bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13496: Impact of Serum Albumin Levels on Long-term Outcomes in Patients Undergoing Percutaneous Coronary Intervention
Authors: Wada Hideki , Dohi Tomotaka , Miyauchi Katsumi , Shitara Jun , Endo Hirohisa , Doi Shinichiro , Naito Ryo , Konishi Hirokazu , Tsuboi Shuta , Ogita Manabu , Kasai Takatoshi , Suwa Satoru , Daida Hiroyuki
Published: April 2024

Background:
Numerous studies have reported that lower serum albumin on heart failure is associated with increased adverse events. However, the relationship between albumin and long-term outcomes in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) is not well known.

Methods:
We studied 2,860 all-comer patients with CAD who underwent their first PCI and available data of pre-procedural serum albumin between 2000 and 2011. Patients were assigned to tertiles based upon pre-procedural albumin levels. We evaluated the incidence of major adverse cardiac events (MACE) including all-cause death and acute coronary syndrome (ACS).

Results:
The mean albumin level was 4.0±0.5 g/dL. Patients with a lower albumin levels were older and had a higher prevalence of ACS and chronic kidney disease (CKD). Patients with a higher albumin values were likely to be higher LVEF and had a higher prevalence of statin use. During a median follow-up period of 7.4 years, Kaplan-Meier curves showed ongoing divergence in rates of MACE among the albumin tertile groups (albumin <3.8g/dl: 44.3% vs. 3.8-4.1g/dl: 38.0% vs. >4.1g/dl: 22.9%; log-rank p<0.0001). After adjustment for established cardiovascular risk factors including age, ACS, BMI and CKD, serum albumin levels were significantly associated with incidence of MACE (HR 1.67 per each 1g/dl decrease, 95%CI 1.32-2.08, p<0.0001) and all-cause mortality (HR 1.75, 95%CI 1.30-2.33, p=0.0002).

Conclusions:
Pre-PCI low serum albumin level was associated with worse long-term outcomes, independent of traditional risk factors. Assessing the albumin levels may have implications for risk stratification in patients with CAD undergoing PCI.
Abstract 13527: Role of Rotor Activation in Persistent Atrial Fibrillation Perpetuated After Pulmonary Vein isolation: Relation to the Complex Fractionated Electrogram Region
Authors: Yamabe Hiroshige , Kanazawa Hisanori , Ito Miwa , Kaneko Shozo , Kanemaru Yusuke , Kiyama Takuya , Ogawa Hisao
Published: April 2024

Background:
Complex fractionated electrogram (CFE) region has been suggested as the substrate of random wave propagation perpetuated after pulmonary vein (PV) isolation in patients with persistent atrial fibrillation (AF). While the rotor has also been suggested as the driving sources. But the relation between CFE and rotor remains unclear.

Objectives:
We elucidated the significance of CFE and rotor for the maintenance of AF perpetuated after PV isolation in persistent AF patients.

Methods:
Endocardial non-contact mapping of the left atrium was performed in 16 patients with persistent AF perpetuated after PV isolation. To define the role of CFE and rotor for the maintenance of AF, the number of pivoting activation involved in the CFE was compared with that involved in the rotor activation. The location of rotor and pivoting activation were also compared between the CFE and non-CFE region. Presence of rotor activation was defined when the circular activation around the functional block line once completed its whole reentrant activation.

Results:
Rotor activation was observed in 11 patients (69%) with a mean number of 2.1±2.0 times/sec. Rotor activation continued at the same site more than once in 2 patients, but shifted to the different location or observed intermittently in the remaining 9 patients. All rotors were observed at CFE region (CFE area; 7.7±2.5 cm2). Total number of pivoting activation was 12.8±4.6 times/sec. The number of pivot activation involved in the CFE region was significantly higher than that in the non-CFE region (12.4±4.9 vs. 0.5±1.0 times/sec, p<0.0001). Thus, 99% of pivoting activations were observed within the CFE region. Pivoting activation involved in the rotor activation was significantly lower than that not involved in the rotor activation (3.5±3.2 vs. 8.7±5.0 times/sec, p<0.01) in the CFE region, but was not different in non-CFE region (0.0±0.0 vs. 0.5±1.0 times/sec, p=NS).

Conclusions:
Rotor activation was observed within the CFE region after PV isolation. However, few rotors sustained at the stable location. Further, most of pivoting activation was not involved in the rotor activation, suggesting that AF was driven by the meandering non-rotor propagation associated with frequent pivoting activation over the CFE region.
Abstract 13747: Addition of Dipeptdyl Peptidase-4 Inhibition to Metformin Mono-therapy Reduces Vascular Inflammation in Humans With Diabetes Mellitus Type 2
Authors: Puppala Venkata K , Branum Amberly , Muhammad Shahreyar , Wang Jingli , Ying Rong , Tanner Michael , Widlansky Michael
Published: April 2024

Introduction:
Endothelial dysfunction precedes the development of atherosclerosis and predicts future adverse cardiovascular events. Systemic endothelial dysfunction is well described in patients with type 2 diabetes (T2DM). Glycemic control that also favorably impacts the vascular endothelium would be an ideal choice for T2DM patients. Prior cell culture and animal work on dipeptdyl peptidase-4 (DPP-4) inhibition suggest these agents could favorably impact human endothelial function. In our study, we looked at the effect of sitagliptin (a DPP4 inhibitor) on endothelial function in T2DM patients on stable metformin therapy.

Methods:
Thirty-eight subjects with T2DM who were on a stable dose of metformin were enrolled in a double-blind cross-over trial of sitagliptin (100 mg/day) for eight weeks versus matching placebo. Endothelium dependent vasodilation was measured by percent flow mediated dilatation (FMD) of the brachial artery 2 hours after the 1st dose of sitaglitin and placebo and following 8 weeks of sitagliptin and placebo administration. A 4 week washout period was interposed between treatment periods. Plasma markers for endothelial cell activation, intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) were also measured following chronic dosing of sitagliptin and placebo.

