform in ‘real-world’ settings, particularly among heart failure (HF) patients with increased risk for stroke and bleeding events, would be helpful. This study compared bleeding risk among newly anticoagulated NVAF patients, overall and in an HF subgroup.

Methods:
Using Humedica de-identified EHR data, newly anticoagulated adult NVAF patients with treatment initiation (index) between 2013 and 2015 were identified. Based on index prescription, patients were assigned to apixaban, rivaroxaban, dabigatran, and warfarin cohorts and followed until the earliest of drug switch, bleeding event (major or clinically-relevant non-major), last encounter, or 180 days post-index. For the HF subgroup, patients had to have an HF diagnosis in the 12 months pre-index. EHR prescription data did not allow accounting for discontinuation. Cox proportional hazard analysis was used to estimate bleeding hazard ratios (HR) for each NOAC compared to warfarin, adjusting for age, sex, region, stroke risk, and baseline comorbidities.

Results:
A total of 118,300 NVAF patients were selected, of which 17,127 were HF patients. Mean age ranged from 71.9 for dabigatran to 74.6 for warfarin. Mean CHADS
2
score was similar across cohorts. Overall, initiation of apixaban (HR: 0.78; 95% CI: 0.73-0.82) and dabigatran (HR: 0.71; 95% CI: 0.66-0.77) was associated with statistically significant lower risk of bleeding compared to warfarin, while rivaroxaban (HR: 1.09; 95% CI: 1.04-1.13) was associated with higher risk of bleeding compared to warfarin. Results were similar in the HF subgroup with the risk of bleeding lower for apixaban (HR: 0.78; 95% CI: 0.67-0.90) and dabigatran (HR: 0.67; 95% CI: 0.54-0.82) and higher for rivaroxaban (HR: 1.19; 95% CI: 1.07-1.32).

Conclusion:
Among NVAF patients, both overall and those with HF, initiating treatment with apixaban and dabigatran was associated with significantly lower risk of any bleeding event compared to initiating warfarin, whereas initiating with rivaroxaban was associated with higher bleeding risk compared with warfarin.
Abstract 13845: Added Value of Coronary Calcification in Prediction of Long-term Cardiovascular Events in Chronic Kidney Disease With and Without Diabetes Mellitus: Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Shroff Gautam R , Sanchez Otto A , Miedema Michael D , Kramer Holly , Ix Joachim H , Duprez Daniel A , Jacobs David R
Published: April 2024

Introduction:
Cardiovascular disease (CVD) is a major cause of morbidity/mortality in chronic kidney disease (CKD). Coronary calcification (CAC) is infrequently used by clinicians for risk prediction in CKD because high values are not felt to be predictive. We analyzed whether CAC can discriminate long-term outcomes in CKD with (CKD-DM) and without (CKD-non-DM) diabetes mellitus.

Methods:
We analyzed 6780 MESA participants (age 45-84 yrs, 19.3% CKD) without clinical CVD enrolled at 6 clinical sites, followed for adjudicated CVD (coronary heart disease, stroke, heart failure, peripheral arterial disease) for 12.1 years. CKD was defined as eGFR<60 ml/min/1.73 m
2
estimated using creatinine & cystatin C (CKD-EPI equation) or spot urine albumin/creatinine ≥ 17 mg/g in men; 25 mg/g in women. Baseline CAC was assessed by computed tomography. Poisson regression analysis was performed to adjust CVD events for demographic, clinical & inflammatory biomarker variables.

Results:
CAC increased across CKD and DM categories (neither condition: 56% had no CAC while 9% had >300 Agatston score; CKD only: 33% had no CAC while 21% had score >300; DM only: 42% had no CAC while 17% had score >300; CKD-DM: 31% had no CAC while 26% had score >300. CVD incidence density per 12.1 years varied greatly across CKD and DM categories (Figure). CVD incidence density per 1000 person-years across CAC categories ranged from 5-21 in non-CKD, non-DM; 7-20 in CKD-non-DM; 9-21 in non-CKD-DM; and 16-29 in CKD-DM. With adjustment for demographics and many risk covariates, baseline CAC added to prediction within each CKD and DM category.

