bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4139510: Nighttime home blood pressure was a crucial indicator in predicting adverse outcomes for patients with stage B heart failure
Authors: Komori Takahiro , Hoshide Satoshi , Kario Kazuomi
Published: November 2024

Background:
Stage B heart failure (HF) was associated with increased cardiovascular and HF events. Hypertension is a risk factor for these events in Stage B HF. Nighttime blood pressure (BP) is more strongly associated with cardiovascular events than daytime BP, but nighttime home BP measurement is not widely used.

Method:
We analyzed 573 stage B HF patients with at least one cardiovascular risk factor who underwent home BP monitoring. Stage B HF was defined as BNP ≥35pg/ml, or NT-proBNP ≥125pg/ml, Troponin T >0.014ng/ml, LVEF <50%, enlarged left ventricular dimensions in diastole (≥60mm in men and ≥54mm in women), enlarged left atrium (>40mm), or increased left ventricular mass (>115g/m
2
in men and >95g/m
2
in women). Morning, evening, and nighttime home BP were measured by home BP devices, and cardiovascular events were followed up.

Results:
During a mean follow-up of 7.6 ± 3.6 years, 65 cardiovascular events occurred. Morning, evening, and nighttime home SBP were higher in the event group than in the non-event group (146±19 vs 140±14 mmHg, p=0.01, 137±17 vs 131±14 mmHg, p<0.01, 129±16 vs 123±14 mmHg, p<0.01, respectively). Kaplan Meier analysis showed that the high BP cut-off group defined by HT guidelines had significantly higher incidents of events in office, morning, and nighttime home SBP (p=0.03, p=0.02, p<0.01, respectively)(Figure). In multivariate Cox regression analysis adjusting for significant variables, nighttime home SBP >120mmHg was a significant predictor of the outcome (Hazard Ratio 2.03, 95% Confidence Interval: 1.13-3.65, p=0.02).

Conclusions:
Elevated nighttime home BP was a significant predictor for cardiovascular outcomes in stage B HF patients.
Abstract 4139515: Association Between Maximum Daily Atrial Fibrillation Duration and Ischemic Stroke Among Patients with Continuous Rhythm Monitoring
Authors: Peigh Graham , Koehler Jodi , Majumder Shubha , Cho Yong , Landman Sean , Sarkar Shantanu , Ziegler Paul , Passman Rod
Published: November 2024

Background:
Recent clinical trials demonstrate the benefit of oral anticoagulation (OAC) for all device-recognized atrial fibrillation (AF) > 6 minutes. However, AF is not binary and those with greater AF burden generally have a higher risk of stroke. To date, there are limited data on a specific threshold of AF duration that is independently associated with the risk of ischemic stroke.

Objective:
To assess the association between baseline maximum daily AF duration (MDAFD) and ischemic stroke among patients with cardiac implantable electronic devices (CIEDs) capable of continuous AF detection.

Methods:
Using the Optum
®
de-identified electronic health record (EHR) (2007-2021) linked with the Medtronic CareLink
®
heart rhythm database, CIED patients with healthcare activity recorded in the EHR
>
12 months pre- and
>
6 months post-CIED implant were identified. Exclusion criteria included presence of a prescription for OAC. MDAFD was assessed during the first 30 days post-implant (baseline period). Associations between baseline MDAFD and ischemic stroke in follow-up were evaluated, adjusting for CHA
2
DS
2
-VASc and chronic kidney disease.

Results:
Of 26,400 patients (68±13 years; 60% male) analyzed, 2,544 (9.6%) had AF at baseline. The distribution of maximum daily AF duration during baseline was as follows: 6 min-<1 hour: 734 (28.9%); 1 hour-<5.5 hours: 565 (22.2%); 5.5 hours-<23.5 hours: 519 (20.4%);
>
23.5 hours: 726 (28.5%). In total, 664 patients (2.5%) suffered an ischemic stroke through 2.6±1.6 years of follow-up. Presence, compared to absence, of AF at baseline was associated with a greater risk of ischemic stroke. Among those with AF, only patients with MDAFD
>
5.5 hours had an increased risk of stroke compared to those with no AF (Figure).

Conclusions:
Within a large cohort of patients with CIEDs without a prescription for OAC,
>
5.5 hours of MDAFD was needed to increase the risk of ischemic stroke compared to those with no AF. These results suggest that there is a threshold of MDAFD, measured in hours, that may benefit from treatment with OAC.
Abstract 4139530: Leveraging Natural Language Processing for Echocardiographic Data Extraction in Hypoplastic Left Heart Syndrome
Authors: Girvin Zachary , Gangireddy Srushti , Coleman Andersen , Ong Henry , Wei Wei-Qi , Kannankeril Prince , Sunthankar Sudeep
Published: November 2024

Background:
Automated data mining performs well with discrete data, and efforts are underway to use natural language processing (NLP) for textual data collection. This method has yet to be proven generalizable to echocardiographic data in congenital heart disease.

Aim:
Assess the accuracy of an NLP algorithm relative to manual record abstraction (MRA) in collecting echocardiographic data in a cohort of patients with hypoplastic left heart syndrome (HLHS).

Methods:
Patients with HLHS at our institution between 2007 and 2022 were identified. MRA collected serial echocardiographic data at 5 predefined points between birth and stage II palliation, focused on right ventricle wall motion (RVWM) and tricuspid regurgitation (TR). Separately, an NLP algorithm was created to abstract the same data. We used our institution’s identified clinical research database, the Research Derivative (RD), which follows the Observational Medical Outcomes Partnership (OMOP) Common Data Model. Echocardiogram reports were identified by report type and matching titles. Regular expression matched phrases for RVWM and TR with qualifier phrases of function. Qualifier phrases were mapped to severity scales: 0 (normal) to 6 (severely depressed) for RVWM; 0 (normal) to 5 (severe regurgitation) for TR. The results of the MRA and NLP collection methods were compared using Cohen’s kappa test.

