bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12955: Clonal Hematopoiesis of Indeterminate Potential: A Novel Risk Factor for Atrial Fibrillation in the UK Biobank Cohort
Authors: Saadatagah Seyedmohammad , Satterfield Benjamin , Dikilitas Ozan , Kullo Iftikhar J
Published: April 2022

Introduction:
The prevalence of atrial fibrillation (AF) increases with age and inflammation plays a key pathophysiologic role. Somatic mosaicism increases with age and promotes inflammation. Therefore, we investigated whether Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a risk factor for incident AF.

Methods:
We assessed exome sequence (ES) data from 200,628 participants in the UK biobank. Using the Genome Analysis Toolkit pipeline, we ascertained a predefined list of CHIP mutations in
DNMT3A
,
TET2
, and
ASXL1
. CHIP was defined as variant allele frequency (VAF) >10% and those with VAF <2% served as controls. AF was ascertained based on self-report and ICD codes. Lone AF was defined as AF in the absence of heart failure, mitral stenosis, mitral valve repair/valvotomy/replacement, and congenital heart disease. Those with AF prior to or at the time of enrollment were excluded from analyses to ascertain incident events. Cox proportional hazard models adjusted for age, sex, self-reported race/ethnicity, diabetes, hypertension, smoking, and obesity were used to identify associations between CHIP and incident AF.

Results:
Of 200,628 participants, 3885 (1.9%) had CHIP. The number of participants with mutations in
DNMT3A
,
TET2
, and
ASXL1
was 2512, 1065, and 439, respectively. During a median follow-up of 9 years, 4,676 incident AF and 3,584 incident lone AF occurred. CHIP was an independent risk factor for developing incident AF and also for developing lone AF. CHIP in
TET2
and
ASXL1
but not
DNMT3A
was associated with AF (
Table 1
).

Conclusions:
The presence of CHIP involving
TET2
and
ASXL1
is associated with an increased risk of incident AF including the subset with lone AF. Our findings reveal somatic mosaicism in blood cells to be a novel risk factor for AF.
Abstract 13242: One Day Intravenous Sotalol Loading for Treatment of Atrial Arrhythmia
Authors: Jacobs Steven , Oren Jess , Storm Randle , Vijayaraman Pugazhendhi , Weaver Keturah , Sauers Nathan , Van Enkevort Erin , Pokharel Parash
Published: April 2022

Introduction:
Sotalol is commonly used for the management of atrial arrhythmias Recently, sotalol was approved for intravenous administration. The intravenous loading protocol is based on a computer simulation of plasma concentration rather than clinical data Availability of IV sotalol offers an opportunity to shorten the loading time. We developed a One Day Sotalol Loading Protocol (ODSL) utilizing the IV sotalol formulation.

Hypothesis:
ODSL feasible & safe. It also results in significant health care cost reduction.

Methods:
Patients undergoing ODSL loading between June 2020 to Dec 2020 for management of AF were included in the analysis. The primary endpoint was successful initiation of sotalol therapy. The secondary endpoint was maintenance of sinus rhythm at 30 days. Safety endpoints included excessive prolongation of the QT
C
interval, ventricular arrhythmias and sinus bradycardia requiring dose adjustment. Patient co-morbidities and demographics were also evaluated. Cost savings analysis was performed to quantify health care savings

Results:
55 patients were included in the analysis (30 paroxysmal AF and 25 persistent AF). The mean age was 70± 9.82 years old and 60.7% were men. The average ejection fraction was 52.91 ± 9.25% and average creatinine clearance was 83.58 ± 44.35mL/min. 51 patients (92.7%) underwent successful ODSL. Of these, 6 patients had dose reduction due to adverse events (fig 1). 7 (12.7%) patients had significant QT
C
prolongation during IV loading. ODSL was terminated in 4 patients: symptomatic bradycardia and prolonged QT
C
(1 pt) and failure of cardioversion (3 pts).42 (76%) of patients remained on sotalol and 32 (58%) maintained sinus rhythm at 30 day follow up. No ventricular arrhythmia was noted during the loading and monitoring period. Same day discharge led to an 18% reduction in health care costs.

Conclusions:
We present first real-world data demonstrating that abbreviated ODSL is feasible, safe, and leads to significant health care savings while freeing up resources and personnel. Further patient enrollment and data analysis is ongoing to further solidify this novel loading approach.
Abstract 13408: Have We Improved? Right Bundle Branch Block and Transcatheter Aortic Valve Replacement: An Analysis of the National Inpatient Database
Authors: Gilchrist Juliann , Maning Jennifer , Grant Jelani , Vincent Louis T , Ebner Bertrand , Hernandez Rafael , Olarte Neal , Olorunfemi Odunayo , Colombo Rosario A
Published: April 2022

Background:
Pre-existing right bundle branch block (pRBBB) is recognized as a significant risk factor for the need of permanent pacemaker (PPM) therapy after TAVR, with early studies suggesting additional risk of mortality and hospitalization. This study aims to explore contemporary in-hospital outcomes of TAVR patients with pRBBB.

Methods:
Using the National Inpatient Database (NIS) we identified patients 18 years and older hospitalized for index TAVR procedure from 2016 to 2018. Primary outcome was incidence of PPM implant post-TAVR. Secondary outcomes included in-hospital mortality and length of stay (LOS). Multivariate analysis model was used to adjust for statistically significant differences in baseline characteristics between the groups.