Conclusion:
CKD-DM had the highest incident CVD events and those with CKD or DM alone had intermediate rates compared to those with neither condition. Contribution to risk prediction was as large from CAC category as from CKD or DM category. Despite the common knowledge that CAC increases in both CKD and DM, assessment of CAC would be helpful in risk stratification in all CKD and DM categories.
Abstract 13863: PGC-1α Mediates Differentiation Arrest of Murine Bone Marrow-derived Endothelial Progenitor Cells in Diabetes
Authors: Sawada Naoki , Sukmawati Dewi , Ito-Hirano Rie , Fujimura Satoshi , Itoh Seigo , Mizuno Hiroshi , Daida Hiroyuki , Tanaka Rica
Published: April 2024

Introduction:
Endothelial progenitor cells (EPCs) in murine bone marrow lineage-negative c-kit+Sca-1+ (BM-KSL) fraction are mobilized in circulation upon tissue injury to mediate a neovascularization process called vasculogenesis, which requires proper differentiative capacity of EPCs. Diabetics suffer defective vasculogenesis, a substantial mechanism for diabetic angiopathy in ischemic limb and heart. How it occurs, however, remains largely unknown. We recently demonstrated that type 1 (T1) and T2 diabetes (DM) induces a transcriptional coactivator PGC-1α in endothelial cells (ECs), and that EC PGC-1α mediates impaired cell migration and angiogenesis in DM. PGC-1α was also found to increase in EPCs cultivated from T2DM patients PB-MNCs. Building on these, we hypothesized roles for PGC-1α in EPC dysfunction.

Methods and Results:
We used Tie2-Cre-driven PGC-1α conditional null mice (KO), with or without T1DM induction by streptozocine. DM increased PGC-1α mRNA in WT BM-KSL cells whereas this induction was blocked in KO cells. DM decreased the differentiation capacity of WT BM-KSL cells and PB-MNCs, as determined by the formation of primitive (pEPC) and definitive (dEPC) colonies. PGC-1α ablation in KO rescued the defective EPCs differentiation in DM, most notably PB-MNCs formation of dEPC colonies, the known vasculogenic population. Consistent with this, endothelial marker gene expression (KDR, CD31, vWF), EPCs abundance, and EPCs vasculogenic functions of PB-MNCs was blunted by DM but rescued by PGC-1α ablation in KO. Importantly, T2DM induction by high-fat diet feeding also caused reduction in the EPCs abundance and EC gene expression of PB-MNCs, which was rescued by PGC-1α ablation in KO.

Conclusions:
Our data demonstrate critical new roles for PGC-1α in vasculogenesis. PGC-1α mediates the vasculogenic differentiation defect of circulating EPCs in T1 and T2 DM, in sharp contrast to the anti-migratory effect of EC PGC-1α in mediating diabetic angiostasis. Our data broadens the relevance of PGC-1α in the etiology of diabetic angiopathy, now with a potential to therapeutically restore EPCs vasculogenicity, and may provide an opportunity to improve the efficacy of autologous adoptive EPC therapy for limb and myocardial ischemia in DM.
Abstract 13884: Predictor of Right Ventricular Reverse Remodeling After Treatment in Patients With Pulmonary Hypertension
Authors: Sano Hiroyuki , Tanaka Hidekazu , Motoji Yoshiki , Fukuda Yuko , Takada Hiroki , Soga Fumitaka , Hatani Yutaka , Matsuzoe Hiroki , Hatazawa Keiko , Shimoura Hiroyuki , Ooka Junichi , Ryo-Koriyama Keiko , Matsumoto Kensuke , Emoto Noriaki , Hirata Ken-ichi
Published: April 2024

Background:
Right ventricular (RV) function is one of the most important determinants of outcome for patients with pulmonary hypertension (PH). Furthermore, mid-term RV reverse remodeling after treatment is also associated with long-term outcome as well as RV remodeling before treatment. However, baseline factors influencing mid-term RV reverse remodeling after treatment remains unclear.

