bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 10766: Analysis of Cardiac Ct Anatomy in Patients With Severe Tricuspid Regurgitation Considered for Transcatheter Intervention
Authors: Ingraham Brenden , Young Katie , Reddy Prajwal , Anand Vidhu , Stulak John M , RIHAL Charanjit , Eleid Mackram F , Foley Thomas A
Published: June 2023

Introduction:
Severe tricuspid regurgitation (TR) is associated with considerable morbidity/mortality in an elderly population with multiple comorbidities. There is interest in transcatheter interventions to manage severe TR in this population. Understanding right heart (RH) anatomy has implications for patient/device selection for transcatheter intervention.

Hypothesis:
We analyzed RH anatomy by CT of patients referred for TR therapy to determine transcatheter tricuspid intervention device sizing needs.

Methods:
Retrospective Mayo Clinic study of 29 patients considered for intervention of severe TR from 3/1/2016-12/15/2020; echocardiogram and CT angiogram obtained in all patients.

Results:
Mean age was 83±8 (83% female), 100% had atrial fibrillation, and 62% had chronic kidney disease ≥3a. 97% were symptomatic, 93% were prescribed loop diuretics, and 24% had device leads. Mean tricuspid annular plane systolic excursion 16.8±4.5 mm, effective regurgitant orifice area (EROA) 81±33 mm
2
, and cardiac index 2.6±0.6 L/min/m
2
. 41% had at least moderate right ventricular (RV) dysfunction with a mean RV systolic pressure of 46±16 mmHg. Patients receiving intervention had significantly larger EROA (101±33 v. 63±22 mm
2
, P=0.033), shorter tricuspid leaflet tenting length (6.5±3.0 v. 8.9±2.7 mm, P=0.042), and smaller annuloplasty diagnostic perimeter during diastole (120.1±16.6 v. 131.1±7.4 mm, P=0.041). Intervention patients tended to have better right ventricular function, smaller RV and IVC size, and more severe symptoms. Max tricuspid annulus diameter in systole and diastole was 51±5 and 53±7 mm, respectively.

Conclusions:
Severe TR patients referred for transcatheter intervention present with severe RH enlargement with a large proportion having tricuspid annulus dimensions outside the range for current devices available in clinical trials. These data have implications for device development/selection and procedural feasibility.
Abstract 10824: Pulsatile Ventricular Assist Device Prior to Pediatric Heart Transplantation is Associated With Favorable Post-Transplant Hemodynamics
Authors: Tadros Hanna John J , Denfield Susan W , Qureshi Athar , Hope Kyle , Puri Kriti , Price Jack , Tunuguntla Hari P , Choudhry Swati , Adachi Iki , Dreyer William , Spinner Joseph
Published: June 2023

Background:
Ventricular assist device (VAD) support is increasingly used in end-stage pediatric heart failure management. The effects of pulsatile VAD (PVAD) and continuous-flow VAD (CVAD) support on hemodynamics (HDS) after pediatric heart transplant (HT) are unknown. We compared the difference in post-HT HDS between patients supported with PVAD vs CVAD.

Methods:
We collected measures of pulmonary vascular resistance index (PVRi), cardiac index (CI), and pulmonary wedge pressure (PCWP) in the 1
st
year post-HT among patients that underwent HT at our institution between 2013-2020. We defined normal HDS as a PVRi < 3Wu/m
2
, CI > 2.5L/min/m
2
, and PCWP < 12mmHg. Linear regression analysis and Cox regression were performed to compare differences in HDS post-HT.

Results:
Demographics/clinical features of the patients supported with PVAD (n=18) and CVAD (n=41)are described in Table 1. PVR, CI, and PCWP are plotted in Figure 1. Accounting for confounders, the mean PCWP over the 1
st
year is lower in the PVAD group (-0.83 [-1.72-0.07], p=0.07) while the mean CI and mean PVR are similar. In the PVAD cohort, 16 (89%) had normalized HDS in the 1st year vs 17 (42%) in the CVAD group (Log Rank: p<0.001). In multivariate analysis, PVAD was the only variable associated with normalization of HDS (HR 3.87 [1.03-14.52], p=0.045). Compared to our non-VAD cohort (n=97), patients with PVAD were as likely to have HDS normalization by 1 year, but CVAD patients trended towards being less likely to normalize (HR 0.58, p=0.08).

Conclusion:
Patients supported with PVAD pre-HT have lower PCWP and were more likely to achieve normalization of HDS post-HT compared to patients supported with CVAD.
Abstract 10842: Progression of COVID-19 Severity Among SARS-CoV-2 Positive Patients Prescribed Selective Serotonin Reuptake Inhibitors
Authors: May Heidi T , Horne Benjamin D , Knight Stacey , Bair Tami L , Anderson Jeffrey L , Le Viet T , Muhlestein Joseph B , Knowlton Kirk U
Published: June 2023

Introduction:
The clinical spectrum of COVID-19 can range from asymptomatic to severe, with severe resulting in part from an intense inflammatory response. Selective serotonin reuptake inhibitor (SSRI) is the most commonly prescribed class of antidepressants and has anti-inflammatory and anti-platelet effects. Recent studies reported greater survival and lesser COVID severity in patients taking SSRIs, specifically fluoxetine/fluvoxamine. Recently, application was made to the FDA for emergency use of fluvoxamine to prevent severe COVID-19, but it was denied based on insufficient data.

Methods:
Patients (n=33,088) testing positive for SARS-CoV-2 between March 14, 2020-December 31, 2021 as outpatients were studied. Patients were matched 3:1 by SSRI prescription at the time of a positive test by propensity score (±0.001). Patients were evaluated for COVID-19 hospitalization within 14-days and death within 3-months of positive SARS-CoV-2 test.

Results:
A total of 8,272 SSRI patients were well-matched to 24,816 no SSRI patients (Table 1). Hospitalization and death were significantly greater in the SSRI group compared to the no SSRI group (Table 1). A total of 2,067 (25.0%) of SSRI patients were taking fluoxetine or fluvoxamine. While attenuated, no SSRI remained associated with a lower 14-day COVID-19 hospitalization risk when compared to fluoxetine or fluvoxamine use, but not with 3-month death (Table 2).