Results:
A total of 152,490 patients underwent TAVR. Pre-existing RBBB was present in 7090 (4.6%) patients. Patients with pRBBB were less likely to be women (34.6% vs 46.8%,
p
< 0.001) and more likely to suffer from heart failure (76.9% vs 74.3%,
p
< 0.001) and diabetes (40.2% vs 37.3%,
p
< 0.001). Those with pRBBB were more likely to undergo PPM implant (29.4% vs 9.1%, OR 3.776,
p
< 0.001). There was no significant difference in in-hospital mortality (1.3% vs 1.5%, p = 0.203) or LOS (4.51 ± 5.15 vs 4.38 ± 5.54 days, p= 0.062) between the groups. Subgroup analysis showed that the incidence of PPM implant (29.1% vs 14.6%,
p
< 0.001), in-hospital mortality (1.4% vs 0.7%,
p
< 0.001), cardiogenic shock (2.1% vs 1.5%,
p
< 0.001) and mechanical ventilation (3.1% vs 2.0%,
p
< 0.001) was higher among patients with pRBBB compared to those with pre-existing LBBB (pLBBB).

Conclusions:
Contrary to previous reports, patients with pRBBB did not show increased risk of in-hospital mortality or LOS compared to those without RBBB. pRBBB was, as expected, associated with increased risk for PPM implant post-TAVR. When compared to patients with pLBBB, those with pRBBB appear to experience worse in-hospital outcomes, suggesting an area for further research.
Abstract 13417: Fluid-Structure Interaction Simulations of Bicuspid Aortic Valve Disease
Authors: Kaiser Alexander D , Shad Rohan , Schiavone Nicole , Hiesinger William , Marsden Alison L
Published: April 2022

Introduction:
Aortic dilation and aneurysm formation is common in patients with a bicuspid aortic valve. Hemodynamics and genetics are both believed to cause dilation, but the relative contributions remain controversial. Further, retrospective studies assess hemodynamics when dilation has already set in. We simulate flows through a tricuspid and three bicuspid aortic valves and study their hemodynamics from a baseline non-dilated aorta.

Hypothesis:
We hypothesize that the bicuspid phenotype determines flow in the ascending aortic, and high velocity jets will correlate with known regions of dilation in patients with bicuspid valves.

Methods:
Using methods we recently developed, we constructed a tricuspid valve and bicuspid valves with left/right (LR), right/non (RN) and non/left (NL) coronary cusp fusion. To isolate the effect of leaflet fusion phenotype, we use one healthy, patient-specific aortic geometry throughout. Fluid-structure interaction simulations were performed.

Results:
Dramatic differences in flow occur between all cases. The tricuspid case shows a relatively uniform flow profile, velocities of ~200cm/s, normalized streamwise momentum <1.5, normalized tangential flow strength of <1.6, <20% reverse flow away from the sinus and sustained pressure gradients <2 mmHg. All bicuspid cases show a localized jet, peak velocities >300cm/s, normalized streamwise momentum >2.0, normalized tangential flow strength >1.0, >50% transient reverse flow and sustained pressure gradients >18 mmHg. With LR fusion, the jet hugs the outer curvature of the aorta from the sinotubular junction through the ascending aorta. With RN fusion, the jet moves from the inner to outer curvature of the aorta.

Conclusions:
With LR and RN cusp fusion, high flow rate jets occur at regions that generally correlate with dilation in prior studies, suggesting that hemodynamic factors alone may be sufficient to cause aortic dilation. This hypothesis should be tested in an animal model.
Abstract 13439: Long-Term Outcomes From Continuous Rhythm Monitoring After Hybrid Convergent Procedure in Longstanding Persistent Atrial Fibrillation Patients
Authors: Kerendi Faraz , Tschopp David , Maningat Alexandra , Hyde Brannon , Coffeen Paul , Punske Bonnie B
Published: April 2022

Introduction:
Endocardial catheter ablation has suboptimal effectiveness and durability in patients with longstanding persistent atrial fibrillation (LSPAF). Hybrid convergent ablation combines epicardial and endocardial ablation to create a transmural lesion set that isolates the left atrial posterior wall and pulmonary veins. The study objective was to evaluate long-term outcomes assessed by continuous rhythm monitoring in LSPAF patients who received hybrid convergent ablation.

Methods:
This was a single-center IRB-approved, observational study. Eligible patients were identified by retrospective chart review and included patients who received hybrid convergent procedures between September 2011 and November 2017. Patients were consented for prospective long-term follow-up visits and continuous cardiac monitoring (7-day ePatch). Baseline characteristics, procedural outcomes, and follow-up data were entered into the TRAC-AF registry. This analysis focused on the patient subgroup with pre-operative LSPAF (AF duration >1 year).

Results:
Of 77 consented patients, 60 had pre-operative LSPAF. Mean age was 66.1 ± 7.9 years, 70% were male, and duration of AF was 6.8 ± 4.8 years. Mean CHA2DS2-VASc score was 2.6 ± 1.4; mean BMI was 32.1 ± 5.9, and 55% (33/60) of patients had previous catheter ablation. Thirty-day major adverse event rate was 5% (3/60) and included 2 inflammatory pericardial effusions and one major bleeding. On continuous monitoring, 71% (41/58) of patients had 0% AF burden at mean follow-up of 61.7 ± 18.9 months. Eight patients (13%) had repeat catheter ablation at mean 21.6 ± 16.3 months since index procedure. Comparison of baseline and follow-up left ventricular ejection fraction (LVEF) from echocardiography revealed a trend of 12.4 ± 13.0 units improvement at mean follow-up of 18.2 ± 23.7 months since baseline in 5 patients with severely reduced (<40%) baseline ejection fraction (p=0.063).

Conclusions:
Long-term follow-up with continuous monitoring revealed a majority of patients with pre-operative LSPAF had 0% AF burden after a mean 61.7 months since the hybrid convergent procedure. These results are aligned with published studies and the CONVERGE trial on the effectiveness of hybrid convergent ablation in LSPAF.
Abstract 13471: HFpEF in Spontaneously Obese Mice Due to Genomic Rearrangement in Non-Coding Region of Chromosome 1
Authors: White Donnell , Wu Jian , Bao Rong , Lauterboeck Lothar , Kesterson Bob A , Yang Qinglin
Published: April 2022

Background:
Obesity is the most common comorbidity and risk factor for heart failure (HF) in patients with preserved ejection fraction (HFpEF), a subclass containing more than 50% of HF cases. However, effective treatment of HFpEF remains scarce due to the incomplete understanding of the mechanisms.