Methods:
We studied 54 PH patients. RV function was calculated by averaging peak speckle-tracking longitudinal strain from RV free-wall (RV free-wall strain). Mid-term RV remodeling was assessed in terms of the RV area, which was traced planimetrically at the end-systole (RVESA). RV reverse remodeling was defined as a relative decrease in RVESA of at least 15% at 10.2 ± 9.4 months after treatment. Long-term follow-up was tracked for 5 years.

Results:
Adverse events occurred in 10 patients (19%). Mid-term RV reverse remodeling after treatment was observed in 37 patients (69%). Patients with mid-term RV reverse remodeling had more favorable long-term outcome than those without (log-lank p=0.01). Multivariate logistic regression analysis showed that RV relative wall thickness (RV-RWT), which was calculated from RV free-wall thickness/RV basal linear dimension at end-diastole, was the independent predictor of mid-term RV reverse remodeling (OR 1.403; 95% CI, 1.090-1.807; p=0.009). In addition, patients with RV-RWT≥0.21 experienced favorable long-term outcome than those without (log-rank p=0.03). Sequential Cox models show that a model based on symptom, hemodynamic parameters was improved by addition of RV free-wall strain (χ
2
=13.3; p=0.08), and was further improved by addition of RV-RWT (χ
2
=28.9; p<0.01).

Conclusion:
RV-RWT could predict mid-term RV reverse remodeling after treatment in PH patients, and was associated with long-term outcomes. Our findings may have clinical implications for better management of PH patients.
Abstract 13920: Common Variant in Pitx2 Contributes to the Pathogenesis of Paroxysmal Atrial Fibrillation by Impairing Sinus Node Function and Progression of Atrial Remodeling
Authors: Tomomori Sunsuke , Nakano Yukiko , Tokuyama Takehito , Sairaku Akinori , Matsumura Hiroya , Amioka Michitaka , Hironobe Naoya , Kihara Yasuki
Published: April 2024

Introduction:
Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with atrial fibrillation (AF). The most notably
PITX2
SNPs have been known to show the strong association with AF, but how these SNPs affect clinical phenotype of AF has not been clarified.

Hypothesis:
We assessed the hypothesis that
PITX2
SNPs influence the cardiac structures and electrophysiological properties, and increase the susceptibility to AF.

Methods:
To investigate the association between the
PITX2
SNP and paroxysmal atrial fibrillation (PAF), we genotyped
PITX2
SNP (rs6817105) in 344 Japanese PAF patients hospitalized in Hiroshima University hospital and 1,507 healthy controls and compared the allele frequencies of the
PITX2
SNP between the PAF patients and controls. The
PITX2
SNP was significantly associated with PAF (minor allele (C) frequency: PAF 64.7% vs control 47.3%, P =3.7х10
−
16
, odds ratio (OR)=2.0). We investigated the relationships between the
PITX2
C risk allele and clinical characteristics, ECG parameters, parameters of cardiac ultrasound, and electrophysiological study.

Results:
There were significant linear correlations between the
PITX2
genotypes(CC, CT, and TT) and the max sinus node recovery time(SNRT) , corrected sinus node recovery time(CSNRT) and left atrial diameter (LAD) (max SNRT, CC: 1328ms, CT: 1235ms , TT: 1225ms , P =1.5х10
−
2
, CSNRT, CC: 482ms, CT: 418ms, TT: 409ms ,P =1.3х10
−
2
, LAD; CC:37.2±5.6mm, CT:34.4±5.3mm, TT:34.1±5mm, P=1.3х10
−
2
, respectively).