Conclusion:
This study did not find a lower risk of progression of COVID-19 severity with the use of any SSRI or fluoxetine/fluvoxamine alone. Results from this study support the FDA’s decision to not recommend their use at an early stage of a COVID-19 infection.
Abstract 10844: Black Race and Risk of Bleeding Events in Patients With Durable Left Ventricular Assist Devices
Authors: Vellanki Nirupama S , kennedy kevin , Motiwala Shweta R , Garan Arthur Reshad , Grandin E. Wilson , Quintero Pablo A , fleming lisa , Sriwattanakomen Roy , Ho Jennifer E , Sabe Marwa
Published: June 2023

Introduction:
An analysis from the MOMENTUM 3 trial showed that black patients have an increased risk of bleeding compared to white patients. We sought to examine racial differences in the risk of long term bleeding (up to 3 years) in patients with cf-LVADs using the INTERMACS database.

Hypothesis:
Black race is associated with an increased risk of bleeding events after cf-LVAD.

Methods:
We included 11,457 patients from the INTERMACS registry, who were implanted with primary CF-LVAD between 2012-2017. Using a cox proportional hazards model, we assessed the relationship between race and bleeding events up to 3 years post LVAD implantation after adjusting for covariates*. Analysis was started at 3 months post implantation to focus on long-term bleeding risk rather than early, post-operative bleeding. These bleeding events were stratified for the two major types of bleeding, GI bleeding (GIB) and intracranial hemorrhage (ICH).

Results:
This study included 2884 black patients (25.8%) and 8505 non-black patients (74.2%). Black patients tended to be younger (52.2 vs 58.6 yr p<0.001) with more women (30.9% vs 17.7% p<0.001) when compared to non-black patients. There were 1442 black patients who had a bleeding event vs 3972 non-black patients (50.0% vs 46.7% p=0.007) over 3 years of follow up (Fig 1). After adjusting for age, sex, and other covariates*, we found that black patients were more likely to have any bleeding event post LVAD implantation compared to non-black patients (adj HR 1.19 p<0.0001). When stratified by type of bleeding, the risk of ICH was similar between the two groups (10.8% vs 9.2%, adj HR 1.12, p 0.35), but the risk of GIB was higher among black vs non-black patients (30.9% vs 29.6%; adj HR 1.36, p<0.0001).

Conclusions:
Black patients have a higher risk of long term bleeding and specifically GIB after LVAD implantation. Further studies are warranted to elucidate this relationship and potential clinical implications including anticoagulation strategies.
Abstract 10847: Tolerability of Sars-cov-2 Mrna Vaccines and Infection for Patients With History of Kawasaki Disease
Authors: Beckley Mikayla A , Olson Aaron K , Portman Michael A
Published: June 2023

Introduction:
Kawasaki disease (KD) and multisystem inflammatory syndrome in children from COVID-19 infections share overlapping symptoms, suggesting KD patients may be at risk for adverse outcomes from exposure to SARS-CoV-2 mRNA vaccine or infection. Through retrospective review of clinical outcome data, we determined tolerance of KD patients to SARS-CoV-2 antigen exposure.

Methods:
We evaluated two cohorts using an existing KD database of 826 patients and reviewed individual electronic medical records for the period spanning January 2020 through Jan 2022 via Epic Care Everywhere which includes Washington State immunization records. Vaccine cohort inclusion criteria were (1) age < 21 years at immunization and (2) received one or more Pfizer-BioNTech or Moderna vaccine doses. The COVID-19 infection cohort included (1) age < 21 years and (2) positive SARS-CoV-2 PCR or nuclear capsid IgG.

Results:
The vaccine cohort contained 153 patients with vaccine distribution by age subgroups shown in Figure 1.
Pfizer-BioNTech
vaccine was provided for 93.5% and the remaining received
Moderna
or a combination. 84.3% were fully vaccinated or received a third-dose booster. No clinically severe adverse events occurred including no vaccine-related hospitalizations or outpatient visits. The COVID-19 infection cohort included thirty-seven patients. No patients required hospitalization. The most common symptoms included low grade fever, fatigue, cough, and myalgia with resolution within a few days. Two patients, 9 and 19 years, had extended cough and fatigue for 3-4 weeks. One patient developed COVID-19 within 6 weeks of receiving IVIG for KD.

Conclusions:
COVID-19 infections and vaccinations are well tolerated in patients with preceding KD. No severe complications occurred in either cohort with only two patients exhibiting prolonged mild symptoms from COVID-19. This study provides assurance regarding vaccine safety and COVID-19 severity for parents of children with KD.
Abstract 10850: Epicardial Adipose Tissue is Associated With Left Atrial Volume and Fibrosis in Patients With Atrial Fibrillation
Authors: Chahine Yaacoub , Askari-Atapour Bahareh , Kwan Kirsten , Anderson Carter , Macheret Fima , Afroze Tanzina , Bifulco Savannah , Cham Matthew D , Ordovas Karen G , Boyle Patrick M , Akoum Nazem W
Published: June 2023

Background
: Obesity is a risk factor for atrial fibrillation (AF) and strongly influences response to treatment. Atrial fibrosis shows similar associations. Epicardial adipose tissue (EAT) may be a link between these associations. We sought to assess whether EAT is associated with body mass index (BMI), left atrial (LA) volume and fibrosis.

Methods:
LA fibrosis and EAT were assessed using Late Gadolinium Enhancement, and Dixon MRI sequences, respectively. We derived 3D models incorporating fibrosis and EAT to assess spatial colocalization: we measured the distance of fibrotic and non-fibrotic areas to the nearest EAT, and calculated the volume of EAT within a radius of 5 mm for every LA surface point.

