bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13759: Adherence to Healthy Lifestyle is Associated With Lower Total and Cause-Specific Mortality Risk Among Patients With Diabetes: The UK Biobank Study
Authors: Han Han , Cao Yaying , Feng Chengwu , zheng yan , Dhana Klodian , Zhu Shu , Shang Cong , Yuan Changzheng , Zong Geng
Published: April 2024

Introduction:
The association of an overall healthy lifestyle, involving 3 emerging factors (less sedentary time, adequate sleep duration, appropriate social connection) and 4 conventional factors (no current smoking, moderate alcohol consumption, regular physical activity, healthy diet) from the prevailing diabetes management guideline, with total and cause-specific mortality risk in patients with diabetes remains to be examined.

Hypothesis:
We hypothesized that an overall healthy lifestyle would be associated with a lower risk of total and cause-specific mortality in patients with diabetes.

Methods:
Analyses included 18,822 participants with diabetes at baseline in the UK Biobank. Lifestyle information was collected via a baseline questionnaire (2006-2010). Cox proportional hazard modeling was used to examine the association of a healthy lifestyle with mortality risk.

Results:
During a median follow-up of 11.2 years, 2,470 deaths occurred after 2 years of enrollment. The fully-adjusted hazard ratios (95% CIs) for patients with 6-7 low-risk lifestyle factors compared with those with 0-2 were 0.44 (0.38-0.51) for total mortality, 0.52 (0.40-0.67) for cancer mortality, 0.38 (0.26-0.56) for CVD mortality, 0.24 (0.13-0.45) for respiratory disease mortality, 0.96 (0.45-2.04) for neurodegenerative disease mortality, and 0.16 (0.04-0.62) for digestive system disease mortality. For each additional low-risk factor, the risk was 17% lower for total mortality and 13-26% lower for cause-specific mortality. The association for a summed score of the emerging factors was stronger in those with a lower score of conventional factors (P-interaction <0.05). The inverse association between a healthy lifestyle and total mortality risk was consistently observed regardless of diabetes duration, vascular disease, glycemic control, and diabetes medication. Besides, the association was stronger in those with earlier diabetes onset or lower socioeconomic status (both P-interaction <0.05).

Conclusions:
For patients with diabetes, a healthy lifestyle is associated with a lower risk of total and most cause-specific mortality. Our findings are consistent across sub-populations, especially for those differing in factors related to diabetes severity.
Abstract 13773: Hyperuricemia is Associated With Increased Mortality in Heart Failure Patients With Preserved Ejection Fraction: A Systematic Review and Meta-Analysis
Authors: Techorueangwiwat Chol , Hansrivijit Panupong , Kanitsoraphan Chanavuth
Published: April 2024

Introduction:
Recent data has emerged suggesting prognostic value of serum uric acid in heart failure with preserved ejection fraction (HFpEF), however, there are conflicting data. This is the first meta-analysis to assess the associations of serum uric acid and clinical outcomes in patients with HFpEF.

Methods:
Comprehensive literature search was conducted from MEDLINE and EMBASE through November 2020. We included cohort studies and post-hoc analyses of randomized controlled trials that investigated the associations between serum uric acid and clinical outcomes in patients with HFpEF. Data was combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate hazard ratios and 95% confidence intervals (CI). Only studies using multivariable analyses were included.

Results:
Six studies were included in this meta-analysis, including 12,976 patients with HFpEF. The studies dated from 2015 to 2020. We found that in patients with HFpEF, hyperuricemia was associated with an increased risk of overall mortality (pooled adjusted HR 1.236, 95% CI 1.002-1.525, p=0.048, I
2
=84.6%) and cardiac mortality (pooled adjusted HR 1.589, 95% CI 1.273-1.984, p<0.05, I
2
= 0%) after multivariable adjustments. The results were significant on sensitivity analysis.

Conclusions:
Our meta-analysis suggested that hyperuricemia was associated with increased mortality in patients with HFpEF. Further studies are warranted to elucidate mechanism underlying this association and possible therapeutic interventions for HFpEF patients with hyperuricemia.
Abstract 13797: Does Alcohol Consumption Have a Cumulative Effect on the Risk of Stroke in Young Adults?
Authors: Chung Jaewook , Lee So-Ryoung , Choi Eue-keun , Park Sang-Hyeon , Lee HuiJijn , Choi JungMin , Han Minju , Lee Seung-woo , Han Kyung-Do , Kim Sunhwa , Oh Seil , Lip Gregory Y
Published: April 2024

Backgrounds:
Alcohol consumption is one of the major and modifiable risk factors for stroke in young people. There is a paucity of information regarding the risk of drinking on stroke development, especially in young adults. We investigated the effect of alcohol consumption on the risk of stroke and its subtypes in young adults.

Methods:
Using the Korean National Health Insurance Service database, a total of 1,523,299 subjects aged between 20 and 39 were identified, who underwent 4 consecutive annual health examinations between 2009 and 2012, with no history of stroke, myocardial infarction, and congestive heart failure. At each annual health examination, the alcohol consumption of the subjects was divided into non, mild (>0 and <105g/week), moderate (≥105g and <210g/week), and heavy (≥210g/week) drinking. Cumulative alcohol burdens were evaluated in the following ways: (1) cumulative number of moderate to heavy drinking at each health examination (0 to 4 times); (2) drinking patterns in each cumulative alcohol burden (total 16 patterns). The incidence of total stroke, ischemic stroke (IS) or hemorrhagic stroke, was evaluated using Cox proportional-hazards models.

Results:
During a median follow-up of 5.6±1.2 years, 3093 (0.20%) subjects were diagnosed with stroke (1732 with ischemic and 1513 with hemorrhagic). Heavy drinkers were associated with an increased risk of total stroke compared to non-drinker (HR 1.256, 95% CI 1.112-1.419). The hazard ratio was proportional to the cumulative alcohol burdens (Fig. panel A). This positive linear relationship was mainly driven by hemorrhagic stroke rather than IS (Fig. panel B). While most drinking patterns were not associated with an increased risk of IS, alcohol burden 3 had a significant association with an increased risk of a hemorrhagic stroke (Fig. panel C).

