bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15656: Global Intracoronary Infusion of Allogeneic Cardiosphere-Derived Cells (CDCs) Immediately After Reperfusion Stimulates Myocyte Regeneration in Remote Viable Myocardium in Swine With Acute Myocardial Infarction
Authors: Suzuki Gen , Weil Brian R , Leiker Merced M , Goelz Andrew , Fallavollita James A , Canty John M
Published: July 2021

Introduction:
Previous studies evaluating regenerative strategies have focused on administering stem cells to the infarct related artery. Unfortunately, this does not stimulate cardiac regeneration nor prevent myocyte loss in viable remote myocardium that becomes dysfunctional due to LV remodeling.

Hypothesis:
We hypothesized that administrating allogeneic CDCs to the entire heart (global CDC infusion) at the time of reperfusion could improve function, stimulate myocyte regeneration and prevent myocyte loss throughout the LV.

Methods:
Yorkshire swine (n=12) underwent a one hour LAD occlusion. Ejection fraction (EF) decreased from 63 ± 2% at baseline to 44 ± 2% after infarction (p<0.05 vs. baseline). Immediately after reperfusion animals were randomized to allogeneic intracoronary CDCs or vehicle in a blinded fashion (n=6 each). Allogeneic CDCs (20 x 10^6 CDCs, cyclosporine 100 mg/day) were infused into the 3 major coronary distributions without interrupting flow. Four weeks later we assessed myocardial function (echo), myocyte proliferation (Ki67), infarct size (TTC), myocyte nuclear density and cell size in comparison to vehicle.

Results:
After 4 weeks, global CDC infusion increased wall thickening and ejection fraction despite the fact that infarct volume was not different (Table). CDCs stimulated myocyte proliferation (Ki67) in border and remote regions by 3-fold. As a result, myocyte number (nuclear density) increased by 34 % and cell size decreased by 7% in viable infarct border and remote regions.

Conclusion:
Global infusion of allogeneic CDCs immediately after reperfusion 1.) stimulates myocyte regeneration in viable myocardium remote from the infarct and 2.) improves regional and global LV function without altering infarct size. Thus, treating viable remote myocardium as well as the infarct related artery with allogeneic CDCs may afford a widely available approach to reverse LV dysfunction in patients with acute myocardial infarction.
Abstract 15669: Generation and LDLR Functional Correction of Familial Hypercholesterolemia iPSC With Physiologically Responsive Non-Integrating BAC Vector
Authors: Ramakrishnan Venkat M , Yang Jeong Yeh , Burchell Patrick O , Tien Kevin T , Bocard Braden R , Maijub John G , Williams Stuart K , Wade-Martins Richard , West Franklin D , Boyd Nolan L
Published: July 2021

Familial Hypercholesterolemia (FH) is a monogenic disorder of low-density lipoprotein receptor (LDLR) dysfunction, resulting in pathological LDL cholesterol levels and accelerated cardiovascular disease. Many FH patients are refractory to pharmacologic therapies and require cholesterol apheresis or liver transplant. Induced pluripotent stem cells (iPSC) are a promising cell-based option for ameliorating such disorders, though clinically relevant approaches for their functional correction remain to be explored. Homozygous FH fibroblasts were used to generate iPSC (FH-iPSC) using non-integrating synthetic modified mRNAs. Pluripotence was confirmed via immunocytochemistry (OCT4, SOX2, SSEA4, TRA 1-60 & TRA 1-81), in vitro spontaneous differentiation, and in vivo teratoma formation. To mitigate LDLR dysfunction, FH-iPSC were non-virally transfected with a physiologically sensitive episomal LDLR BAC-based plasmid, circumventing cytotoxic LDLR over-expression, insertional mutagenesis, and transgene activation. Transfected colonies (FH-iPSC-LDLR) were selected via Hygromycin-B resistance. After six months of continuous culture, the plasmid was rescued by alkaline lysis, isolated, and introduced into CHO-a7 (LDLR-/-) cells. AgeI restriction digest analysis was performed and DiI-LDL uptake qualitatively demonstrated plasmid functionality. FH-iPSC were also differentiated into hepatocyte-like cells (FH-HLC) and tested for definitive endoderm (SOX17, HNF4α, GATA4) and hepatocyte lineage (AFP, Albumin) markers via PCR and immunocytochemistry. FH-HLC stored lipids and cleared Indocyanine Green. Corrected FH-HLC (FH-HLC-LDLR) qualitatively exhibited markedly increased DiI-LDL internalization compared to dysfunctional FH-HLC (Figure 1). These experiments support a proof-of-principle that patient-specific iPSC can be generated and functionally rescued with clinically relevant vectors to produce therapeutic cell lines.
Abstract 15674: Notch3/rbpjk Signaling Pathway in the Coronary Arteries is Involved in the Development of Heart Failure in Response to Hypertension
Authors: Monfort Astrid , Ragot Hélène , Polidano Evelyne , Merval Regine , Delcayre Claude , Chatziantoniou Christos , Samuel Jane-Lise , Cohen-Solal Alain
Published: July 2021

Background:
Notch3, a receptor expressed in vascular smooth muscle cells (VSMC), plays a key role in the integrity of resistance arteries by controlling the maturation of VSMC through RBPJk, a canonical Notch transcriptional factor. We hypothesized that Notch3 signaling pathway in the VSMCs of the coronary arteries might play a key role in the cardiac adaptation to pressure-overload.

Methods:
To eliminate congenital defect biases, we used mice in which conditional tamoxifen- selective deletion of RBPJk in VSMC was induced at the age of 4 weeks (SMMHC-CRE ER T2, RBP-JK loxp/loxp). Seven weeks later, hypertension was induced in control (C) mice (n= 10) and those with RBPJk deletion (SM-RBPJ-KO, n = 13) by infusion of Angiotensin 2 (Ang2) (1μg/kg/min) using Alzet minipumps after surgery.