Methods:
A mouse line (C57/B6J) of Floxed-stop Overexpression of IF1 (FEI) was generated and maintained for Cre-mediated conditional IF1 overexpression. We observed that severe obesity became a fixed phenotype in inbred FEI mice after inbreeding for 5-6 generations. Targeted-Locus-Amplification (TLA) analyses revealed that FEI inbreeding triggered a genomic rearrangement in a non-coding region of chromosome 1. A heterozygous line with genotype and phenotype fixation was obtained via outbreeding with wild type mice. In the present study, we focus on assessing the cardiac phenotype of FEI mice using echocardiography, histology, and exercise tolerance tests.

Results:
The early onset of obesity was consistent in the heterozygotes of obese FEI mice with increased peripheral fats and circulating tissue lipids, as well as reduced systemic metabolic rates. FEI mice also exhibited increased food intake, fasting blood glucose, insulin, and leptin with impaired glucose/insulin tolerance. Echocardiography revealed that the FEI mice developed concentric left ventricular hypertrophy with preserved ejection fraction. However, E/A ratio results from Doppler flow measurement at mitral valve suggest diastolic dysfunction in the FEI mice. Heart weight to tibial length ratio was significantly increased in FEI compared with WT mice. H&E and Trichrome blue staining on heart sections exhibited increased cardiomyocyte hypertrophy and cardiac fibrosis. Treadmill exercise tolerance test revealed a significantly decreased exercise tolerance in FEI mice.

Conclusions:
We conclude that the cardiac phenotypes in the obese FEI mice closely recapitulate obese patients who suffer from HFpEF. Thus, further studies on these mice should yield novel and translational insight into the molecular and metabolic mechanisms underlying the HFpEF development, leading to improved treatments.
Abstract 13594: Cyclosporine-A Reduces Myocardial Damage in Donation After Circulatory Death Hearts
Authors: Akande Oluwatoyin E , Chen Qun , Cholyway Renee , Toldo Stefano , Lesnefsky Edward J , Quader Mohammed
Published: April 2022

Background:
Mitochondria contribute to ischemia and reperfusion injury (IRI) in donation after circulatory death (DCD) donor hearts. Cyclosporine A (CyA), an inhibitor of mitochondrial permeability transition pore (MPTP) opening, limits IRI. CyA administration at the onset of reperfusion is essential for therapeutic efficacy. DCD heart transplantation (HTx) is a unique setting for controlled administration of CyA.

Hypothesis:
CyA administered to DCD hearts during reperfusion is cardioprotective.

Methods:
Under general anesthesia Sprague Dawley rats underwent simulated clinical DCD setup with a global ischemia of 25 minutes. Control beating-heart donor (CBD) hearts served as controls (n=10). Hearts were reanimated
ex-vivo
with Krebs-Henseleit buffer (KH) perfusion at 37
o
C for 90 minutes. DCD hearts were randomly assigned to receive CyA (0.5mM) or DMSO added to KH buffer for the first 15 minutes of perfusion (n=10 each). The hearts were collected to measure oxidative phosphorylation (OXPHOS) and calcium retention capacity (CRC). Additional CBD (n=5) and DCD (with or without CyA, n=15) hearts underwent heterotopic HTx in recipient rats to measure developed pressure (DP) and rate pressure product (RPP) at 48 hours.

Results:
Compared to CBD hearts, OXPHOS in DCD hearts was significantly reduced. CyA improved OXPHOS and was similar to CBD hearts. CRC was reduced in DCD hearts compared to CBD hearts (317 vs.578nM/mg) and was increased with CyA treatment (413 vs. 317nM/mg; p<0.05, Figure). Infarct size decreased significantly with CyA treatment (15% vs. 25%). In transplanted DCD hearts, DP and RPP were significantly reduced compared to CBD hearts (80 vs.153mmHg and 17639 vs. 29545mmHg*bpm). CyA treatment improved DP (124vs.80mmHg; p<0.05) and RPP (35491vs.17639mmHg*bpm; p<0.05) which was comparable to CBD hearts.

Conclusions:
CyA administered at reperfusion reduces mitochondrial damage, limits infarct size, and preserves function in transplanted DCD hearts.
Abstract 13612: An mPGES-1 Inhibitor Halts Abdominal Aortic Aneurysm Formation in Mice
Authors: Weaver Lauren M , Stewart Madeline J , Ding Kai , Zhou Shuo , Loftin Charles , Zheng Fang , Zhan Chang-Guo
Published: April 2022

Background:
Abdominal aortic aneurysm (AAA) is a deadly, permanent balloon of the aortic artery. Surgery is the only option available to patients, but it is risky. In addition, there are currently no FDA-approved pharmacological treatments for AAA available. Notably, microsomal prostaglandin E
2
synthase-1 (mPGES-1) is recognized as a promising target for development of a next generation of anti-inflammatory drugs. Through computational modeling and
in vitro
experiments, we have recently discovered a novel type of mPGES-1 inhibitors as possible anti-inflammatory drug candidates.

Objectives:
The purpose of this study was to assess the capability of an mPGES-1 inhibitor to alter the growth of AAA in the angiotensin (Ang)-II induced mouse model.

Methods:
For 28 days, 12-week-old male
ApoE-/-
were infused with Ang-II (1,000 ng/kg/min) plus either an mPGES-1 inhibitor (UK4b) starting day 7 (10 mg/kg SC, BID;
N
= 6) or no drug (control group,
N
= 9). Maximal aortic diameter was measured by ultrasound (Vevo 3100) on day 0 (baseline), 2, 5, 7, 12, 16, 21, and 28. Aorta tissues were collected after sacrifice on day 28 and measured.