Conclusions:
Moderate to heavy alcohol consumption has a cumulative association with a higher risk of stroke, especially for hemorrhagic stroke in young adults.
Abstract 13852: Key Value of Inspiratory Muscle Performance and Training in a Home-Based Program to Improve Functional Capacity in Older Heart Failure Patients
Authors: Shah Rohan V , Cahalin Lawrence P , Haus Jacob M , Allsup Kelly , Delligatti Amanda , Kostra James , Cody Wolf , Gottlieb Daniel J , Byard Thomas , Forman Daniel E
Published: April 2024

Introduction:
Patients with heart failure (HF) often have reduced exercise tolerance. Exercise training has putative value but is often limited by poor adherence or the effects of frailty. Baseline inspiratory muscle performance (IMP) may predict exercise limitation, and inspiratory muscle training (IMT) may have important clinical benefit, including offsetting the metaboreflex which may improve functional capacity by reducing sympathetic peripheral vasoconstriction induced by respiratory fatigue. We hypothesize that low IMP is an important predictor of exercise performance in older adults with HF and that IMT may be an effective home-based training program.

Methods:
Thirty-four male patients with HF (age and left ventricular ejection fraction of 69±7 years and 37±11%, respectively) were randomized into IMT (n=11) or aerobic and/or strength training (AST; n=23) for a 12-week home-based program. IMT was performed progressively from 50-85% of maximal inspiratory pressure (MIP) with the PrO
2
device (Smithfield, RI) which tracked data and adherence for comparison to AST regimens of cycle ergometry/walking and strength training individually advanced to achieve moderate to high intensities. Study endpoints included MIP, peak oxygen uptake (VO
2
), 6-minute walk distance (6MWD), 30-second sit-to-stand (STS), grip strength, and leg strength (endurance, 1-rep max, and power).

Results:
IMT was well-tolerated with greater adherence (92±10% vs 79±34%) and a significantly greater MIP rise (25.3±25.0% vs 3.6±11.0%, p<0.05). Baseline MIP greater than the median of 66 cmH
2
O across all exercise forms (n=18) was associated with significantly greater baseline and post-intervention peak VO
2
(16.4±5.0 vs 12.9±3.9 and 17.5±5.3 vs 13.4±3.1, p<0.05) and was significantly correlated positively to change in 6MWD, STS, grip strength, and leg strength (r=0.352-0.504, p<0.05).

Conclusion:
Home-based IMT significantly improved IMP and greater baseline IMP was associated with greater cardiorespiratory fitness, functional capacity, and trainability in older HF patients due likely to metaboreflex attenuation and greater adherence. Further study is needed to assess IMP and IMT performed alone or combined with AST regimens to address the growing HF population.
Abstract 13893: In an Aortic System of Care Model, Adherence to Guideline Based Care Ii Hampered by Gaps in the Collection, Reporting, and Communication of Echocardiogram Data
Authors: Gordon Lucia , Solsbery Laney , Rogers Terreal , Wirtz Katy , Scharnott Michelle , Myers Gary
Published: April 2024

Introduction:
Aortic Stenosis (AS) is one of the most common and serious valve diseases, affecting 5% of Americans age 65 or older. Currently, there lacks a national system of care addressing the AS care continuum. The American Heart Association (AHA) has a history of success in systems of care and seeks to apply this experience to create similar for the AS patient through the program, Target: AS.

Hypothesis:
A key step in an Aortic Stenosis system of care is the identification of the patient’s diagnosis echocardiogram (echo). In some cases, the echo is initially performed at a location other than the tertiary hospital, and a consistent method of reporting the results to valve center does not currently exist. This inconsistency impacts guideline-based care.

Methods:
Target: AS pilot measures, following current guidelines, were developed with guidance from the AHA’s aortic stenosis scientific advisory group. Hospitals entered 2020 baseline data into the Target: AS data collection tool. Data elements were collected towards the measure: “Percentage of moderate aortic stenosis patients receiving a follow-up echocardiogram during the measurement period that is within 24 months of prior echocardiogram.” Sites reviewed data 24 months prior to the baseline year for the initial echo data.

Results:
123 patients in 8 pilot hospitals met inclusion criteria. Overall performance - 53% of patients had a follow-up echo with 24 months. Range was 0% - 65%. All but one patient that failed the measure was due to missing or unavailable prior echo. Engagement with sites through 1:1 interviews, data abstractor calls, and quarterly learning collaboratives revealed that hospitals are not able to find initial echo data in medical records, or that the information is not provided in a discrete manner.

Conclusions:
The 2020 ACC/AHA Guideline for the Management of Patients with Valvular Heart Disease states that patients diagnosed with moderate aortic stenosis should have a follow-up echo within 24 months of the diagnostic echo. Early data demonstrates that in all but one case, when hospitals cannot meet this guideline, it is due to not having the initial echo results. A hospital cannot monitor its adherence with guideline-based care when it does not have access to necessary data.
Abstract 13911: Regulation of STAT3 Phosphorylation Through β
IV
-Spectrin Interaction and Its Role in Concentric versus Eccentric Hypertrophy
Authors: Nassal Drew , Mohta Shivangi , Patel Nehal , Xu Xianyao , Han Mei , Mohler Peter J , Hund Thomas J
Published: April 2024

