bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12970: Exploring Experiences Associated With Aortic Stenosis Diagnosis, Treatment and Life Impact Among Middle-Aged and Older Adults: An Interview Study
Authors: Picou Kylie , Heard Debbie , Shah Pinak B , Arnold Suzanne V
Published: April 2022

Background:
Although multiple studies have examined various clinical aspects of diagnosis, treatment, and management of patients with aortic stenosis (AS), there are limited data collected from patients regarding experiences related to symptoms, diagnosis, treatment decisions, and personal impacts of living with AS.

Methods:
Adults aged ≥40 years diagnosed with AS were recruited from national patient networks and through professional recruiters. Participants were separated into 3 cohorts: medically managed, surgical aortic valve replacement (SAVR), and transcatheter aortic valve implantation (TAVI). Semi-structured interviews were conducted via teleconference using open ended questions and probes. Interview recordings were transcribed verbatim and inductive thematic analyses were conducted.

Results:
A total of 45 interviews were conducted (15 per treatment group). The majority of participants were male (55.6%, 25 of 45), white (95.6%, 43 of 45), and non-Hispanic (93.3%, 42 of 45). Median time from symptom onset to diagnosis was 6 months (IQR: 1-12). Participants noting longer times to diagnosis reported mild symptom onset and experiences of misdiagnoses. Some participants described that healthcare professionals explained the AS diagnosis clearly and understandably, while others left the encounter confused with unanswered questions. Participants described a strong reliance on their healthcare professionals to guide them through their treatment decisions, which were influenced by the effects of anticoagulation, future valve interventions, and recovery. Medically managed participants reported making lifestyle modifications to manage AS symptoms, including chronic anxiety and fatigue. In contrast, participants who underwent TAVI or SAVR reported positive sentiments, including gratitude and freedom to live life normally following the procedure.

Conclusions:
The diverse but challenging experiences of individuals with AS suggest that increasing both the availability and use of patient resources may improve patients’ understanding of AS and facilitate informed treatment decisions. Common reports of delayed AS diagnosis also indicate a need for additional healthcare professional education on referral to a heart valve team.
Abstract 12974: Transthyretin Amyloid Cardiomyopathy Associated With the P.V142I Transthyretin Variant is an Inherently Aggressive Form of Transthyretin Amyloid Cardiomyopathy Associated With Significant Functional Impairment and Poor Prognosis
Authors: Razvi Yousuf , Ganesananthan Sashiananthan , Chacko Liza , Patel Rishi , Blakeney Iona , Kaza Nandita , Law Steven , Rowczenio Dorota , Gilbertson Janet , Hutt David , Mahmood Shameem , Lachmann Helen , Wechalekar Ashutosh , Wisniowski Brendan , Whelan Carol , Venneri Lucia , Martinez-Naharro Ana , Hawkins Phillip , Fontana Marianna , Gillmore Julian D
Published: April 2022

Introduction:
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognised cause of heart failure. 3-4% of individuals of African descent carry a
TTR
gene mutation encoding the p.V142I variant, a powerful risk factor for development of variant ATTR-CM; this equates to 1.6 million carriers in the USA. We report deep phenotyping in p.V142I ATTR-CM.

Hypothesis:
The phenotype of p.V142I ATTR-CM is an aggressive form of ATTR CM.

Methods:
A retrospective study of 395 patients with p.V142I ATTR-CM from the UK National Amyloidosis Centre. Patients were diagnosed at the Centre through a comprehensive evaluation comprising clinical and functional assessment, echocardiography, radionuclide scintigraphy, histology and biomarker analysis; a subgroup had cardiac magnetic resonance imaging. 395 wild-type ATTR-CM patients matched for independent predictors of prognosis (NAC Disease Stage, age, decade of diagnosis) were used as a comparator group.