Results:
In response to Ang2, SM-RBPJ-KO and control mice showed similar hypertension (159 ±7 mmHg vs 150±10 mmHg). By day 8 after surgery, SM-RBPJ-KO mice only developed a severe heart failure with anarsaca. These mice showed a decrease in shortening fraction (-42%, p<0.01), a left ventricular dilatation (+15%, p<0.01), and a ventricular hypertrophy (+12%, p<0.05) when compared to C + Ang2. As expected, C + Ang 2 hearts showed an increase in ANP, B-MHC and Gal-3 (+76%, +55%, +46%, p<0.05 respectively vs C) mRNA expressions, whereas SM-RBPJ-KO hearts exhibited even higher induction of ANP (+48%, p<0.01), Gal-3 (+74%, p<0.01), CD68 (+55%, p<0.05) and collagen-3 (+78%, p<0.01) when compared to C + Ang2. This cardiac phenotype confirmed the severe heart failure. Interestingly, immuno-morphometric analysis showed an arteriolar rarefaction in SM-RBPJ-KO + Ang2 mice associated with a lack of angiogenic signaling pathway revealed by a decrease in VEGFa and angiopoietin 2 mRNAs (-50%, and -52%, p<0.05, respectively vs. C + Ang2).

Conclusion:
We provide evidence that in adulthood, dysfunction of the Notch3/RBPJk signaling pathway in the coronary arteries contributes in the aggravation of heart failure in response to rapid increase in blood pressure.
Abstract 15722: Demographic Factors for 30 Day Readmission Following Percutaneous Coronary Intervention Procedure: Analysis of Nationwide Inpatient Sample Data
Authors: Aggarwal Sourabh , Gupta Vishal
Published: July 2021

Introduction:
Acute myocardial infarction is a major cause of morbidity and mortality in USA with percutaneous coronary intervention (PCI) as a mainstay of therapy. Short term hospital readmissions account for a significant portion of health care budget and much of the focus recently has been on reducing 30 day readmission rate. This study was done to determine demographic parameters associated with 30 day readmission rate after index PCI.

Methods:
Nationwide Inpatient Sample (NIS) data was used to extract data of patients discharged after PCI during index admission for years 2009-2011. Patients were identified by Clinical Classification Software code 45, corresponding to ICD 9 procedure codes of 00.66, 17.55, 36.01, 36.02 and 36.05. NIS represents 20% of all hospital data in US. Patients readmitted within 30 days were identified and demographic parameters associated with high readmission rate identified.

Results:
We identified a total of 1,784,929 hospitalizations where PCI was performed with 13.04% readmitted within 30 days after index hospitalizations. Elder age (65+), female gender, Medicaid insurance, low median income for zip code and metropolitan areas were associated with high 30 day readmission rate.

Conclusions:
This first national study identifies the demographic parameters associated with high 30 day readmission rate. Strategies to reduce morbidity and healthcare cost should be targeted more on these groups with high readmission rate. Study was limited by the fact that the admission for staged PCI could not he differentiated from unplanned readmission. Further studies might be needed to supplement the results.
Abstract 15730: Ankle-Brachial Index and Physical Function in Community-Based Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Matsushita Kunihiro , Ballew Shoshana , Sang Yingying , Kalbaugh Corey , Loehr Laura , Hirsch Alan , Tanaka Hirofumi , Heiss Gerardo , Windham B. Gwen , Selvin Elizabeth , Coresh Josef
Published: July 2021

Background:
Lower extremity peripheral artery disease (PAD), commonly defined by an ankle-brachial index (ABI) <0.9, increases mortality risk and also reduces physical function. All prior studies of the impact of PAD on objectively measured physical function have been in restricted populations with known PAD or physical inactivity, leaving uncertainty regarding its impact in the community.

Methods:
We studied 5,351 ARIC participants (age 71-90 years during 2011-2013) who underwent the assessment of ABI and the Short Physical Performance Battery (SPPB, 0-12 scale), a summary measure of physical function based on three domains (4-meter walk velocity, timed chair stands, and standing balance). Logistic regression models examined the association of ABI with poor physical function (SPPB score <6), adjusting for potential confounders including a history of other cardiovascular diseases.

Results:
There were 463 participants (8.2%) with ABI <0.9 and 506 participants (9.0%) with ABI ≥1.3, a potential manifestation of PAD reflecting noncompressible pedal arteries. Both ABI <0.9 and ≥1.3 were significantly and independently associated with higher odds of having poor physical function compared to those with a normal ABI (1.1-1.2). The 469 participants (8.8%) with a “borderline” low ABI (0.9-1.0) also demonstrated significantly poor physical function. Low ABI was significantly associated with poor performance in every SPPB domain, whereas none were statistically significant for high ABI. The results were largely consistent among those without a history of stroke or heart failure.

Conclusion:
In our population of community-dwelling older adults, ~25% had low, borderline low, or high ABI suggestive of PAD and demonstrated poorer physical function compared to those with normal ABI. Since physical function is a key element for independent living in older adults and several therapeutic options for PAD exist, our findings may have broad and important implications.
Abstract 15751: A New Role of Sox6 in Renin Regulation
Authors: Gomez Jose , Sum Eric , Keyte Anna , Hodgkinson Conrad , Hutson Mary , Dzau Victor , Mirotsou Maria
Published: July 2021

Introduction:
The renin-angiotensin system (RAS) is an important component of blood pressure regulation in mammals. Renin catalyzes the rate limiting step of RAS, is produced and stored by Juxtaglomerular (JG) cells in the kidney. However, the transcriptional mechanisms that govern the specification of renin expressing cells under normal or pathophysiological conditions remain poorly understood. During blood pressure changes the number of adult renal cells expressing renin increase through a process termed JG recruitment. We found that this process involves differentiation mesenchymal stromal-like cells (MSC) to renin expressing cells. Our aim in this study was to determine new regulators of renin cell fate during kidney development and JG recruitment.