Conclusions:
To the best of our knowledge, this was the first report showing that
PITX2
risk allele was related to the sinus node dysfunction and progression of atrial remodeling in humans. The result was meaningful for considering the mechanism of why
PITX2
contributes to the pathogenesis of AF.
Abstract 13925: Association of Ankle-Brachial Index With Incident Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Bekwelem Wobo , Norby Faye , Agarwal Sunil K , Matsushita Kunihiro , Coresh Josef , Alonso Alvaro , Chen Lin Y
Published: April 2024

Introduction:
A normal ankle-brachial index (ABI) is defined as 1.0 to 1.4; abnormal ABI is defined as ≤0.90 whereas >0.9 to <1.0 is considered “borderline” and >1.40 indicates noncompressible arteries. Although peripheral arterial disease has been shown to be associated with incident AF, it is unclear whether borderline ABI or noncompressible arteries are associated with incident AF. We aimed to evaluate this association of borderline ABI and ABI >1.4 in the ARIC study, a population-based prospective cohort study.

Methods:
We included 14,794 participants (age, 54.2 ± 5.8 yrs, 55% women, 26% blacks) who attended the baseline exam (1987-89) and without prevalent AF. Incident AF was identified from hospital discharge records, death certificates, and ECGs. We used Cox proportional hazard models to evaluate the association between ABI categories and incident AF.

Results:
During a mean follow-up of 19.8 years, there were 2288 incident AF cases. After full adjustment in Model 2, compared with ABI 1.0-1.4, the hazards ratio (HR) (95% CI) of ABI <1.0 for incident AF was 1.13 (1.01-1.27). ABI of >0.9 to <1.0, but not >1.4 was associated with an increased risk of AF (Table).

Conclusions:
This study is the first to show that borderline ABI is independently associated with AF further supporting that borderline ABI is not benign. Our findings also suggest that detection of preclinical and early clinical atherosclerosis may identify individuals at increased risk of AF.
Abstract 13944: Right Heart Myocarditis: A Cardiac MRI Perspective
Authors: Mikolich Brandon M , Mikolich J Ronald
Published: April 2024

Introduction:
In 1961 J. A. Hayes from Boston City Hospital reported in the British Heart Journal a case of myocarditis in a young man who died. Autopsy revealed inflammatory cells confined to the right heart. With the advent of cardiac MRI in the 1990s and its capability of detecting myocardial edema due to inflammation, it became apparent the some cases of arrhythmogenic right ventricular dysplasia (ARVD) were actually myocarditis. Since then, there has been no systematic study of right heart myocarditis.

Hypothesis:
Myocarditis confined to the right heart is detectable with cardiac MRI.

Methods:
An institutional cardiac imaging database was queried for all cases of CMR diagnosed myocarditis using published criteria, requiring 2 of the following 3 criteria: Myocardial enhancement on T2 weighted imaging (T2E), “early” myocardial gadolinium uptake (EGE) and standard late gadolinium enhancement (LGE). Patients with CMR evidence of myocarditis confined to the right heart constituted the study population. These patients were also required to have no evidence of left heart myocarditis, ie no T2E, EGE or DHE of LV myocardium.

Results:
172 of 3,250 patients (5.3%) had evidence of myocarditis by CMR criteria. Of these 172 patients with myocarditis, 16(9.3%) were confined to the right heart. A typical case of right heart myocarditis is shown below, a T2 weighted 4 chamber CMR image showing myocardial enhancement(edema). All 16 patients complained of fatigue and palpitations. 4 of 16 had mild right heart failure on exam and RV hypokinesis on CMR or 2-D echo. 14 of 16 had documented atrial or ventricular tachy-arrhythmias. 14 of 16 had contiguous focal pericarditis (also confined to the right heart).