Results:
A total of 707 echocardiograms from 180 patients were compared. The NLP model correctly identified RVWM in 93.9% (664/707) and TR in 82.6% (584/707). There was a high degree of agreement for both features (RVWM: k=0.84 [0.88-0.98]; TR: k=0.93 [0.80-0.89]). The most common reason for a no-match scenario was an absence of descriptive text available in the RD that was available in the electronic health record (EHR); 19% (8/43) and 66% (81/123) of no-match in RVWM and TR respectively. Misidentification by NLP algorithm accounted for 37% (16/43) of RVWM and 15% (19/123) of TR no-matches. These represent the algorithm assigning an incorrect score due to misinterpretation of echocardiogram report language, most commonly those with complex verbose descriptions of features.

Conclusion:
The NLP algorithm demonstrates high proficiency in collecting echocardiogram data when text is available for extraction. Its use is limited in reports containing complex descriptive language. These data suggest its utility as an accompaniment for data abstraction to increase data collection efficiency and reduce MRA errors.
Abstract 4139584: Serendipitously Discovered Wild-Type Transthyretin Cardiac Amyloidosis in the Setting of Familial Hypertrophic Obstructive Cardiomyopathy
Authors: Santer Matthew , Bianco Christopher
Published: November 2024

Introduction:
We present a case of hypertrophic obstructive cardiomyopathy (HOCM) with incidental wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) discovered after septal myectomy.

Case presentation:
A 62-year-old male with a history of bilateral carpal tunnel syndrome as well as a family history of sudden cardiac death consistent with HOCM on autopsy (patient's father) presented to the clinic with symptoms of exertional shortness of breath, hypotension, and pre-syncope. An external monitor revealed one episode of non-sustained supraventricular tachycardia, otherwise was unremarkable. He experienced worsening symptoms for which emergency department evaluation revealed anterior lead T-wave inversions on EKG. Cardiac catheterization revealed non-obstructive coronary artery disease. Shortly thereafter, a cardiac MRI was significant for probable HOCM based on septal hypertrophy, late gadolinium enhancement (LGE) with mid-wall fibrosis in the basal/mid inferolateral segments, and systolic anterior motion (SAM) of the mitral valve. Pre-stress echocardiogram revealed a sigmoid septum with septal wall thickness of 1.6 cm and no left ventricular outflow tract (LVOT) gradient. Post-stress echocardiogram revealed severe SAM with septal contact, LVOT gradient of 70 mmHg, as well as hypotension. Genetic testing was negative, and the patient underwent successful septal myectomy with papillary muscle reorientation and resection of secondary chordae. The pathology of the myocardium obtained during surgery resulted with histological features suggestive of HOCM in addition to confirmed ATTRwt-CA for which tafamidis was initiated.

Discussion:
Literature reporting HOCM and ATTRwt-CA within the same patient is rare. Both conditions cause increased myocardial thickness which can present phenotypically similar, making diagnosis difficult. Utilization of modern imaging modalities such as cardiac MRI and echocardiography should provide valuable information for differentiation, but as in our case, direct tissue visualization can be required for diagnosis. Each diagnosis has unique imaging characteristics that help define them such as asymmetric septal hypertrophy with dynamic LVOT obstruction, SAM of the mitral valve, and fibrotic areas on LGE in the setting of HOCM compared to diffuse and symmetric global subendocardial LGE and concentric hypertrophy with ATTRwt-CA.

Conclusion:
Our case reveals the importance of avoiding anchoring bias as concomitant diagnoses can present.
Abstract 4139600: Characteristics and Pattern of Stress Cardiomyopathy in High Grade Subarachnoid Hemorrhage
Authors: Chiu Michael , Mckenzie Erica , Wong Kimberly , Wong Justin , Kramer Andreas
Published: November 2024

Background:
Cardiac injury after subarachnoid hemorrhage (SAH) is a well-recognized phenomenon with electrocardiogram (ECG) changes, arrhythmias and myocardial dysfunction. Neurocardiac injury has been commonly reported with increased severity of SAH, however much of the evidence has focused on high grade SAH requiring hemodynamic support or mechanical ventilation. In this study we focused on neurocardiac injury with high grade World Federation of Neurological Surgeons (WFNS) grade 3-5 SAH requiring intensive care management.

Methods:
Patients admitted to our intensive care unit from 2009-2019 with an WFNS 3-5 aneurysmal SAH with an echocardiogram within 7 days of admission were included in our study. Electrocardiogram, cardiac biomarkers and data regarding mortality and neurological complications were collected retrospectively.

Results:
A total of 242 patients were included in our study analysis with 11 (5%), 89 (37%), and 142 (59%) had WFNS grade 3, 4 or 5 SAH, respectively. Of the 95 patients that underwent echocardiography in the first week, 38 (40%) had a reduced ejection fraction, which was mild (LVEF 40-52%) in 13 (14%), moderate (LVEF 30-39%) in 14 (15%), and severe (LVEF < 30%) in 11 (12%). Independent predictors of reduced ejection fraction included a lower presenting GCS score (OR 1.2 per one point reduction in (Glasgow Coma Score) GCS, 95% CI 1.0-1.5, p = 0.03), elevated troponin T concentration (OR 6.1, 95% CI 1.2-31.3, p = 0.03) and T wave inversion on ECG (OR 9.1, 95% CI 1.6-52.3, p = 0.01). In patients with reduced ejection fraction, classical apical wall motion abnormality was more prevalent in older populations (median age 64 years (apical) vs 50 years (basal wall motion abnormality) and 52 years (other) p = 0.03). In all wall motion abnormality groups, there was a female predominance. Classic Takotsubo wall motion was associated with an anterior SAH aneurysm location (p = 0.03) and highest proportion of moderate to severe LV dysfunction (p = 0.04). ICU mortality did not differ based on the pattern of wall motion abnormalities.