Results:
103 AF patients (64% paroxysmal, 73% male) were analyzed. LA volume index was 54.9 [41.2, 69.7] mL/m
2
, LA EAT index was 17.4 [12.7, 22.9] mL/m
2
, and LA fibrosis was 17.1 [12.4, 23.1] %. LA EAT was significantly correlated with BMI (R=0.557, p<0.001); as well as with LA volume and LA fibrosis after BSA adjustment (R=0.579 and R=0.432 respectively, p<0.001 for both) (Panel A). Multivariable analysis showed LA EAT to be independently associated with LA volume and fibrosis. Aggregation of local EAT proximity values in all models revealed that the minimum distance to fat was significantly greater for fibrotic LA surface regions compared to non-fibrotic areas (6.97 mm [3.28, 12.13] vs 5.71 mm [2.58, 10.35], p<0.001) (Panel C). The proportion of LA surface points having fat within a radius of 5 mm was greater for non-fibrotic compared to fibrotic regions (37.6% [23.4, 48] vs 41.6% [31.2, 58.1] respectively, p=0.021). Thus, 3D registration of fat and fibrosis around the LA showed no clear spatial overlap between EAT and fibrotic LA regions (Panel B).

Conclusion:
LA EAT is associated with obesity (BMI) as well as LA volume and fibrosis. Regions of LA EAT are not colocalized with fibrotic areas, suggesting a systemic or paracrine mechanism rather than EAT infiltration of fibrotic areas.
Abstract 10881: Assess Response of Phosphodiesterase-5 Inhibitor in Pulmonary Artery Hypertension by Flow Mediated Dilation of Brachial Artery
Authors: Kumar Ujjawal
Published: June 2023

Introduction:
Endothelial dysfunction is a significant component in the development of pulmonary artery hypertension (PAH). Current treatment guidelines recommend phosphodiesterase-5 inhibitors (PDE-5i) in PAH. The responder status to PDE-5i is not assessed unlike invasive vasoreactivity testing done for calcium channel blockers. This study aims to determine the effectiveness of PDE-5 inhibitors by non-invasively testing flow mediated dilation (FMD) of brachial artery.

Hypothesis:
We hypothesise that FMD of brachial artery predicts the responsiveness of the PDE-5i earlier than fall in pulmonary artery pressures on echocardiography.

Methods:
It is a single centre prospective study over a period of 18 months where we randomly assigned PAH patients with PDE-5i. FMD in brachial artery, pulmonary arterial pressure by right ventricular systolic pressure (RVSP) by TR jet velocity and tricuspid annular planar systolic excursion (TAPSE) is measured before and after starting PDE-5i at 1
st
week and at 6
th
month. Primary end point is to predict the response of PDE-5i by FMD of brachial artery earlier than fall in pulmonary artery pressures through echocardiography. Secondary end point is to determine the 6
th
month outcome of patients with PAH by FMD and echocardiography by RVSP and TAPSE.

Results:
In this study we enrolled 21 randomized cases with mean age of 40.00 ± 10.79 years, majority being females (n=17; 81%). Over a period of 18 months, primary end point is reached in 29% patients (p=0.05). Secondary end points of RVSP is achieved by 57% patients (p= 0.0014), TAPSE by 76% patients (p<0.002). FMD was seen in 14 cases after 1 week and 16 cases after 6 months. Of these 14 cases all of them had a fall in RVSP and improvement in TAPSE after 6 months. Mean RVSP after 1 week is 49.24±9.56 mmHg and after 6 months is 46.00 ± 9.18 mmHg (p<0.006). Mean TAPSE at 1 week is 17.10 ± 2.86 mm and at 6 months is 17.90±2.49 mm (p<0.002).

Conclusions:
In conclusion patients having PAH initiated on PDE-5i, FMD of brachial artery predicts the responsiveness of this drug earlier than fall in pulmonary artery pressures on echocardiography by as early as 1
st
week. It is a non-invasive method that helps in assessing the response of this commonly used drug in PAH in clinics.
Abstract 10883: Cigarette Smoking and Mitochondrial Function in Peripheral Artery Disease
Authors: Guo Michelle , McDermott Mary M , Dayanidhi Sudarshan , Leeuwenburgh Christiaan , Wohlgemuth Stephanie , Ferrucci Luigi , Peterson Charlotte , Kosmac Kate , Tian Lu , Zhao Lihui , Sufit Robert , Ho Karen , Criqui Michael H , Xu Shujun , Zhang Dongxue , Greenland Philip
Published: June 2023

Introduction:
In humans without peripheral artery disease (PAD) and animal models, exposure to cigarette smoke is associated with reduced mitochondrial respiratory function. Many people with PAD smoke cigarettes, but the association of smoking with mitochondrial function in lower extremity skeletal muscle of people with PAD is unknown.

Methods:
From the Chicago, IL area, 31 people with PAD (ankle brachial index (ABI)
<
0.90) were enrolled and consented to gastrocnemius muscle biopsy. Mitochondrial oxidative capacity in gastrocnemius muscle was measured with respirometry. Western blots were performed to quantify mitochondrial membrane abundance via voltage-dependent anion channel (VDAC), mitochondrial biogenesis via peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) , and electron transport chain complexes I-V.

Results:
Among 31 people with PAD (mean 72.1 years, mean ABI 0.64), 14 (45.2%) smoked cigarettes currently. Participants who currently smoked had higher abundance of PGC-1α (0.75 vs. 0.45 arbitrary units (AU), P<0.01), VDAC (0.62 vs. 0.37 AU, P=0.022), electron transport chain complex I (0.46 vs. 0.21 AU, P=0.031), and complex III (0.76 vs. 0.42 AU, P=0.031), compared to those who did not currently smoke. After normalizing to VDAC, participants who currently smoked had lower mitochondrial oxidative capacity per unit of mitochondrial membrane compared to those who did not currently smoke (complex I+II-mediated oxidative phosphorylation (156.3 vs. 287.0 AU, P=0.017), complex I+II-mediated electron transport chain capacity (184.8 vs. 343.1 AU, P=0.019), complex I-mediated fatty acid oxidative phosphorylation (45.9 vs. 82.1 AU, P=0.034)). After statistical adjustment for age, sex, race, ABI, and body mass index (BMI), most associations were attenuated but remained statistically significant for the higher abundance of VDAC (0.65 vs. 0.35 AU, P=0.037) and complex I (0.50 vs. 0.18 AU, P=0.038) in participants who currently smoked compared to those who did not currently smoke.

