bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16329: Multimorbidity and Quality of Life in Heart Failure Patients With Poor Self-care Behavior
Authors: Matsuoka Shiho , Tsuchihashi-Makaya Miyuki , Okada Akiko , Kayane Takahiro , Yamada Michiyo , Wakabayashi Rumi , Yazawa Miyuki
Published: March 2022

Introduction:
Multimorbidity, the co-occurrence of various chronic conditions, is of major concern in patients with heart failure (HF) because it is associated with impaired quality of life (QOL) and adverse outcomes. Effective self-care is an essential adjunct to evidence-based medical treatment aimed at delaying progression of HF.

Hypothesis:
This study investigated the relationships between multimorbidity, QOL and level of self-care in HF patients.

Methods:
Study subjects completed questionnaires on HF-related quality of life (Minnesota Living with Heart Failure questionnaire), HF-related self-care behaviors (European Heart Failure Self-Care Behavior Scale), HF-related knowledge (Japanese heart failure knowledge scale) and depression symptoms. Comorbidities and other clinical and social characteristics were also assessed. Analyses of covariance and multivariate linear regression were used to assess associations between multimorbidity and QOL.

Results:
A total of 231 outpatients with HF were assessed; 119 with poor self-care (self-care score< 34) and 112 with adequate self-care (self-care score≥34); mean age 65.8 ± 13.9 and 69.8 ± 13.7 years, respectively. Of these patients, 57.6% had three or more additional chronic conditions; the most prevalent being hypertension (56.0%) and chronic kidney disease (46.6%). Patients with multimorbidity had worse QOL than patients without (P < 0.01). Subjects with poor self-care and multimorbidity had worse QOL than those without multimorbidity (P < 0.01); however, there was no association between multimorbidity and QOL in patients with adequate self-care. Multivariate analysis controlling for the effects of other variables showed that multimorbidity was an independent determinant of QOL overall and in poor self-care patients (sβ = 0.15, P = 0.04; sβ = 0.28, P < 0.01, respectively). However, in patients with adequate self-care, multimorbidity was not associated with QOL.

Conclusions:
Multimorbidity is an independent determinant of QOL in HF patients with poor self-care. To improve their QOL, both reinforcement of adequate self-care behavior regarding their HF and a multidimensional approach to enhancing self-management of their comorbidities are needed.
Abstract 16338: Dna Hypomethylation in Long Non-coding Rna Promoter During Calcific Aortic Valve Stenosis: Implication for the Notch Pathway
Authors: Hadji Fayez , Boulanger Marie-Chloé , Lavoie-Charland Émilie , Gaudreault Nathalie , Guauque-Olarte Sandra , Bouchareb Rihab , Nsaibia Mohamed , Bouchard Luigi , Bossé Yohan , Mathieu Patrick
Published: March 2022

Introduction:Calcific aortic valve stenosis (CAVS) is the most common valvular heart disease. Transdifferentiation of valve interstitial cells of the aortic valve (VICs) into osteogenic cells is an important process in the pathology. However, the molecular mechanisms involved in gene expression during osteogenic transition are still poorly understood.

Hypothesis:Long non-coding RNAs (lncRNAs) regulate gene expression pattern and may be involved in the osteogenic transdifferentiation during the development of the CAVS.

Methods:Transcriptomic by RNA sequencing (RNA-seq) and DNA genome-wide methylation studies were performed in human aortic valves. In addition, the role of a lncRNA on the mineralization was explored and the molecular mechanisms by which it promotes osteogenic transdifferentiation was documented.

Results:Transcriptomic profiling of CAVS and control valves revealed that a lncRNA was highly expressed in mineralized valves. The CpG islands in the promoter region of the gene coding this lncRNA were hypomethylated (n=23). These data were confirmed by q-PCR (n=152), fluorescence in situ hybridization (FISH) and pyrosequencing (n=60). Methylation status of the lncRNA promoter was inversely related to expression level and in isolated VICs a treatment with 5-aza-2’-deoxycytidine, which causes DNA demethylation, increased the expression of lncRNA by 2,5-fold. Knockdown or overexpression experiments showed that lncRNA play an important role in the osteogenic transdifferentiation via the Notch1 pathway. Promoter studies coupled with luciferase and chromatin immunoprecipitation (ChIP) revealed that this lncRNA interferes with the activity of Notch1 by physically interacting with the promoter. LncRNA-induced mineralization of VICs was rescued by a co-transfection of a vector encoding for the Notch intracellular domain (NICD).

Conclusions:During CAVS the hypomethylation in the promoter region promotes the overexpression of a lncRNA. This lncRNA promotes the dysfunction of the Notch signaling pathway and induces the osteogenic transdifferentiation of VICs.
Abstract 16363: The Association Between Cerebral Oxygenation and Brain Waves Measured by Cerebral Oximetry and Electroencephalography (EEG) During Cardiopulmonary Resuscitation (CPR): A Feasibility Study
Authors: Reagan Elizabeth M , Nguyen Robert T , Ravishankar Shreyas , Chabra Vikram , Fuentes Barbara , Spiegel Rebecca , Parnia Sam
Published: March 2022

Background:
Cerebral ischemia following cardiac arrest (CA) is associated with significant morbidity and mortality. A major hurdle to improving CA outcomes has been the lack of a real-time detection system capable of identifying cerebral ischemia/oxygenation as well as brain function during CPR as markers of global ischemia. In particular no studies have examined the feasibility of real-time EEG and cerebral oximetry monitoring during CPR to evaluate for these parameters.

Methods:
This was a single center study using a convenience sample of CA patients enrolled between 03/2014 and 03/2015. Inclusion criteria: In/out of hospital CA, age ≥ 18 years. Portable EEG (Masimo) and cerebral oximetry (Nonin) were used during CPR cases lasting >10 minutes. Raw EEG data were captured as consecutive images (1/second) during each pause in CPR (10 seconds), while oximetry was captured continuously.