Conclusion:
Predictors of neurocardiac injury in high grade SAH include troponin elevation, T wave abnormalities and lower presenting GCS. Aneurysm location was associated with wall motion abnormalities and degree of LV dysfunction. Patients with WFNS 3-5 SAH are at increased risk of neurocardiac injury. ECG changes, cardiac biomarker elevation and aneurysm location can help identify patients who warrant echocardiography.
Abstract 4139615: X-linked LAMP2B p.Val397Ile variant leads to late-onset Danon disease in females with hypertrophic cardiomyopathy
Authors: Tran Alex , Yuan Victoria , Omi Kazuhiro , Fan Judy , Chang Sunny , Wang Jessica
Published: November 2024

Introduction:
Danon disease is an X-linked dominant disorder in lysosome-associated membrane protein 2B (LAMP2B) that presents with cardiomyopathy and in males, intellectual disability. Dysfunction of LAMP2B, a lysosomal transmembrane protein in muscle, prevents macroautophagy and causes intracytoplasmic accumulation of cellular debris. Loss-of-function mutations in LAMP2B manifest as full Danon disease while missense mutations drive milder phenotypes. There is currently no effective therapy.

Existing literature reports two transmembrane missense mutations, which presented as late-onset cardiac hypertrophy, but do not explore mutation pathogenicity. In our work, we investigate the mechanism of a novel transmembrane missense variant p.Val397Ile in two unrelated females who presented with late-onset hypertrophic obstructive cardiomyopathy with patient myectomy sample.

Methods:
Myectomy heart tissue was analyzed via Western blot and RT-qPCR for protein and RNA levels.
In vitro
overexpression of reference and alternate missense alleles was conducted in HEK293 cells, then analyzed by Western blot, RT-qPCR, and immunofluorescence. Immunofluorescence image analysis compared LAMP2B signal intensity and distribution between variant and wild-type proteins.

Results:
Patient heart tissue showed increased LAMP2 degradation and decreased autophagy markers by Western blot. EndoH treatment to investigate
N-
linked glycosylation patterns further revealed decreased total LAMP2 in patient samples. RT-qPCR showed increased RNA expression in the variant allele. LAMP2 overexpression in HEK293 cells resulted in reduced LAMP2B molecular weight and subcellular mislocalization. Fluorescent image segmentation revealed increased aggregation of variant LAMP2B around nuclei and surrounding structures compared to wild-type. Collectively, these results suggest arrested protein maturation in the Golgi apparatus and increased RNA expression to compensate for reduced functional protein.

Conclusion:
Our study demonstrated that the LAMP2B missense variant c.1189G>A p.Val397Ile is implicated with increased degradation of LAMP2B protein, reduced protein levels of autophagy markers, and elevated LAMP2B RNA expression in cardiomyocytes. Our
in vitro
studies suggest that missense mutations may cause myocardial dysfunction via abnormal LAMP2B maturation and localization. Our work enhances mechanistic understanding of LAMP2B-related pathogenicity and may inform future therapeutic strategies for Danon disease.
Abstract 4139640: Differential progression of cardiac structure and function in transthyretin cardiac amyloidosis (ATTR-CA) following treatment with tafamidis and diflunisal
Authors: Scharf Rebecca , Schmidt Alexander , Ullah Ikram , Gopal Deepa , Siddiqi Omar , Ruberg Frederick
Published: November 2024

Introduction:
Transthyretin cardiac amyloidosis (ATTR-CA) is an important cause of heart failure for which tafamidis is the only FDA-approved therapy. Diflunisal is an NSAID that is also effective in improving cardiovascular outcomes in ATTR-CA and is utilized in regions where tafamidis is unavailable or cost-prohibitive. Data comparing the efficacy of these agents are lacking.

Research Question:
To compare longitudinal changes in cardiac structure by echocardiography and cardiac biomarkers among patients with ATTR-CA treated with tafamidis or diflunisal over 36 months.

Methods:
Among 425 sequential ATTR-CA patients seen at the Boston University Amyloidosis Center between 2016 and 2022, following exclusion for single visits (194) and for receiving TTR-silencer or multiple therapies (67), the final cohort was 164 patients: 109 were treated with tafamidis (ATTR-CA-T, 86% wild-type) and 55 with diflunisal (ATTR-CA-D, 54% wild-type). Echocardiographic wall thickness was re-measured by a single observer, while LVEF, global longitudinal strain (GLS, expressed in absolute value), NT-proBNP, troponin I, prealbumin, and creatinine were collected from the electronic health record at baseline and 36 months with differences between the measures calculated for each patient and compared using paired t-tests.

Results:
At baseline, while the ATTR-CA-D cohort was older and had a higher proportion of variant ATTR-CA (p<0.001), the ATTR-CA-T cohort had more advanced disease as demonstrated by increased wall thickness, lower LVEF, worse GLS, higher creatine, and worse cardiac biomarkers (Table 1). After 36 months of treatment compared to baseline (n=23 for ATTR-CA-D and n=36 for ATTR-CA-T), the ATTR-CA-D group showed increase in septal thickness (0.5mm, p=0.04) and posterior wall thickness (0.6mm, p=0.006), while GLS (-5.6%, p<0.001) and LVEF (-5.9%, p=0.02) were decreased. There were no significant echocardiographic changes after 36 months in the ATTR-CA-T group and cardiac biomarker change was similar.