Conclusions:
Results suggest that among people with PAD, current cigarette smoking may stimulate a compensatory increase in mitochondrial biogenesis that may counteract effects of reduced oxidative capacity per unit mitochondrial membrane.
Abstract 10885: Integrin β
3
Directly Inhibits Galpha
13
-p115rhogef Interaction and Its Role in Regulating Platelet Exocytosis
Authors: Zhang Yaping , Du Xiaoping
Published: June 2023

G protein-coupled receptors (GPCRs) and adhesion receptor integrins are fundamental to a cell’s response to extracellular stimuli. GPCRs, through Gα
q
and Gα
i
, activate integrins and, through the Gα
13
-p115RhoGEF-RhoA pathway, stimulate contractility and integrin-independent exocytosis (granule secretion). Gα
13
also interacts with integrins and mediates outside-in signaling, cell spreading and integrin-dependent exocytosis. However, it was unknown whether there was crosstalk between integrins and the Gα
13
/p115RhoGEF-mediated RhoA signaling pathway. It was also unclear with the role of Gα
13
-integrin interaction in regulating GPCR- and integrin- mediated platelet exocytosis. In this study, we demonstrate that binding of the integrin β
3

cytoplasmic domain to Gα
13
through its ExE motif, directly disrupts the interaction between p115RhoGEF and Gα
13
, thus inhibiting Gα
13
-p115RhoGEF-mediated RhoA activation and signaling. In platelets, this inhibitory effect of integrins greatly reduces GPCR-mediated integrin-independent granule secretion. On the other hand, the Gα
13
-integrin interaction stimulates integrin outside-in signaling and integrin-dependent granule secretion. Furthermore, we demonstrate that the inhibitor peptide derived from the Gα
13
-binding β
3
ExE motif disrupts the β
3
-Gα
13
interaction to inhibit GPCR-induced integrin-independent granule secretion and also inhibits outside-in signaling and integrin-dependent granule secretion. This dual effect results in robust inhibition of granule secretion without affecting primary platelet aggregation, suggesting a new therapeutic approach for the development of selective inhibitors of platelet granule secretion. In conclusion, we have discovered a mechanism underlying direct integrin-GPCR crosstalk that regulates the Gα
13
-p115RhoGEF-RhoA signaling pathway. Our data also demonstrate an approach to potently inhibit platelet granule secretion without impairing primary platelet adhesion/aggregation and hemostasis.
Abstract 10890: A Simplified Method for Correction of Effective Regurgitant Orifice and Flow Underestimation by Pisa in Non-Circular Orifices: An in vitro Study
Authors: Hanif Waqas , Arce Javier , Makkiya Mohammed , Wake Nicole , Goldberg Ythan , Ho Edwin , Schenone Aldo L , Zhang Lili , Slipczuk Leandro , Pu Min , Garcia Mario J
Published: June 2023

Introduction:
The proximal isovelocity surface area (PISA) method has been validated for quantifying severity of mitral regurgitation (MR) in orifices with circular geometry. However, functional MR often has an elliptical orifice, which alters the proximal isovelocity contour from a hemisphere to a hemi-ellipsoid. Studies have previously shown that PISA underestimates regurgitant flow (RF) and effective regurgitant orifice (ERO) in functional MR.

Hypothesis:
The application of a simplified hemi-ellipsoid formula based on biplane color Doppler improves accuracy in calculating RF and ERO across elliptical orifices.

Methods:
An in vitro model for flow quantification was used for all experiments. Multiple size orifices with minor to major ratios ranging from 1:1 to 1:9 were constructed by 3D printing. Flow was adjusted at multiple intervals to generate peak flow velocities ranging from 4.1 to 5.5 m/s and aliasing velocities from 12 to 18 cm/s. Isovelocity contours were evaluated by biplane color Doppler (Figure 1A). RF and ERO were estimated using the traditional hemispheric PISA (HS-PISA) formula and a simplified hemiellipsoid formula (HE-PISA) based on two orthogonal diameter measurements (Figure 1A and 1B). The estimated RF and ERO values were compared and validated against those derived from a magnetic flowmeter (FM).

Results:
Isovelocity contours changed from hemisphere to hemi-ellipsoid orifices with increasing ellipticity ratios. HS-PISA significantly underestimated RF (116 ± 27 vs FM 155 ± 20 ml/s) and ERO (26 ± 4 vs FM 34 ± 1 mm
2
). Underestimation was significantly reduced by HE-PISA (135 ± 17 ml/s and 30 ± 2.5 mm
2
, both p<0.001).

Conclusions:
A simplified hemi-ellipsoid PISA method provides more accurate assessment of RF and ERO in regurgitant orifices with non-circular geometries.
Abstract 10895: Actigraphy-Derived Rest-Activity Rhythms Are Associated With Metabolic Markers and Type 2 Diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Makarem Nour , St-Onge Marie-Pierre , Sun Yifei , Sears Dorothy D , Aggarwal Brooke A , Baccarelli Andrea , Shea Steven , Marinac Catherine , Zee Phyllis , Ouyang Pamela , Redline Susan
Published: June 2023

Introduction:
Individual behaviors in the 24h rest-activity cycle have been linked to cardiometabolic health (CMH). Studies that integrate the overall multidimensional pattern of 24-h rest-activity rhythms (RAR) and evaluate its unique relation with CMH and type 2 diabetes (T2D) are limited.

Hypothesis:
Disrupted RAR are associated with poorer glycemic control and T2D.