Conclusions:
Myocarditis confined to the right heart is evident in approximately 9% of patients with a CMR diagnosis of myocarditis. Palpitations and fatigue are the most common symptoms. Nearly all have a documentable arrhythmia and evidence of contiguous pericarditis on CMR.
Abstract 13989: Detection of Micro Intimal Tear at a Very Early Stage in Patients With Acute Aortic Intramural Hematoma
Authors: Nakashima Masaki , Kaji Shuichiro , Murai Ryosuke , Sasaki Yasuhiro , Ota Mitsuhiko , Kim Kitae , Yamane Takafumi , Kitai Takeshi , Kobori Atsushi , Ehara Natsuhiko , Kinoshita Makoto , Furukawa Yutaka
Published: April 2024

Background:
Although rupture of the vasa vasorum is thought to be the main cause of acute aortic intramural hematoma (IMH), previous studies have suggested the existence of micro intimal tear at the onset, which supported a common pathophysiologic mechanism of aortic dissection (AD) and IMH. A better understanding of the pathophysiology of IMH may lead to successful identification of high-risk patients and appropriate management. The purpose of this study was to investigate the prevalence and clinical outcome of micro intimal tear detected by multi-detector computed tomography (MDCT) in patients with IMH at a very early stage.

Methods and Result:
We retrospectively analyzed 50 patients with IMH who underwent 64-row MDCT at admission: 34 patients underwent MDCT within 3 hours (early scan group) and 16 patients more than 3 hours after the onset (late scan group). Micro intimal tear was defined as continuity disruption of the inner layer of thrombosed false lumen with tiny inflow of contrast medium, which suggested small flow communication. Localized contrast pooling in aortic wall, which is considered as a pseudoaneurysm of branch artery, was not regarded as micro intimal tear and excluded from the analysis. In early scan group, 18 (52%) patients had 27 micro intimal tears. Of these, 12 tears were located in aortic arch, 2 in proximal descending aorta (PD), 1 in mid descending aorta (MD), 9 in distal descending aorta (DD) and 3 in abdominal aorta (AA). In late scan group, 5 (31%) patients had 6 micro intimal tears; 1 in arch, 4 in DD and 1 in AA. Micro intimal tear observed in aortic arch was significantly more frequent (12/34) in early scan group than late scan group (1/16, p=0.03). During initial hospitalization, progression of micro intimal tears was observed in 11 of 18 patients (61%) in early group and 4 of 5 patients (80%) in late group (p=0.41). On the other hand, 2 micro intimal tears observed in arch regressed in early scan group.

Conclusion:
Early MDCT scan within 3 hours after the onset detected micro intimal tear in a considerable portion of patients with IMH, most frequently in aortic arch. These findings may suggest common pathophysiologic mechanism of AD and IMH.
Abstract 14016: Severity Assessment of Brain Damage With rSO2 monitoring for Extracorporeal Cardiopulmonary Resuscitation After Out-of-hospital Cardiac Arrest
Authors: Unoki Takashi , Nishiyama Kei , Ito Noritoshi , Orita Tomohiko , Arimoto Hideki , Beppu Satoru , Abe Mitsuru , Endo Tomoyuki , Yasuda Hideto , Nagao Ken
Published: April 2024

Introduction:
Decisions regarding extracorporeal cardiopulmonary resuscitation (E-CPR) for patients after out-of-hospital cardiac arrest (OHCA) are difficult to make.

Hypothesis:
We hypothesized that regional brain oxygen saturation (rSO2) value monitoring in the emergency room was useful for speculating on brain damage severity for prognostication for E-CPR after OHCA.

Methods:
The J-POP registry is a prospective multicenter cohort study to test whether rSO2 predicts neurological outcomes after nontraumatic OHCA. We measured rSO2 values in OHCA patients immediately after hospital arrival with a near-infrared spectrometer placed on the forehead. The primary endpoint was neurological outcome (cerebral performance category: 1, 2) 90 days after OHCA.