Results:
FMD% was not significantly different across all time points (5.6±2.3% pre-sitagliptin 6.3±2.4 post acute sitagliptin, 5.8±2.3 post chronic sitagliptin, 5.2±1.8 pre-placebo, 5.6±2.1 post acute placebo, 6.0±2.9 post chronic placebo, P=0.31 by repeated measures ANOVA). No differences were noted in the hyperemic flow responses as well (P=0.26). Plasma ICAM-1 ( endothelial cell activation ICAM) levels were significantly lower following 8 weeks of sitagliptin compared to placebo [192±70 vs. 228±73 ng/mL (P<0.0001)]. Plasma VCAM-1 was not significantly different following 8 weeks of each treatment [(520±155 vs. 620±96 ng/mL (P=0.67)].

Conclusions:
While the addition of DPP-4 inhibition with sitagliptin did not alter endothelium-dependent vasodilation in humans with T2DM on metformin therapy, vascular inflammation may be reduced which could provide an added benefit to these patients.
Abstract 13806: Association Between Coronary Angiography With or Without Percutaneous Coronary Intervention and Outcomes After Out-of-Hospital Cardiac Arrest
Authors: Vadeboncoeur Tyler F , Chikani Vatsal , Spaite Daniel W , Hu Chengcheng , Mullins Margaret , Bobrow Bentley J
Published: April 2024

Introduction:
Coronary angiography (CA) is recommended after out-of-hospital cardiac arrest (OHCA) when ST-elevation is present but the ideal timing and benefit of CA when ST-elevation is not present are unknown.

Methods:
Prospective observational study of adult (age >17) OHCA of presumed cardiac etiology from 1/01/2010-12/31/2014 who were admitted to one of 40 recognized cardiac receiving centers within a state resuscitation center network. DNR patients, those who did not achieve ROSC, and/or those who died in the ED were excluded since the likelihood of percutaneous coronary intervention (PCI) impacting outcome in these patients is low. An in-hospital database was linked with a statewide OHCA database.

Results:
Among 6,615 cases, 1,247 remained for analysis after exclusion [DNR (1254); failed to achieve ROSC/died in ED (4,020); missing prehospital variable (92); and missing outcome (2)]. Median age was 63 and 70% were male. There were 62% witnessed arrests, 54% received bystander CPR and the initial rhythm was VF/VT in 55%. Sixty-four percent survived to hospital discharge, 82% of which had a CPC score of 1 or 2. Of the 326 STEMI cases, 298 (91%) underwent CA with resultant PCI in 206 (63%). Of the 849 non-STEMI cases, 361 (43%) underwent CA with resultant PCI in 107 (13%). Overall survival was: 54% in cases without CA; 73% in cases with CA but without PCI; and 73% in those with PCI. Survival in non-STEMI cases was: 55% in cases without CA; 82% in cases with CA but without PCI; and 80% in those with PCI. In non-STEMI cases, the adjusted odds of survival for CA without PCI vs no CA was 2.70 (95% CI: 1.81, 4.02) and for PCI versus no CA it was 2.01 (95% CI: 1.16, 3.48).

Conclusion:
In this statewide analysis over 90% of OHCA cases with STEMI underwent CA. In cases that were not STEMI, CA was strongly and independently associated with survival regardless of whether PCI was performed. Since there is no reason to believe that CA without PCI confers a survival benefit, these findings suggest a component of selection bias in those without STEMI who undergo CA.
Abstract 13814: DMGV is a Novel Marker of Liver Fat and Predicts Future Development of Type 2 Diabetes
Authors: O’Sullivan John F , Morningstar Jordan E , Zheng Baohui , Jeanfavre Sarah , Scott Justin , Yang Qiong , Fernandez Celine , Vasan Rakmachandran S , Long Michelle T , Melander Olle , Wang Thomas J , Fox Caroline , Peterson Randall T , Clish Clary , Corey Kathleen , Gerszten Robert E
Published: April 2024

Background:
Unbiased “non-targeted” metabolite profiling techniques hold considerable promise for biomarker and pathway discovery, though there have been few successful applications to human disease. We aimed to uncover novel biomarkers of non-alcoholic fatty liver disease (NAFLD) and cardiometabolic disease using non-targeted metabolomic profiling in well-phenotyped human cohorts.

Methods:
Non-targeted metabolite profiling was performed using hydrophilic interaction chromatography on a UHPLC Q-Exactive hybrid orbitrap LC/MS system. We searched HMDB, Metlin, Chemspider, and Pubchem databases using a 5-ppm mass tolerance for potential identifications of unknown metabolites. Following unambiguous metabolite identification, a high-throughput targeted metabolite assay was generated using a triple quadrupole MS. Stepwise logistic regression was used to determine the association of metabolites with clinical traits and outcomes.

Results:
The non-targeted platform was applied first to a discovery cohort of 1066 Framingham Heart Study (FHS) Gen 3 participants, of whom 470 underwent a CT scan as part of a comprehensive assessment of adipose depots, including liver fat. An unknown metabolite with a mass/charge ratio of 202.1185 had the strongest association with CT-defined liver fat, which was quantified using the liver-to-phantom ratio (P=1.16E-10, adjusting for age, sex, smoking, alcohol consumption, HDL and triglyceride concentration, HOMA-IR, hypertension, and BMI). Following structural elucidation by LC-MS and the synthesis of a chemical standard, we confirmed the peak identity as α-keto-δ-(N
G
N
G
-dimethylguanidino)-valeric acid (DMGV). DMGV was significantly associated with non-alcoholic steatohepatitis (NASH), in a cohort of 36 patients with biopsy-proven NASH and 36 age, sex, and BMI-matched controls (OR=1.96, P=0.011, conditionally adjusted for age, sex, and BMI). Further, DMGV was predictive of future type 2 diabetes mellitus (T2D) in 196 cases of incident diabetes and 126 controls in the Malmo Diet and Cancer Study (OR=1.56, P=8.6E-4, adjusting for age, sex, fasting glucose, and BMI; mean follow-up 12.8 years).