Hypertrophic growth is a critical determinant of cardiac function in the development of heart failure. In pressure overload, hypertrophy is divided by early adaptive remodeling defined by concentric growth, while chronic hypertrophy associates with eccentric growth and loss in cardiac output. The mechanisms regulating this transition and the impact each profile has in influencing heart function are largely unknown. Importantly, previous work identified a role for the structural protein β
IV
-spectrin and its interaction with the transcription factor, STAT3, in coordinating hypertrophic profiles. Specifically, mice expressing truncated β
IV
-spectrin lacking interaction with the hypertrophic signaling molecule CaMKII (

qv
3J

mice) were resistant to β
IV
-spectrin degradation and presented with sustained concentric hypertrophy and ejection fraction (EF) compared to WT following 6 weeks transaortic constriction (TAC). Alternatively, mutant β
IV
-spectrin mice (

qv
4J

) lacking the STAT3/β
IV
-spectrin binding domain had reduced EF and LV dilation, consistent with eccentric remodeling, suggesting STAT3/β
IV
-spectrin is a key regulator of hypertrophic profiles. To evaluate how STAT3 function was altered, we used the STAT3 activator, lipopolysaccharide, on isolated cardiomyocytes, which identified impaired STAT3 Ser727 phosphorylation in

qv
4J

myocytes compared to WT. The significance of this phosphorylation site was investigated using STAT3 Ser727 phospho-ablated mice (STAT3-S727A), which resulted in accelerated eccentric hypertrophy and HF in response to TAC. Furthermore, we identified elevated Ser727 phosphorylation in the

qv
3J

TAC mice, which present with sustained concentric growth, compared to WT mice which transition to eccentric growth. The relationship of STAT3/β
IV
-spectrin and hypertrophic orientation was further examined by adenoviral overexpression of the hypertrophic driver, MEK1/2, on isolated myocytes. While MEK increased the width of WT myocytes, STAT3-S727A and

qv
4J

myocytes increased in length. Together, these data identify a novel role for β
IV
-spectrin in coordinating STAT3 Ser727 phosphorylation to tune specific hypertrophic profiles in response to chronic stress and influencing cardiac function.
Abstract 13924: NLRP3 Inflammasome Activation in Macrophages Drives Adverse Right Ventricular Remodeling and Dysfunction
Authors: Lima Patricia D , Al-qazazi Ruaa , Prisco Sasha Z , Potus Francois , Das Gupta Asish , Chen Kuang-Hueih , Tian Lian , Mewburn Jeffrey , Jones Oliver , Wu Danchen , Maurice Donald , Bonnet Sebastien , Provencher Steeve , Prins Kurt W , Archer Stephen L
Published: April 2024

Introduction:
Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasculopathy that causes right ventricle failure (RVF) and death. This study evaluates the role of the pyrin domain-containing protein 3 (NLRP3) inflammasome activation within RV macrophages in RVF.

Hypothesis:
In PAH, the NLRP3 inflammasome is activated in macrophages infiltrating the RV and contributes to RVF.

Methods:
We compared inflammation in monocrotaline (MCT=25; PBS=21) rats, which have decompensated RV hypertrophy (RVH), and pulmonary artery banding (PAB=11; Sham=11) rats, which have compensated RVH. RV function was assessed by echocardiography and right heart catheterization. Macrophages’ abundance and polarization were evaluated by confocal microscopy and flow cytometry. NLRP3 inflammasome activation was assessed by western blot and
in vitro
strategies. On day 14 post-MCT injection, rats were treated daily with SC-144 (a GP130 antagonist) or MCC950 (an NLRP3 inhibitor). We assessed macrophage abundance and NLRP3 activity in PAH-RVF patients (n=12) and controls (n=9).

Results:
Macrophage abundance was significantly higher in MCT-RV compared to controls (p=0.023 microscopy; 0.004 flow cytometry), but it was insignificant between PAB and sham-RVs. While MCT-RV macrophages were inflammatory, lung macrophages carried an anti-inflammatory phenotype. NLRP3, cleaved caspase1 and IL1β were highest in MCT-RVs (p= 0.021, 0.008, 0.027). The macrophage-NLRP3 pathway was also upregulated in PAH-RVF patients. Cultured MCT monocytes revealed increased NLRP3:ASC interaction upon Nigericin stimulation, which MCC950 inhibited.
In vivo
, MCC950 reduced NLRP3 activation (p=0.012) and improved RV function. SC-144 significantly reduced RV macrophage count, STAT3 and NLRP3 activation (p= 0.0001, 0.042, 0.05), while improving RV function without regressing pulmonary vascular disease.

Conclusion:
The concept that PAH-RVF results, in part, from local RV inflammation rather than a passive consequence of elevated afterload is new. Blocking the inflammasome pathway reduces RV-macrophage accumulation and NLRP3 inflammasome activation. It also improves RV function, despite persistent pulmonary vascular remodeling offering a new therapeutic paradigm.
Abstract 13975: Macrophage Specific Lipoxygenase Deletion Amplify Cardiac Repair Activating Treg in Chronic Heart Failure
Authors: Grilo Gabriel A , Serhan Charles N , nadler jerry , Kain Vasundhara , Halade Ganesh V
Published: April 2024

Introduction:
Splenic leukocytes, particularly macrophage (Mφ)-expressed lipoxygenases, facilitate the biosynthesis of resolution mediators essential for cardiac repair. Next, we asked whether deletion of 12/15 lipoxygenase (12/15LOX) in Mφ may impede resolution mediators and impair cardiac remodeling after coronary ligation in heart failure (HF).

Hypothesis:
To determine Mφ-specific inflammation-resolution signaling in cardiac repair and HF, we tested whether Mφ-specific deletion of 12/15LOX delays resolution of inflammation in HF.

Methods:
Using 12/15
flox/flox
and LysMcre scheme, we generated Mφ-specific 12/15LOX (Mφ-12/15LOX
-/-
) mice and LOX deletion validated in Mφ. Risk-free young adult (8-12-week-old) C57BL/6J wild-type (WT; n=43) and Mφ-12/15LOX
-/-
male mice (n=40) were subjected to permanent coronary artery ligation surgery (MI; myocardial infarction). Mice were monitored at day (d)1, d5 (as acute HF; AHF), and to d56 (chronic HF; CHF) post-MI, maintaining no-MI mice as d0 naïve controls. Cellular and molecular events of cardiac repair were determined in AHF and CHF.