Results:
We consecutively enrolled 1,921 OHCA patients. After 90 days, 79 (4%) patients had good neurological outcomes and a median lower rSO2 level of 15% (95% confidence interval (CI): 15-20%). Receiver operating curve analysis indicated an optimal rSO2 cutoff point was about 40% for predicting good neurological outcome (area under curve = 0.91 [95% CI: 0.90 - 0.92], P < 0.01). Compared to patients without return of spontaneous circulation (ROSC) upon arrival at the hospital, those with ROSC had significantly higher rSO2 levels (56% [95% CI: 39-65%] vs. 15% [95% CI: 15-17%], respectively; P < 0.01). In patients without ROSC upon arrival at the hospital (n=1773), the percentage of patients with a good 90-day neurological outcome increased significantly in proportion to their rSO2 levels upon arrival at the hospital (P < 0.01, Figure). In patients with E-CPR (n=121), the percentage of patients with a good 90-day neurological outcome increased significantly if their rSO2 levels upon arrival at the hospital was >40% (5/16, 31% vs 6/105, 6%, P < 0.01).

Conclusions:
rSO2 value monitoring in the emergency room was useful for speculating on brain damage severity for prognostication for E-CPR after OHCA.
Abstract 16588: Relationship Between Sleep Debt and Obesity in Older Women: Findings From the Women’s Health Study
Authors: Child Stephanie T , Durazo Eva M , Powell-Wiley Tiffany , Slopen Natalie , Prather Aric , Redline Susan , Zaslavsky Alan , Buring Julie E , Williams David R , Albert Michelle A
Published: April 2024

Background:
Obesity is increasingly prevalent in older women and is associated with heightened risk of cardiovascular disease (CVD) and Type II diabetes (diabetes). Sleep disturbance has been shown to affect weight through numerous mechanisms, including metabolic and hormone dysregulation and diet. However, whether sleep debt, a measure of sleep deficiency during the week compared to the weekend,is associated with greater risk of obesity among older women with and without diabetes is relatively unknown.

Methods and Results:
Among women participating in the Women’s Health Study (WHS) 2012-2013 follow-up stress cohort, we examined the relationship between sleep debt and obesity in 21,726 women without a history of cancer or CVD. Sleep debt was defined as the difference between self-reported total weekday and weekend sleep hours of ≥ 2 hours (dichotomizedas ‘yes’ = 1 or ‘no’ = 0). Mean age was 72.0 ±6.0 years, 23.1% of women reported a body mass index ≥30 kg/m
2
, and 9.9% of participants had diabetes. Sleep debt was reported by 6.5% of women. Compared to women without sleep debt, women with sleep debt were more likely to be less physically active and diabetic, and to report more cumulative psychological stress (e.g., a composite score of acute and chronic stressors including work, work-family spillover, financial, traumatic life events, negative life events, discrimination, relationship, and neighborhood). Logistic regression models revealed a positive association between sleep debt and obesity (OR=1.16, 95% CI: 1.02-1.33) after adjusting for age, race/ethnicity, education and income levels, physical activity, alcohol use, smoking history, and depression and anxiety symptoms (Table). However, this association does not remain significant after control for cumulative psychological stress. In analyses stratified by diabetes status, sleep debt is similarly associated with greater risk of obesity among non-diabetic women (OR=1.17, 95% CI: 1.02-1.36), however, this association does not remain significant once depression and anxiety symptoms and cumulative stress are added to the model. There was no association found between sleep debt and obesity among women with diabetes.

Conclusion:
Among older, non-diabetic women participating in the WHS, sleep debt was associated with greater risk of obesity.
Abstract 16591: Exosome-Mediated Endothelial Cell Apoptosis and Network Disruption by Lymphangioleiomyomatosis-Smooth Muscle Cells (LAM-SMCs) Derived from Human Induced Pluripotent Stem Cell (iPSC)
Authors: Ho Mirabelle S , Ho Miriel , Julian Lisa M , Stanford William L , Stewart Duncan J
Published: April 2024

Introduction:
In LAM, SMC-like cells invade the lung thus compromising respiratory function which is dependent on normal vascular and alveoli structure. We posit that while healthy mural SMCs stabilize fragile neovessels and maintain vascular homeostasis, LAM-SMCs promote disruption of lung microvasculature by inducing endothelial cell (EC) apoptosis.