Methods:
Gene expression profiles of MSC and JG cells were performed with Affymetrix Mouse 430 2.0 array.
In vitro
assays were performed in adult renal MSCs isolated from C57BL6 Ren1c YFP mice. Renin expression
in vitro
was induced by treatment with IBMX and Forskolin. MSC were transduced with lentivirus carrying vectors for Sox6, Sox6 shRNA or controls.
Ex vivo
analysis was performed in embryonic kidneys (14.5 dpc) isolated and transduced with Sox6 or scrambled shRNA, kidneys were then cultured for 4 days and the expression of Sox6 and Renin analyzed by IHC.

Results:
Data showed that the transcription factor Sox6 is expressed in renin producing cells in the developing kidney (n=4) and in the adult kidney after stimulation that promotes JG recruitment (n=3). Overexpression of Sox6 (n=3, P<0.05) enhanced differentiation of renal MSCs to renin producing cells
in vitro
, and Sox6 knockdown reduced differentiation of renal MSC to renin producing cells
in vitro
(6-fold, n=4, P<0.01). Furthermore, knockdown of Sox6 in an
ex vivo
model of kidney development resulted in a 5-fold reduction in renin expressing cells (n=4, P<0.05).

Conclusion:
These results support a novel role for Sox6 in the development of renin expressing cells. This may have implications for renal development and physiology, opening new possibilities of addressing questions regarding both developmental and physiological regulation of renin.
Abstract 15758: High Intensity Focused Ultrasound Can Produce Noninvasive Myocardial Infarction in Mice
Authors: Walton Chad , Castel Nikki , Shohet Ralph V
Published: July 2021

High Intensity Focused Ultrasound (HIFU) can destroy biological tissue at specific focal depths without affecting intervening anatomical structures. We have used a custom ultrasound instrument coupled to a stereotactic targeting frame, in a non-surgical, external application of a 1.1 MHz HIFU transducer in order to target the aortic root to disrupt blood flow in the Left Anterior Descending coronary artery, effectively inducing a myocardial infarction. The optimized ultrasound parameters include 20 cycles with an energy equaling a mechanical index (MI) of ~13. This flexible and customizable HIFU-based ultrasound platform permits a more physiological infarction model in mice than is presently available using invasive surgical techniques. The advantages of this approach include avoiding the trauma of intubation, thoracotomy, and direct manipulation of the heart. We expect that this approach will improve the speed of recovery, reduce mortality, and more closely recapitulate the situation of myocardial infarction in human patients. Recognizing the novelty of the method we compared it to conventional LAD ligation. This new technique produces similar infarctions, evaluated by ECG, echocardiography, and histology. This nonsurgical approach to myocardial infarction should be useful in a broad range of cardiac investigations.
Abstract 15817: Tricuspid Valve Imaging by 3D Transesophageal Echocardiography: Feasibility of Coaptation Length Measurement and Its Relationship With Severity of Regurgitation
Authors: Obase Kikuko , Weinert Lynn , Mor-Avi Victor , Lang Roberto M
Published: July 2021

Background:
The coaptation length (CL) of the mitral valve leaflet decreases with increasing mitral regurgitation. Visualization of the CL of the tricuspid valve (TV) is challenging using conventional 2D echocardiography. The aims of this study were: (1) to test the feasibility of visualizing and quantifying the CL of the TV using three-dimensional (3D) transesophageal echocardiography (TEE), and (2) to study it relationship with the severity of tricuspid regurgitation (TR).

Methods:
Full-volume 3D TEE datasets of the TV were obtained in 24 patients from the transgastric approach. Using multiplanar reconstruction, short-axis plane depicting an en-face view of the TV was used to mark the central coaptation point (Fig. A). Three planes cutting through this point were then selected to view the 3 coaptation lines between: (1) anterior and posterior, (2) septal and anterior, and (3) septal and posterior TV leaflets (Figs. B-D). The CL was measured in each of these planes to obtain mean CL. The severity of tricuspid regurgitation was graded qualitatively as “none”, “trace”, “mild” and “moderate”.

Results:
Visualization of leaflet coaptation was feasible in 17/24 patients (71%). The mean CL was 0.89±0.03 cm in patients with no TR (N=4), 0.64±0.13 with trace TR (N=6), 0.50±0.07 with mild TR (N=3) and 0.13±0.11 with moderate TR (N=4). Since there was no overlap between the “moderate” group and the other 3 groups, the threshold of average CL for moderate TR was estimated to be between 0.25 (highest value in the “moderate” group) and 0.39 cm (lowest value in the other groups) (Fig. E).

Conclusion:
Visualization of the TV leaflet coaptation length from transgastric 3D TEE images is feasible in the majority of patients. TV coaptation length is inversely related to the severity of TR. The ability to visualize and quantify the CL of the TV may be useful when planning tricuspid valve repair surgery. Our findings suggest that CL below the threshold may indicate clinically significant TR.
Abstract 15840: Electrogram Morphology Recurrence Analysis Identifies Areas of Consistent Activation Directions and Rotor Activity in a Rapid Atrial Pacing Model of Atrial Fibrillation
Authors: Gordon David , Arora Rishi , Aistrup Gary L , Goldberger Jeffrey J , Ng Jason
Published: July 2021

Introduction:
Electrogram morphology recurrence (EMR) analysis is a novel mapping technique which characterizes morphology patterns during atrial fibrillation (AF). Using high resolution electrical mapping, we tested the hypothesis that EMR analysis could identify areas of consistent activation directions and rotor activity in a canine rapid atrial pacing model of AF.