Results:
Post ligation, Mφ-12/15LOX
-/-
mice showed increased survival (88% vs. 56%) and limited heart dysfunction compared with WT. In AHF, Mφ-12/15LOX
-/-
mice have increase biosynthesis of CYP2J-derived epoxyeicosatrienoic acid (EET), particularly 11,12 EET in the infarcted heart. Overall, myeloid cell profiling from both heart and spleen indicated that Mφ-12/15LOX
-/-
mice showed a higher number of immune cells during AHF. In addition, the detailed immune profiling revealed reparative Mφ phenotype (Ly6C
low
) in Mφ-12/15LOX
-/-
mice with higher expression of Arg-1 in a splenocardiac manner post-MI. Mφ-12/15LOX
-/-
mice showed an increase in myeloid population in CHF that coordinated increase of T
regs
(CD4+/ Foxp3+) in spleen and injured heart compared with WT.

Conclusions:
Thus, deletion of 12/15 LOX in Mφ direct reparative phenotype to facilitate cardiac repair marked with biosynthesis of EETs in acute HF and activated T
regs
in CHF thereby improved survival. The presented study outlines the complex role of 12/15LOX in Mφ plasticity, T
reg
cell signaling, and indicate that resolution mediators are viable target to expedite cardiac repair in HF.
Abstract 13986: De Novo Occurrence Of Fragmented QRS Waves In V5 And 6 Leads After Successful Nuss Surgery For Pectus Excavatum Considering QRS Wave Axis And Width And Heart Compression On Computed Tomography
Authors: Funabashi Nobusada , Nakamura Kohki , sasaki takehio , Naito Shigeto , Kobayashi Yoshio
Published: April 2024

Introduction:
On ECG, fragmented QRS waves (fQRS), otherwise known as a notch in the QRS complex, may indicate conduction abnormalities. Pectus excavatum (PEX) physically depresses the heart (mainly the right and left aria (RA, LA)). The Nuss operation is a minimal invasive technique for PEX repair.

Hypothesis:
We hypothesize that fQRS may occur in PEX even in patients without right bundle branch block (RBBB), and that the Nuss operation would reduce these, depending on the Haller index (HI) of anatomical severity as calculated from CT imaging (CLINICS 2007; 62:599).

Methods:
17 patients (14 male, 12±6 years) underwent the Nuss operation for PEX, all of which were successful. HI was significantly improved from 5.62±2.29 to 3.29±0.65 (P=0.0002). Before the Nuss operation, 6 patients had incomplete RBBB; of the 11 without RBBB, 6 (55%) had fQRS waves. We evaluated the degree of RA and LA compression in these PEX patients by CT.

Results:
We compared 6 patients with fQRS waves but no RBBB before surgery with 5 patients without fQRS waves but no RBBB before surgery, and only LA diameter on CT before surgery was significantly greater in the former than the latter (P=0.004) (Table). Of 6 patients with fQRS waves but no RBBB before surgery, 3 patients (50%) had de novo fQRS waves in V5 and 6 after surgery. There were no significant differences of QRS axis and width before and after surgery in these3 patients who had de novo fQRS waves in V5 and 6 after surgery. Of 5 patients without any fQRS waves but no RBBB before surgery, 4 patients (80%) had de novo fQRS waves in V5 and 6 after surgery. There were no significant differences of QRS axis and width before and after surgery in these 4 patients who had de novo fQRS waves in V5 and 6 after surgery.

Conclusions:
In patients with PEX, de novo fQRS waves can occur after a successful Nuss operation, especially in the V5 and V6 leads, even in patients without RBBB and without changes of QRS axis and width. This may be caused by heart rotation or some effects of the Nuss procedure.
Abstract 13991: Angiopoietin-2 in Patients With Atrial Fibrillation - Associations With Clinical Characteristics and Outcomes
Authors: Benz Alexander P , Hijazi Ziad , Lindbäck Johan , Connolly Stuart J , Eikelboom John W , Kastner Peter , Ziegler Andre , Oldgren Jonas , Siegbahn Agneta , Wallentin Lars
Published: April 2024

Introduction:
Natriuretic peptides and cardiac troponin are associated with clinical outcomes in patients with atrial fibrillation (AF) but the search for disease-specific biomarkers is ongoing. We evaluated a novel candidate biomarker of endothelial remodeling and vascular growth, Angiopoietin-2 (Ang2), and its associations with clinical characteristics and outcomes in patients with AF not receiving oral anticoagulation.

Methods:
We used a prototype electroimmunoassay (Roche Diagnostics) to measure levels of Ang2 in plasma samples obtained at baseline from patients with AF randomized to aspirin monotherapy in two clinical trials. Associations of Ang2 with clinical characteristics and outcomes were explored using linear and Cox regression models.

Results:
A total of 2,987 patients were included (median age 71 years, 58% male and 13% with prior stroke). Median (25th-75th percentile) Ang2 plasma level was 3.12 (2.15-4.88) ng/mL. In adjusted analyses, Ang2 showed significant associations with AF-rhythm on the baseline ECG, age, heart failure, non-paroxysmal AF, female sex, active smoking, higher body mass index, creatinine and diabetes. Adjusting for age and other clinical characteristics, Ang2 was associated with subsequent ischemic stroke (third vs. first quartile, hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.19-2.61), heart failure hospitalization (HR 1.75, 95% CI 1.27-2.41), cardiovascular (HR 2.01, 95% CI 1.36-2.97) and all-cause death (HR 1.24, 95% CI 1.01-1.53), but not major bleeding. The association with heart failure remained after additional adjustment for N-terminal pro-B-type natriuretic peptide (p=0.002). There was no interaction with cardiac rhythm at baseline for any of the outcomes.