Results:
16 patients were recruited; mean age = 70±13 years; 11 males and 5 females. All subjects exhibited interpretable EEG patterns, while 50% (n=8/16) had >1 interpretable pattern. There were 428 EEG images. 40.7% (n=174/428) were artifactual due to electrical interference, poor electrode adhesion or movement. 59.3% (n=254/428) were interpretable with seven distinct patterns identified: marked voltage attenuation (MVA) (78%), theta (8%), delta (5%), diffuse quasi-periodic discharge (4%), burst suppression (2%), spike/wave (2%), generalized rhythmic delta activity (1%). Based on known neurological associations, these patterns were further categorized as a) favorable (theta/delta) or b) unfavorable (the remaining patterns). No significant association was observed between cerebral oxygenation (rSO2) and favorable vs. unfavorable EEG patterns (median rSO2 (IQR) = 43.8% (39-48%) vs. 47.5% (42-52%) respectively).

Conclusions:
Real-time monitoring of cerebral oxygenation and function during CA is feasible. While MVA is the commonest EEG pattern, other distinct patterns also exist. Further studies are needed to explore the association between cerebral oxygenation and EEG patterns during CA as well as to identify intra-CA EEG and oximetry thresholds as markers for therapeutic interventions aimed at ameliorating cerebral ischemia during CA in real-time.
Abstract 16388: Fibrinogen Genetic Variants Promote Atherosclerosis by Altering the Inflammatory Process and Coagulation in Patients With Essential Hypertension and Diabetes Mellitus
Authors: Papageorgiou Nikolaos , Briasoulis Alexandros , Hatzis George , Miliou Antigoni , Kozanitou Maria , Androulakis Emmanuel , Charakida Marietta , Siasos Gerasimos , Toutouzas Kostas , Pallantza Zoi , Tousoulis Dimitris
Published: March 2022

Introduction:
Hypertension (HTN) and diabetes mellitus (DM) are associated with atherosclerosis and affect coagulation and inflammation.

Hypothesis:
We aimed to investigate the role of fibrinogen genetic variants (rs180070 and rs2070011) on coagulation and inflammation in patients with combined DM and HTN.

Methods:
744 subjects (HTN and DM) were enrolled in our study. Fibrinogen polymorphisms were determined by PCR-RFLP technique. Fibrinogen, interleukin-6 (IL-6), high sensitivity C-reactive protein (hsCRP) CD40L, D-dimers and factors V, X activity were measured with appropriate laboratory methods.

Results:
In HTN patients, hsCRP levels were higher in the group of patients with higher fibrinogen levels compared to patients with lower and intermediate fibrinogen levels [0.28(0.12-0.42) vs 0.17(0.04-0.38) vs 0.18 (0.09-0.39), p=0.032)]. In addition, we found a significant effect of the rs180070 polymophism on IL-6 levels among HTN and DM. In HTN, IL-6 levels were higher in AA homozygotes of the rs180070 compared to all other genotypes (AG or GG) (4.96±0.69 vs 3.7±0.2, p=0.046). Similarly, DM patients homozygotes for the A allele (rs180070) had higher IL-6 levels (6.72±0.99 vs 4.01±0.35, p=0.016). In multivariable analysis, the only independent predictor of IL-6 levels in DM was the AA genotype [β(SE): 0.216 (1.76), P = 0.047]. In hypertensives, AA (rs180070) homozygosity was the only adjusted independent predictor of IL-6 levels [β(SE): 0.151 (0.642), P = 0.032]. Subgroup analysis of HTN and DM patients did not reveal any differences of CD40L levels in the presence of AA genotype (rs180070) (p=0.919 for DM and p=0.144 for HTN). We did not observe any significant change in IL-6 or CD40L levels with the presence of the AA genotype of the rs2070011 among the studied subgroups. Finally, we found that the AA homozygosity (rs180070) was associated with increases D-dimer levels in both DM and HTN (DM: 741.6±109,4 vs 487.3±35.6, p=0.028, HTN 623.3±79.6 vs 388.6±23.5, p=0.048).

Conclusions:
The AA homozygosity (rs180070) was associated with higher IL-6 levels and CD40L. We demonstrated for the first time, that the AA homozygosity (rs180070) is associated with increased D-dimer levels. These were also associated with higher fibrinogen levels.
Abstract 16413: MicroRNAs Mediate Cardiac RNA-induced Inflammatory Response
via
Toll-like Receptor 7
Authors: Feng Yan , Chen Hongliang , Zou Lin , Yan Dan , Xu Ganqiong , Chao Wei
Published: March 2022

Introduction:
We have reported that RNA released from necrotic cells induces cytokine production and may contribute to myocardial ischemia/reperfusion (I/R) injury. Our previous study has also demonstrated that RNA isolated from the heart elicits a robust cytokine response in both cardiomyocytes (CMs) and immune cells, but the type of RNA responsible for the inflammatory effect is unknown. We hypothesize that extracellular microRNAs (miRs) mediate the inflammatory effects.

Methods:
I/R model:
mice were subjected to sham procedure or coronary occlusion for 45 min followed by reperfusion.
miR array
: 68 miRs in the plasma were quantified.
Cytokine detection
: CMs and macrophages (Mф) were treated with synthetic miRs for 18 h. Cytokines in media were measured by ELISA.
miR uptake
: Uptake of fluorescent-labeled miR in Mфs was detected by fluorescent microscopy and flow cytometry.
miR inhibition
: Locked nucleic acid-based inhibitors complementary to 6 target miRs were mixed as anti-miRs-combo.