Conclusions:
DMGV is a novel marker of NAFLD and NASH, and is a predictor of future T2D.
Abstract 13816: Readmission in Patients With Atrial Fibrillation Treated With Dofetilide versus Other Anti-arrhythmic Drug Therapy
Authors: Cao Zhun , Rublee Dale , Baumer Dorothy , Robinson Scott B , Chambers Richard , Ashkenazy Rebecca , Lipkin Craig B
Published: April 2024

Introduction:
An estimated 3 million people in the U.S. are affected by atrial fibrillation (AF), and its prevalence is projected to increase significantly as the population ages. This study examined time trends of 30-day hospital readmission rates in AF patients treated with dofetilide vs those treated with other antiarrhythmic drug therapy (ADT) and those without ADT (controls).

Methods:
A retrospective cohort study was conducted using Premier Healthcare Database. The first adult inpatient discharge with ICD-9 diagnosis code 427.31 between 1/1/2007-11/30/2014 was included. Unadjusted descriptive analysis was used to describe the trends of 30-day all-cause and AF-related readmission rates in patients treated with dofetilide, compared to patients with other ADT (amiodarone, sotalol, flecainide, propafenone and dronedarone) and those without ADT. Logistic regressions were used to estimate the association between 30-day readmission and type of anti-arrhythmic treatment.

Results:
2,664,043 AF discharges were included. 30-day all-cause readmission rate for dofetilide patients decreased from 10.42% in 2007 to 6.75% in 2014, compared to 3.35% for patients with other ADT, and 3.40% for controls. 30-day AF-related readmission rates dropped by 3.28% in dofetilide, compared to 1.85% in other ADT cohort and 2.42% in controls. Using the no-ADT cohort as reference, the adjusted odds ratios (OR) of 30-day all-cause readmission were 0.76 (95% CI: 0.73-0.80, p<0.001) for dofetilide and 1.10 (95% CI: 1.09-1.11, p<0.001) for other ADT. The adjusted OR of 30-day all-cause readmission were 0.91 (95% CI: 0.86-0.97, p=0.002) for dofetilide and 1.13 (95% CI: 1.12-1.14, p<0.001) for other ADT. The adjusted 30-day all-cause readmission rates were 12.20% for dofetilide, 16.62% for other ADT, and 15.41% for controls. The adjusted AF-related readmission rates were 10.81% for dofetilide, 13.05% for other AA, and 11.71% for controls.

Conclusions:
There was an 8-year decline in 30-day readmission rates for all cohorts (p<0.001), with a faster decrease in dofetilide patients (p<0.001). The dofetilide treated patients had the lowest adjusted risk of 30-day all-cause and AF-related readmission, while patients undergoing other ADT had the highest readmission rates.
Abstract 13854: Micro-RNA Regulation of Collagen Production by Vascular Smooth Muscle Cells Mediated by La Ribonucleoprotein Domain Family Member 6: Potential Mechanisms Underlying Stable Phenotype of Atherosclerotic Plaque by Insulin-like Growth Factor 1
Authors: Higashi Yusuke , Danchuk Svitlana , Sukhanov Sergiy , Blackstock Christopher , Li Zhaohui , Snarski Patricia , Delafontaine Patrice
Published: April 2024

Collagen is a major constituent of the extracellular matrix in atherosclerotic plaques and supports plaque stability. La ribonucleoprotein domain family member 6 (LARP6) is an RNA binding protein, which assists translation of fibrillar collagen, thereby promoting mature collagen deposition. In Apoe-null mice, insulin-like growth factor 1 (IGF1) promoted stable features of plaques by increasing smooth muscle cell (SMC) numbers and mature collagen fibril deposition without increasing plaque burden. To study mechanisms underlying the IGF1’s plaque stabilizing effects, we exposed human aortic SMCs to proatherogenic oxidized LDL (oxLDL) or IGF1 and determined collagen expression levels. OxLDL downregulated collagen (I) by 36.0±3.2% (P<0.05), along with LARP6 (40.9±10.4 % decrease, P<0.05) and procollagen (I) (49.0±8.9 % decrease, P<0.05), which are consistent with decreased translation of procollagen (I) mRNA. IGF1 abolished oxLDL effects, reversing LARP6 and procollagen (I) protein levels, and thus increased collagen (I) to the levels comparable with native LDL-treated control. As we found previously, the IGF1 upregulation of collagen (I) was mediated by enhanced expression of LARP6, however IGF1 did not alter LARP6 mRNA levels, suggesting translational/post-translational mechanisms. Micro RNA regulates translation of mRNAs; in fact, miR-126, miR-744, and miR-1976 target LARP6 mRNA. In human aortic SMCs, oxLDL upregulated miR-1976 by 40.4±0.5 %, implying miR-mediated suppression of LARP6 translation. Intriguingly, IGF1 abrogated the oxLDL upregulation of miR-1976; moreover, IGF1 decreased miR-126 (by 25.0±1.0 %, P<0.05) and miR-744 (by 24.0±0.4 %, P<0.01), further suggesting that downregulation of miRs mediated IGF1 upregulation of LARP6. To evaluate LARP6 expression in human atherosclerotic plaques, atherosclerotic carotid artery sections were stained for LARP6, and it was detected mainly in SMCs in the medial layer and in the plaque fibrous cap, where collagen fibrils are integral components supporting plaque stability. Our findings suggest a novel mechanism of collagen accumulation by miR-dependent LARP6 expression, and provide a basis for a novel therapeutic approach to enhance plaque stability by targeting miR.
Abstract 13879: Drug-Coated Balloon Angioplasty for Recurrent Multimetal-Layered In-Stent Restenosis Impact of Previous Stent Fracture
Authors: Miura Katsuya , Kadota Kazushige , Habara Seiji , Kuwayama Akimune , Ohya Masanobu , Shimada Takenobu , Amano Hidewo , Kubo Shunsuke , Hyodo Yusuke , Otsuru Suguru , Tada Takeshi , Tanaka Hiroyuki , Fuku Yasushi , Goto Tsuyoshi
Published: April 2024

Objective:
We aimed to investigate the clinical outcomes of patients with recurrent drug eluting stent (DES) in-stent restenosis (ISR) (multimetal-layered ISR) treated with Drug-coated balloon (DCB).