Conclusions:
Plasma levels of circulating Ang2 were associated with clinical characteristics and outcomes in patients with AF not receiving oral anticoagulation. Ang2 was a particularly strong predictor of heart failure hospitalization.
Abstract 14133: Hepatic Deletion of the Cargo Receptor
Surf4
Causes Marked Hypocholesterolemia in Mice
Authors: Tang Vi T , Emmer Brian T , McCormick Joseph , Ginsburg David
Published: April 2024

Introduction:
High plasma concentration of low-density lipoprotein (LDL) is a strong risk factor for coronary artery diseases. Circulating LDL level is a balance between the secretion of its precursor, very low-density lipoprotein (VLDL), and LDL uptake by tissues. Central to these processes are the secretion of APOB - a protein component of VLDL, and PCSK9 - a negative regulator of LDL uptake. We previously demonstrated that the cargo receptor SURF4 mediates the secretion of PCSK9 heterologously expressed in HEK293T cells. We now report the generation and characterization of hepatocyte-specific
Surf4
knockout (

Surf4
LKO

) mice.

Methods and Results:
Hepatic deletion of
Surf4
results in a marked reduction of plasma cholesterol (5.1 mg/dl vs. 71.3 mg/dl, n=5) and triglycerides (17.6 mg/dl vs. 80.4 mg/dl, n=5) as compared to wild-type (WT) littermate controls. Despite modest increases in liver mass (1.14±0.03 g vs. 0.94±0.03 g, n=5) and liver lipid content (3.54±0.46% vs. 0.80±0.57% liver mass, n=4),

Surf4
LKO

mice show no signs of liver dysfunction or hepatosteatosis as evaluated by serum liver function markers and histology. Consistent with a role for SURF4 in PCSK9 secretion, plasma PCSK9 levels are reduced in

Surf4
LKO

mice (17.8±2.6 μg/ml vs. 46.0±7.7 μg/ml, n=6) while liver PCSK9 levels remain unchanged. Given that
Pcsk9
-/-
mice exhibit an approximately 50% reduction in plasma cholesterol, the magnitude of hypocholesterolemia in

Surf4
LKO

mice suggests that other cargoes involved in lipoprotein metabolism might also depend on SURF4 for secretion. Indeed, an unbiased secretomic study by mass spectrometry revealed that secretion of several lipoproteins, including APOA1, APOA2, and APOB, is reduced in SURF4 null Huh7 cells. As expected,

Surf4
LKO

mice show reduced APOB and lipoprotein secretion rate. In contrast to Huh7 cells, which demonstrate broad transcriptional changes in response to
SURF4
deletion, the livers from

Surf4
LKO

mice exhibit few transcriptional changes, including the downregulation of genes involved in fatty acid synthesis.

Conclusions:
These results indicate that the cargo receptor SURF4 has pleiotropic functions in mammalian lipoprotein regulation and may represent a promising target for therapeutic development.
Abstract 14141: Role of Pak1 in Sinus Node Function
Authors: Pereira Carlos H , Varma Disha , Banach Kathrin
Published: April 2024

Introduction:
Sinus node (SN) dysfunction (SND) and atrial arrhythmia frequently occur simultaneously with a hazard ratio of 4.2 for new onset atrial fibrillation (AF) in SND patients. We demonstrated previously that loss of p21-activated kinase 1 (Pak1), a serine/threonine kinase increases the propensity for AF by increasing cellular production of reactive oxygen species (ROS). Since pacemaker current (HCN4) is negatively regulated by cellular ROS we hypothesized that loss of Pak1 leads to attenuated SN function.

Methods:
Heart rate regulation was quantified in wild type (WT) and Pak1 deficient mice (Pak1
-/-
) in vivo and the isolated Langendorff perfused heart using ECGs, bipolar and multi-electrode array derived atrial electrograms. Unpaired t-test was used to compare means between groups.

Results:
In vivo WT and Pak1
-/-
animals exhibited no difference in basal heart rate (WT: 450 ± 26 bpm, n=16; Pak1
-/-
: 440 ± 24 bpm, n=13), but intrinsic HR after autonomic blockage, was reduced in Pak1
-/-
(WT: 399 ± 32 bpm, n=16; Pak1
-/-
: 365 ± 34 bpm, n=13, p<0.05). The result was confirmed in the Langendorff configuration (WT: 359 ± 47 bpm, n=12; Pak1
-/-
: 293 ± 47 bpm, n=21, p<0.01) suggesting attenuated SN impulse generation. To determine the contribution of the Ca clock, hearts were perfused with cyclopiazonic acid (5 μM) a blocker of the sarcoplasmic reticulum Ca ATPase. CPA attenuated the HR in WT and Pak1
-/-
(WT: -19.6 ± 6.6 % n=2 ; Pak1
-/-
: -15.8 ± 7.5 %, n=5) but did not eliminate the difference in HR (WT: 320 ± 37 bpm, n=2; Pak1
-/-
: 255 ± 26 bpm, n=5, p<0.05). Block of HCN4 by ivabradine (3 μM), reduced the HR in WT and Pak1
-/-
(WT: -45.1 ± 6.3 %, n=6; Pak1
-/-
: -22.2 ± 8.6 %, n=7, p<0.001) and eliminated differences in spontaneous activity (WT: 186 ± 43 bpm, n=6; Pak1
-/-
: 234 ± 41 bpm, n=7). In vivo the change in HR in response to ß-blocker propranolol (WT: -13.5 ± 2.5 %, n=6; Pak1
-/-
: -18.4 ± 1.5 %; n=4, p<0.01) and muscarinic receptor blocker atropine (WT: 9.7 ± 5.0%, n=10; Pak1
-/-
: 4.6 ± 4.4 %; n=9, p<0.05) revealed that the attenuated SN impulse generation in Pak1
-/-
mice was compensated by an increased sympathetic and attenuated parasympathetic tone.