Methods:
Three weeks of rapid right atrial pacing (600 bpm) was performed in six dogs. A triangular plaque was used to obtain 117 simultaneous bipolar AF electrograms from two right and three left atrial locations. EMR plots for each electrogram recording were created by cross-correlation of each activation waveform with each other. The percentage of the most common morphology (REC%) and the mean cycle length (CL) of activations with the most common morphology (CLR) were computed. Activation pattern for each site was classified as either having stable rotors, passive activity, or chaotic activity. Activation vectors were computed and a vector index (VI) was used to measure vector consistency.

Results:
Figure A shows an example of an EMR plot map from recordings in the left atrium with red indicating areas of high EMR. The sites with the shortest CL had an average CL of 81±13 ms. The sites with the highest REC% had an average value of 99±2%. The sites with the shortest CLR had an average value of 91±17 ms. REC% was highly correlated with VI (Figure B). Minimum CL was only moderately shorter in rotor sites compared to chaotic and passive sites (Figure C). Maximum REC% was significantly higher in rotors sites than in chaotic sites, but not different from passive sites (Figure D). Minimum CLR in the rotor sites were significantly less than both the chaotic and passive sites (Figure E).

Conclusions:
EMR analysis is a new mapping technique that correlates well with activation vector consistency and can identify rotor activity. This is a promising method for mapping AF that may identify sources that can be targeted for ablation.
Abstract 15857: Aortic Valve Calcification is Reduced by COX2 Inhibition
Authors: Wirrig Elaine E , Hinton Robert B , Yutzey Katherine E
Published: July 2021

Calcific aortic valve disease (CAVD) is a significant cause of morbidity and mortality in the United States and is characterized by calcific nodule formation and stenosis of the valve. The molecular mechanisms underlying valve calcification are poorly understood and surgical replacement remains the most common treatment option for severe aortic stenosis. Molecular mechanisms and treatment strategies for CAVD were examined in klotho-deficient mice, which develop aortic valve (AoV) calcification in association with accelerated aging. Through a microarray screen comparing AoV tissues from klotho-deficient and wild type mice, the gene encoding COX2 (cyclooxygenase 2/ ptgs2) was observed to have significantly increased expression in calcified AoV tissues of klotho-deficient mice. Since COX2 activity contributes to bone differentiation and homeostasis, we hypothesize that COX2 activity also contributes to valve calcification through induction of osteogenic mechanisms. In klotho-deficient mice, COX2 expression is increased throughout regions of valve calcification and is induced in the valvular interstitial cells (VICs) prior to the presence of detectable calcification. Similarly, COX2 expression is increased in human diseased AoVs in regions of valve calcification. Treatment of cultured porcine aortic VICs with osteogenic media induces bone marker gene expression, which is blocked by inhibition of COX2 activity, supporting a therapeutic strategy of COX2 inhibition in CAVD. In vivo, genetic loss of function of COX2 cyclooxygenase activity partially rescues AoV calcification in klotho-deficient mice. Moreover, pharmacologic inhibition of COX2 activity in klotho-deficient mice via celecoxib-containing diet reduces AoV calcification and blocks bone marker gene expression. Thus, COX2 expression is upregulated in CAVD and inhibition of COX2 activity is an effective treatment for reducing AoV calcification in klotho-deficient mice. The data presented show for the first time that COX2 activity contributes to bone marker gene induction and AoV calcification and that COX2 inhibition effectively reduces valve calcification in a mouse model of CAVD.
Abstract 15954: Both Tetrahydrobiopterin Depletion and eNOS S-Glutathionytion Contribute to eNOS Uncoupling in Coronary Disease Patients
Authors: Varadharaj Saradhadevi , DePascali Francesco , Crestanello Juan , Kilic Ahmet , Boslett James , Hemann Craig , Chen Chun-An , Zweier Jay L
Published: July 2021

Background:
Vascular endothelial dysfunction (VED) is associated with increased oxidative stress due to eNOS uncoupling with increased superoxide (•O2-) production and has important prognostic clinical implications for subsequent cardiovascular events. Our recent studies in hypertensive rats revealed a novel redox-regulated pathway through which eNOS is uncoupled due to S-glutathionylation. However, its role in human vascular disease remains unclear. Hence, we studied eNOS S-glutathionylation and uncoupling and in aortic tissue from patients undergoing cardiovascular surgery and heart transplantation (N=25).

Methods:
Studies were performed using vessels from spontaneously hypertensive rats (SHRs), control WKY rats and aortic tissue from patients undergoing cardiovascular surgery. S-glutathionylation was determined with anti-glutathione and anti-eNOS, and an antibody specific for eNOS S-glutathionylation at C689 (anti-eNOS Cys689-SG). •O2- was measured using fluorescent probe DHE in the absence/presence of the NOS inhibitor, L-NAME, DTT, or the SOD mimetic, MnTBAP. The NOS cofactor, BH4, was measured by HPLC.