Methods:
Participants were n=2127 adults (mean age: 69 ± 9 y, 54% women, 62% non-White) in the MESA Sleep Study (2010-13). Interdaily stability (IS), intradaily variability (IV), most active 10 h period (M10) and least active 5 h period (L5) timing and counts, and relative amplitude (RA) (defined in Table) were derived from 7-d actigraphy data using nonparametric rhythm analysis. Multivariable linear and logistic regression was used to examine cross-sectional and prospective associations with glycemic markers and T2D at baseline and after 6 y of follow-up (2016-18).

Results:
Higher IS (more stable sleep-wake and rest-activity patterns across days), M10 counts (more active wake period), and RA (greater overall RAR robustness) were related to lower fasting glucose, insulin, and HOMA-IR, while higher IV (more fragmented RAR, less efficient sleep) and L5 counts (less restful sleep) were related to higher levels of these metabolic markers (Table). In cross-sectional and prospective analyses, those in the highest vs. lowest quintile of IS, M10 counts, and RA had up to 75% lower odds of T2D, while being in the highest vs. lowest quintile of IV, L5 counts, and L5 midpoint (later sleep period) was associated with up to 79% higher T2D odds with evidence of a dose-response relationship (p-trend <0.05 for all outcomes).

Conclusions:
A less robust and stable RAR, lower wake time activity, and a less restful and later sleep period are associated with T2D. Targeting the strength, timing, and regularity of rest-activity and sleep-wake patterns to enhance the rhythmicity of diurnal behaviors may enhance CMH and prevent T2D.
Abstract 10897: Severe Atrial Dysfunction and Sick Sinus Syndrome in a Patient With Scn5a Mutation
Authors: Font Cristina , Ho Tiffany , Torbey Estelle
Published: June 2023

Introduction:
SCN5A mutations are associated with numerous cardiovascular conditions, including dilated cardiomyopathy, atrial fibrillation, and sick sinus syndrome. Specific variants in patients with severe atrial dysfunction may be associated with increased risk of stroke even in young patients.

Case:
This case describes a previously healthy 38-year-old male of French descent who presented with intermittent palpitations and presyncope associated with atrial flutter followed by prolonged conversion pauses up to 7.5 seconds, then followed by junctional bradycardia. Echocardiogram showed a mildly dilated left atrium. Electrophysiology study demonstrated extensive scarring in the left atrium with normal sinus node function and right atrial voltage. No atrial fibrillation was noted. He was also found to have typical atrial flutter and mitral flutter. He underwent cavotricuspid isthmus ablation and mitral annular flutter ablation. Due to his vagal-mediated pauses and junctional rhythm, he also underwent cardioneuroablation aimed at partial denervation. Following this, he had further episodes of junctional rhythm on the days after exercise. He underwent further total cardioneuroablation and was found to have progressive scarring at the sinus node area and sinus node dysfunction, so a permanent pacemaker was placed. He underwent genetic testing which demonstrated SCN5A heterozygous missense pathogenic variant c.2823G>A.

Conclusion:
The SCN5a gene encodes the alpha subunit of the cardiac sodium channel, which is responsible for initiation and propagation of action potentials. SCN5A variants are associated with a number of cardiovascular conditions. There are reports of stroke in young French patients with severe atrial dysfunction and SCN5A mutations, including variant c.2823G>A, demonstrating that severe atrial dysfunction is a risk factor for stroke regardless of CHADS2VASc score, and specific SCN5A mutations may be associated with increased risk of stroke. Given these reports and absence of relevant guidelines, apixaban was continued indefinitely for prevention of stroke. At follow-up two months later, the patient resumed physical activity and reported symptomatic improvement, without any episodes of syncope or near syncope.
Abstract 10900: Implication of the Post-Translational Formation of Hypusine in Eif5a in Pulmonary Arterial Hypertension
Authors: Lemay Sarah-Eve , Grobs Yann , Shimauchi Tsukasa , Martineau Sandra , Breuils Bonnet Sandra , SALEM MABROUKA , Potus Francois , Provencher Steeve , Bonnet Sebastien , Boucherat Olivier
Published: June 2023

Pulmonary Arterial Hypertension (PAH) is characterized by progressive pulmonary arteries (PAs) obstruction leading to heart failure and death. PA smooth muscle cells (PASMCs) of PAH patients display a “cancer-like” phenotype that contributes to PA remodeling. Eukaryotic translation initiation factor 5A (eIF5A) was shown to provide cancer cells with a competitive advantage by increasing translation of mRNAs with oncogenic proprieties, many of them containing proline/glycine-rich patterns. Strikingly, eIF5A is the only protein containing the unique, polyamine-derived amino acid hypusine, which is required for its function. Hypusine formation is catalyzed by the sequential actions of deoxyhypusine synthase (DHPS) and deoxyhypusine hydrolase (DOHH). We hypothesized that increased eiF5A
Hyp
in PAH-PASMCs is required to promote translational efficiency of a set of factors conferring a higher survival and fibroproliferative capacity, leading to pulmonary vascular remodeling.

Data derived from a comparative proteomic analysis (LC-MSMS) between normal and PAH-PASMCs and confirmed by Western blot indicate that DHPS and DOHH are overexpressed in PAH-PASMCs compared to controls (p<0.05). Consistently, both total and hypusinated forms of eIF5A were found up-regulated in dissected PAs and PASMCs from PAH patients and animal models (MCT and Su/Hx rats, p<0.05).
In vitro
, inhibition of DHPS and DOHH, using GC7 and ciclopirox, respectively, significantly attenuates PAH-PASMCs survival and proliferation, (Annexin V; Ki67 labeling and EdU incorporation, p<0.01). These effects were confirmed by a reduced expression eiF5A
Hyp
, MCM2, PCNA and Survivin (p<0.01) and a downregulation of BRD4, EP300 and COL1, three factors implicated in PAH containing proline/glycine-rich patterns.
In vivo
, inhibition of DHPS using GC7 in MCT rats with established PAH improves hemodynamics (RVSP, mPAP, CO, p<0.05) and vascular remodeling (EVG, p<0.05). Furthermore, preliminary data indicate that smooth muscle cells-targeted inactivation of one allele of
Dhps
tends to confer protection against Su/Hx-induced PAH in mice.