Backgrounds:
Little is known about the efficacy of DCB treatment for multimetal-layered ISR.

Methods:
The study population comprised 123 patients (145 lesions) who underwent DCB angioplasty for multimetal-layered ISR lesions. Two serial angiographic follow-up were routinely planned for the patients (at 6 and 18 months after procedure).

Results:
Early follow-up angiography was performed for 132 lesions (91.0%). Recurrent restenosis occurred 36 lesions (27.3%) and target lesion revascularization (TLR) was performed for 26 lesions (19.7%). Late follow-up angiography was performed for 94 lesions (88.7%) of the remaining 106 lesions (excluding TLR lesions). Late recurrent restenosis occurred 25 lesions (26.6%) and TLR was performed for 16 lesions (17.0%). Proportion of right coronary artery (RCA) and incidence of previous stent fracture were significantly higher in patients with recurrent restenosis (43.3% vs. 66.7%, p = 0.008, and 6.0% vs. 30.0%, p = 0.001). Multivariate analysis revealed RCA ostial lesion (odds ratio [OR]: 4.28; 95% confidence interval [CI]: 1.06 to 22.0; p = 0.04) and previous deployed stent fracture (OR: 6.14; 95% CI: 2.04 to 23.1; p = 0.001) was an independent risk factor of recurrent restenosis. Cumulative event rates of TLR and MACE (All-cause mortality, myocardial infarction, and TLR) were significantly higher in previous stent fracture group (60.6% vs 27.0%, log rank p = 0.007 and 65.0% vs. 35.3%, log rank p = 0.007).

Conclusion:
Our study suggests that previous stent fracture was a risk factor of recurrent restenosis after DCB angioplasty for multimetal-layered ISR. Further study was necessary to identify the optimal treatment for multimetal-layered ISR with stent fracture.
Abstract 13934: Echocardiographic Predictors of Change in Renal Function With Intravenous Diuresis for Decompensated Heart Failure
Authors: Gannon Stephen , Mukamal Kenneth J , Chang James D
Published: April 2024

Title:
Echocardiographic Predictors of Change in Renal Function with Intravenous Diuresis for Decompensated Heart Failure

Background:
Worsening or improved renal function occurs in a significant proportion of patients with decompensated heart failure who receive intravenous diuretic therapy. The direction of change in renal function has been difficult to predict with current biochemical, physical exam and imaging assessments.

Hypothesis:
We proposed the following hypotheses: (1) Patients with right ventricular (RV) dilation and systolic dysfunction would be more likely to experience improved renal function (IRF) with diuresis compared to those with normal RV size and function; (2) Patients with heart failure and a preserved left ventricular ejection fraction (LVEF) would be more likely to experience worsening renal function (WRF) with diuresis than those with a reduced LVEF (≤40%).

Methods:
Retrospective review of 363 patients admitted to a single center from January, 2011 to November, 2014 for decompensated heart failure who underwent intravenous diuresis and transthoracic echocardiography. Data regarding chamber quantification, right and left ventricular systolic function, valvular lesions and diastolic function were collected. Change in renal function was determined using validated GFR estimates based on serum creatinine.

Results:
Within our study population, 36.4% of patient experienced a decrease in eGFR by at least 10%, 34.7% had stable renal function and 28.9 had an improvement in eGFR by at least 10%. Patients with WRF were more likely to have a preserved LVEF (81/132; 61%) compared to those with stable (59/126, 47%) or improved (47/105, 45%) renal function (p-value 0.015). Patients with IRF were more likely to have a dilated, hypokinetic RV (p-value 0.008). Left atrial size, left ventricular internal diastolic dimension and diastolic dysfunction did not significantly predict change in renal function.

Conclusions:
Patients with WRF during diuresis for decompensated heart failure are more likely to have a preserved LVEF than those with stable or improved renal function. Those with IRF are significantly more likely to have a dilated, hypokinetic RV.
Abstract 13936: The Role of Telehomecare in Blood Pressure Monitoring for Heart Failure Patients
Authors: Sahakyan Yeva , Abrahamyan Lusine , Shahid Nida , Stanimirovic Aleksandra , Ryan Welson , Pechlivanoglou Petros , Mitsakakis Nicholas , Krahn Murray , Rac Valeria E
Published: April 2024

Introduction:
Introduced in 2007 by the Ontario Telemedicine Network, the Telehomecare program provides monitoring of patient’s parameters and coaching sessions. To date, no study evaluated the effect of Telehomecare on patient clinical monitoring parameters in Ontario.

Hypothesis:
We hypothesized that blood pressure (BP) would be improved among heart failure patients participating in the Telehomecare.

Methods:
We applied a time series study design to analyze patients’ BP values, transmitted via telemonitoring devices on a daily basis. The cohort included heart failure patients enrolled in the Telehomecare program from July 2012 to July 2015. The outcome of interest was the change in average (biweekly) systolic and diastolic BP levels over the 6-month program duration. The baseline BP levels were defined as the average of daily measurements for the first 2-week period after enrolment. Data was analysed by repeated measures with generalized linear mixed model procedures in SAS. Sensitivity analyses were conducted for per-protocol cohort, defined as those who had fully completed 6-month program duration.