Results & Conclusion:
S-glutathionylation of eNOS (eNOS-SG) was evident by immunohistology in SHR vessels compared to respective WKY control rat vessels. Similarly, immune assays of the aortic samples from vascular disease patients (VD) showed an increase in eNOS-SG protein when compared to no-disease control tissues (ND) and increased •O2- production was detected. Addition of DTT or β-ME decreased the levels of eNOS-SG with decreased •O2- generation. BH4 content was markedly decreased in the vessels of patients with coronary disease. BH4:BH2 ratio was decreased by over 5-fold also contributing to eNOS uncoupling. This provides the first evidence for an association of both eNOS S-glutathionylation and BH4 depletion leading to eNOS uncoupling with loss of endothelial dependent vasodilation in vessels of coronary disease patients.
Abstract 15967: Risk of Ventricular Tachyarrhythmias Following Ejection Fraction Improvement in Patients With Implantable Cardiac Defibrillators Implanted for Primary Prevention of Sudden Cardiac Death
Authors: Pillarisetti Jayasree , Gopinathannair Rakesh , Haney Matthew , Reddy Madhu , Reddy Sandeep , Khalafi Mehdi , Kanmantha Reddy Arun , Adabala Niveditha , Yarlagadda Vivek , Bommana Sudharani , Lakkireddy Dhanunjaya
Published: July 2021

Introduction:
In patients who undergo cardiac device (ICD) implantation for primary prevention of sudden cardiac death (SCD), data is unclear if their generator needs to be replaced at end of life if their ejection fraction improves. Despite improvement in EF however, the underlying scar may remain the same.

Methods:
A retrospective study was performed at two high volume centers. Data on 280 patients who underwent ICD implantation for primary prevention of SCD was obtained after excluding patients with incomplete follow-up data. These patients were followed until November 2013 for any improvement in EF and if they underwent a generator change at device ERI. All arrhythmic events and appropriate and inappropriate shocks/ATP were all recorded. Mortality records were obtained from social security death index and chart review.

Results:
Thirty percent (n=86/280) of patients improved their EF to > 35% of which 41% (n=36) underwent a generator change by the study ending period for ERI/lead malfunction/infection issues with the rest not yet at ERI. Mean baseline EF in patients with and without EF improvement was 26±7% and 23±7%, p=0.2. Data for arrhythmic events was unavailable in n=25 patients in those with EF improvement and n =39 patients in those without EF improvement. Among the remaining 61 patients, appropriate events (shock+ATP) were noted in 22% of patients (n=14/61) and inappropriate shocks and ATP in 6% of (n=4/61) patients after their EF improved to > 35%. Two patients received a prior shock when their EF was low. In contrast, in patients who had no improvement in EF, 31% (n=48/155) received an appropriate event (p=<0.01) while 14% (n=22/155) (p<0.02) received inappropriate shocks and ATP. All-cause mortality in patients without subsequent improvement in EF versus those with EF improvement (38% vs. 17% (p=.006). Mean time to EF improvement was 44±35 months and mean duration of follow-up since EF improvement was 38±27 months.

Conclusions:
Although patients with improvement in EF had fewer total events (ATP+shock) than those without improvement, the percentage of patients with ICD therapy post EF improvement with no prior ICD discharges is high enough (20%, n=12/59) to warrant an ICD despite EF improvement.
Abstract 15976: Results of the Full Cox-Maze Procedure: EKG vs 24-Hour Holter vs One-Week Long-Term Holter Monitoring
Authors: Ad Niv , Stone Lori E , Holmes Sari D
Published: July 2021

Introduction:
Much of work published on Cox-Maze procedure results has utilized EKGs or 24-hour Holter without information on anti-arrhythmic drugs (AAD). The purpose of this study was to explore results at 6 and 24 months following the Cox-Maze procedure using various rhythm monitoring techniques.

Hypothesis:
It was hypothesized that long-term monitoring (LTM) would identify more patients who experienced atrial arrhythmia (AA) at each time point than other monitoring techniques.

Methods:
Cox-Maze III/IV patients off AAD were offered 1-week LTM with n=220 at 6 and n=94 at 24 months. EKG, 24-hour Holter, and LTM were ascertained at the same time. The HRS definition (AA >30 seconds) was used for ablation failure.

Results:
At 6 months EKG found n=216 returned to sinus rhythm (SR), 24-hr Holter found n=211 returned to SR, while n=203 were in SR by LTM (FIGURE). Of patients experiencing AA at 6 months, duration <1 hour was documented in 56% by 24-hr Holter and 59% by LTM (FIGURE). At 24 months, EKG found n=89 returned to SR, 24-hr Holter found n=88 returned to SR, while n=85 were in SR by LTM. Of patients experiencing AA at 24 months, duration <1 hour was documented in 50% by 24-hr Holter and 67% by LTM. At 6 months, percent in SR differed for EKG vs LTM (p<0.001) and 24-hr Holter vs LTM (p=0.02). At 24 months, monitoring methods did not differ.

Conclusions:
The Cox-Maze procedure demonstrated high return to SR off AAD, regardless of monitoring technique. However, LTM provides more accuracy earlier in postoperative period and should be used when discussing discontinuation of anticoagulation. Due to clinical and financial challenges in applying LTM, patients in which LTM has most value should be identified.
Abstract 15995: Role of Kir Channels in Flow-Induced Vasodilatation
Authors: Ahn Sang Joon , Bian Jing-Tan , Schwab Sarah , Szczurek Mary , Phillips Shane A , Levitan Irena
Published: July 2021

Introduction:
Flow-induced vasodilation (FIV) is an important physiological stimulus for regulating vascular tone. A loss of endothelial-dependent FIV is an early indication of endothelial dysfunction. Earlier studies proposed that endothelial inwardly-rectifying K
+
channels (Kir) are putative flow sensors, but the role of Kir in the regulation of vascular tone is not known.

Hypothesis:
Kir channels play a key role in FIV.