We showed for the first time that hypusine signaling is implicated in PAH development and represents a new promising therapeutic target.
Abstract 10915: Microvascular Obstruction Identifies a Subgroup of Patients Who Benefit From Intracoronary Stem Cell Delivery Following ST-Elevation Myocardial Infarction
Authors: Davidson Sarah J , RONCALLI JEROME , Surder Daniel , Chugh Atul R , Yang Phillip C , Henry Timothy D , Stanberry Larissa I , Lemarchand Patricia , Beregi Jean-Paul , Corti Roberto , Luscher Thomas F , Traverse Jay H
Published: June 2023

Aims:
Microvascular obstruction (MVO) following ST-elevation myocardial infarction (STEMI) is associated with greater infarct size, adverse left-ventricular (LV) remodeling and reduced ejection fraction. We hypothesized that patients with MVO may constitute a subgroup of patients that would benefit from intracoronary stem cell delivery with bone marrow mononuclear cells (BMCs) given previous findings that BMCs tended to improve LV function only in patients with significant LV dysfunction.

Methods and Results:
We analyzed the cardiac MRIs of 356 patients (303 M, 53 F) with anterior STEMIs who received autologous BMCs as part of 3 clinical trials that included the Cardiovascular Cell Therapy Research Network (CCTRN) TIME trial and its pilot (n=157), the multi-center French BONAMI trial (n=91) and the SWISS-AMI trial (n=108). All patients received 100 - 150 million intracoronary autologous BMCs or placebo / control 3 - 7 days following primary PCI and stenting. LV function, volumes, infarct size and MVO were assessed prior to infusion of BMCs and 1 year later. Patients with MVO (n=210) had reduced LVEF and much greater infarct size and LV volumes compared to patients without MVO (n=146) (all p < 0.01) (TABLE). At 12 months, patients with MVO who received BMCs had significantly greater recovery of LVEF compared to those patients with MVO who received placebo (absolute difference = 2.7 %; p < 0.05). Similarly, the changes in left-ventricular end-diastolic (LVEDV) and end-systolic volumes (LVESV) were consistent with significantly less adverse remodeling in patients with MVO who received BMCs compared to placebo ( % change; LVEDV = -9.7%; p < 0.05 and LVESVI = -14.7 %; p = 0.006). In contrast, patients without MVO experienced no benefit of BMC administration compared to placebo.

Conclusion:
The presence of MVO on cardiac MRI following STEMI identifies a subgroup of patients who may benefit from intracoronary stem cell delivery of BMCs.
Abstract 10940: Cardiovascular Magnetic Resonance Imaging Patterns of Acute Covid-19 Vaccine Associated Myocarditis in Young Male Patients
Authors: Evertz Ruben , Schulz Alexander , Lange Torben , Backhaus Soeren J , Vollmann Dirk , Kowallick Johannes , von Haehling Stephan , Hasenfuss Gerd , Schuster Andreas
Published: June 2023

Introduction:
The risk of myocarditis after mRNA vaccination against COVID-19 has emerged, recently. Current evidence suggests that young male patients are predominantly affected. In the majority of the cases only mild symptoms were observed. However, little is known about mRNA vaccination related myocarditis cardiac magnetic resonance (CMR) imaging patterns and their differences to classical viral myocarditis in the acute phase of inflammation.

Methods:
10 mRNA vaccination associated myocarditis patients were retrospectively enrolled in this study and compared to 10 patients suffering from viral myocarditis, matched with age, sex, comorbidities and laboratory markers. All patients (n = 20) were hospitalized and underwent a standardized clinical examination as well as an echocardiography and a CMR. Both, clinical and imaging findings were compared between both groups.

Results:
All patients described chest pain as the leading reason for their initial presentation. CMR volumetric and functional parameters did not differ significantly between both groups. In all cases the lateral left ventricular wall showed late gadolinium enhancement without significant differences in terms of the localisation or in-depth tissue characterization.

Conclusions:
COVID-19 mRNA vaccination associated myocarditis does not show specific CMR patterns during the very acute stage in the most affected patient group of young male patients. The observed imaging markers are closely related with regular viral myocarditis and did not yield any evidence implying adverse outcomes in the investigated patient group.
Abstract 10957: Six Month Patency of Bioengineered Human Acellular Vessels in a Primate Model of Coronary Artery Bypass Grafting
Authors: Williams Adam R , Nellis Joseph , McCartney Sharon , Mehta Sachin , PODGOREANU Mihai V , Daubert Melissa A , Kirkton Robert , Nash Kevin , Rhew Christopher J , Argotti Derek , Regan Daniel N , Sanderson Derek , Niklason Laura , Kypson Alan
Published: June 2023

Introduction:
Limitations of coronary artery bypass grafting (CABG) include the availability, quality, and long-term patency of autologous saphenous vein grafts. An “off-the-shelf” human acellular vessel (HAV) bioengineered from banked human vascular cells, decellularized before implantation, and capable of host cellular regeneration may address these issues. Therefore, we assessed early patency and tolerability of a small diameter HAV as a CABG conduit in a baboon surgical model.

Methods:
Adult male, non-immunosuppressed baboons (n = 3; 30.5 - 37.0 kg) underwent CABG via sternotomy with cardiopulmonary bypass. The right coronary artery (RCA) was ligated and bypassed with a 3.5 mm inner diameter HAV. Intraoperative blood flow was determined by transit-time flow measurement (TTFM). HAV patency was assessed by computed tomography angiography (CTA) at 1, 3 and 6 months, and confirmed by left heart catheterization at the 6 month study endpoint. Explanted tissues were processed for histological analysis of host cellular repopulation and HAV remodeling.