Conclusion:
These data suggest that tafamidis may be more effective than diflunisal in arresting echocardiographic progression in ATTR-CA. Further studies are necessary to assess the association of these changes with cardiovascular outcomes.
Abstract 4139672: 12,13-diHOME Attenuates Pro-Arrhythmic Effect of High-Fat Diet
Authors: Buck Benjamin , Areiza Natalia , xu Xianyao , Elliott Austin , Wan Xiaoping , Nassal Drew , Lane Cemantha , Nirengi Shinsuke , James Natasha Maria , Baer Lisa , Deschenes Isabelle , Chinthalapudi Krishna , Gallego-Perez Daniel , Stanford Kristin , Hund Thomas
Published: November 2024

Introduction:
Obesity is a risk factor for atrial fibrillation (AF) and its incidence that has tripled over the past 30 years. Obesity is associated with dramatic changes in atrial structure and electrophysiology through unclear mechanisms. The linoleic acid metabolite 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a signaling lipid released by brown adipose tissue that acts in an endocrine manner on myriad tissues including the heart. 12,13-diHOME enhances cardiac myocyte Ca
2+
cycling and overall function, though the precise mechanisms are undetermined. This study tested the hypothesis that 12,13-diHOME inhibits the pro-arrhythmic molecule Ca
2+
/calmodulin-dependent kinase II (CaMKII). We propose that obesity-induced loss of 12,13-diHOME promotes CaMKII dysfunction,
in vitro
ectopy and atrial arrhythmia (AA).

Methods:
Adult male and female mice were fed either high fat diet (HFD, 60% kcal from fat) or normal chow (NFD) (21% kcal from fat) for 8-16 weeks. Atrial myocytes were isolated for action potential (AP) measurements using whole-cell patch clamp ±12,13-diHOME (5 μM). To test the effect of 12,13-diHOME on AA inducibility, a second cohort of mice was fed HFD and subjected to weekly tissue nanotransfection for non-viral delivery of either Ephx1/2 (HFD-TNT), enzymes responsible for production of 12,13-diHOME, or empty plasmid (HFD-con). Following treatment, mice underwent intracardiac pacing studies to determine AA inducibility. The ability of 12,13-diHOME to directly interact with and inhibit CaMKII was tested using purified components with
in vitro
radioassay and microscale thermophoresis.

Results:
HFD induced atrial myocyte AP duration prolongation and a higher incidence of spontaneous depolarization compared to NFD, both of which were reversed by 12,13-diHOME (figure). HFD-TNT exhibited decreased phospho-CaMKII compared to HFD-con mice. In parallel, HFD-TNT trended toward reduced inducibility of AA (0/7 mice inducible, 0%) compared to TNT-CON mice (5/7, 58%) (p=0.07). Radioassay revealed that 12,13-diHOME inhibits CaMKII; thermophoresis demonstrated direct binding with
K
1/2
= 19 mM.

Conclusion:
HFD induces dysregulation in 12,13-diHOME and CaMKII signaling together with defects in atrial myocyte excitability and AA in mice. Non-viral overexpression of 12,13-diHOME shows promise in normalizing CaMKII activity and reducing AA burden. 12,13-diHOME represents a novel avenue for direct regulation of CaMKII signaling and downstream pathology in the heart.
Abstract 4139715: The impact of CSL112 and atorvastatin on lipid core stiffness in murine atherosclerotic plaques
Authors: Rezvani Sharif Alireza , Ashok Avinash , Watson Anna , Velkoska Elena , Greene Brandon , Chen Yung-Chih , Muir Ineke , Peter Karlheinz , Dagastine Raymond , Kingwell Bronwyn
Published: November 2024

Background:
Plaque structural stress (PSS) is the stress within the body of atherosclerotic plaques, resulting from the dilation and stretching of vessels due to arterial pressure. Plaque rupture often occurs at sites of elevated PSS, especially when the stress level exceeds the mechanical strength of the plaque. Notably, a significant difference in stiffness between the softer lipid core and the stiffer fibrous cap significantly increases PSS. By increasing the elastic modulus (a measure of material stiffness) of lipid cores and thus reducing the stiffness disparity between plaque components, it may be possible to transition vulnerable plaques from a state of instability to stability.

Hypothesis:
Both CSL112, a human plasma-derived apolipoprotein A-I formulation that enhances reverse cholesterol transport, and atorvastatin increase the stiffness of plaque lipid cores.

Methods:
Rupture-prone atherosclerotic plaques were induced in 47 ApoE knockout male mice using a carotid tandem stenosis model after a 7-week high-fat diet. After surgery, mice were treated with either CSL112 (100 mg/kg) intravenously twice weekly (n=15), saline intravenously (n=15), or atorvastatin (10 mg/kg) daily by gavage for 5 weeks (n=17). All animals were euthanized at 20 weeks of age. Multiple sections from the first proximal segment of the right common carotid artery were extracted for stiffness measurements and adjacent tissues were sliced for histological examination to identify lipid cores. Using atomic force microscopy, nano-indentation tests were conducted on the lipid-rich regions of plaque samples, and the elastic moduli were determined by fitting the Hertzian contact model to the force-indentation data. Measurements were conducted in a blinded manner with respect to treatment groups.

Results:
The CSL112 group had the highest lipid stiffness, with a mean elastic modulus of 5.27 kPa (95% CI [4.74, 5.80]), followed by the atorvastatin group at 3.02 kPa (95% CI [2.51, 3.53]), and the saline group at 2.11 kPa (95% CI [1.54, 2.68]). Statistical analysis indicated that CSL112 significantly increased the elastic modulus of lipid cores compared to both atorvastatin and saline (p <0.001), while lipid stiffness was also significantly higher in the atorvastatin group compared to saline (p = 0.039).

Conclusion:
The increase in lipid pool stiffness within atherosclerotic plaques treated with CSL112 and atorvastatin may reduce the level of PSS and enhance plaque structural stability.
Abstract 4139716: Acetylation of Electron Transfer Flavoprotein Alpha Is a Possible Regulatory Mechanism of Fatty Acid Oxidation in Diabetic Hearts
Authors: Tatekoshi Yuki , Yano Masaki , Hosoda Ryusuke , Saga Yukika , Kuno Atsushi
Published: November 2024

Background:
Augmented fatty acid oxidation (FAO) adversely affects cardiac function in diabetic patients. Mitochondrial protein lysine (K) acetylation is a critical mechanism modifying metabolic flux, yet specific acetylation targets enhancing FAO are unknown.