Methods:
FIV was assessed in mouse mesenteric arteries isolated from wild type (WT) and Kir2.1
+/-
heterozygous mice. Briefly, resistance arteries were isolated, cannulated and pressurized in an organ chamber with glass micropipettes. Preparations were visualized in real time and the inner diameter of the vessels was measured using acquired images. Kir channels in arteries isolated from WT mice were downregulated by a dominant-negative subunit of Kir2.1 or blocked by Ba
2+
. The role of Kir channels in flow-induced release of NO was tested by Diaminorhodamine-4M, NO specific fluorescence dye.

Results:
Our results show that FIV is significantly inhibited in mesenteric arteries isolated from Kir2.1
+/-
mice that have reduced Kir2.1 expression as compared with WT mice (42%±3% relaxation in Kir2.1
+/-
vs 94.06%±2.2% in WT mice, n=11, p<0.05). Moreover, blocking Kir channels with Ba
2+
or downregulating its activity with a dominant-negative subunit of Kir2.1 also resulted in significant inhibition of FIV in arteries isolated from WT mice (47%±3% relaxation in the presence of Ba
2+
, 43%±5% in arteries infected with dnKir2.1 vs 94.06%±2.2% in WT n=3, p<0.05). As expected, inhibiting NO release by LNAME, a nitric oxide synthase inhibitor, reduced FIV in WT arteries (39%±5%, n=4, p<0.05), but no effect was observed in arteries isolated from Kir2.1
+/-
mice. Furthermore, flow-induced release of NO was significantly reduced (1.5-fold decreased, p<0.05). In contrast, inhibiting Ca
2+
-dependent K
+
channels (SK/IK) had an additive effect to Kir suppression suggesting that SK/IK and Kir channels regulate FIV by parallel pathways.

In conclusion, our results indicate that Kir channels contribute significantly to FIV by regulating NO release.
Abstract 16017: Atrial Fibrillation is Associated With Increased Risk for Myocardial Infarction in the Cardiovascular Health Study (CHS)
Authors: Tattersall Matthew C , Stein James H , Bartz Traci , Gepner Adam D , Heckbert Susan R , Burke Gregory L , Korcarz Claudia E , Wasmund Stephen L , Kronmal Richard A , Hamdan Mohamed H
Published: July 2021

Background:
Atrial fibrillation (AF) is highly prevalent and poses a significant public health burden on the aging population. We hypothesized that AF independently predicts myocardial infarction (MI) in the Cardiovascular Health Study (CHS).

Methods:
AF was evaluated longitudinally in participants free of cardiovascular disease at baseline in the CHS. Participants were followed for a mean (standard deviation, SD) 12.7 (5.8) years for development of fatal or nonfatal MI. Cox regression models were utilized to assess the associations of time-updated AF and MI in fully adjusted models and models with gender interaction.

Results:
Of the 5888 participants in the CHS, 4158 met the inclusion criteria. The mean (SD) age was 72.3 (5.4) years old (38.3% male, 14.3% African-American). Eighty-two had prevalent AF; 1005 developed incident AF during follow up (AF group, n=1087). To avoid bias, participants diagnosed with AF at the same time as their MI were not included in the AF group. Baseline total cholesterol (212.4 [38.6] mg/dL), systolic blood pressure (SBP, 136.1 [21.4] mmHg), and diabetes mellitus prevalence (13.6%) were similar between groups. AF updated as a time-varying exposure was associated with a higher risk of MI: hazard ratio (HR) 1.61, [95% CI 1.32-1.96], after adjusting for age, gender, race, SBP, total and high-density lipoprotein cholesterol, current smoking, fasting glucose, education, alcohol use, C-reactive protein, body-mass index, diabetes, anti-arrhythmic use, and time-updated use of aspirin, anti-hypertensive and lipid medications. Women were at higher risk (HR 2.00 [95% CI 1.53-2.62]) than men (HR 1.33 [95% CI 0.99-1.77]) (p for interaction=0.02).

Conclusion:
In a large cohort study with over a decade of follow-up, AF was associated with an increased risk for MI. This association was more pronounced in women.
Abstract 16121: Recombinant Human Placental Growth Factor 2 is a Safe and Effective Therapy for Ischemic Cardiomyopathy in Atherosclerotic Mice
Authors: Wu Ming , Swinnen Melissa , Caluwe Ellen , Gillijns Hilde , Vanden Driessche Nina , Pokreisz Peter , Janssens Stefan
Published: July 2021

Aim:
Angiogenic growth factor therapy carries a risk of stimulating atherosclerotic plaque growth. We evaluated whether systemic infusion of recombinant human placental growth factor (rhPlGF) 2 improves myocardial neovascularization, left ventricular (LV) function and adverse remodeling in a murine model of advanced atherosclerosis and chronic myocardial infarction (MI) without increasing atherosclerotic plaque size and plaque vulnerability.

Methods:
ApoE
-/-
mice were fed a high cholesterol diet and MI was induced 4 weeks (w) later using 60 min LAD occlusion followed by reperfusion. After 8 w, we assessed LV function using echocardiography and randomized mice to receive rhPlGF2 (450μg/kg/day, n=20) or PBS (n=20) via osmotic minipumps for 28 days. Echocardiography and histological analyses were performed at 12 and 20 w.

Results:
Infusion of rhPlGF2 increased PlGF plasma levels for 3 w up to ~1600-fold without adverse side effects, or changes in total cholesterol and high sensitive CRP levels. In rhPlGF2-treated mice, capillary and arteriolar density was significantly higher in ischemic myocardium (2813±212 capillaries/mm
2
at 12 w vs 2144±478 in PBS,
P
<0.05; 125±18 arterioles/mm
2
at 20 w vs 77±13 in PBS,
P
=0.001). RhPlGF2 significantly improved ejection fraction (EF), reduced LV end-systolic and end-diastolic volume indices at 12 w and prevented further LV dilation and EF deterioration at 20 w (Figure). RhPlGF2 did not increase plaque area in the aortic arch, or the degree of fibrosis, calcification, capillary or arteriolar density and MAC3-positive

cell areas in plaques at 12 and 20 w.