Results:
On day 28, there was a significant difference between the maximal aortic diameters of the control and drug treated groups (2.08±0.22 mm, 1.34±0.02 mm;
p
< 0.005). Comparing day 28
in vivo
and
ex vivo
measurements of aortas, there was no significant difference (
p
= 0.898), validating the use of ultrasound as an
in vivo
measurement method in this study.

Conclusions:
In summary, the mPGES-1 inhibitor UK4b, was able to halt the progression of AAA in these mice. There was a significant difference in the size of aortas between the two groups which was validated by
ex vivo
assessment. These preliminary results show promise for the use of an mPGES-1 inhibitor in the treatment of AAA.
Abstract 13626: Aerobic Training Corrects Bbb Dysfunction Within Preautonomic Areas In Heart Failure Rats By Normalizing The Augmented Transcytosis
Authors: de Ataides Raquel Hiviny , Masson Gustavo , Martins Pérego Sany , Colquhoun Alison , Jensen Leonardo , Michelini Lisete C
Published: April 2022

Introduction:
Besides intense renin-angiotensin system activation and sympathoexcitation, heart failure (HF) is accompanied by marked autonomic dysfunction. We showed previously in hypertensive rats that blood-brain barrier (BBB) dysfunction in preautonomic areas aggravated the autonomic dysfunction but is corrected by aerobic training (T). There is no information in HF

Hypothesis:
We hypothesized that BBB dysfunction within the paraventricular hypothalamic nucleus (PVN) contributes to the autonomic imbalance, which may be ameliorated by T

Methods:
Wistar rats were submitted to anterior descending coronary artery occlusion or Sham surgery and echocardiography. Four weeks later, HF (ejection fraction≤40%) and Sham rats underwent a T (55% of maximal exercise capacity) or sedentary (S) protocol for 8 weeks and were chronically cannulated for hemodynamic/autonomic recordings and determination of BBB permeability (intra-arterial injection of fluorescent dyes with high and low molecular weight). To investigate the mechanisms underlying HF- and T-induced BBB changes, the PVN was harvested and processed for transmission electron microscopy

Results:
HF-S exhibited reduced arterial pressure (AP, -10%), increased sympathetic activity to vessels and heart (+45% on average), decreased spontaneous baroreflex sensitivity (BrS, -19%), large increase in systolic AP variability (+53%), and 4-fold increase in PVN BBB leakage (11.3±1.4 vs. 2.8±0.2 %area in Sham-S). HF-S also exhibited increased transcytotic vesicles (+80%) in PVN capillaries’ endothelium, without any change in tight junctions’ expression, capillary diameter, and pericytes’ coverage. These changes were completely normalized in HF-T rats. In Sham rats T only caused resting bradycardia, increased BrS, and a mild reduction of transcytotic vesicles and PVN leakage. There were significant correlations between the number of transcytotic vesicles x PVN BBB leakage (Y=0.82x -1.74, r
2
=0.843, P<0.001) and BBB leakage x sympathetic activity (Y=0.66x +4.37, r
2
=0.415, P<0.001)

Conclusions:
HF courses with PVN BBB dysfunction, which is due to increased transcytosis without changes in the paracellular pathway. Training ameliorates HF’s autonomic control by normalizing transcytosis
Abstract 13878: Activated Fibroblasts and IL-1β Mediate Fibrotic Cardiac Remodeling Observed in Premature Ventricular Contraction-Induced Cardiomyopathy
Authors: Medina Contreras Juana Maria de Lourdes , Balderas Villalobos Jaime , Samso Montserrat , Ramirez Rafael J , Y. Tan Alex , Kaszala Karoly , Huizar Jose F , Eltit Jose M
Published: April 2022

Introduction:
The relevance of fibrosis in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remains unclear. Recent studies suggest that fibrosis promotes adverse extracellular matrix (ECM) remodeling that has been implicated in arrhythmogenesis. However, fibrotic areas and fibroblast activation have not been characterized in PVC-CM. The objective of this study was to assess cardiac remodeling by collagen fiber deposition, fibroblast activation (using αSMA as a marker), and the pro-fibrotic cytokine IL-1β level in LV myocardium.

Hypothesis:
Activation of fibroblasts promotes adverse cardiac remodeling in PVC-CM.

Methods:
Modified pacemakers were implanted in canines, half of them developing PVC-CM after 12 weeks of bigeminal PVCs (50% burden at 200-220 ms coupling interval), while the remaining were not exposed to PVCs (sham). Paraffin-embedded or simple formalin-fixed cardiac samples were sectioned and stained with Sirius Red/Fast Green (SR/FG) or immunofluorescence (IF) to assess collagen fiber deposits and αSMA content, respectively. Expression of IL-1β and αSMA were assessed by Western blot.

Results:
The percentage of fibrosis was three times greater in PVC-CM tissues compared to sham (10.2 ± 0.98 vs 3.3 ± 0.53, p = 0.014), consistent with an increase in αSMA (1 ± 0.08 vs 1.93 ±0.33, p < 0.05) and IL-1β expression (1 ± 0.09 vs 1.69 ± 0.11, p < 0.01). The figure shows differences in collagen fibers with SR/FG and αSMA with IF in (A) sham and (B) PVC-CM. Increased αSMA and IL-1β support the hypothesis that fibroblast activation is a key component in the PVC-CM phenotype.

Conclusion:
These findings strongly suggest that fibroblast activation during PVCs promote ECM expansion causing persistent structural remodeling which may disrupt electrical signal propagation and potentially contribute to arrhythmogenesis and worsening ventricular function associated with PVC-CM.
Abstract 14084: Computationally Identified Shape Differences In The Left Atrium On Pre-ablation Ct Scans Appear To Be Associated With Recurrence Of Atrial Fibrillation
Authors: Asaeikheybari Golnoush , Hiremath Amogh , Shiradkar Rakesh , El-harasis Majd , Shoemaker M. Benjamin , Barnard John , Gupta Amit , Chung Mina K , Madabhushi Anant
Published: April 2022

Introduction:
Catheter-based ablation is an increasingly utilized management strategy for atrial fibrillation (AF); however, a major problem is AF recurrence post-ablation. There is increasing interest in the use of advanced image analysis to better understand differences in left atrial (LA) shape that may be associated with a higher recurrence risk and potential sites of recurrence.