Purpose:
This study aimed to identify proteins whose acetylation increases FAO activity in diabetic hearts using multi-omics analyses.

Methods:
We used Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats, a type 2 diabetes model aged 32-38 weeks, which display early-stage cardiomyopathy, and Long-Evans-Tokushima-Otsuka (LETO) rats as controls. Metabolomics, acetylomics, and proteomics were performed on samples from these hearts.

Results:
OLETF had elevated blood glucose (194.0 vs 137.9 mg/dL, P = 0.0022) and
Myh7
mRNA expression (7.11 vs 4.41 units, P = 0.0063) compared to LETO, indicating diabetes and cardiac dysfunction. Metabolomics revealed a decreased fumarate/succinate ratio in OLETF (0.51 vs 0.99 units, P = 0.0083), indicating suppressed activities of TCA cycle and complex II in the electron transport chain (ETC). FAO provides reducing equivalents through acetyl-CoA supply into TCA cycle and directly to ubiquinone via electron transfer flavoprotein (ETF), highlighting ETF's role in FAO upregulation in diabetic hearts. Acetylomics in mitochondrial fractions identified 55 acetylated K residues on 24 mitochondrial proteins increased by 1.5-fold (P < 0.05) in OLETF compared to LETO, with these proteins enriched in the FAO pathway. Specifically, K69-Ac, K75-Ac, and K126-Ac on ETFA, a subunit of ETF, were detected. To determine whether increased acetylation or protein expression contributed to the acetylomics signals, proteomics was performed on identical samples. Of 24 proteins, 22 were measurable, with several critical FAO-related proteins (e.g., ACADVL, ACADM, HADHA, HADHB, ACOT2) significantly more expressed in OLETF than in LETO, while ETFA expression remained similar (1.01 vs 1.00 units, P = 0.84). This suggests increased acetylation signals in FAO-related proteins are mainly due to upregulated protein expression, except for ETFA.

Conclusions:
While increased expression is commonly seen in FAO genes in diabetic hearts, protein acetylation of ETFA appears to be a crucial compensatory mechanism to transfer reducing equivalent to ETC from the FAO under the reduced TCA cycle activity. These findings provide insights into the mechanisms underlying metabolic disturbance in the early stage of cardiomyopathy.
Abstract 4139767: Automated IVUS Image Analysis for Cardiac Allograft Vasculopathy Surveillance in Heart Transplant Recipients
Authors: Birs Antoinette , Lyu Wenzhou , Ang Lawrence , Adler Eric , Mahmud Ehtisham , Contijoch Francisco
Published: November 2024

Background:
Cardiac allograft vasculopathy (CAV) is a heterogenous and poorly understood process of immune and non-immune factors occurring within the coronary artery and a leading cause of graft failure in heart transplant recipients. Intravascular ultrasound (IVUS) is used as an adjunct to angiography to significantly increase the sensitivity for detection disease, however by current standards < 1% of IVUS images are graded for maximal intimal thickness (MIT) or scored for severity of CAV. The majority of IVUS frames remain unanalyzed.

Aims:
Demonstrate the application of pre-trained DeepIVUS machine learning model to annotate IVUS images obtained from transplant patients, establishing the accuracy of this tool in a new patient population.

Methods:
We reviewed 963 clinically annotated IVUS frames from heart transplant recipients, 706 were selected after screening for completeness. DeepIVUS was used to segment the frames and create predictions of the vessel lumen, plaque area and intimal thickness (IT) measurements around the entire vessel lumen. To compare with expert annotations, typically a single caliper measurement, the 90th percentile value of DeepIVUS-predicted IT was used. A confusion matrix was used to assess the model's ability to accurately classify predicted and true IT values, utilizing a threshold of 0.5 mm.

Results:
In 163/706 frames (23.1%), DeepIVUS labeling resulted in segments with jagged or non-physiologic shapes. These were automatically discarded using a quantitative ovalness criteria, Figure 1. Agreement between DeepIVUS predicted MIT and expert measured MIT in the remaining 543 frames yielded a strong Pearson correlation coefficient of 0.81 with an R2 of 0.65, Figure 2A. The linear fit was used to determine the DeepIVUS IT cutoff (0.554mm) which corresponded to clinical cutoff of 0.5mm. Using this value, DeepIVUS correctly classified 86.6% of frames (sensitivity 85.1%, specificity 87.9%, aF1 0.86), Figure 2B.

Conclusion:
We present a first use applcation of a pre-trained Deep IVUS image analysis in a transplant population demonstrating good agreement with expert clinical annotation. In current practice, a small fraction of images from each IVUS study are annotated. With an ovalness criteria providing quality control, DeepIVUS may be applied to non-annotated frames, allowing significantly more frames per IVUS study to be analyzed. Future studies are warranted to understand the prognostic capabilities of these automated annotations.
Abstract 4139769: Fluoxetine, a Novel Therapeutic Strategy for Early Repolarization Syndrome Caused by a
KCND3
Gain-of-Function Variant
Authors: Byambajav Tserenlkham , Takayama Koichiro , Zankov Dimitar , Horie Minoru , Ohno Seiko
Published: November 2024

Introduction:
Kv4.3 encoded by
KCND3
is an α-subunit of the I
to
channel and is highly expressed in both brain and heart. Several
KCND3
variants have been shown to be related to inherited arrhythmias and neurological disorders. We have reported a gain-of-function (GOF)
KCND3
variant, p.G306A, which was identified in a young patient with early repolarization syndrome (ERS) and refractory epilepsy (RE). The variant increased peak current densities and slowed inactivation of I
to
. Micromolar quinidine inhibited increased I
to
and accelerated its delayed inactivation. In addition, administration of quinidine to our patient prevented his lethal arrhythmia and epileptic attack. Thus, the suppression of increased I
to
can be an effective treatment for ERS and RE. However, it remains unknown if other medicine except for quinidine is effective to suppress the GOF effect on I
to
.