Results:
Overall we analyzed data for 2186 heart failure patients (50% women) with average age of 76.0±11.4 years. At baseline, the systolic and diastolic BP levels were 129.2 ±19.8 and 70.4 ±12.7 mm Hg respectively. Over 6-month period systolic BP decreased by -3.5 mm Hg (95% CI: -4.2 to -2.8) and diastolic by -2.5 mm Hg (95% CI: -3.0 to -2.0). At baseline, one third of the patients (n=721) had elevated BP with an average systolic BP of 150.9±10.15 mm Hg and diastolic BP of 78.3±14.1 mm Hg. In a subgroup analyses of this population the reduction in systolic BP was -12.3 mm Hg (95% CI: -13.4 to -11.1) and in diastolic BP was -6.9 mm Hg (95% CI: -7.8 to -6.0) adjusted for age and gender. Similar changes were observed in per-protocol cohort.

Conclusions:
The systolic and diastolic BP levels significantly decreased in patients with heart failure enrolled in the Telehomecare program. These changes were more pronounced in patients with uncontrolled BP at program entry. Hence Telehomecare program might be a promising tool to help patients in BP management
Abstract 13965: Aerobic Exercise After an ICD: Results of the Psychological and Quality of Life Outcomes in the Anti-Arrhythmic Effects of Exercise After an ICD Trial
Authors: Dougherty Cynthia M , Glenny Robb L , Kudenchuk Peter J , Burr Robert L
Published: April 2024

Introduction:
The Anti-Arrhythmic Effects of Exercise Trial reported aerobic exercise training for 8-24 weeks after an implantable cardioverter defibrillator (ICD) significantly improved cardiopulmonary function. The purpose of this report is to outline the 8 and 24 week quality of life and psychological outcomes of the trial.

Methods:
160 subjects with a prior ICD implant (40% primary and 60% secondary prevention), mean age 55 ±12 years, 77.5% male, 84% Caucasian, 100% beta-blocked, and EF%=40%, entered a RCT comparing aerobic exercise (EX) to usual care (UC). EX= aerobic training x 8 weeks of home walking 1 hour/day on 5 days/week at 60-80% of maximum HR, followed by aerobic maintenance x 16 weeks of home walking for 150 min/week. At baseline, 8 and 24 weeks, participants completed questionnaires: Quality of Life (SF-36), Anxiety (State-Trait Anxiety Inventory), Depression (PHQ-9), and Symptoms (Patient Concerns Assessment). Adherence to exercise was tracked with Polar HR monitors and pedometers. Analysis of variance was used to determine group x time effects on study outcomes and by adherence groups.

Results:
There were no differences noted between EX and UC on quality of life, symptoms, or anxiety at 8 or 24 weeks using intent-to-treat. There was a significant reduction in depression severity between EX vs UC at 8 weeks (p=0.05). When comparing those who exercised at ≥80% (N=48) to <80% (N=36) and UC (N=76), there were statistically significant improvements in quality of life [positive health transition, (p=0.006) and social function (p=0.03)], with a reduction in fear of dying (p=0.04), anxiety (p=0.02), and depression severity (p=0.04) at 8 weeks in those who exercise at ≥80%. Those who continued to exercise at ≥80% for 16 more weeks, had a significant continued improvement in quality of life [positive health transitions (p=0.006), physical function (p=0.01), vitality (p=0.04), social function (p=0.03), and role emotional (p=0.02)], while anxiety (p=0.002) and symptoms (p=0.003) were reduced. Depression by adherence groups at 24 weeks was unchanged.

Conclusions:
Aerobic exercise training and maintenance for those who actually exercised as prescribed, had benefits in improved quality of life, with reductions in symptoms and psychological distress.
Abstract 13973: Time Course of Reverse Remodeling Following Catheter Ablation of Persistent Atrial Fibrillation
Authors: Kanda Takashi , Masuda Masaharu , Fujita Masashi , Iida Osamu , Okamoto Shin , Ishihara Takayuki , Nanto Kiyonori , Sunaga Akihiro , Tsujimura Takuya , Okuno Shota , Masuda Yasuhiro , Yanaka Koji , Ohashi Takuya , Kawai Hiroyuki , Tsuji Aki , Hata Yosuke , Uematsu Masaaki
Published: April 2024

Introduction:
Preservation of sinus rhythm following catheter ablation (CA) for persistent atrial fibrillation (PeAF) brings about structural reverse remodeling and recovery of cardiac function. However, the time course of reverse remodeling has not been well defined.

Purpose:
This study aimed to evaluate the time course of echocardiographic parameters following CA of PeAF.

Methods:
We enrolled 89 consecutive patients with PeAF undergoing CA. Patients with AF recurrence during the follow-up were excluded. Echocardiography was performed to evaluate the cardiac function on day 1, and 1, 3, and 6 months after CA.

Results:
Forty-five patients who remained in sinus rhythm after ablation were included (69±6 years old, 40 (89%) males, AF duration 28.7±42.8 months, and CHADS2 score 1.8±1.1). The atrial filling velocity (A), peak mitral annular late diastolic velocity (a’) and deceleration time of the early diastolic filling velocity significantly increased for 1 month and then reached a plateau. Early diastolic filling velocity (E) and E/A ratio significantly decreased for 1 month and then reached a plateau. The left atrial volume index and left atrial dimension significantly decreased gradually until 3 months (Figure). The left ventricular end-diastolic and systolic dimensions, left ventricular ejection fraction, peak early diastolic velocity of the mitral annulus (e’), and raito of the E to e’ did not change significantly.