Results:
Compared to the sham procedure, 31 out of 68 miRs were significantly increased by > 2-fold at 4 h following I/R. To test whether miR induces inflammatory response, we treated CMs and Mфs with selected 8 miR mimics (0.5 - 1500 nM) and found that 6 of them (miR-34a, -122, -133a, 142a, -146a, -208a) induced cytokine response in a dose-dependent manner. The effects were abolished by pre-treatment of RNase (but not DNase) and by mutations (U→A). Similar to cardiac total RNA, miR-induced cytokines was completely diminished in TLR7
-/-
or MyD88
-/-
, but not in TLR3
-/-
or Trif
-/-
Mфs, and significantly inhibited by a specific TLR7 inhibitor in CMs. After incubation with fluorescent miR-133a, TLR7
-/-
Mфs had similar cellular fluorescence as WT Mфs. Importantly, anti-miRs-combo significantly decreased cardiac RNA-induced cytokine production in both Mфs and CMs.

Conclusions:
Our data demonstrate that 1) Multiple cellular miRs are released to circulation during I/R; 2) Six miR mimics induce cytokine production specifically
via
TLR7-MyD88 signaling. 3) Endogenous miRs mediate in part cardiac RNA-induced cytokine response. These data suggest that cellular miRs are potent proinflammatory ligands that act through TLR7-MyD88 signaling.
Abstract 16436: The Relationship Between Radiation Dose Volume and Adverse Cardiovascular Events in Cancer Survivors Who Received Thoracic Radiation
Authors: Reilly Carolyn M , Higgins Melinda , Schreibmann Eduard , Esiashvili Natia
Published: March 2022

Objective:
The purpose of this retrospective case-controlled study was to examine the contribution of radiation therapy (RT) dose distribution on the development of significant CVD events in cancer patients within the previous 5 years.

Methods:
Patients receiving initial cancer and subsequent medical care at a large Southeastern medical center were culled from medical records and databases for a sample of 28 with and 28 without secondary CVD development. All demographic and clinical variables including CVD risk and outcome data were gleaned through medical record and billing review. The risk due to RT was isolated from known CVD risk factors present at the initiation of cancer treatment. Secondly, a novel means of applying dose volume histograms (DVHs) to summarize the radiation dose delivered to the heart and each of the three main coronary arteries was calculated by a medical physicist and radiation oncologist. Analysis used paired t-tests and Logistic Regression Modeling.

Results:
Case to control matching was made based upon age at cancer diagnosis [cases 62.29 +/- 8.9; controls: 61.93 +/- 9.0; (p=.571)]; gender; and cancer type. There were no significant differences between the RT dose statistics or delivery between pairs. A significant difference was observed with more cases having multiple risk factors at the time of cancer diagnosis: Cases had significantly higher BMIs (p=.009), systolic blood pressure (p=.028), glucose levels (p=.022), and calculated Framingham risk (w/BMI), (p=.001). More cases than controls were observed to have a history of CVD (McNemar’s p=.022), and diabetes (McNemar’s p=.003). No significant differences between cases and controls was observed for: ethnicity; marital status; comorbidities; smoking history; hyperlipidemia; alcohol abuse; chemotherapy type; nor use of hormone therapy.

Conclusion:
The cases all had significantly greater typical CVD risk factors upon cancer diagnoses and did not receive any greater or differing amounts of thoracic radiation. A logistic regression model revealed subjects with high systolic BP, CVD history and diabetes had much higher odds of being a CVD case. After accounting for these variables, no other radiation parameters (dose, DVH, nor shape) entered the model.
Abstract 16441: Novel Calmodulin Mutations Cause Congenital Long QT Syndrome and Affect Calcium Current in Human Cardiomyocytes
Authors: Pipilas Daniel C , Webster R. Gregory , Schlaepfer Jurg , Fellmann Florence , Sekarski Nicole , Johnson Christopher N , Schwartz Peter J , Chazin Walter J , Crotti Lia , Bhuiyan Zahurul A , George Alfred L
Published: March 2022

Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including the congenital long QT syndrome (LQTS). We identified two novel CaM mutations in children with LQTS associated with cardiac arrest, and performed studies to elucidate the functional consequences of each molecular defect. The first mutation was discovered in a male infant with a ventricular septal defect and fetal bradycardia born to healthy parents. His ECG on postnatal day 1 revealed bradycardia and very prolonged QTc (651 msec). At age 2-days, he developed 2:1 AV block, profound bradycardia (50 bpm) and cardiogenic shock. He was resuscitated and received a pacemaker. Targeted DNA sequencing revealed a de novo mutation in CALM2 (D132H). A second novel mutation was discovered in a three year-old boy who suffered witnessed cardiac arrest. His initial rhythm was ventricular fibrillation, and after successful defibrillation an ECG recording revealed a QTc of 574 msec. The parents were healthy with normal QTc intervals. Exome sequencing of the parent-child trio demonstrated a de novo mutation in CALM1 (D132V). Both novel mutations affect the same conserved aspartate residue within the C-domain EF-hand-IV Ca2+ binding motif. Further studies elucidated biochemical and functional effects of the mutations. Measurements of Ca2+ binding affinity of CaM-D132H indicated extremely weak binding to the C-domain (Kd > 150 μM) with significant structural perturbations. Voltage-clamp recordings of human induced pluripotent stem cell (iPSC) derived cardiomyocytes transiently expressing wildtype or mutant CaM demonstrated that both mutations caused impaired Ca2+-dependent inactivation (CDI) of voltage-gated Ca2+ current. Neither mutant affected voltage-dependent inactivation of Ba2+ currents. Our findings implicate impaired CDI in human cardiomyocytes as the plausible mechanism for LQTS associated with CaM mutations.
Abstract 16450: The Impact of Left Ventricular versus Simultaneous Biventricular Pacing on Structural and Biochemical Reverse Remodeling in Patients With Heart Failure: Insights From the EvAluation of Resynchronization Therapy for Heart Failure (EARTH) Trial
Authors: Skaf Sabah , Thibault Bernard , O’Meara Eileen , Khairy Paul , Fortier Annik , Prylutska Halyna , Pitre Céline , White Michel , Ducharme Anique
Published: March 2022

Introduction:
Cardiac Resynchronization Therapy (CRT) with simultaneous biventricular pacing (BiVP) is recommended for patients with heart failure and wide QRS, however up to a third of patients do not respond. GREATER-EARTH has demonstrated similar benefits with BiVP or LV pacing (LVP). Herein, we evaluate the effects of these two CRT modes on cardiac remodeling, evaluated by echocardiography and circulating biomarkers.