Conclusion:
Systemic rhPlGF2 infusion significantly improves neovascularization and contractile function, and prevents LV adverse remodeling in chronic ischemic cardiomyopathy without increasing atherosclerotic plaque burden or plaque vulnerability. RhPlGF2 may represent a promising and safe therapeutic strategy in chronic ischemic cardiomyopathy.
Abstract 16160: Common Autosomal Variants are Associated With Bicuspid Aortic Valve in Turner Syndrome
Authors: Prakash Siddharth , Silberbach Michael , Asch Federico , Limongelli Giuseppe , Michelena Hector ,   GenTAC Registry Consortium, Guo Dongchuan , Maslen Cheryl , Bondy Carolyn A , Milewicz Dianna M
Published: July 2021

Introduction:
The prevalence of bicuspid aortic valves (BAV) is enriched thirty-fold in women with Turner Syndrome (TS) in comparison with the general population.

Hypothesis:
Common autosomal variants influence the development of BAV in TS women, who may be uniquely sensitized to these variants by the loss of one X chromosome. We sought to identify autosomal BAV susceptibility genes in a cohort of TS women (average age 30 years, 38% BAV, 18% coarctation).

Methods:
A total of 106 TS women of European ancestry with BAV and 173 TS women with tricuspid aortic valves were genotyped on Illumina Omni-Express arrays. Valve phenotypes were determined by independent review of echocardiograms from the enrolling sites. Tests of association were performed using logistic regression without adjustment for covariates and were summarized in a meta-analysis.

Results:
Xp dosage was inversely and quantitatively associated with BAV status (P=0.02). Large, recurrent copy number variants in 1p36.13, 3q29, 8p23.1 and 9p24.3 were significantly enriched in BAV cases. After exclusion of 26 outlier samples in multidimensional scaling analysis, there was no significant genomic inflation (lambda= 1.02). The strongest genome-wide association signals were observed in 1p36.23, 3q23, 12q21.2, 18q21 and 22q13.31, and did not overlap with previously reported loci for BAV. A total of 13 SNPs in 18q21 were positively associated with BAV (OR=2.5-4.3) with a minimum P value of 1x10-7. Replication of these regions in independent groups of cases is ongoing.

Conclusion:
Our results demonstrate that autosomal variants with large magnitudes of effect contribute to BAV in TS women, confirming our hypothesis, and provide evidence for gene-gene interactions in BAV formation.
Abstract 16255: Wearable Cardioverter Defibrillator Treatment Characteristics and Outcomes in Recent Myocardial Infarction Patients With Heart Failure
Authors: Perumal Ramu , Sun Jackie , Szymkiewicz Steven J
Published: July 2021

Introduction:
Previous studies report patients (pts) with acute myocardial infarction (MI) complicated by heart failure (HF) have poorer outcomes than non-ischemic HF pts. We determined the clinical and arrhythmia characteristics and outcomes in recent (< 40 days) MI pts with HF versus non-ischemic (NICM) HF pts treated by the wearable cardioverter defibrillator (WCD).

Methods:
WCD pts with a medical history of HF treated for VT or VF between 1/2007 and 11/2013 were identified from the manufacturer-maintained registry. Pts were classified as recent MI if they were identified as having a “recent MI with ejection fraction (EF) ≤ 35%” or given an ICD-9 diagnostic code of 410.xx (acute MI). Pts were classified as non-ischemic if they had no epicardial coronary vessels with ≥ 75% stenosis, no history of myocardial infarction, and no coronary revascularization. Data were reviewed for demographics, ECG recordings, and 24-hour survival. Electrical storm was defined as 3 or more unique VT/VF events requiring WCD therapy over a 24-hour time period.

Results:
Total of 346 pts met the study criteria, with 56% classified as recent MI with HF (MI-HF). MI-HF group was more likely to have risk factors for ischemic disease such as being older, male, hypertensive, diabetic, etc. (Table). The mean difference in EF between the two groups was less than 5%. MI-HF pts were 1.7 times more likely to be in VT versus VF at initial shock and 2.1 times more likely to have an electrical storm. Conversion of VT/VF events to slower rhythms by WCD treatment shock was 98% or greater in both groups. 24-hour post-treatment survival was 92% for all pts, with no difference between the two groups.

CONCLUSIONS:
Recent MI pts with HF who were treated by the WCD were likely to be older and male, with risk factors for ischemic disease. In addition, MI-HF pts exhibited increased incidence of VT versus VF events and electrical storm. The WCD was effective in terminating arrhythmic events with a high post-treatment survival in both groups.
Abstract 16308: Non-Invasive Three Dimensional Cardiac Electrical Imaging: A Clinical Study
Authors: Yu Long , Jin Qi , Zhou Zhaoye , Wu Liqun , He Bin
Published: July 2021

Introduction:
Ventricular arrhythmias have been a major threat to human health in developed countries. Each year, more than 300,000 sudden cardiac death cases have been reported in the U.S. alone. The aim of this study is to evaluate a novel Cardiac Electrical Sparse Imaging technique (CESI) for noninvasive mapping and localizing the origin of ventricular arrhythmias in patients undergoing cardiac catheter ablation.

Method:
Pre-surgical ECG mapping and CT scans were performed in patients (n=13) with symptomatic Premature Ventricular Contraction (PVC, >10,000 beats /24h). Data analysis was performed upon the ectopic beats (n=130) to image the foci and propagation pattern. The imaged activation patterns were compared with the Local Activation Time (LAT) determined from CARTO 3 system and the CESI imaged initiation sites were compared with the last ablation sites.