Conclusions:
Preservation of sinus rhythm following PeAF CA brought about the hemodynamic reverse remodeling first, followed by the structural reverse remodeling.
Abstract 16586: Parasympathetic Stimulation via Muscarinic Receptor 2 (M2R) is Mediated by Nitric Oxide (NO) Signaling in Cardiomyocytes
Authors: Baine Stephen , Bonilla Ingrid , Carnes Cynthia , Gyorke Sandor
Published: April 2024

Several decades of evidence has shown a strong role of the sympathetic nervous system in the pathogenesis of HF. However, much less is known about the influence of the parasympathetic nervous system and HF. Recent data from our group suggests that parasympathetic stimulation by the muscarinic agonist carbachol (CCh) creates “smart” regulation of the cardiac ryanodine receptor 2 (RyR2); a major participant in excitation-contraction coupling (ECC) in the heart. Carbachol mediates phosphorylation of serine- 2808 through muscarinic receptor subtype 2 (M2R). Previous studies from our group have shown that a downstream effector of M2, PKG, is involved in increasing phosphorylation of ser-2808 of RyR2. Therefore, we hypothesized that pharmacological blockade of NOS1 would reduce NO levels and thus decrease RyR ser-2808 phosphorylation. Pharmacological inhibition of NOS1 through S-Methyl-L-Thiocitrulline was employed to investigate the role of NOS1 in CCh mediated RyR2 ser-2808 phosphorylation. Experimental data suggests that inhibition of NOS1 with 300nM SMLT is sufficient to prevent an increase in CCh mediated RyR2 ser-2808 phosphorylation. To further investigate the role of NO in CCh mediated parasympathetic stimulation, we used fluorescent DAF-FM diacetate dye to measure NO levels in isolated cardiomyocytes. In response to 10uM CCh; NO levels increased significantly vs. control (baseline) conditions. Following CCh treatment, cells were treated with Spermine NONOate as a positive control for maximal response. However, if cells were treated with a M2R receptor antagonist atropine (10uM) in the presence of CCh, NO levels decreased significantly vs. control conditions. These experiments support the role of the M2R-NO signaling axis in CCh mediated parasympathetic stimulation. Finally, a transverse aortic constriction model of heart failure in mice was used to investigate the role of CCh mediated parasympathetic stimulation in heart failure. We found that in failing cardiomyocytes, CCh fails to significantly increase levels of NO suggesting a role for impaired parasympathetic and NO signaling in heart failure. These pathways may contribute to the impaired contractility and adverse structural remodeling which are hallmarks of heart failure.
Abstract 16589: First Demonstration That Small Lp(a) Particles, With Kringle IV Repeats of 24 or Less, but Not Large Lp(a) Particles (More Than 24 Kringle IV Repeats), Are Atherogenic
Authors: Vazquez Gustavo , Brown Brad , Marvasty Idean B , Guillot Etienne , Janiak Phillip , Muslin Anthony , Bansal Aruna , Davis Harry , Newton Roger S , Voros Szilard
Published: April 2024

Introduction:
It has been demonstrated using statistical methods that smaller lipoprotein (a) [Lp(a)] particles are more strongly associated with atherosclerosis. However, the exact relationship between Lp(a) size (defined by the number of kringle IV repeats) and atherogenicity has not been elucidated.

Hypothesis:
We hypothesized that smaller, but not larger, Lp(a) particles are atherogenic, with a clear size cut-point.

Methods:
We determined Lp(a) levels and precise isoform size (defined by number of kringle IV repeats) in 340 subjects in the GLOBAL clinical study (NCT01738828). Atherosclerosis was quantitatively phenotyped using cardiovascular computed tomography angiography, analyzed in central core laboratory. We generated cumulative incidence curves (CIC) to assess relationship between isoform size, concentrations and atherosclerosis. Once we determined cut-point for small vs. large Lp(a), we compared levels by Mann-Whitney test; p<0.05 was significant.

Results:
Mean age was 56.2±0.72; 49% were male. Lp(a)-mass, particle number and Lp(a)-cholesterol were significantly higher in those with atherosclerosis (Table). In 12 patients who had single isoform only, there was sharp stepdown in atherogenicity with >24 kringle IV repeats (Figure; A); median isoform size was 26 vs. 16 in Controls vs. Atherosclerosis (p<0.05) (Figure; B). Small Lp(a) (24 kringle IV repeats or less) levels were significantly higher in Atherosclerosis; large Lp(a) levels were not different (Figure; D). Increasing levels of small, but not large, Lp(a) particles was associated with atherosclerosis (Figure; E, F).

Conclusions:
We demonstrated for the first time that 24 kringle IV repeats represent a sharp demarcation between small/atherogenic and large, non-atherogenic Lp(a) particles in humans.
Abstract 16593: Deficiency of Myocardial miR-17-92 Cluster Exacerbates Ischemic Injury and Abrogates Rapamycin-Induced Protection in Diabetic Mice
Authors: Samidurai Arun , Roh Sean K , Salloum Fadi N , Kukreja Rakesh C , Das Anindita
Published: April 2024

Background:
Chronic treatment with rapamycin (RAPA, an mTOR inhibitor) improves cardiac function in type 2 diabetic (T2D) mice through attenuation of oxidative stress and alteration of antioxidants and contractile protein expression. The miR-17-92 cluster is indispensable for the cardiac development; its deletion leads to neonatal lethality due to severe anomalies of the cardiovascular system. Following microRNA array analysis, we identified that miR-17 and miR-20a were significantly up-regulated in diabetic hearts with RAPA treatment. We therefore investigated their role in RAPA-induced protection in diabetic mice following ischemia/reperfusion (I/R) injury.