Conclusion:
Attenuated Pak1 expression results in suppressed SN impulse generation likely by ROS dependent attenuation of HCN4 expression.
Abstract 14178: Artificial Intelligence (AI)-ECG Derived Biological Age Identifies Accelerated Aging in the Lamin A/C Gene (
LMNA
) Mutations
Authors: Shelly Shahar , Milone Margherita , Chacin-Suarez Audry , Cohen-Shelly Michal , Medina-inojosa Jose , Kapa Suraj , Attia Zachi , Chahal Anwar , Somers Virend K , Friedman Paul , Lopez-Jimenez Francisco
Published: April 2024

Introduction:
LMNA
encodes the nuclear envelope proteins lamin A/C that are involved in ageing processes. Mutations in
LMNA
cause a spectrum of phenotypes which include muscular dystrophy, arrhythmogenic dilated cardiomyopathy, peripheral neuropathy, progeroid syndrome and overlap syndrome. Early diagnosis is crucial to prevent sudden cardiac death. We hypothesized that
LMNA
mutations result in an ECG biological age older than chronological age.

Methods:
In this study, we used AI-enabled ECG network to investigate standard digital 12-lead ECGs in genetically characterized
LMNA
patients.

Results:
We identified 33
LMNA
patients with 331, 12-lead ECG available for analysis. Median age at symptoms onset was 23.5 (range: <1 to 61 years;15 females). Mean follow up time was 86 months (range: <1 to 367 months). Symptoms at onset included muscle weakness (n=10) or cardiac symptoms (n=18) and asymptomatic (n=5). We included a total of 1532 age sex matched controls. We found significant differences in positive age-gap (biologically older than chronological age) comparing
LMNA
patients (median of 17.5) versus controls (4.9 years; p<0.001,
Figure 1
). AI-ECG age with 10 years or higher age-gap was observed in 73% of
LMNA
patients compared to 27% in the controls (p<0.001). Consecutive serial analysis for all ECG’s in the study versus predicted age showed faster aging when comparing the rates of age-gap overtime in the
LMNA
group compared to controls (p<0.0001,
Figure 2
). Moreover, the subset analysis of 23 ECG in the 5 asymptomatic patients versus controls also showed significantly higher AI-ECG age-gap (p=0.004)

Conclusions:
An AI-ECG algorithm to detect biological age effectively demonstrates accelerated aging in patients with LMNA mutations related to physiological aging. Our findings further validate the role of AI-ECG to detect accelerated aging, expanding previous studies demonstrating higher mortality among individuals with in increased positive age-gap.
Abstract 14196: Early Postoperative Atrial Fibrillation Combined With Preoperative Structural and Electrophysiological Parameters Are Good Predictors of Late Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery
Authors: Kawczynski Michal , Isaacs Aaron , Gilbers Martijn , Maessen Jos G , Bidar Elham , Schotten Ulrich
Published: April 2024

Introduction:
Atrial fibrillation (AF) in the early postoperative phase (E-POAF) is likely caused by a combination of an arrhythmogenic substrate and surgery-induced stressors. Although E-POAF is regarded as a transient arrhythmia, recent findings suggest that patients with E-POAF also show late AF recurrences. The aim of this study is to determine the incidence of late postoperative AF (L-POAF) within 1 year of cardiac surgery and to identify its predictors.

Hypothesis:
The occurrence of L-POAF is associated with preexisting functional and structural atrial changes, and with occurrence of E-POAF.

Methods:
Ninety-two patients without history of AF undergoing first cardiac surgery were prospectively included. Intraoperatively, all patients received an implantable loop recorder (Reveal LINQ, Medtronic, USA) for continuous rhythm monitoring. Preoperative transthoracic echocardiograms (TTE), 12-lead electrocardiograms (ECG), blood samples, and clinical data were analyzed.

Results:
Eighty-five patients completed 1-year of follow-up. Incidence of L
5
-POAF (AF between 5-365 days after surgery) was 31.8%, whereas incidence of L
30
-POAF (AF between 30-365 days after surgery) was 15.3%. Independent predictors for L
5
-POAF were left atrial maximum volume indexed for body surface area (LAVi) and occurrence of E
5
-POAF (p=0.02, p<0.01, respectively). Independent predictors for L
30
-POAF were PR-interval and occurrence of E
30
-POAF (p=0.02, p=0.01, respectively). Predictive models for L-POAF based on TTE, biomarkers, and ECG showed moderate performance while addition of E-POAF strongly improved sensitivity and specificity (L
5
-POAF: 94.1% & 95.2%; L
30
-POAF: 83.3% & 91.0%, respectively) to predict L-POAF (see figure).

Conclusion:
Predictive models based on preoperative LAVi, increased PR-interval, and occurrence of E-POAF show excellent diagnostic accuracy for predicting occurrence of L-POAF.
Abstract 14210: Impaired Mitophagy and Reduced Parkin Expression in Human Pulmonary Arterial Smooth Muscle Cells (PASMCs) in Pulmonary Arterial Hypertension (PAH)
Authors: Rehman Rakhshinda , Karuthedath Vellarikkal Shamsudheen , Dieffenbach Paul B , Lam Hilaire C , Filippakis Charilaos , Fredenburgh Laura E
Published: April 2024

Introduction:
Mitophagy is the key mitochondrial quality control process of selective removal of damaged mitochondria which is necessary for maintaining cellular homeostasis. While studies have demonstrated that abnormalities in mitochondrial metabolism drive a hyperproliferative phenotype of pulmonary vasculature in PAH, there is limited understanding of mitophagy dysregulation in PAH. Recent studies have shown that hypoxia induced Parkin/Pink1-mediated mitophagy promotes vascular remodeling, however another report suggests that loss of Pink1 and reduced mitophagy in hypoxia promotes PASMC proliferation. The role and mechanisms of altered mitochondrial dynamics/mitophagy dysregulation in driving pulmonary vascular remodeling in PAH remain incompletely understood.