Methods:
121 patients (LVEF≤35% and QRS≥120ms) referred for defibrillator implantation were randomized to BiVP or LVP for consecutive 6-month periods with cross-over. The primary endpoint was the change in LV end-systolic volume (LVESV) between patients with BiVP vs LVP from baseline to 6 months. Secondary endpoints included changes in LVEF, mitral regurgitation, RV and diastolic function. Changes in levels of markers of cardiac remodeling were also compared.

Results:
Both CRT pacing modes led to remodeling benefits after 6-months of therapy: LVESV decreased from 162±57mL at baseline to 130±63mL with BiVP vs 130±60 mL with LVP (p=0.68 between CRTs), with a positive response (≥15% LVESV reduction) being observed in 49% of patients with BiVP and 33% of LVP, p=0.09. Similarly, RV remodeling (dimension and RV-MPI) was equally improved with both pacing strategies (p=0.69 and p=0.38 respectively, between CRTs). Interestingly, estimated systolic PAP (from 43±14 to 37±10 and 41±14, p=0.008), selected indices of LV diastolic function such as indexed LA volume (p=0.045) and diastolic dysfunction grade (p=0.019), as well as changes in MR grade (p=0.004) were significantly improved only with BiVP. In parallel, there was a non-statistically significant decrease in NT-proBNP, from 2559±3296 to 1554±2092 and 1630±1950 ng/L, with BiVP and LVP respectively (p=0.093) as well as a trend in decreasing PIIINP levels, from 8.3±3.0 to 7.5±2.7 and 7.6±2.3 with BiVP and LVP respectively, p=0.097.

Conclusions:
In this prospective, multicenter, randomized, double-blind study, both BiVP and LVP resulted in improvements in LV remodelling assessed by echocardiography, while more patients responded to BiVP. BiVP may be superior to LVP to improve multiple aspects of myocardial remodeling and should remain the preferred mode of CRT in patients with advanced HF.
Abstract 16484: The Transcriptional Repressor NR1D2 is Associated With Congenital Heart Disease and Plays an Evolutionarily Conserved Role in Cardiac Development
Authors: Priest James R , Vogler Georg , Nurnberg Sylvia , Portman Michael , Gelb Bruce D , Ashley Euan A , Bodmer Rolf , Quertermous Thomas
Published: March 2022

Title:
The Transcriptional Repressor NR1D2 is Associated with Congenital Heart Disease and Plays an Evolutionarily Conserved Role in Cardiac Development.

Introduction:
Congenital heart disease (CHD) is a leading cause of morbidity and mortality in young children and the underlying genetic etiology is complex and poorly defined. Recent genetic studies of mixed cardiac phenotypes focusing on de novo events have identified novel disease loci in up to 10% of participants and uncovered new functional categories of genes related to cardiac development.

Hypothesis:
We hypothesize that exome sequencing of patients with CHD will uncover novel genes related to cardiac disease and development.

Methods:
To identify disease-associated mutations, we analyzed exome sequencing data in a multi-institutional discovery cohort of 59 trios with a novel analytical pipeline. We phenotyped knockout animals for orthologous genes across multiple genetic phyla (mouse and fruit fly) for aspects of cardiac development. Additionally we performed Chromatin Immuno-Precipitation Sequencing (ChIP-seq) in a HL-1 mouse atrial cell line.

Results:
Exome sequencing uncovered a de novo missense variant R175W in the highly conserved DNA binding domain of NR1D2 a key component of the molecular clock. Knockout mice for Nr1d2tm1-Dgen display atrioventricular septal defects and related malformations, while knockdowns of the drosophila homolog Eip75B displays abnormal heart tube fusion during late embryonic development. ChIP-seq data for Nr1d2 suggests transcriptional repression at key loci controlling differentiation into both valve development (Twist1, Twist2, Bmpr1b) and atrial left-right patterning (Pitx2, Cited2).

Conclusions:
A patient with a deleterious de novo mutation in NR1D2 and knockout in multiple model organisms show cardiac defects, while genomic analysis of ChIP-seq data supports a modulatory role for this transcriptional repressor in the complex 3-dimensional process of cardiac morphogenesis. In conclusion, these data suggest that NR1D2 plays an evolutionarily conserved role in cardiac development and congenital heart disease. Further experiments are needed to understand the mechanism by which NR1D2 might link the molecular clock to cardiac development.
Abstract 16496: Relationship Between Sleep Duration and Ideal Cardiovascular Health in a Large Employee Population: The Baptist Health South Florida Employee Study
Authors: Aneni Ehimen , Younus Adnan , Osondu Emeka , Rouseff Maribeth , Das Sankalp , Guzman Henry , Tran Thinh H , Maziak Wasim , Ahmad Rameez , Latif Muhammad A , Malik Rehan , Ogunmoroti Oluseye , Feldman Theodore , Agatston Arthur S , Veledar Emir , Nasir Khurram
Published: March 2022

Introduction:
There has been increased focus on the relationship between sleep duration and cardiovascular disease, however, there is limited understanding of the association of sleep duration with cardiovascular health (CVH). In this study we examine the relationship between sleep duration and the American Heart Association’s ideal CVH in a large employee population.