Methods/Results:
iPSCs derived from LAM patients or healthy subjects were differentiated into SMCs using a teratoma protocol. Co-culture of healthy iSMCs with HUVECs on Matrigel improved EC network persistence for ≥72Hrs, while LAM-SMC co-culture led to rapid network collapse in <15Hrs. Culture of ECs with LAM-SMC conditioned media (24-72Hrs) increased EC apoptosis as assessed by Annexin V/PI flow cytometry, confirmed by increases in cleaved Caspase-3 protein expression. To further elucidate mechanism and kinetics of EC apoptosis, Annexin V/PI flow cytometry and Western Blot with Caspases 8,9,12 were performed in parallel at 3hr intervals from 0-12 Hrs. Increase in EC apoptosis at 9hrs, corresponded with a 6-fold increase in Cas-12 protein expression, followed by a 3-fold increase in Cas-9 at 12hrs with little change in Cas-8. This is in line with our RNAseq study showing dysregulation in endoplasmic reticulum and mitochondria related genes in LAM-SMC. Culture of HUVECs with LAM-SMC exosomes similarly induced EC apoptosis, with a profound decrease in EC gene expression (eNOS,TIE2,TAL1; 5-7 fold; p<0.05) but increase expression of vessel-destabilizing, ANGPT2 (6-fold; p<0.05). Scratch-wound assay also showed ~60% reduction (p<0.05) in EC migratory capacity. Intriguingly, apoptotic ECs released exosomes containing translationally controlled tumor protein, TCTP, which were taken up by LAM-SMCs, as evidenced by immunofluorescence studies, associated with increases in the levels of proliferation-associated phospho-mTOR-and-S6k protein.

Conclusions:
LAM-SMCs derived exosomes resulted in EC apoptosis and network destabilization. Conversely, apoptotic ECs enhanced LAM-SMC growth, possibly by Caspase-dependent exosome release of TCTP, a positive regulator of mTOR signaling. These novel mechanisms may promote both microvasculature disruption and uncontrolled growth of LAM-SMCs.
Abstract 16594: Clinical Outcomes in Digital Electrocardiography: Evaluation of Mortality in Atrial Fibrillation (Code Study)
Authors: Paixao Gabriela , Silva e Silva Luis Gustavo , Gomes Paulo , Ferreira Milton , Oliveira Derick , Ribeiro Manoel , Ribeiro Antonio , Nascimento Jamil , Cardoso Gustavo , Araujo Rodrigo , Santos Bruno , Canazart Jessica , Ribeiro Leonardo , Ribeiro Antonio
Published: April 2024

Introduction:
Telehealth system is an important tool to improve access and quality to health assistance.Large electrocardiogram (ECG) databases, linked to mortality or hospitalization data, can be useful in determining the prognostic value of ECG markers. Atrial fibrillation (AF) is a public health problem with increasing prevalence as the population ages, associated with cardiovascular mortality and morbidity.

Hypothesis:
Evaluate the association between the presence of AF with overall and cardiovascular mortality in a large electronic cohort of primary care patients of Minas Gerais.

Methods:
This is an observational retrospective study. Patients over 16 years old who performed digital electrocardiograms by Telehealth Network of Minas Gerais from 2013 to 2016 were assessed. A probabilistic linkage between data from the national mortality information system and our ECG database was made. Clinical data were self-reported, and ECGs were interpreted by a team of trained cardiologists and automatic software (Glasgow and Minnesota).The diagnosis of AF was considered if there was concordance between the cardiologist′s report and one of the automatic systems. In cases of disagreement, ECGs were reviewed manually.Only the first ECG made was analysed. To assess the relation between AF and mortality, Cox regression was used, adjusted by age, sex and clinical conditions.