Hypothesis:
We hypothesized that impaired mitophagy and reduced Parkin expression may drive the apoptosis-resistant, hyperproliferative phenotype in PAH PASMCs.

Methods:
Mitophagy was assessed in human PASMCs from control donors and PAH patients stably expressing mtKeima protein and in lungs from hypoxia-exposed mtKeima transgenic mice. Parkin expression was assessed by Western blotting and immunocytochemistry. Immunofluorescence staining for Parkin was performed in lungs from mice exposed to chronic hypoxia. Human PASMCs from control donors were transfected with siControl and siParkin and assessed for proliferation and apoptosis by Ki67 and Annexin V/PI flow cytometry and PCNA expression.

Results:
PASMCs from PAH patients showed reduced KeimaRed vs. KeimaGreen ratio compared to control donors indicating reduced mitophagy i.e. further confirmed by decreased Parkin in PAH PASMCs. Parkin deficient PASMCs demonstrated more Ki67 and less Annexin V/PI positive cells and increased PCNA. Interestingly, lungs from hypoxia-exposed mtKeima transgenic mice showed increased KeimaRed vs. KeimaGreen ratio and increased Parkin in lungs of hypoxia-exposed mice.

Conclusions:
PAH PASMCs demonstrate impaired mitophagy and reduced Parkin expression; Parkin deficiency promotes proliferation and inhibits apoptosis in PASMCs. Our findings suggest that Parkin may regulate remodeling phenotypes in PASMCs and thus may represent a potential therapeutic target in PAH.
Abstract 14240: Disparities in Implementation of Advanced Heart Failure Therapies Among Patients With HIV: An Analysis of the NIS Database
Authors: Hernandez Rafael J , Gilchrist Juliann , Maning Jennifer , Grant Jelani , Vincent Louis T , Ebner Bertrand , Olarte Neal , Olorunfemi Odunayo , Colombo Rosario A
Published: April 2024

Background:
Highly active anti-retroviral therapy has transformed human immunodeficiency virus (HIV) infection into a chronic disease. HIV+ patients now experience increased mortality from chronic conditions such as heart failure (HF). Nonetheless, limited data has been published on the implementation of advanced HF therapies among this patient population. The aim of our study is to assess current disparities in therapies among HIV+ patients.

Methods:
We performed a retrospective analysis using the National Inpatient Database (NIS) from 2011 to 2018 to identify patients admitted for HF exacerbation. Patients were stratified according to HIV status. Baseline characteristics and clinical status were recorded. Primary outcome was implementation of advanced HF therapies (left ventricular assist device, LVAD and/or transplantation, HTX). Multivariate analysis models were adjusted for statistically significant differences in baseline characteristics between the groups.

Results:
A total of 39,527,306 HF patients were identified, of these 207,394 (0.52%) were HIV+. HF/HIV+ patients were less likely to be females (33.6% vs 49.8%, p < 0.001) and obese (11.6% vs 19.1%, p < 0.001). The prevalence of renal disease (50.9% vs 40.1%, p < 0.001) and dialysis dependance (19.7% vs. 5.2%, p < 0.001) was higher among the HF/HIV+ patients. The use of mechanical circulatory support was lower among HF/HIV+ (0.5% vs 0.7%, p < 0.001), despite higher incidences of cardiogenic shock (1.9% vs 1.8%, p = 0.001) among these patients. HF/HIV+ were less likely to go for LVAD (n=65, 0% vs n=2997, 0.1%, OR = 0.245, p < 0.001) or HTX (n=55, 0% vs n=21,089, 0.1%, OR = 0.266, p < 0.001).

Conclusions:
Access to advanced HF therapies among patients with HIV-associated cardiomyopathy appears to be limited and unequal. These results should encourage further studies to evaluate the short- and long-term clinical outcomes of advanced HF therapies among HF/HIV+ patients.
Abstract 14246: Septic Shock and Myocardial Infarction
Authors: kamat Ishan , Nazir Salik , Plana Juan C , Kulkarni Prathit , NAMBI VIJAY , Bozkurt Biykem , Jneid Hani
Published: April 2024

Introduction:
Septic shock (SS) is a life-threatening host response to infection, contributing to significant mortality, morbidity, and cost burden in the United States. Although the inflammatory link between SS and myocardial infarction (MI) has been established, outcomes of patients who concomitantly develop types 1 or 2 MI have not been directly studied.

Purpose:
To examine patient profiles and the associations of type 1 and type 2 MI with hospital-related clinical outcomes in patients admitted with SS.

Methods:
The National Readmission Database 2018 was queried to identify patients whose hospital discharge diagnoses were either SS without MI, SS with type 1 MI, or SS with type 2 MI. Complex-sample multivariable logistic and linear regression models were used to determine the associations of these conditions with clinical outcomes including in-hospital mortality, length of stay, discharge to nursing facility, 30-day all-cause readmission and hospital cost.

Results:
A total of 354,528 patients with SS were included in this study. Among them, 11,519 (3.2%) had type 1 MI, and 13,970 (3.9%) had type 2 MI. Compared to SS without MI, SS with type 1 MI was more likely to be associated with significantly higher in-hospital mortality (adjusted odds ratio [aOR] 1.67, 95% confidence interval [CI] 1.57-1.77), hospital cost (adjusted parameter estimate [aPE] 4,571, 95% CI 3,020-6,122), and discharge to nursing facility (aOR 1.13, 95% CI, 1.05-1.22). In contrast, SS with type 2 MI was associated with similar in-hospital mortality, discharge to nursing facility, and higher hospital cost (aPE 1,798, 95% CI, 549-3,047) compared to SS without MI. Type 1 MI was associated with higher in-hospital mortality (aOR 1.74, 95% CI, 1.60-1.90, p<0.001) than type 2 MI.