Hypothesis:
Selective serotonin reuptake inhibitor, fluoxetine which has inhibitory effect for I
to
normalizes the GOF effect caused by
KCND3
variants.

Aims:
To utilize the fluoxetine for the treatment of ERS and RE, we aimed to elucidate the pharmacological effect of fluoxetine on Kv4.3-G306A comparing those to Kv4.3-wild type (WT).

Methods:
Plasmids with Kv4.3 WT or G306A were transiently transfected to Chinese Hamster Ovary cells with KChIP2, and reconstituted I
to
was measured using whole-cell patch-clamp method at 37
0
C degrees. Fluoxetine loading at 1-100 µM was applied externally.

Results:
The peak current densities of I
to
at +50 mV were 135.7±19.8 for WT and 321.0±116.7 pA/pF for G306A, and they were decreased to 101.1±20.9 and 199.6±63.6 pA/pF by application of 20 µM fluoxetine (Figure A and B). Fluoxetine inhibited I
to
peak current with IC
50
of 41.6±7.1 µM for WT and 83.7±16.7 µM for G306A. Although the inactivation in G306A was significantly slower than WT, they were almost normalized after 20 µM fluoxetine application (Figure A and Table). The inhibition effect of fluoxetine was concentration dependent for both peak current densities and inactivation time constants.

Conclusion:
Fluoxetine rescued the GOF effect on I
to
reconstituted by
KCND3
G306A variant, suggesting that fluoxetine could be an effective therapeutic for ERS and RE.
Abstract 4139801: Predicted efficacy of Inclisiran compared to active comparators on Cardiovascular Outcomes in patients with established atherosclerotic cardiovascular disease: results from the In Silico SIRIUS trial
Authors: Cariou Bertrand , Angoulvant Denis , Amarenco Pierre , Bastien Alexandre , Bechet Emmanuelle , Boissel Jean-Pierre , Courcelles Eulalie , Filipovics Anne , Granjeon-Noriot Solene , Kahoul Riad , Mahe Guillaume , Peyronnet Emmanuel , Portal Lolita , Wang Yishu , Steg Philippe , Boccara Franck
Published: November 2024

Background:
Inclisiran, an siRNA targeting PCSK9 mRNA, administered twice-yearly, substantially and sustainably reduced LDL-C. Data quantifying how lowering LDL-C with inclisiran translates into a reduced risk of major adverse cardiovascular events (MACE) and comparison to available lipid-lowering therapies are lacking. In silico trials applying a disease computational model to virtual patients receiving various treatments allow such predictions in large scale clinical trials.

Purpose:
The aim of the
in silico
SIRIUS trial (NCT05974345) was to predict the effect of inclisiran compared to ezetimibe or evolocumab on MACE in participants with atherosclerotic cardiovascular disease (ASCVD).

Methods:
Two distinct in silico trials were conducted using knowledge-based mechanistic computational model of ASCVD applied to virtual populations (Vpop) with ASCVD and LDL-C ≥ 70 mg/dL, each virtual patient being its own control. This model was previously calibrated to reproduce the results of FOURIER and ORION-10 trials and validated based on the results of other trials results including ODYSSEY-OUTCOMES. The first trial compared inclisiran efficacy to ezetimibe as an adjunct to high-intensity (HI) statins, while the second one compared inclisiran efficacy to evolocumab as adjunct to HI statin and ezetimibe. In both trials, the main outcome was a 3-Point-MACE defined as a composite of time to first occurrence of cardiovascular (CV) death, nonfatal myocardial infarction or nonfatal ischemic stroke over 5 years.

Results:
In a Vpop of 162,453 ASCVD patients under HI statin, the difference in mean percentage reduction in LDL-C with inclisiran as compared to ezetimibe was 32.7% from a median baseline value of 91.1 mg/dL to 48.3 mg/dL and 77.2 mg/dL at 5 years. Inclisiran was more effective than ezetimibe to lower the risk of 3P-MACE (11.3 vs. 13.3%; HR 0.82, low degree of prediction uncertainty).

In a Vpop of 42,238 ASCVD patients under HI statin and ezetimibe, similar mean percentage reduction in LDL-C with inclisiran as compared to evolocumab was achieved at 5 years. Inclisiran and evolocumab had similar efficacy on lowering the risk of 3P-MACE (12.5 vs. 12.4%; HR 1.01, medium degree of prediction uncertainty).

Conclusions:
These in silico trials provide early insights into the potential effect of inclisiran on ASCVD events compared to alternative treatments suggesting a higher 3P-MACE reduction compared to ezetimibe and a similar effect compared to evolocumab.
Abstract 4139823: Decline In Treatment, Testing and Control of Lipids Amongst Diabetic Patients, a Population-Level Analysis
Authors: King Daniel , Harris Daniel , Akbari Ashley , Gravenor Michael , Halcox Julian
Published: November 2024

Background:
In patients with diabetes mellitus (DM), lipid-lowering therapy (LLT) with statins +/- adjuvant LLT are recognised treatment approaches. It is unknown what proportion of patients with DM are prescribed LLT, have documented low-density lipoprotein cholesterol (LDL-C) levels, or achieve guideline LDL-C targets.

Aims:
To document population trends in (i) the incidence and prevalence of DM, (ii) prescribing of LLT, and (iii) testing and achievement of LDL-C targets in patients with or without atherosclerotic cardiovascular disease (ASCVD).