Results:
Good correlation was obtained between the CESI imaged activation and the measured LAT with an averaged Correlation Coefficient of 0.79±0.04 and Relative Error of 0.23±0.05 over 130 beats analyzed. The Relative Temporal Shrinkage was as low as 0.01±0.01, indicating 99% of the temporal resolution was preserved. PVCs were found to originate from RV, RVOT and LV. The focal mechanism was well captured with the foci localized 8±0.9 mm away from the last successful ablation sites. In each individual patient, the activation sequence could be imaged with only one beat and the propagation pattern remained stable among all recorded beats.

Conclusion:
The present results indicate that CESI is feasible to image the activation pattern and localize the ectopic foci in both RV and LV. The imaged activation patterns are in good agreement with the intra-cardiac measured ones over the endocardial surface, and the localized initiators showed concordance with the real ablation outcome. The present promising results suggest the CESI technique can potentially assist clinical management of ventricular arrhythmias.
Abstract 16318: Clinical and Economic Value of Maximizing Response to Cardiac Resynchronization Therapy (CRT): Evidence From 5 Randomized Controlled Trials
Authors: Chung Eugene S , Singh Jagmeet P , Martin David O , Abraham William T , Tsintzos Stelios I , Rogers Tyson B , Eggington Simon , Bril Sarah L , Goss Tom F , Ptak Devon , Brüggenjürgen Bernd , Cowie Martin R
Published: July 2021

BACKGROUND:
Cardiac Resynchronization Therapy (CRT) is clinically effective and cost-effective, although some patients realize 6-Month (6M) improvements while others do not. Long-term differences in outcomes among short term “responders” and “non-responders” are not reported. We compared survival, burden of Heart Failure (HF) hospitalization, and Average Length of Stay (ALOS), by Clinical Composite Score (CCS) at 6M post-implant, which was used to assess short-term CRT response.

METHODS:
MIRACLE, MIRACLE-ICD, InSync III Marquis, PROSPECT and Adaptive CRT were pooled. Classification of responder status was made at 6M; patients who died post-implant and before CCS assessment at 6M were excluded. We adjusted for differences in baseline characteristics between CCS. HF hospitalizations before 6M were excluded from HF rate calculations. Hospitalizations resulting in death were excluded from the ALOS analysis. Mortality was assessed via Kaplan-Meier curves and Cox regression; HF hospitalization rates using Poisson regression with robust variance estimates; long-term extrapolations used Markov modelling.

RESULTS:
We identified 1,089 Improved (“I”, 67.94%), 235 Unchanged (“U”, 14.66%) and 279 Worsened (“W”, 17.4%) patients. 18M post-implant, 91.5% I patients were alive vs. 89.9% U and 69.9% W (Unadjusted HR I vs. U 0.68 (0.37-1.27), I vs. W 0.24 (0.15-0.37), and U vs. W 0.34 (0.18-0.65), Log-Rank p<0.001). I patients were projected to survive 8.007 years vs. 7.967 U and 1.815 W. Post-CCS assessment HF hospitalization rates in the first year were 0.13 for I, 0.27 for U and 0.90 for W (p<0.0001) leading to a lifetime projection of 1.04, 2.14 and 2.54 total hospitalizations per patient respectively. Adjusted ALOS was directionally favoring I (4.87, 8.06 and 8.38 respectively) but non-significant (p=0.14).

CONCLUSIONS:
Patients who improve or remain unchanged 6M after CRT implant are projected to live longer and consume fewer resources than patients who worsen.
Abstract 16418: The Impact of MitraClip® Procedure on Left Atrial Strain and Strain Rate
Authors: Gucuk Ipek Esra , Qasim Atif , Viloria Esperanza , Feldman Ted , Grayburn Paul A , Foster Elyse
Published: July 2021

Background:
Left atrial (LA) remodeling due to mitral regurgitation (MR) is associated with abnormal LA strain parameters which may correlate with degree of fibrosis. Although reverse atrial remodeling has been shown after MitraClip placement, changes in LA strain and strain rate have not been evaluated in these patients or compared with mitral valve repair (MVr).

Methods:
We measured peak positive LA strain (ε) and strain rates [peak systolic (SRp), peak early diastolic (SRe) and peak late diastolic (SRa)] in 107 subjects (mean age 61±12 yrs) with degenerative MR enrolled in the randomized EVEREST II trial. Individuals with paced rhythm, atrial fibrillation, functional MR and poor image quality were excluded. LA strain measures were obtained from 4-chamber and 2-chamber views and averaged at baseline and at 1 year follow up.

Results:
At one year all 44 MVr subjects had ≤2+ MR, whereas 22 of the 63 MitraClip had >2+ MR. Baseline average ε, SRp, SRe and SRa values were similar in MitraClip and MVr groups (Table 1). At one year follow up there was a significant decrease in LA volumes in the surgical group and in those with MR ≤2+ after MitraClip. Overall average ε was significantly reduced after MVr. There was a small decrease or no change in average ε after MitraClip. SRe was significantly decreased 1 year after MVr and also in the MitraClip arm, regardless of whether there was significant MR reduction. There were no changes in SRp and SRa at 1 year in either group.

Conclusion:
Average peak positive LA strain either decreased modestly or did not change after treatment of MR in chronic degenerative MR subjects. There was a significant decrease in SRe in both treatment arms at 1 year. This occurred despite evidence of reverse LA remodeling. Further investigation and replication in additional cohorts is needed to explore these findings, which may suggest persistence of LA dysfunction after correction of chronic MR, or irreversible fibrosis.

Disclosure:
EVEREST II was funded by Abbott Vascular.