Methods:
Data for this study was collected from participants at the 2014 health risk assessment in which they reported their average hours of sleep, their dietary patterns. In person, participants were weighed and their heights were measured. They also had blood pressure, blood glucose, total cholesterol measurements as well as breath carbon monoxide tests for smoking. The ideal for each CVH metric was estimated for each of the 7 metrics. Sleep duration was grouped into less than 6 hours, 6 to 7.9 hours and 8 or more hours. Ideal CVH was classified as presence of 6-7 ideal metrics.

Results:
A total of 9700 participants (mean age 43yrs, 74% female) completed the 2014 health risk assessment and had complete data on the variables of interest. Overall, more females and persons without college degrees slept for less than 6 hours. Compared to those with less than 6 hours of sleep, those with 8 or more hours of sleep had 1.6 times the odds of ideal diet (95% CI: 1.1-2.6), 1.7 times the odds of having ideal BMI (95% CI: 1.4-2.1), 1.3 times the odds of having ideal BP (95% CI: 1.1-1.5) and 2.4 times the odds of achieving ideal physical activity (95% CI: 2.4 - 2.9) after controlling for age, sex and educational levels. Comparing to those with less than 6 hours of sleep and with a reference of 0-2 ideal metrics, participants with 8 or more hours of sleep were 2.7 times as likely to have ideal CVH (see figure).

Conclusions:
Our study findings underscore the importance of promoting sleep health for optimizing ideal CVH. Further studies are needed to determine generalizability of our results.
Abstract 16522: Structural Insights Into Destabilizing HERG PAS Domain Mutations Linked to Long Qt Syndrome
Authors: Anderson Corey L , Kuzmicki Catherine E , Childs Ryan R , Hintz Caleb J , January Craig T , Balijepalli Ravi C
Published: March 2022

Introduction:
Hundreds of HERG potassium channel mutations are linked to type 2 Long QT Syndrome (LQT2). Most mutations are trafficking defective but correctable by culturing cells at reduced temperature (27 C) or with the pore blocker E4031. For a few intracellular Per-ARNT-Sim (PAS) domain mutations, trafficking phenotypes have been shown to correlate with PAS domain stability. Since HERG intracellular domains are mutational hotspots containing 1/3 (>100) of all LQT2 mutations, domain destabilization may be a major mechanism underlying LQT2. However, most mutations have not been studied and structural insights are lacking.

Results:
Using a recombinant PAS domain solubility assay as a proxy for stability, we tested 57 mutations and found a strong correlation between domain solubility and trafficking phenotype (trafficking defective and uncorrectable < temperature correctable < temperature and E4031 correctable < trafficking competent). For buried residues V41 and C64, we used the protein stability prediction tool FoldX and immunoblot to show that domain stability and trafficking phenotype becomes more severe as the side chain becomes larger suggesting overpacking of the PAS domain core as a mechanism for LQT2-V41F and LQT2-C64W. This was further validated by designing second-site suppressor mutations to relieve potential side chain clashes. Immunoblot analysis showed that trafficking of LQT2-V41F is improved at 27 C with C39G or C64G, while C64A improved trafficking at 37 C. Immunoblot and current density analysis showed that trafficking of LQT2-C64W (3.8±0.8 pA/pF, n=4) is improved at 37 C with C39G (37.8±3.5 pA/pF, n=3) or Q61G (69.6±12.7 pA/pF, n=3) and LQT2-I42N (2.2±0.7 pA/pF, n=3) is improved at 37 C with Q61G (41.9±6.3 pA/pF, n=6). Additionally, site-saturation mutagenesis of residue V113 revealed loss of backbone (and not side chain) interactions as the structural basis for LQT2-delV113.

Conclusions:
This study identifies HERG PAS domain destabilization as a major mechanism underlying LQT2 and demonstrates a novel bioinformatics and structure-based method for analyzing disease-associated HERG mutations. These results are also a proof of concept that strategies to improve HERG domain stability could be a viable therapeutic approach.
Abstract 16551: Pathways of Prognosis and Effective Treatment Interventions in Hypertrophic Cardiomyopathy
Authors: Maron Barry , Rowin Ethan J , Casey Susan A , Maron Martin S
Published: March 2022

Background:
Hypertrophic cardiomyopathy (HCM) is a genetic heart disease with diverse clinical course, including extended periods of stability and possibly normal longevity, but also major complications for which there are now effective therapeutic options. The proportion of patients with sudden death (SD), heart failure progression, or atrial fibrillation/stroke within established cohorts and likelihood that patients incur multiple disease pathways during their clinical course is unknown.

Methods:
We studied 1893 consecutive HCM patients (40 ± 19 years) from the Minneapolis Heart Institute/Tufts Medical Center, over average follow-up of 10.7 years, and identified 3 hallmark endpoints and disease complication pathways: (1) SD or an appropriate ICD intervention for VT/VF; (2) progression of heart failure to NYHA class III/IV refractory to drugs; (3) ≥1 episode or persistent atrial fibrillation (AF).

Results:
Of 1893 patients, 953 (50%) survived without reaching any endpoint or requiring major interventions, and were in NYHA class I/II at follow-up. Another 680 patients (36%) progressed along 1 major adverse disease pathway, most commonly progressive heart failure (n=376) due to outflow obstruction or diastolic dysfunction, or AF (n=233), or SD events (n=71). Only 237 patients (13%) experienced 2 major complication pathways, most commonly AF or progressive heart failure unrelated to AF (n=198); and 23 patients (1%) incurred all 3 adverse pathways. Of the 1893 patients, 70 (3%) died of HCM, with 5-year and 10-year survival, 98% and 94%, and 1693 patients (89%) were in class I/II at follow-up. HCM mortality was: 1 adverse disease pathway: 7%, 2 pathways: 8%, 3 pathways: 26% (p=0.002 for 3 pathways).