Hypothesis:
Factors which lead to the post-ablation recurrence prompt LA differential remodeling. The significant shape difference regions among AF recurrence (AF+) and AF non-recurrence (AF-) patients can be identified from pre-ablation CT scans. Those regions could potentially represent future sites of recurrence and hence could be targets for ablation.

Methods:
This study included pre-ablation CT-scans of 51 AF+ and 51 AF- patients. Two separate atlases were created by registering Left atrial CT volumes of AF+ and AF- patients to their representative templates (T+ and T- respectively). The atlases were co-registered to a common canonical frame of reference (T-) and a non-parametric General Linear Model (GLM) based t-test with 500 permutations was used to identify the regions (Surface of interest (SOI)) that are statistically significant (p-value<0.1) between the two classes. To reduce sensitivity in the template selection, we constructed an ensemble SOI based on SOIs obtained from 10 different templates and made the frequency map of overlap SOIs.

Results:
The registration accuracy in the final common frame in terms of average Dice similarity coefficient was in the range of 0.85-0.94 over the 10 SOI constructions. The frequency map revealed the maximum overlap of SOIs in an area where left pulmonary veins enter the left atrium. This could potentially represent a new target for ablation.

Conclusions:
An ensemble atlas-based shape differentiation method revealed SOI regions that are structurally associated with recurrence and might potentially represent targets for ablation.
Abstract 14092: Arachidonate 5 Lipoxygenase Deficiency Drives Age-Related Obesity, Macrophage Dysfunction in Cardiac Repair, and Omnipresence of Inflammation
Authors: Kain Vasundhara , Halade Ganesh V
Published: April 2022

Introduction:
Age-related inflammation is the primary hallmark of heart failure with reduced and preserved ejection fraction; however, the fundamental source of inflammation is unclear. Arachidonate 5 lipoxygenase (ALOX5) is known to direct the biosynthesis of leukotrienes and proinflammatory mediators (PIMs) that orchestrate the initiation of inflammation following myocardial infarction (MI).

Hypothesis:
Thus, we set out to test the role of ALOX5 to understand inflammation-resolution signaling in acute HF in aging.

Methods:
Male C57Bl/6J and ALOX5
-/-
mice were divided into two groups: 1) young (2-4 months) and 2) aging (18 months). Mice were subjected to MI surgery that develops acute heart failure maintaining no-MI as naïve controls. Cellular and molecular mechanisms are detemined.

Results:
The absence of ALOX5 leads to age-related obesity with series of metabolic defects, including fatty liver. Next-gen sequencing analysis revealed that immune regulating pathways of infarcted myocardium were dysregulated in young and aging ALOX5
-/-
mice compared to respective age-matched controls. In response to cardiac injury, ALOX5
-/-
mice fail to initiate an inflammatory response with reduced leukotrienes B
4
and PIMs, with marked obesity-related chronic inflammation in immune defense hubs: spleen bone marrow and LV infarcted site. At the molecular level, ALOX5 deletion also reduced resolution mediators (specialized proresolving mediators; SPMs), thereby making macrophage dysfunctional with the decrease in SIRP-α. Aging superimposed on ALOX5 deficiency triggers macrophage dysfunction with the increase in proinflammatory phenotype (Ly6C
hi
) and notable upregulation of CXCR4 and downregulation of resolution receptor formyl peptide receptor 2; in infarcted heart post-MI.

Conclusions:
Presented age-related outcome provides translational insight that ALOX5 serves as a connector for initiating PIM (turn-on) and SPMs (turn-off) essential for macrophage function and cardiac repair processes. Thus, future research is warranted to validate the role of ALOX5 in cardiometabolic defects, PIMs, and resolution mediators (SPMs) in heart failure with reduced and preserved ejection fraction.
Abstract 14093: Open Thoracic Surgical Implantation of Cardiac Pacemakers in Rodents
Authors: Yin Rose T , Chen Sheena W , Lee Kyongjune B , Choi Yeon Sik , Koo Jahyun , Yang Quansan , Knight Helen S , Gutruf Philipp , Rogers John A , TRACHIOTIS Gregory D , Efimov Igor R
Published: April 2022

Introduction:
Cardiovascular science has greatly benefited from bioelectronics and genetic engineering. However, combinations of these approaches have been hampered by challenges in genetic engineering of large animals and implantation of cardiac devices in rodents. New surgical approaches to reliably interface bioelectronics to the heart with minimal disruption to the native physiology are necessary for validation of novel bioelectronics therapies and bioelectronics-enabled in vivo studies of physiology.

Objective:
To develop an effective and reproducible surgical approach to implant epicardial devices in rodents.

Methods:
All rat surgeries (n = 138) were performed according to protocols approved by The George Washington University Institutional Animal Care and Use Committee. Inhaled isoflurane vapors provided general anesthesia. After orotracheal intubation, an intercostal incision was made and retracted in order to view the target cardiac implantation area (a). The electrode pad of a novel leadless battery-free pacemaker (b) was sutured or attached by bioadhesive to the epicardium with the device body placed subcutaneously. The ribs, muscle, and skin were subsequently closed. Post-operative care included injectable analgesics. Daily pacing trials confirmed device functionality.

Results:
Rats survive and quickly recover from the operation without complications. Electrocardiograms reveal that implanted miniature battery-free cardiac pacemakers pace the heart for up to 32 days after surgery (c). Echocardiography and assessment of biomarkers demonstrate no disruption to mechanical function (d) and no evidence of myocardial ischemia (e) or heart failure (f), respectively.