Methods and Results:
Adult male db/db T2D mice were treated daily with RAPA (0.25 mg/kg, i.p.) for 28 days. RAPA significantly reduced myocardial infarct size following global I (30 min) and R (60 min) in Langendorff mode (
Fig. A
). Real-time PCR showed that miR-17 and -20a, part of miR-17-92 cluster, were induced in hearts from RAPA-treated db/db mice (
Fig.B
). To further elucidate their role in RAPA-induced protection in diabetes, wild type (WT:MCM:NTG:miR-17-92
flox/flox
) and cardiac-specific miR-17-92-deficient (miR-17-92-def:MCM:TG:miR-17-92
flox/flox
) mice were fed with high-fat-diet (HFD) for 16 weeks. HFD-fed mice exhibited impaired glucose tolerance (
Fig. C
). Treatment with RAPA improved blood glucose level, cardiac function and reduced infarct size following I/R in diabetic WT mice, which were abolished in diabetic tamoxifen-inducible miR-17-92-deficient mice (
Fig. D, E, F
). In addition, miR-17-92-deficient mice had larger infarct size after I/R compared to WT controls
(Fig F)
.

Conclusion:
Cardiac miR-17-92 plays a critical role in RAPA-induced protection against I/R injury in diabetic mice. Future studies are required to identify downstream targets of miR-17-92 responsible for cardioprotection.
Abstract 16596: Dominant Mouse Mutagenesis Screen Unveils a Complex Genetic Architecture for Congenital Heart Disease
Authors: Wang Michael , Tan Tuantuan , Hildebrand Sara , Bais Abha , Ho Sebastian , Wang Yiming , Sonnenberg Daniel , Kukkillaya Manisha , Radomile Caleb , Meyer Lauren , Devine William , Reinholdt Laura , Beutler Bruce , Wu Yijen , Lo Cecilia
Published: April 2024

Introduction:
Human studies show congenital heart disease (CHD) has a complex non-Mendelian genetic etiology. We previously conducted a recessive N-ethyl-N-nitrosourea (ENU) mouse mutagenesis screen using fetal ultrasound and recovered over 150 recessive mutations causing CHD. In the present study, we conducted a sensitized screen with driver mutations to recover dominant mutations causing CHD. We hypothesize this dominant screen can help to elucidate the complex genetic architecture of CHD.

Methods:
G1 males with heterozygous ENU induced mutations were mated to females harboring heterozygous “driver” mutation in
Kif7, Anks6, or Sap130
that can cause CHD when homozygous. The resulting G2 offspring were screened for CHD by fetal ultrasound. Mutations in G1 males were identified by whole exome sequencing and the G2 offspring were genotyped using Ion Torrent sequencing. Linkage analysis was conducted to identify the CHD causing mutation.

Results:
We found 9.3% of the G1 pedigrees (n=551) yielded CHD mutants, similar to the 8.2% observed in the previous recessive screen. However, only 2.5 mutants were recovered per line vs. 4.5 in the recessive screen despite having screened similar number of embryos, supporting non-Mendelian genetics in the dominant screen. Genotype-phenotype analysis revealed only 32%, 45%, and 55% of the CHD mutants recovered carried the
Kif7, Anks6,
or
Sap130
driver mutations, respectively, suggesting the driver mutations are not required for CHD pathogenesis. For mouse line 4142 with DORV/OA, we identified a heterozygous p21/Rac-activated kinase 2 (
Pak2)
mutation as disease causing (p=4.8e-12). CHD penetrance was 83% among
Pak2
+/m embryos. Among surviving 4142 G2 offspring, only 14% have the
Pak2
mutation vs. 50% expected. We observed 75% of the surviving
Pak2
mutant mice also carry a mutation in
Zbtb2,
a gene identified to regulate p21, suggesting this may act as a protective modifier.

Conclusion:
We showed the feasibility of using mouse mutagenesis to recover dominant mutations causing CHD, and showed for the first time a role for Pak2 in CHD. These findings demonstrate that the genetic diversity created by ENU mutagenesis can provide the genomic context to investigate the complex genetics and genetic architecture of CHD.
Abstract 16601: Evaluation of Vascular Response After Balloon Angioplasty for In-Stent Restenosis Assessed by Optical Frequency Domain Imaging
Authors: Yoshihara Nagataka , Miki Kojiro , Akahori Hirokuni , Imanaka Takahiro , Kawai Kenji , Yanaka Koji , Tanaka Takamasa , Masuyama Tohru , Ishihara Masaharu
Published: April 2024

Background and aim:
The optimal balloon angioplasty (BA) procedure for in-stent restenosis (ISR) was not established. The aim of this study was to investigate vascular response after BA in ISR lesions using optimal frequency domain imaging (OFDI).

Methods and results:
This study consisted of 22 ISR lesions that were treated with BA. OFDI analysis were performed for 10mm longitudinal ISR segment including minimum lumen area before and after BA, furthermore morphology of ISR neointimal tissue and volumetric measurements were assessed. We analyzed at 1mm interval cross-sectional OFDI images of lesions before BA, and at every slices per each lesion, the neointimal tissue was divided into 2 morphologic patterns: homogeneous pattern and non-homogeneous pattern. Then, the neointimal tissue morphological characteristics of each lesion was expressed according to “homogeneous ratio”, defined as the number of homogeneous pattern slices divide by a total of slices. In volumetric OFDI measurements, lumen gain rate was calculated as (lumen volume (LV) after BA - LV before BA) / LV before BA, stent expansion rate as (stent volume (SV) after BA - SV before BA) / SV before BA and neointimal volume (NV) reduction rate as (NV before BA -NV after BA) / NV before BA. There was no correlation between homogeneous ratio and lumen gain ratio. There was positive correlation between homogeneous ratio and stent expansion ratio, and there was negative correlation between homogeneous ratio and neointimal volume reduction ratio (figure).

Conclusions:
OFDI assessment is useful to understand the vascular response by BA for ISR lesions. The mechanism of lumen gain in BA procedure for ISR lesions with homogeneous tissue is mainly obtained by stent expansion, whereas for lesions with non-homogeneous tissue is by neointimal tissue compression.
Abstract 16610: Waitlist Characteristics and Outcomes Following the 2016 Revision of US Pediatric Heart Allocation Policy
Authors: Magnetta Defne A , Godown Justin , West Shawn , Zinn Matthew , Miller Susan , Feingold Brian
Published: April 2024

Background:
US pediatric heart allocation was revised in March 2016 to more appropriately categorize candidates with the most urgent need for heart transplantation (HT), including children with congenital heart disease (CHD) listed status 1A on inotropic support. We sought to assess the impact of these revisions on waitlist (WL) characteristics and mortality.