Conclusion:
In this referral-based HCM population, almost 90% of patients had a benign clinical course or reached one major end-point associated with effective management options. Evolution along 2 or 3 disease pathways was uncommon (14%), but also amenable to treatment, although mortality was highest in patients with 3 complications. With contemporary management strategies, HCM has become a treatable disease with low overall mortality (0.5%/year).
Abstract 16602: The Clinical Significance of Mif, Mif-2 and Mif Genotype in Patients Exhibited to Myocardial Ischemia/reperfusion Injury
Authors: Stoppe Christian , Goetzenich Andreas , Kraemer Sandra , Emontzpohl Christoph , Soppert Josefin , Bucala Richard , Weber Christian , Bernhagen Jürgen
Published: March 2022

Background:
Cardiac surgery is increasingly been performed on an aging patient population with increased numbers of comorbid conditions. These patients are frequently exposed to myocardial ischemia/reperfusion with deleterious consequences and development of organ dysfunctions. The pleiotropic cytokine macrophage migration inhibitory factor (MIF) is an upstream regulator of the immune response and rapidly released from pre-formed cytoplasmatic pools in response to activating stimuli such as hypoxia, infection or inflammation. Yet, its interaction with related mediators such as its homolog, D-dopachrome tautomerase (MIF-2) is largely unknown. Therefore, we aimed to investigate the interaction and clinical significance of MIF and MIF-2 in patients undergoing cardiac surgery with myocardial ischemia/reperfusion. Methods and Results: Circulating levels of MIF and MIF-2 were measured peri-operatively in 100 patients that underwent elective cardiac surgery and showed a rapid increase upon myocardial ischemia. Intra-operative MIF levels reached maximum during myocardial reperfusion and were independently associated with a reduced risk for the development of AF in the post-operative period (odds ratio 0.99 (0.98-1.00); p=0.007), whereas circulating levels of MIF-2 were associated with an increased frequency of organ dysfunction and predicted the occurrence of atrial fibrillation (area under the curve (AUC)=0.663;p=0.041) and pneumonia (AUC=0.708;p=0.040). Known functional MIF allelic variants were analyzed and patients with high-expression MIF-genotype exhibited reduced incidence of organ dysfunction (3 vs. 25; p=0.042).

Conclusion:
Our findings present the first description of the kinetics and potential clinical relevance of the MIF, MIF-2 and MIF genotype in myocardial ischemia/reperfusion (I/R) in the setting of cardiac surgery. The present study demonstrated that increased intra-operative MIF levels may provide organoprotective effects, whereas elevated serum levels of MIF-2 were associated with the development of organ dysfunctions in patients after cardiac surgery. Patients with a high-expression MIF genotype experienced a significantly lower incidence of organ dysfunctions.
Abstract 16640: Prognostic Importance of Pulmonary Hypertension Severity by Invasive Hemodynamics in Patients With Severe Aortic Stenosis
Authors: Cavalcante Joao L , Althouse Andrew , Campbell-Massa Ryan , Maddula Mitika , Gleason Thomas G , Katz William , Crock Frederick , Harinstein Matthew , Navid Forozan , Kliner Dustin , Schindler John T , Lee Joon S
Published: March 2022

Introduction:
The prevalence and impact of pulmonary hypertension (PH) severity on clinical outcomes for patients with severe AS is unclear and controversial. Our goal was to compare the correlation of mortality to degree of PH as measured by transthoracic echocardiography (ECHO) versus invasive hemodynamics (CATH).

Methods:
Retrospective data collection of patients with severe aortic stenosis (AV area index ≤ 0.6 cm2/m2) and measured pulmonary artery systolic pressure (PASP) by ECHO and CATH within 60 days of one another from 2010-2014. According to guidelines, patients were classified as having no PH (PASP<35mmHg), mild PH (PASP 35-45mmHg), moderate PH (PASP 46-59mmHg), and severe PH (PASP≥60mmHg) by each method. Multivariate Cox-proportional hazard model was used for risk-adjustment comparisons.

Results:
A total of 186 patients were identified with mean age of 77 ± 10 years, 62% male and 38% diabetic. The median time difference between the 2 procedures was 4 days (IQR: 1-13 days). After a median follow-up of 18 months (IQR: 5-27 months), there were 63 deaths (34%). Moderate/Severe PH was prevalent by either ECHO or CATH (47% vs. 62%, p<0.0001, respectively) although with modest agreement between ECHO and CATH PH severity (kappa=0.37). Both PH severity assessments were strongly associated with mortality; however, CATH showed better stratification with moderate PH associated with equally significant mortality risk (Figure 1). After adjustment for AVR (HR=0.23, 95% CI 0.11-0.48,p<0.01), age, gender, BMI, diabetes, and NYHA class, presence of moderate PH by CATH remained associated increased mortality risk (HR=2.25, 95% CI 1.04-4.89, p=0.04).

Conclusions:
Moderate or greater PH is common among severe AS patients and is more commonly diagnosed by CATH. Ascertainment of PH severity by CATH is important as even moderate PH correlates with increased 1-yr mortality despite adjustment for AVR and other comorbidities.
Abstract 16687: A Genetic Contribution to Postoperative Complete Heart Block Following Congenital Heart Surgery
Authors: Smith Andrew H , Flack English C , Crum Kimberly , Kannankeril Prince J
Published: March 2022

Background:
A familial variant of complete heart block (CHB) is described in association with a substitution mutation in Connexin-40 (GJA5 Q58L) resulting in impaired gap junction formation. We sought to identify genomic predictors that may independently predispose children to the development of early postoperative complete atrioventricular (AV) block following congenital heart surgery.