Conclusions:
This surgical technique reliably implants epicardial devices in rodents. It has broad applications to verify the long-term functionality and biocompatibility of innovative bioelectronics and to conduct in vivo studies of cardiovascular physiology.
Abstract 9423: Virtual Reality (VR) Guided Telerobotic Cardiac Catheter Ablation is Feasible Over Low Bandwidth Network Connection
Authors: Seslar Stephen P , James Ryan C , Hannaford Blake , Saour Basil , Monsky Wayne
Published: April 2022

Introduction:
Telerobotic operation in which a remote surgeon performs an operation over distance has long held the promise of providing a more equitable distribution of healthcare in rural and underserved regions of the world. One of the technological limitations that has hampered the adoption of telerobotic surgery is the need for a broadband connection to transmit high-resolution video of the operative field.

Hypothesis:
We hypothesized that we could develop a low-bandwidth system for telerobotic cardiac catheter ablation that deploys a virtual reality (VR)-based surgical guidance system to allow remote operation without the need for high-resolution video transmission.

Methods:
We assembled a portable pre-clinical telerobotic catheter ablation system from commercial-grade components by 3
rd
party vendors. Raw sensor data from the catheter ablation system requiring a bitrate of less than 100kb/sec was streamed in real-time over distance using a standard internet connection. We used a proprietary service (DOPL Technologies, Seattle, WA) and an Oculus Quest (Oculus, Inc. Menlo Park, CA) to generate a shared, virtual operative field and operating room environment. No video data was transmitted. The Institutional Animal Care and Use Committee of the University of Washington (Seattle, WA) approved the study performed on a 14-week (27 kg) Yorkshire pig. The operator was located 6 miles from the OR at the time of the operation.

Results:
A successful proof of concept telerobotic cardiac catheter ablation in an animal model was performed without video transmission. The remote surgeon applied radiofrequency energy lesions in the animal’s cavotricuspid isthmus region. The visual depiction of the operative environment was successfully constructed in virtual reality from sensor data generated from the animal subject and surgical instruments. The remote operator conducted the ablation while interacting in a shared virtual OR environment with members of the surgical team present in the physical operating room and three remote observers.

Conclusions:
Telerobotic cardiac catheter ablation is feasible without video transmission. This approach could reduce network bandwidth requirements for telerobotic operations in rural areas.
Abstract 9567: Association Between Parity and Markers of Inflammation: The Multi-Ethnic Study of Atherosclerosis
Authors: Ezeigwe Angelica K , Ogunmoroti Oluseye , Minhas Anum , Rodriguez Carla , Kazzi Brigitte , Fashanu Oluwaseun E , Osibogun Olatokunbo I , Kovell Lara , Harrington Colleen , Michos Erin
Published: April 2022

Introduction:
Grand multiparity (≥5 live births) is associated with a future risk of cardiovascular disease (CVD). Inflammation also increases the risk for adverse CV outcomes and may be a mechanism linking parity to CVD. We aimed to investigate the association between parity and several markers of inflammation.

Methods:
We studied 3,454 female MESA participants (age 45-84 and free of CVD) who had data on parity and inflammatory markers measured at baseline. Parity (live births) was categorized as 0 (reference), 1-2, 3-4, or ≥5. Progressively adjusted linear regression models were used to evaluate the association between parity and natural log-transformed levels of fibrinogen, D-dimer, GlycA, high sensitivity C-reactive protein (hsCRP), and interleukin-6 (IL-6).

Results:
Mean age at the baseline visit was 62±10 yrs. The proportion of women with nulliparity (0), 1-2, 3-4, and ≥5 live births were 620 (18%), 1357 (39%), 1004 (29%) and 473 (14%), respectively. There was no association between parity and fibrinogen. Women with grand multiparity had 28%, 10% and 18% higher levels of hsCRP, IL-6 and D-dimer, respectively, compared to nulliparous women, after adjustment for demographic factors (Model 1). Additionally, women with 1-2 and 3-4 live births had higher hsCRP and women with 1-2 live births had higher GlycA compared to nulliparous women in the fully adjusted model (Table).

Conclusion:
In this diverse cohort of mid-life women free from clinical CVD, we found a history of higher parity was positively associated with specific inflammatory markers; however, these associations were largely attenuated after adjustment for lifestyle and CVD risk factors. There was no clear dose-response relationship between higher parity status and higher inflammatory levels. Future studies are needed to evaluate how inflammation may influence the link between parity and CVD, and whether lifestyle/pharmacotherapy targeting inflammation can reduce CVD risk among multiparous women.
Abstract 9744:
Cardiovascular Stroke Nursing Best Abstract Award
: Investigating Sexual Identity Disparities in Hypertension and Hypertension Treatment Among Adults
Authors: Sharma Yashika , Taylor Jacquelyn Y , Hughes Tonda , Caceres Billy
Published: April 2022

Introduction:
Recent evidence suggests that sexual minority (e.g., gay/lesbian, bisexual) adults are at increased risk for hypertension. However, sexual identity disparities in the use of anti-hypertensive medications among adults with hypertension have not been examined. We sought to investigate sexual identity differences in diagnosis of hypertension and use of anti-hypertensive medication among adults in the United States.

Hypothesis:
Sexual minority adults will have higher odds of hypertension and use of anti-hypertensive medication than heterosexual adults.

Methods:
We analyzed data from the Behavioral Risk Factor Surveillance System (2015-2019) to examine sexual identity differences in diagnosis of hypertension and use of anti-hypertensive medication. We ran sex-stratified logistic regression models to estimate the odds ratios of diagnosis of hypertension and use of anti-hypertensive medication among sexual minority and heterosexual adults (reference group). Models were adjusted for demographics, insurance, body mass index, and smoking status.