Methods:
Children (<18 yo) listed for heart transplantation (HT) in the UNOS database between 12/16/11 and 11/7/17 were stratified based on whether they were listed before (PRE) or after (POST) criteria revision. Comparisons were made using Chi-Square or Wilcoxon rank sum tests and WL mortality was compared by competing outcomes analyses.

Results:
After criteria revision: 1) the proportions of status 1A candidates decreased at listing (69 vs. 53%, p<0.001) and HT (89 vs. 82%, p<0.001); 2) patients with CHD comprised a greater proportion of 1A candidates at listing (47 vs. 64%, p<0.001) and at HT (42 vs. 51%; p<0.008); 3) the use of status 1A exceptions among CM patients increased (5 vs. 24%, p<0.001); and overall WL mortality and WL mortality for those listed status 1A were unchanged (fig 1a-b). When stratified by diagnosis, overall CHD WL mortality improved with no difference in CM WL mortality following criteria revision, and CHD WL mortality remains nearly twice that of CM candidates (fig 1c-d). However, when comparing CHD and CM candidates listed 1A without exception, CHD WL mortality was unchanged while CM WL mortality increased (fig 1e-f).

Conclusions:
As intended, there are fewer status 1A listings and enrichment of CHD patients in the status 1A group following criteria revision. Though overall WL mortality for CHD candidates improved, it remains nearly twice that of CM. Also, the lack of improvement in WL mortality for status 1A CHD candidates may be due to the marked increase in status 1A exemptions for CM candidates. Additional policy changes may further narrow the disparity in WL survival between CHD and CM.
Abstract 16613: Stories to Save Lives: A Qualitative Assessment to Identify Opportunities for Prevention of Sudden Unexpected Death
Authors: Mirzaei Mojtaba , Mihas Paul , Masoudi Elham A , Seidman Rachel F , Patel Neil P , Simpson Ross J
Published: April 2024

Introduction:
Despite significant reduction in cardiovascular mortality, the incidence of sudden unexpected death (SUD) has not decreased substantially. Risk management by doctors and community health workers has the potential to reduce SUD in rural communities. We performed a qualitative assessment to understand behavioral constructs that might aid their efforts.

Methods:
The archives of the Southern Oral History Program (SOHP) contain about 6000 interviews. Using keywords related to SUD prevention, we selected 171 interviews. Stratified purposeful sampling identified information-rich cases from rural areas. We coded transcripts based on both predetermined and emerging codes and wrote memos for each transcript. A final code report synthesized information from these memos into themes.

Results:
We assessed 23 interviews with people of diverse ethnicities (42% African-Americans) who were mainly farmers (46%) or textile workers (29%). Four themes emerged from the interviews: "sense of surrender", "social support", "instrumental doctor-patient relationship" and "lack of proactivity". (Table 1) The "sense of surrender" emerged when people talked about the heightened period of symptoms, often characterized by limited health knowledge and preparation. "Social support" among neighbors and family was strong and evident during hardship. The "instrumental doctor-patient relationship" highlights a shift to one-way communication of absolute diagnoses and recommendations. The "lack of proactivity" emerged when people did not take ownership of their health to modify risk factors and waited for serious conditions before seeking medical help

Conclusion:
We found that even individuals showing proactivity in work and home life often have a sense of surrender in their relation to their health. Our findings can guide interventions on how doctors and community health workers can promote partnerships for prevention of sudden unexpected death in rural communities.
Abstract 16614: Single-Cell RNA Sequencing Reveals ZEB2 as a Cardioprotective Factor After Ischemic Injury
Authors: Gladka Monika M , Kohela Arwa , Molenaar Bas , Versteeg Danielle , Kooijman Lieneke , Groenewold Vincent , Vos Harmjan R , Huibers Manon M , Huylebroeck Danny , Giacca Mauro , van Rooij Eva
Published: April 2024

Heart failure is the leading cause of death worldwide. Identification of factors that promote cardiac repair is of major importance. Here we show that the transcription factor ZEB2 confers cardioprotective effects after ischemia. Exposure of cardiomyocyte-specific ZEB2 knock out mice to a myocardial infarction reduced survival and impaired cardiac contractility and infarct healing. Conversely, cardiomyocyte-specific ZEB2 overexpression improved survival, infarct healing and cardiac function. To unveil the molecular mechanisms behind the cardioprotective effects of ZEB2 we performed mass spectrometry on conditioned medium from cardiomyocytes overexpressing ZEB2. We identified TMSB4, PTMA, RACK1 and DYNLL1 as main circulating factors in response to ZEB2 overexpression, which were reported to be cardioprotective, pro-angiogenic or anti-apoptotic. In line with this observation, we could validate the regulation of those factors in our gain- and loss-of-function mouse models, suggesting a role of ZEB2 in regulating their expression and release from cardiomyocytes
in vivo.
To test for the therapeutic effect of increasing the level of ZEB2 specifically in cardiomyocytes after ischemic injury we made use of both AAV9-mediated ZEB2 delivery directly to the heart and systemic antimiR-208 delivery that causes Zeb2 de-repression specifically in heart muscle cells. Both approaches prevented cardiac dysfunction after ischemic damage and promoted the activation of a cardioprotective gene program. Our data suggest that the increase in ZEB2 in cardiomyocytes in response to stress protects the heart from ischemic damage via non cell autonomous effects of cardioprotective factors. These findings reveal ZEB2 as a cardioprotective factor during ischemic injury, which may hold great promise for future heart failure therapies.