Results:
From a dataset of 1,773,689 patients, 1,075,531 were included. The mean age was 51.4 years, 40.5% male.The prevalence of AF was 1.15%. There were 2.9% deaths for all causes in 2.69 years of mean follow up. In univariate analysis, AF was a risk factor for death from all causes (HR 6.98, 95%CI 6.68-7.28). After adjustment for age, sex and comorbidities, AF remained an independent risk factor for all-cause mortality (HR 2.49; 95% CI 2.39 - 2.61). AF was also a predictor of risk for cardiovascular mortality after adjustment for age, sex and clinical conditions (HR 2.35, 95% CI 2.01-2.73). In multivariate analysis by sex, adjusted for age and comorbidities, AF women had higher risk of death for all causes (HR 3.06; 95% CI 2.86-3.26) than men (HR 2.18; 95% CI 2.06-2.32). There were no difference between sex in cardiovascular mortality (HR 2.34; 95% CI 2.01-2.73 for male sex e HR 2.49; 95% CI 2.14-2.90 for female).

Conclusions:
AF was a strong predictor of mortality for all causes and cardiovascular mortality in primary care population with increased risk in women for deaths for all cause.
Abstract 16599: Mutations In KCNE1 Alters Multiple K
+
Channels To Cause APD Instability And Polymorphic Ventricular Tachycardia (PVT) In Transgenic Long QT Syndrome Type 5 Rabbits
Authors: Kim Tae Yun , Kabakov Anatoli , Terentyev Dmitry , Terentieva Radmila , Arunachalam Karuppiah , Li Yichun , Odening Katja , Varró András , Bosze Zsuzsanna , Koren Gideon , Choi Bum-Rak
Published: April 2024

Introduction:
LQT5 is caused by mutations in KCNE1, an accessory subunit of slowly activating delayed rectifier K
+
channel (I
Ks
), and is associated with polymorphic ventricular tachycardia (pVT) and sudden cardiac arrest.

Methods:
Optical mapping of intact heart and single myocyte voltage clamp were used to investigate arrhythmia mechanism in LQT5 rabbit hearts.

Results:
LQT5 rabbits show slight prolongation of APDs as compared to littermate control (LMC) (179±12 vs. 165±10 ms at 350 ms pacing, p<0.05). APD restitution in LQT5 rabbits was non-monotonic and steeper at longer diastolic interval compared to LMC rabbits (τ=24±3 vs.16±2 ms), accompanying by APD alternans. Isoproterenol (ISO, 140 nM) alone did not induce pVT but the sudden acceleration of heart rate (HR) with S1S2S3S4 stimulation in the presence of ISO induced pVTs (n=9/11 in LQT5 vs. 0/5 LMC hearts (panel A). The mapping of pVT initiation showed that the sudden HR acceleration produced large APD oscillations (red line) and progressively increased APD dispersion of S2S3S4 beats (blue line, panel B), which is associated with triggered focal activity (stars, panel C) to form reentry. Patch clamp data showed that transient outward K
+
current (I
to
) in LQT5 myocytes is markedly altered with slow inactivation (τ=14 and 99 ms for double exponential curve fit) and slow recovery from inactivation kinetics (τ=217 and 3100 ms for I
to,f
and I
to,s
, respectively). These results suggest that in addition to I
Ks
, KCNE1 mutation also modifies I
to
thereby cause large APD oscillations and increase APD dispersion particularly during abrupt heart rate acceleration, resulting in pVTs in LQT5 rabbit.

Conclusion:
KCNE1 mutation in LQT5 affects multiple K
+
channels including I
to
, causing large APD variation and dispersion that trigger pVTs during sudden HR acceleration.