Methods:
We conducted a retrospective, population-level, observational study using linked anonymised health record data amongst 269,735 diabetic patients in Wales (UK). Associations between patient characteristics and (i) statin prescription and (ii) achievement of LDL-C target of (<1.8 mmol/L) were evaluated.

Results:
The prevalence of DM increased from 6,519 to 8,128 per 100k, and incidence increased from 543 to 633 per 100k per year (2010-21). The proportion of patients prescribed any LLT decreased from 89.5% to 82.9% in those with ASCVD and from 53.2% to 37.8% without. An increasing and greater proportion of patients with ASCVD were prescribed high-intensity statin therapy (14.1% to 36.1%) over the study period, compared to those without (2.3% to 5.1%; Figure 1).

The proportion of patients with documented LDL-C decreased (from 68.1% to 52.3% in those with ASCVD and 64.7% to 48.3% without) over the study period. A greater proportion of those with ASCVD achieved an LDL-C <1.8 mmol/L (43.1% to 45.4%) than those without (22.2% to 22.0%). In a multivariate logistic regression, presence of ASCVD and history of hypertension were associated with prescription of statin therapy (ORs = 4.01, 1.75, respectively; both p < 0.01). Male sex and presence of ASCVD were associated with achievement of LDL-C target (ORs = 1.25, 8.15; both p < 0.01).

Conclusions: The incidence and prevalence of DM is increasing over time, but the overall quality of lipid management is decreasing, as evidenced by documented testing, treatment and control of LDL-C. In order to realise the full evidence-based benefit from LLT, improvement in the implementation of guideline-recommended care is required.
Abstract 4139839: Sex, Race and Rural-Urban Disparities in Acute Myocardial Infarction-Related Mortality Rates Among Younger and Older Diabetic Adults; Data from CDC Wonder 1999-2020
Authors: Ali Eman , Latif Fakhar , Samad Muhammad Ammar , Afzal Urwah , Cheema Huzaifa Ahmad , Ahmad Adeel , Rehman Wajeeh , Alim Ur Rahman Hafsah , Dani Sourbha
Published: November 2024

Introduction:
Diabetes mellitus type 2 (T2DM) is an established risk factor for acute myocardial infarction (AMI). Current data suggests that mortality risk of AMI in diabetics remains significantly higher than non-diabetics. Therefore, we aim to examine the trends in AMI-related deaths among younger and older diabetic adults in the United States from 1999 to 2020.

Methods:
We used CDC Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) to access mortality data from 1999 to 2020. AMI and T2DM-related deaths, age ≥ 35 years, were identified from multiple causes of death and were represented as age-adjusted mortality rates (AAMR) per 1,000,000 population using ICD codes for AMI including (I21.0-I21.9, I22.0-I22.1, I22.8-I22.9) and T2DM (E11.0-E11.9). Joinpoint regression was used to examine trends and annual percentage change (APC) overall and stratified by sex, race, and rural-urban distribution.

Results:
Between 1999-2020, 164,260 individuals died from AMI and T2DM with an overall AAMR of 43.2 (95% CI: 43, 43.4). AAMRs related to AMI and T2DM modestly increased from 42 in 1999 to 46.8 in 2005 (APC 2.84, 95% CI: 0.1, 8.43), followed by a significant decline to 38.8 in 2014 (APC -1.95, 95% CI: -4.17, -1.29), with subsequent significant increment to 52.2 in 2020 (APC 4.26, 95% CI: 2.73, 6.90). Men had higher AAMRs when compared to women (AAMRs men: 57.2; women: 32.5). After an initial rise from 1999-2003 in men and 1999-2005 in women, AAMRs declined in both men and women till 2014 (AAMRs men: 52; women: 28.3), followed by a significant rise till 2020 (AAMRs men: 71.5; women: 36.3). Among the race groups, AAMR was highest in American Indian or Alaska Natives (75.8), followed by Hispanics (56.4), Non-Hispanic (NH) Blacks (54.5), NH Whites (NHWs) (40.8), and lastly Asian or Pacific Islanders (38.2). According to the rural-urban classification, non-metropolitan areas demonstrated higher AAMRs than metropolitan areas (AAMRs: non metropolitan: 57.2; metropolitan: 40.3).

Conclusion:
Lesser urbanization, men, and American Indian or Alaska Natives are associated with higher mortality rates. Further in-depth research is needed to comprehend the underlying mechanisms interlinking AMI and T2DM and provide tailored interventions for mortality reduction among patients with concomitant AMI and T2DM.
Abstract 4139874: Contemporary Trends in New-onset Atrial Fibrillation after Transcatheter Aortic Valve Implantation and Surgical Aortic Valve Replacement
Authors: Shrestha Dhan , Kansakar Sajog , Shtembari Jurgen , Biswas Monodeep , Shantha Ghanshyam , Storey James , Katz Daniel
Published: November 2024

Background:
New-onset atrial fibrillation (AF) frequently occurs after cardiac procedures, such as transcatheter aortic valve replacement (TAVI) and surgical aortic valve replacement (SAVR), and is linked with significant morbidity and mortality. In the context of improving TAVI technology and physician expertise, we investigated the recent trends in procedure volume, in-hospital mortality, and atrial fibrillation associated with TAVI and SAVR.

Method:
We conducted a retrospective study using the National Inpatient Sample (NIS) data from 2016 to 2020. We identified all TAVI and SAVR admissions using ICD-10 codes and compared the temporal trends in procedure volume, in-hospital mortality, and AF.