Results:
Three animals were successfully bypassed with a 3.5 mm HAV as aorta-RCA CABG conduits with resulting TTFM blood flow rates of 22 ± 7.7 mL/min. CTA at 1, 3 and 6 months demonstrated patency of the HAV with no significant stenosis or dilatation. There were no HAV related adverse events for the duration of the study. Histological staining of 6 month explanted tissues showed recellularization and remodeling of the HAV with a microcapillary-containing neo-adventitial layer, alpha smooth muscle actin expressing cells within the HAV wall, and endothelialization of the HAV lumen.

Conclusion:
A small diameter, readily available HAV was successfully implanted in a primate model of CABG and remained patent up to 6 months with no evidence of dilatation. In addition, the HAVs were thoroughly recellularized and remodeled by host cells. These bioengineered vessels may prove to be durable long-term conduit options in CABG.
Abstract 10979: Long Term Risk of Coronary Artery Disease in Breast Cancer and Lymphoma Patients After Chemotherapy Plus Radiation Treatment vs Chemotherapy Only
Authors: Garcia-Arango Mariana , Larsen Carolyn M , Toro-Manotas Rafael E , Vallejo Bryan , Mogollon Renzo J , Quintero Martinez Juan , Scott Christopher , Fong de los Santos Luis E , Cerhan James , Haddad Tufia C , Thompson Carrie , Mutter Robert W , Stan Daniela , Villarraga Hector R
Published: June 2023

Introduction:
patients exposed to chest, breast or mediastinal RT, may present with accelerated atherosclerosis and CAD due to diffuse micro and macrovascular fibrosis. However, CAD risk has not been well established in a community-based study.
Aims:
Describe CAD risk in patients treated with chemotherapy with and without RT and evaluate the cumulative incidence of CAD (coronary revascularization, MI and abnormal stress test and coronary angiogram).

Methods:
From 1985-2010, we identified 744 patients with a new diagnosis of breast cancer or lymphoma, using the Rochester Epidemiology Project (REP) who received chemotherapy with or without RT. CAD risk was assessed by a proportional hazards model for time to event. RT was treated as a time dependent co-variable, with index date being chemotherapy start date, significance was considered as a p<.05. Characteristics were evaluated by a multivariable Cox model to consider RT and time censoring.

Results:
744 patients treated with chemotherapy were identified, of these 488 (65.6%) had breast cancer, 256 (34.4%) lymphoma, and 367 (49%) also received RT. The mean total RT dose was 5.5
±
1.2 (Gy) for those that had CAD and 5.4 (Gy)
±
1.1 for non-CAD patients, p=0.4. The cumulative incidence of CAD events (accounting for death as a competing risk) at 5 and 10 years of follow-up was 1.9% (CI 1.14-3.2) and 3.06% (CI 2.01-4.7), respectively p<.05 figure1. Baseline differences between those receiving RT or not, were not significant for DM and HTN; however, males and ages 70-79 were less likely to receive RT, table1. In a multivariable model, there was no difference in the CAD outcomes between those with and without RT, HR= 1.21 [0.48-3.06] p=.69, after adjusting for age, gender, DM, and HTN and those <49 y/o had a lower risk of CAD. Table2

Conclusion:
In this REP retrospective cohort study, the risk of developing a CAD event was similar between chemotherapy plus RT and chemotherapy only regimens, even after considering gender, age, HTN and DM.
Abstract 10991: Incidence of Pacing-Induced Cardiomyopathy in Leadless and Traditional Pacemakers: A Retrospective Analysis of 198 Patients
Authors: Prasad Rohan M , Qutrio Baloch Zulfiqar , Saeed Al-Asad Khalid , Martinez Salazar Adolfo , Ukponmwan Esosa , Ali Abbas , Ip John
Published: June 2023

Introduction:
Transvenous pacemaker (TVP) with right ventricular (RV) apical pacing over 40% has been associated with a 17-25% risk of Pacing-Induced Cardiomyopathy (PICM), defined as a decrease in ejection fraction (EF) by 10% or more. It’s been postulated that a septally placed Leadless Pacemaker (LP) causes less risk of PICM, but the exact incidence is unknown.

Methods:
We performed a single-center retrospective analysis of adults who received an LP or TVP between January 1, 2014 and April 1, 2022 and had echocardiograms before and after the pacemaker. This study’s outcomes were the RV pacing percentage, change in EF, the need for cardiac resynchronization therapy (CRT) upgrade, and follow-up duration. A Wilcoxon rank-sum test calculated the change in EF. RV time, defined as the duration from pacemaker to echocardiogram in months multiplied by the RV pacing percentage, served as a surrogate for how long the RV was paced.

Results:
A total of 614 patients were screened and 198 patients were included in the study, where 72 received LP and 126 received TVP. The median follow-up was 480 days. The average of the reported 161 patients with RV percentage pacing for LP was 63.43% and TVP was 71.30% (p=0.14). The incidence of PICM and CRT upgrade in the LP group was 44% and 9.7% in LP and TVP was 37% and 9.5% in TVP (p=0.3 and p>0.9), respectively. After accounting for age, age, sex, LP vs TVP, atrioventricular nodal ablation, RV pacing percentage, and follow-up duration, univariate analysis showed that RV time was significantly different between pacemakers (LP 1,353.97 ± 1,420.56 months vs TVP 926.47 ± 1,395.17 months, p=0.009), but not with CRT (No CRT 1,211.37 ± 1,447.45 months vs CRT 919.34 ± 1,199.54 months, p=0.5).

Conclusions:
This analysis demonstrated that the incidence of PICM was high in both groups (LP 44% vs TVP 37%). Despite significantly more RV time in patients with LP, there was no difference in CRT upgrade.
Abstract 10992: Higher Social Vulnerability is Correlated With Maladaptive Coping in Informal Caregivers of Adults With Heart Failure
Authors: Matus Austin M , Quinn Ryan , Thomas Gladys , Goba Miatta , Garo Jenna , Gordon debbie , Riegel Barbara J
Published: June 2023

Background:
Social factors are known to influence health outcomes, but the mechanism by which these factors exert their influence is unclear. We explored the relationships between social vulnerability, stress, and coping in a sample of adults caring for patients with chronic heart failure (HF).