Results:
The sample included 424,084 participants; 95.8% were heterosexual, 1.8% were gay or lesbian, and 2.3% were bisexual. Participants had a mean age of 49.6 (±16.9) years. Compared to heterosexual participants of the same sex, gay men (AOR 1.24, 95% CI = 1.08-1.42) and bisexual women (AOR 1.17, 95% CI = 1.02-1.35) were more likely to report having been diagnosed with hypertension. Among men diagnosed with hypertension those who identified as gay were more likely than heterosexual men to report current use of anti-hypertensive medication (AOR 1.44, 95% CI = 1.13-1.83). Among women with diagnosed hypertension, bisexual women had lower odds of current use of anti-hypertensive medication (AOR 0.70, 95% CI = 0.55-0.89). No differences were identified when lesbian women and bisexual men were compared to their heterosexual peers of the same sex.

Conclusion:
Gay men and bisexual women had a higher prevalence of hypertension than their heterosexual counterparts of the same sex. Bisexual women may also be at higher risk for under-treated hypertension than heterosexual women. Future research should examine factors that contribute to hypertension disparities among gay men and bisexual women.
Abstract 9747: Safety, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of AZD8233, Targeting PCSK9, in Patients with Dyslipidemia
Authors: Hofherr Alexis , Nilsson Catarina A , Rekic Dinko , Knoechel Jane , Goldwater Ronald , Han David , Kusnir Jorge , Overcash J. Scott , Waters Michael , White Alexander , Hurt-Camejo Eva , Wernevik Linda , Isaksson Rikard , Wang Yanfeng , Bhanot Sanjay , Ryden-Bergsten Kristina , Koren Michael , Carlsson Bjorn C
Published: April 2022

Introduction:
Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cardiovascular risk by lowering low-density lipoprotein-cholesterol (LDL-C) levels. AZD8233 is an antisense oligonucleotide in development for the treatment of dyslipidemia. In a single ascending dose study (NCT03593785), AZD8233 was well tolerated and effectively reduced PCSK9 and LDL-C levels in patients with elevated LDL-C. Here, we report results from a multiple ascending dose study of AZD8233.

Methods:
This was a phase 1, randomized, single-blind, placebo-controlled study (NCT04155645) in patients with dyslipidemia. Participants were receiving statins for ≥ 3 months, had an LDL-C in the range 70-190 mg/dL, and were 18-65 years old. Three cohorts of 11 participants received four subcutaneous injections over an 8-week period (days 1, 8, 29, and 57) of either AZD8233 (15 mg, 30 mg, or 90 mg; n = 8) or placebo (n = 3), and were followed up for 16 weeks post dose. The primary objective was to assess safety and tolerability; secondary objectives included assessment of pharmacokinetics and pharmacodynamics of AZD8233; circulating LDL-C was estimated using the Friedewald formula.

Results:
Overall, 34 patients were randomized and data are available from 33 patients; 15 were male, the mean age was 58 years, and baseline PCSK9 and LDL-C levels were comparable across treatment groups. Treatment with AZD8233 did not result in any clinically relevant safety or tolerability findings. Peak plasma concentrations of AZD8233 were reached within 0.5 to 5 hours post dosing, followed by a biphasic decline. A decrease from baseline in PCSK9 (69.7%, 79.9%, and 95.3%) and LDL-C levels (63.8%, 65.7%, and 83.3%) was observed at 12 weeks for the AZD8233 15 mg, 30 mg, and 90 mg groups, respectively vs placebo (
Figure
).

Conclusions:
Multiple doses of AZD8233 were generally safe, well tolerated, and reduced PCSK9 and LDL-C levels in a dose-dependent manner in statin-treated patients with dyslipidemia.
Abstract 9770: Endothelial Loss of Amphiregulin Drives Inflammation and Endothelial Apoptosis in Pulmonary Hypertension
Authors: Florentin Jonathan , Zhao Jingsi , Tai Yi-Yin , Sun Wei , Ohayon Lee , O'Neil Scott , arunkumar anagha , zhang xinyi , Al Aaraj Yassmin , Watson Annie , Sembrat John C , rojas mauricio , Chan Stephen Y , Dutta Partha
Published: April 2022

Pulmonary hypertension (PH) is a vascular disease characterized by elevated pulmonary arterial pressure (PAP), leading to right ventricular failure and death. Pathogenic features of PH include endothelial apoptosis and vascular inflammation, which drive vascular remodeling and increased PAP. Re-analysis of the whole transcriptome sequencing comparing human pulmonary arterial endothelial cells (PAECs) isolated from PH and control patients identified
AREG
, which encodes amphiregulin, as a key endothelial survival factor. PAECs from PH patients and mice exhibited downregulation of
AREG
and its receptor epidermal growth factor receptor (EGFR). Moreover, the deficiency of
AREG
and
EGFR
in ECs
in vivo
and
in vitro
heightened inflammatory leukocyte recruitment, cytokine production and endothelial apoptosis, and diminished angiogenesis. Correspondingly, hypoxic mice lacking
Egfr
in ECs (
cdh5
cre/+
Egfr
fl/fl
) displayed elevated RVSP, Fulton index, and pulmonary remodeling. Computational analysis identified
NCOA6, PHB2,
and
RRP1B
as putative genes regulating
AREG
in endothelial cells. The master transcription factor of hypoxia HIF-1αbinds to the promoter regions of these genes and upregulate their expression in hypoxia. Silencing of these genes in cultured PAECs decreased inflammation and apoptosis, and increased angiogenesis in hypoxic conditions. Our pathway analysis and gene silencing experiments revealed that BCL2-associated agonist of cell death (BAD) is a downstream mediator of
AREG
.
BAD
silencing in ECs lacking
AREG
, mitigated inflammation and apoptosis and suppressed tube formation. In conclusion, loss of amphiregulin and its receptor EGFR in PH is a crucial step in the pathogenesis of PH, promoting pulmonary endothelial cell death, vascular recruitment of inflammatory myeloid cells, and vascular remodeling.
Group 3 Pulmonary Hypertension: From Bench to Bedside
Authors: Singh Navneet , Dorfmüller Peter , Shlobin Oksana A. , Ventetuolo Corey E.
Published: April 2022