Results:
A total of 296,275 TAVI and 298,300 SAVR were performed between 2016-2020. There was an increase in the annual volume of TAVI performed from 40,005 to 75,740 (p trend <0.01), along with a decrease in in-hospital mortality (1.85% to 1.19%, p trend <0.01) and new-onset AF (39.5% to 23.5%, p trend <0.01), this could be due to broadening of TAVI indications. For SAVR, there was a decrease in annual procedural volume (70,895 to 46,090, p trend <0.01) and associated new-onset AF (45.3% to 37.0%, p<0.01), but an increasing trend in in-hospital mortality (3.31% to 4.04%, p trend=0.03). AF was associated with 51% of TAVI and 77% of SAVR admissions. The predictors of AF included age, female sex, white race, chronic kidney disease, chronic lung disease, heart failure, coronary artery disease, diabetes mellitus, hypertension, chronic liver disease, obesity, smoking, and coagulopathy. In multivariate analysis, AF was not solely associated with in-hospital mortality after SAVR (aOR 0.78, 95% CI 0.65-0.79, p<0.01) or TAVI (aOR 1.1, 95% CI 0.94-1.29, p=0.24).

Conclusion:
In this real-world study using contemporary data from NIS, we observed that annual TAVI numbers are increasing compared to SAVR, and associated AF and in-hospital mortality is decreasing. This is likely due to improved TAVI valves, techniques, and expertise in the field, as well as broadening TAVI indications to a relatively healthier AS patient population. In our analysis, AF did not predict in-hospital mortality for TAVI or SAVR.
Abstract 4139891: Endothelial Cell-Related Proteins in Plasma Predict Major Adverse Cardiovascular Events and Worsening Heart Failure in Patients with Hypertrophic Cardiomyopathy
Authors: Tamura Shogo , Akita Keitaro , Fifer Michael , Tower Rader Albree , Maurer Mathew , Reilly Muredach , Shimada Yuichi
Published: November 2024

Introduction:
Hypertrophic cardiomyopathy (HCM) often causes major adverse cardiovascular events (MACE) and worsening heart failure (WHF). Endothelial cell (EC) dysfunction is known to occur in patients with HCM. However, the prognostic value of proteins related to EC function in HCM is unknown. The present study aimed to test the hypothesis that the levels of plasma proteins related to EC function predict future MACE and WHF in patients with HCM.

Methods:
In this multicenter prospective cohort study of patients with HCM, we measured plasma levels of 90 proteins related to EC function upon enrollment. The primary outcome measure was MACE, defined as the composite of sudden cardiac death, death due to HF, heart transplant, HF hospitalization, any increase of New York Heart Association (NYHA) class, new-onset atrial fibrillation, and stroke. The secondary outcome measure was WHF, defined as increase in NYHA class or HF hospitalization. We developed EC protein-based LASSO classification models to predict MACE or WHF using data from one institution (training set). We tested the predictive ability in independent samples from the other institution (test set) and performed time-to-event analyses.

Results:
The study included 722 patients (n=458 in the training set and n=264 in the test set). During the median follow-up period of 3.3 years, the outcome event of MACE occurred in 192 (27%) patients and WHF in 139 (19%) patients. The area under the receiver-operating-characteristics curve to predict MACE was 0.71 (95% confidence interval [CI] 0.64-0.77.
Figure 1a
) and that for WHF was 0.69 (95% CI 0.61-0.77.
Figure 1b
). When we divided the test set into high- and low-risk groups according to the predicted probabilities derived from the training set, log-rank tests and Cox proportional hazards models revealed that the high-risk groups had significantly higher risks of developing MACE and WHF (log-rank P<0.001, HR 2.45 [95% CI 1.47-4.10], P=0.0006.
Figure 2
) and WHF (log-rank P<0.001, HR 2.62 [95% CI 1.52-4.54], P=0.0006.
Figure 3
) compared with the low-risk groups.

Conclusions:
The present multicenter prospective study demonstrated that plasma proteins related to EC function predict MACE and WHF in patients with HCM. These EC-related proteins have a potential to become novel biomarkers for risk stratification in HCM to improve current prediction models.
Abstract 4139907: Evaluating the Associations Between Medications and Cusp Fusion Patterns on Aortic Growth in Children with Bicuspid Aortic Valve
Authors: Burns Joseph , Stephens Sara , Kyle William , Cai Yu , Morris Shaine
Published: November 2024

Background:
Children with bicuspid aortic valve (BAV) often have progressive aortic dilation, conferring an increased risk of dissection in adulthood. Data describing medication use in aortic dilation in children with BAV are limited. This study aims to evaluate longitudinal trends of aortic growth, comparing those on angiotensin receptor blockers (ARBs) or beta-blockers (BBs) to no medical therapy.

Methods:
This retrospective cohort included subjects with BAV with first echo <18 years from 2010-2023 with
>
1 echocardiogram with root or ascending z-score
>
3.5 and
>
2 available echocardiograms. The primary exposure was medication status, stratified as none, ARB, or BB. Outcomes evaluated were trends in 1) ascending aortic (AscAo) z-score and 2) aortic root z-scores over time using multivariable mixed-effects linear regression to account for changing medication regimens over time.

Results:
In total, 115 patients (76% male) were included; 61 patients (53%) were treated at some point during the period of interest (17% ever on ARBs, 27% on BBs, and 9% on dual therapy).

Regarding clinical features, for AscAo z-scores, only lower baseline AscAo z-score was associated with higher rate of growth; sex and cusp fusion type were not. On multivariable analyses controlling for baseline z-score, AscAo z-score decreased in patients on BBs relative to those not on medication (relative difference -0.1
+
0.03 z/year, p:<0.0001, Figure).

For root z-score, lower baseline z-score was again associated with faster growth. Right-left fusion was also associated with increased change in root z-score compared to unicuspid valves (relative change +0.09, p=0.027 respectively); sex was not associated. In multivariable analysis controlling for baseline root z-score BBs and cusp fusion type, there was no difference in root-z-score change by medication (Figure).

Conclusions:
In this cohort of children with BAV and aortic dilation with z-score
>
3.5, BB use was associated with a reduction in the ascending aorta z-score relative to patients not on medications. To date this is the largest study comparing change in aortic dimensions by medication class in children with BAV.