Methods:
Baseline data from a sample of 212 caregivers was analyzed. Social vulnerability (SV) was measured using a modification of the PRAPARE tool with 14 categories (i.e., sex, race, ethnicity, employment, veteran status, education, income, insurance, material security, transportation, social integration, social support, need to support others, early retirement for caregiving) tallied to yield a score between 0-22; higher scores indicate higher SV. Stress was measured with the Perceived Stress Scale (higher is worse). Coping styles were measured as active (scores: 0-45), avoidant (0-30), and minimization (0-30). Higher scores indicate more use of that style. Correlation analysis was used to explore relationships between SV, stress, and coping. Multivariable regression analysis with stepwise variable selection was used to identify which SV factors were the best determinants of coping styles.

Results:
The sample was predominately White (61.2 %), female (84.2%) older adults (
x
55.2
+
14 years). SV scores were low (range 0-14, 4.0 ± 2.2). SV exhibited a weak correlation with stress (r = .17, p = 0.01) and was not significantly associated with active coping (r = .13, p = 0.05). SV was most strongly correlated with avoidant (r = .30, p < 0.0001) and minimization coping (r = .25, p < 0.001) styles. In multivariable analysis, race, income, and ‘supporting others’ were the strongest predictors of avoidant coping; avoidance scores were 2.5
+
0.9 units greater for non-White caregivers (p<0.0001), 3.1
+
1.3 units greater (p<0.05) for low-income caregivers, and 1.9
+
0.6 units greater (p<0.001) for each additional person supported. Race was the strongest determinant of minimization coping; minimization scores were 4.5
+
0.8 units greater for non-White caregivers (p < 0.0001).

Conclusion:
These results suggest that caregivers with higher social vulnerability may be avoiding and minimizing to cope with the challenges associated with caregiving.
Abstract 11004: Investigator-Reported versus Adjudicated Clinical Events for Worsening Heart Failure
Authors: Keane Ryan R , Carroll Aubrie M , sun jie-lena , Khan Mohammad S , Alhanti Brooke , Hernandez Adrian F , Butler Javed , OConnor Christopher , Mentz Robert J , Greene Stephen J
Published: June 2023

Introduction:
Clinical event committee (CEC) adjudication is the gold standard for event reporting in clinical trials. In some instances, investigator-reported events may be an appropriate substitute to reduce operational complexity and costs of heart failure (HF) trials, but the level of agreement between CEC and trial investigators for defining worsening HF (WHF) events is not well described.

Methods:
The ASCEND-HF trial compared nesiritide vs. placebo among patients hospitalized for HF, regardless of ejection fraction, and adjudicated endpoints through 30-day follow-up. This post-hoc analysis included patients with death or rehospitalization within 30 days. Concordance between the CEC and site investigators for WHF death and rehospitalization was measured using simple kappa (ĸ) statistics. Factors independently associated with discordance were identified using a backward selection model.

Results:
Over 30-day follow-up, there were 105 investigator-reported WHF deaths and 154 CEC-classified WHF deaths (p<0.001), with a modest level of agreement (ĸ 0.59) (
Figure 1A
). For 30-day WHF rehospitalization, there were 355 events reported by investigators and 426 classified by CEC, with high levels of agreement (ĸ 0.77). Older age was independently associated with higher likelihood of CEC-investigator discordance for WHF death (OR 1.16 [1.01-1.33] per 5-year increase). For WHF rehospitalization, older age (OR 0.91 [0.84-0.98] per 5-year increase) and higher systolic blood pressure (OR 0.82 [0.71-0.94] per 10 mmHg increase) were associated with lower likelihood of discordance. Agreement for WHF endpoints varied by geographic region (
Figure 1B
).

Conclusions:
CEC and trial investigators had modest rates of agreement for characterizing WHF death and high rates of agreement for WHF rehospitalization. Multiple patient factors were associated with CEC-investigator discordance and levels of agreement for WHF endpoints varied across geographic regions.
Abstract 11009: A Novel Patient-Patient Network Medicine Approach to Refine Hypertrophic Cardiomyopathy Subgrouping: Implications for Risk Stratification
Authors: Wang Ruisheng , Rowin Ethan J , Maron Barry J , Maron Martin S , Maron Bradley A
Published: June 2023

Introduction:
In hypertrophic cardiomyopathy (HCM), the presence of left ventricular (LV) apical aneurysm warrants implantable cardioverter defibrillator (ICD) therapy consideration for primary prevention of sudden death (SD). However, a significant proportion of these patients may never experience an SD event. Thus, identifying parameters that modify SD risk in this population may be important clinically, but likely requires phenotyping methods that include robust patient-level information.

Methods:
Clinical, demographic and echocardiographic parameters were compiled for a large HCM referral population. Variables (N=52) were normalized to the cohort and the Pearson’s correlation was calculated between patients using r>0.6 (after Benjamini-Hochberg correction), selected to maximize the patient:edge ratio. The SD event/risk profile was defined as: SD event/
≥
1 major HCM SD risk factor.

Results:
From N=3,412 HCM patients (male, 62%; 49 17 years at diagnosis) in the network, the clinical profile included maximum LV thickness, 18 4 mm; left atrial diameter, 41 7 mm; LV outflow tract gradient 30 mmHg, and N=68 (3%) patients with LV apical aneurysm. We identified N=17 distinct patient modules (range, N=19-483 patients/module). Module #15 was highly enriched for LV apical aneurysm (N=56/56); however, the SD event rate was significantly less compared to LV apical aneurysm patients in all other modules (N=12; 4% vs. 75%; P<0.0001). Lower blood pressure and smaller left atrial size delineated LV apical aneurysm patient in module #15.

Conclusions:
This proof-of-concept patient-patient network analysis suggests that lower blood pressure and smaller left atrial size may contribute to a favorable SD risk profile among HCM LV apical aneurysm patients.