Methods:
Subjects undergoing congenital heart surgery at our institution were consecutively recruited and enrolled from September 2007 through December 2014. In addition to DNA, demographic and perioperative clinical data were obtained from all subjects.

Results:
Over the course of the study period, there were 1466 subjects enrolled who underwent 1986 operative procedures; DNA was available for analysis in 1756 cases (1424 subjects). The incidence of at least one episode of postoperative complete AV block was 3.7% (n=65). Genotyping of the common missense polymorphism rs10465885 in GJA5 among subjects yielded allele frequencies in Hardy Weinberg equilibrium (p=0.73), and analysis demonstrated a gene-dose effect association between T allele presence and incidence of postoperative complete AV block (linear by linear association, p=0.009). Multivariate logistic regression analysis demonstrates that TT homozygosity is associated with a two-fold increased odds of new onset complete AV block (OR 2.1, 95%CI 1.2-3.5, p=0.006), independent of other significant univariate predictors including patient weight (p<0.001), operative procedure including closure of a ventricular septal defect (p<0.001), chromosomal anomaly (p=0.016), cross clamp time (p<0.001), ionized calcium and serum lactate on admission (both p<0.001), inotrope use on admission (p<0.001), and preoperative digoxin administration (p<0.001).

Conclusions:
A common missense single nucleotide polymorphism within a gene encoding Connexin-40 is associated with the development of early postoperative complete heart block, independent of established risk factors. A refined understanding of genotype-phenotype relationships may serve to guide early postoperative care following congenital heart surgery.
Abstract 16726: Association of Renin-angiotensin System Inhibitors With Reduced Adverse Cardiac Events in Patients With Ischemic Mitral Regurgitation After Acute Myocardial Infarction
Authors: Kim Kitae , Kaji Shuichiro , Yamane Takafumi , Kitai Takeshi , Kobori Atsushi , Ehara Natsuhiko , Kinoshita Makoto , Furukawa Yutaka
Published: March 2022

Background:
Ischemic mitral regurgitation (IMR) portends a poor prognosis during long-term follow-up and has been identified as an independent predictor of heart failure (HF) and reduced long-term survival. Renin-angiotensin system inhibitors (RASI) including angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARB) may improve prognosis in patients with IMR after acute myocardial infarction (AMI). The purpose of this study was to investigate the association of RASI with the incidence of adverse cardiac events in patients with IMR after AMI.

Methods:
We screened 867 consecutive patients admitted for AMI and underwent emergency coronary angiography between January 2000 and December 2008. A total of 388 patients who were diagnosed to have mild or greater MR evaluated by transthoracic echocardiography within 2 weeks after the onset were enrolled.

Results:
The mean age was 67±11 years and 297 patients (77%) were men. A total of 297 patients (77%) received RASI before hospital discharge. Patients without RASI were older and more likely to have higher creatinine level compared with patients with RASI. Left ventricular ejection fraction, peak CPK level, prevalence of prior MI were comparable between the two groups. The mean follow-up period was 5.4±3.4 years. During the follow-up, 22 cardiac deaths and 39 HF events occurred. Kaplan-Meier analysis revealed that freedom from cardiac death and HF was significantly higher in patients with RASI than in those without RASI (p<0.001 and p=0.001, respectively). After adjustment with the inverse probability treatment weighting, Cox regression analysis showed a significant beneficial effect of RASI therapy in reducing cardiac death (hazard ratio [HR]: 0.20; p<0.001) and HF (HR: 0.41; p=0.008).

Conclusions:
RASI was associated with a lower incidence of adverse cardiac events in patients with IMR after AMI.
Abstract 16746: Cardiovascular Disease Outcomes After Breast Cancer in Postmenopausal Women: Results From the Women’s Health Initiative
Authors: Park Na-Jin , Chang Yuefang , Bender Catherine , Conley Yvette , Davidson Nancy E , Van Londen G J , Foraker Randi , Wassertheil-Smoller Sylvia , Stefanick Marcia L , Chlebowski Rowan , Kuller Lewis
Published: March 2022

Introduction:
A growing population of older breast cancer (BC) survivors may be at risk of cardiovascular disease (CVD). Pre-existing CVD risk factors may impact on subsequent development of CVD after BC among postmenopausal women.

Objectives:
(1) To describe baseline CVD risk factors among postmenopausal women with and without BC prior to diagnosis of BC; and (2) To examine independent associations of BC with individual and composite CVD events (i.e., the first occurrence of coronary heart disease [CHD], angina, coronary revascularization, congestive heart failure, peripheral arterial disease, and stroke) and mortality outcomes (i.e., all-cause, CVD, and CHD death) after BC adjusting for baseline characteristics and CVD risk factors.

Methods:
This prospective cohort study included 101,916 women in the Women’s Health Initiative (WHI) (including 4,340 women with invasive BC) aged 50-79 years without CVD at baseline (1993-1998) through December 2010. Over a period of 10 years after BC, CVD morbidity and mortality outcomes were identified and age-adjusted rates per 1,000 person-years and hazard ratios (HRs) with 95% confidence intervals (CIs) from Cox models were determined for women who did and did not develop BC.

Results:
Regardless of BC status, baseline CVD risk factors prior to BC, such as smoking, hypertension, diabetes and hypercholesterolemia, were strong predictors of CVD outcomes in postmenopausal women. Multivariable Cox models revealed that women who developed BC (n = 4,340) had a similar risk of composite CVD (HR = 0.91, 95% CI, 0.82-1.02), but a higher risk of CHD (HR=1.33, 95% CI, 1.12-1.58), compared with women without BC (n = 97,576). Women aged 70-79 and on hormonal therapy at the WHI entry with localized BC during follow-up period had the highest CHD death rate. The results were similar after excluding women with baseline cancer at the WHI study entry.