Conclusions:
In hospitalized patients with SS, the development of type 1 MI is associated with higher mortality and resource utilization in the United States, whereas type 2 MI was only associated with higher resource utilization.
Abstract 14278: Lessons From COVID-19 Pandemic: Using Telemedicine in Ambulatory Care Delivery for Pediatric Heart Failure and Heart Transplant Patients
Authors: Bano Maria , Sutcliffe David L , Hernandez Nathanya B , Power Alyssa , Dubke Curtis , Butts Ryan J
Published: April 2024

Introduction:
COVID-19 related restrictions necessitated a rapid transition to telemedicine (TM) ambulatory services for pediatric heart failure (HF) and heart transplant (HT) patients. The impact on patient related outcomes remains unknown. We report the feasibility of incorporating TM in routine ambulatory care delivery to pediatric HF and HT patients at a large academic center during the COVID era (04/2020-04/2021).

Methods and Results:
A total of 650 HF patients, median age 10 (0-25) years and 200 HT recipients, median age 10 (0-22) years were followed at our center during the COVID era. A center-specific, risk stratified model based on patient characteristics (Table 1) and local COVID restrictions were used to determine patient eligibility for TM only, TM + in-person (IP) or IP care only. There were 2 unexpected deaths in the HT and 0 deaths in the HF patients during the COVID era compared to 1 death in HT and 0 deaths in HF patients in the pre-COVID era (01/2019-12/2019). Both deaths in the COVID era were due to non-cardiac causes and neither patient utilized the TM platform for care. There was a significant decrease in emergency room use and unplanned hospital admissions during the COVID-19 era compared to pre-COVID era (Table 2, Fig 1).

Conclusions:
TM can safely be incorporated in routine ambulatory care delivery for appropriately selected pediatric patients with HF and HT.
Abstract 14297: Spatially Synchronized Electrogram Islands Within Atrial Fibrillation Predict Termination by Ablation
Authors: Ganesan Prasanth , Deb Brototo , bhatia neal , Rodrigo Miguel , Feng Ruibin , Alhusseini Mahmood , Rogers Albert J , Krummen David , Clopton Paul L , Rappel Wouter-Jan , Narayan Sanjiv M
Published: April 2024

Introduction:
It is unclear how persistent atrial fibrillation (AF) terminates by any spatial arrangement of ablation lesions.

Hypothesis:
We hypothesized that AF that exhibits spatial organization with islands of 1:1 synchronized electrograms within the disordered milieu and, specifically, that patients with larger area islands may be more likely to terminate than those without.

Methods:
We recruited n=60 patients (72% male, age 63±10 years) in whom AF terminated by ablation (n=30; “Term”) or did not (n=30, “Non-term”). Unipolar AF electrograms were recorded by 64-pole basket catheters in both atria. For all possible 2X2 electrode grids, synchronization was assessed by correlation (repeating shapes + relative timings, coefficient, Fig A). Ablation targeted organized sites (rotational/ focal), then pulmonary vein isolation.

Results:
Fig A shows (top) AF EGMs in a Term patient showing 1:1 patterns at D2-D3-E2-E3 over time (correlation>0.9). For the entire left atrium, there was a large synchronized island >25% of mapped atria (Fig B, red). Bottom panels show less synchronization in a Non-term patient (Fig A), with <5% area (Fig B). For all patients, synchronized islands (with correlation >0.8) were larger for Term (black) than Non-term (gray) patients over a range of time durations (Fig C, p<0.01 ANOVA). Area of synchronized regions predicted AF termination with c-statistic 0.68, and the optimum cut-point provided sensitivity 87% (specificity 43%).

Conclusions:
Persistent AF shows organized islands of synchronized electrograms, whose size and duration predict the likelihood of termination by ablation. Future studies should investigate the pathophysiology of synchronized islands in AF.
Abstract 14312: Inhibition of the Electron Transport Chain and Inflammasome Pathway Preserve Function in Donor Hearts After Circulatory Death
Authors: Cholyway Renee M , Akande Oluwatoyin E , Chen Qun , Lesnefsky Edward J , Toldo Stefano A , Quader Mohammed
Published: April 2024

Introduction:
Hearts by donation after circulatory death (DCD) have the potential to increase the number of transplantable hearts. However, the DCD process promotes ischemia and reperfusion injury (IRI). Mitochondrial damage and NLRP3 inflammasome activation contribute to the DCD heart damage. Blockade of electron transport chain (ETC) with the reversible inhibitor amobarbital (AMO) or the NLRP3 inhibitor 16773340 (NLRP3-I) can mitigate IRI.

Hypothesis:
AMO and/or NLRP3-I given to the DCD hearts at the moment of heterotopic heart transplantation afford lasting protection to the DCD hearts.

Methods:
We induced the DCD process in anesthetized rats that were intubated and ventilated by paralyzing the animal with vecuronium bromide and removing the ventilatory support. Treatment groups were AMO (1 mM), NLRP3-I, AMO+NLRP3-I, and vehicle (N=8-10/group). The DCD hearts were procured after 25 min of in-body ischemia then flushed with ice-cold cardioplegia solution supplemented or not with the AMO. NLRP3-I was administered orally (100 mg/kg) to the recipient before HTx and once a day. Control beating-heart donors (CBD) were procured without ischemia by giving the cardioplegia. The donor hearts underwent heterotopic transplantation in the abdomen of recipients. After 14 days, the function of the DCD heart was measured using an intraventricular balloon.

Results:
The developed pressure (DP), the peak -dP/dt, and the rate pressure product (RPP) of DCD hearts were significantly reduced compared to the CBD controls (63±7% vs 99±8%; -851±113 vs -1221±123; 20,729±2,268 vs 11,874±1,987, respectively; all p<0.05). AMO, NLRP3-I, and AMO+NLRP3-I preserved the DCD heart function (all parameters, p<0.03). Double treatment AMO+NLRP3-I trended toward a better improvement without reaching statistical significance over single treatments.

Conclusions:
Inhibition of ETC with AMO alone or combined with NLRP3 inhibition preserved the function of DCD hearts.