Pulmonary hypertension (PH) because of chronic lung disease is categorized as Group 3 PH in the most recent classification system. Prevalence of these diseases is increasing over time, creating a growing need for effective therapeutic options. Recent approval of the first pulmonary arterial hypertension therapy for the treatment of Group 3 PH related to interstitial lung disease represents an encouraging advancement. This review focuses on molecular mechanisms contributing to pulmonary vasculopathy in chronic hypoxia, the pathology and epidemiology of Group 3 PH, the right ventricular dysfunction observed in this population and clinical trial data that inform the use of pulmonary vasodilators in Group 3 PH.
Understanding the Pathobiology of Pulmonary Hypertension Due to Left Heart Disease
Authors: Huston Jessica H. , Shah Sanjiv J.
Published: April 2022

The development of pulmonary hypertension (PH) is common and has adverse prognostic implications in patients with heart failure due to left heart disease (LHD), and thus far, there are no known treatments specifically for PH-LHD, also known as group 2 PH. Diagnostic thresholds for PH-LHD, and clinical classification of PH-LHD phenotypes, continue to evolve and, therefore, present a challenge for basic and translational scientists actively investigating PH-LHD in the preclinical setting. Furthermore, the pathobiology of PH-LHD is not well understood, although pulmonary vascular remodeling is thought to result from (1) increased wall stress due to increased left atrial pressures; (2) hemodynamic congestion-induced decreased shear stress in the pulmonary vascular bed; (3) comorbidity-induced endothelial dysfunction with direct injury to the pulmonary microvasculature; and (4) superimposed pulmonary arterial hypertension risk factors. To ultimately be able to modify disease, either by prevention or treatment, a better understanding of the various drivers of PH-LHD, including endothelial dysfunction, abnormalities in vascular tone, platelet aggregation, inflammation, adipocytokines, and systemic complications (including splanchnic congestion and lymphatic dysfunction) must be further investigated. Here, we review the diagnostic criteria and various hemodynamic phenotypes of PH-LHD, the potential biological mechanisms underlying this disorder, and pressing questions yet to be answered about the pathobiology of PH-LHD.
New Mutations and Pathogenesis of Pulmonary Hypertension: Progress and Puzzles in Disease Pathogenesis
Authors: Aldred Micheala A. , Morrell Nicholas W. , Guignabert Christophe
Published: April 2022

Pulmonary arterial hypertension (PAH) is a complex multifactorial disease with poor prognosis characterized by functional and structural alterations of the pulmonary circulation causing marked increase in pulmonary vascular resistance, ultimately leading to right heart failure and death. Mutations in the gene encoding BMPRII-a receptor for the TGF-β (transforming growth factor-beta) superfamily—account for over 70% of families with PAH and ≈20% of sporadic cases. In recent years, however, less common or rare mutations in other genes have been identified. This review will consider how these newly discovered PAH genes could help to provide a better understanding of the molecular and cellular bases of the maintenance of the pulmonary vascular integrity, as well as their role in the PAH pathogenesis underlying occlusion of arterioles in the lung. We will also discuss how insights into the genetic contributions of these new PAH-related genes may open up new therapeutic targets for this, currently incurable, cardiopulmonary disorder.
The youngest and first Lebanese representative of the family Saucrosmylidae (Insecta, Neuroptera) from the Cenomanian
Authors: AZAR DANY , NEL ANDRÉ
Published: April 2022

Lebanosmylus leae gen. et sp. nov., the youngest and first representative of the family Saucrosmylidae, is described from the marine lithographic Cenomanian limestone of the Konservat-Lagerstätte of Hjoula, Lebanon, on the basis of a wing compression. The paleobiogeographic implications are briefly discussed.
Coarazuphium bambui (Carabidae: Zuphiini), a new cave-dwelling beetle from the threatened region of Serra do Ramalho, Brazil
Authors: PELLEGRINI THAIS GIOVANNINI , BICHUETTE MARIA ELINA , VIEIRA LETÍCIA
Published: April 2022

To date, 20 species of obligate cave-dwelling beetles are known from Brazil, and 12 belong to the Coarazuphium genus. In this paper, we describe Coarazuphium bambui sp. n., from two specimens, one male and one female, collected in the Gruna Boca da Lapa cave located in the municipality of Feira da Mata (Bahia state, Brazil). The most striking difference between C. bambui and other species of the genus is the presence of three pairs of fixed setae posteriorly on the head, combined with the slightly elytral sinuosity. We also provide an updated key for species identification of the Coarazuphium genus. Finally, we highlight the importance of the Serra do Ramalho karst area for the conservation of troglobite diversity in the Brazilian context.
Decadal variation of the rainfall predictability over the maritime continent in the wet season
Authors: Li Xiaojing , Tang Youmin , Song Xunshu , Liu Ting
Published: April 2022

Maritime continent (MC) rainfall plays an important role in global climate variability, but its prediction remains extremely challenging. Based on a long-term state-of-the-art hindcast product recently completed by the authors’ group, this work investigates the decadal variation of the MC rainfall predictability in the wet season for the first time. The prediction skills were relatively high before 1940 and after 1980, but relatively low between these years. In a diagnostic analysis of the controlling factors of the decadal variation, the signal strength represented by the variance of the rainfall variability was identified as the dominant factor. Further analysis concluded that the El Niño Southern Oscillation (ENSO) phases are the key controlling sources. The MC rainfall was more predictable during periods dominated by El Niño events than during periods dominated by La Niña events because El Niño elicits stronger ocean–atmosphere interactions in the tropics, providing a stronger signal of MC rainfall than La Niña events.