Conclusions:
These results emphasize the great need for identification and timely management of pre-existing CVD risk factors for postmenopausal women with BC. CVD accounts for almost as many deaths as BC among women with localized disease, indicating that improved effort to prevent and treat CVD risk factors could improve survival of postmenopausal BC survivors.
Abstract 16770: The Road to Durable Pulmonary Vein Isolation by Means of Radiofrequency Ablation Annotation Algorithm
Authors: Tanaka Nobuaki , Inoue Koichi , Tanaka Koji , Toyoshima Yuko , Oka Takafumi , Okada Masato , Okamura Atsunori , Koyama Yasushi , Iwakura Katsuomi , Fujii Kenshi
Published: March 2022

Background:
Recurrence of atrial fibrillation (AF) after catheter ablation by means of circumferential pulmonary vein isolation (CPVI) is common and often related to the recovery of conduction pulmonary vein (PV) and left atrium (LA) following an initially successful CPVI. The ablation annotation system (CARTO3 System, VISITAG Module,) uses an algorithm for the automated annotation of RF ablation applications based on objective, predefined parameters. It could be helpful in accomplishing durable CPVI for AF.

Objective:
The objective of this study was to compare procedure parameters and outcomes between VISITAG-guided and non-guided CPVI.

Methods:
We include in this study 93 AF patients underwent CPVI. All ablations were performed by single operator using ThermoCool SmartTouch catheter. In 51 patients (group A, paroxysmal AF 29/51:56.8%), RF ablation was guided by an automated algorithm with predefined criteria of catheter stability range of motion ≤ 1.5mm ,catheter stability duration >5 seconds, and force over time (contact force≧5g, time≧25%). When this condition is satisfied, new tag appears. Tag diameter was 6mm and we intended to move catheter to next position to appear the new tag where was overlapped with the former tag. When force time integral (FTI) of the tag becomes 100-150gs, the color of tag changed from white to red and we moved catheter to the next position. In 42 control patients (group B, paroxysmal AF 30/42:71.4%), ablations were performed by contact force guided ablation without automated algorithm.

Results:
CPVI at the initial anatomical line was achieved more often in group A than in group B (66.7% vs 36.9%; P=0.001). The frequency of time dependent conduction recovery was lower in group A (14 of 102 pairs of PVs [13.7%]) than in group B (26 of 84 pairs of PVs [30.9%] ; P=0.0055). During 6-month follow up with 3 month blanking period, 94.1% patients in group A and 76.2% patients in group B were free from any atrial tachyarrhythmias (P=0.019).

Conclusion:
In CPVI, automated ablation lesion annotation by optimal settings was effective in reducing the acute resumption of LA-PV conduction. Better durability of CPVI may improve long-term outcomes.
Abstract 16798: The Influence of Heart Failure With Preserved or Reduced Ejection Fraction on Relationships Between Cardiac Power and Stroke Work With VO2
Authors: Van Iterson Erik H , Snyder Eric M , Borlaug Barry A , Olson Thomas P
Published: March 2022

Introduction:
Invasive measurement of cardiac power (CP) and stroke work (SW) during exercise are robust indices of cardiac function and relate to syndrome severity and prognosis in heart failure patients with preserved (HFpEF) or reduced (HFrEF) ejection fraction. Because invasive measurement via catheterization laboratories are not always readily available, non-invasive cardiopulmonary exercise testing to estimate cardiac function is routinely performed in the clinical evaluation of HFpEF and HFrEF. However, it is unknown how VO
2
relates with CP and SW in HFpEF vs HFrEF. We compared relationships between CP and SW with VO
2
at rest and peak exercise in HFpEF vs HFrEF.

Methods:
30 HFpEF and 32 HFrEF (EF: 62±2 vs 22±1%; males: 17 vs 30; age: 70±2 vs 55±2 yrs; BMI: 34±1 vs 28±1 kg/m
2
; wt: 98±4 vs 86±3 kg (all p<0.05)) participated in exercise testing during right heart catheterization. Oxygen consumption (VO
2
) was measured continuously from rest to peak work. Invasive measures at rest and peak work included mean radial arterial pressure (MAP), right atrial pressure (RAP), and pulmonary capillary wedge pressure (PCWP). We calculated CP=(MAP–RAP) x Q
I
x 2.22х10
-3
and SW=(MAP–PCWP) x SV
I
x 0.133.

Results:
At rest, R
2
between VO
2
and CP or SW were not different between HFpEF (CP=0.41, SW=0.30) and HFrEF (CP=0.39, SW=0.15). Slopes did not differ significantly between HFpEF (CP=0.13, SW=0.01) and HFrEF (CP=0.16, SW=0.01) for regressions between VO
2
and CP or SW; but, fitted intercepts of the regression showed significantly higher intercepts in HFrEF (CP=0.89, SW=1.16) vs HFpEF (CP=0.05, SW=0.27) for VO
2
vs CP and SW, respectively. At peak exercise, R
2
between VO
2
and CP or SW were not different between HFpEF (CP=0.48, SW=0.64) and HFrEF (CP=0.70, SW=0.67). Slopes did not differ between HFpEF (CP=0.18, SW=0.02) and HFrEF (CP=0.15, SW=0.02) for regressions between VO
2
and CP or SW, whereas the fitted intercepts the slope of the regression were significantly higher in HFrEF (CP=5.1, SW=4.4) vs HFpEF (CP=3.2, SW=2.0) for VO
2
vs CP and SW, respectively.

Conclusion:
Our data suggest that despite lower VO
2
relative to CP and SW in HFpEF, both the strength of relationship and rate of increase in VO
2
relative to CP and SW are similar between HFpEF and HFrEF at rest and peak exercise.