Results:
At time of diagnosis, patients with p.V142I ATTR-CM had significant functional impairment by NYHA classification (NHYA ≥ III; 38.2%) and impairment of echocardiographic parameters; mean LVEF 43%, global longitudinal strain -9.1%, TAPSE 14.2mm, E/E prime 17.4, E/A ratio 2.47 with high frequency of at least moderate mitral (44%) and tricuspid (51%) regurgitation. Uni and multivariate cox regression analysis identified troponin T, TR, LVEF, TAPSE and lower systolic blood pressure as independent predictors of prognosis. Prognostic parameters and 5yr survival (27% v 46%, p<0.001) were significantly worse than in wtATTR-CM.

Conclusion:
p.V142I ATTR-CM has an aggressive phenotype characterised by functional impairment, regurgitant valvular disease and systolic impairment resulting in poor survival. LV systolic impairment, TAPSE, serum troponin and TR were independent predictors of survival, whereas LV wall thickness was not, suggesting as yet unrecognised disease mechanisms.
Abstract 13208: Deletion of the Type I Interleukin-1 Receptor Prevents the Development of Cardiomyopathy Associated With Aging in Mice
Authors: Narayan Pratyush , Trikantzopoulos Elefterios , MEZZAROMA Eleonora , Mauro Adolfo G , Vohra Habeebah , Abbate Antonio , Toldo Stefano A
Published: April 2022

Background:
Aging is associated with metabolic and structural changes causing heart failure with preserved ejection fraction (HFpEF). Interleukin-1 (IL-1) is a pro-inflammatory cytokine involved in aging-related inflammation. We sought to determine whether IL-1 mediates aging-related changes in the heart as seen in HFpEF.

Hypothesis:
We hypothesize that mice with genetic deletion of IL-1RI, not responsive to IL-1β, would be protected from age-associated cardiac dysfunction.

Methods:
We studied age-matched young (4-month-old), middle-aged (14-month-old) and old (23-month-old) wild-type (WT) C57BL/6J and IL-1 receptor type I deficient (IL1RI-KO) male mice. Echocardiography was used to left ventricular (LV) dimensions and systolic/diastolic function, and a pressure-transducer was used to measure the LV end-diastolic pressure. Picrosirius red stain was used to assess for myocardial interstitial fibrosis (MIF) at pathology.

Results:
WT and IL-1RIKO mice showed a normal cardiac phenotype at young age, without any differences in between the two groups. With aging, the WT mice developed LV concentric hypertrophy (as measured by a significant increase in LV mass [+42%, P<0.01] and relative wall thickness [+34%, P<0.01]), whereas the aging IL-1RI-KO mice did not (Figure 1a,b). With aging the WT mice also developed diastolic dysfunction (as measured by a significant increase in isovolumetric relaxation time [+148%, P<0.01] and a significantly higher LV end diastolic pressure [+174%, P<0.01]), whereas the aging IL1RI-KO did not (Figure 1c,d). With aging WT mice showed a significant increase in MIF (+124%, P<0.01) at cardiac pathology, whereas the aging IL-1RI-KO did not (Figure 1e).

Conclusions:
Genetically-modified mice lacking the IL-1RI receptor, not responsive to IL-1, are protected from aging-related LV hypertrophy, fibrosis and diastolic dysfunction. These data support a central role of IL-1 in the pathophysiology of aging-related HFpEF.
Abstract 13214: Coping With Heart Failure: Association Between Coping Strategies and Health Outcomes in Patients With Heart Failure
Authors: Alanazi Mohammed O , Deka Pallav , Given Charles , Wyatt Gwen
Published: April 2022

Introduction:
Coping is an essential element of self-management in chronic conditions such as heart failure (HF) where patients experience poor physical and emotional health outcomes. Coping strategies (problem-focused, active, and avoidant) often determine patients’ well-being. Although multiple factors are known to be associated with the selection of coping strategies in HF, the evidence is limited and inconclusive. Specifically, clarity on the association between HF patients’ demographics (age, sex, education, income), disease duration, and symptom severity with coping strategies is needed.

Research Questions:
This in-progress study seeks answers to the following questions: 1) Identify the association between demographics, disease duration, and symptom severity and coping strategies (problem-focused, active and avoidant); 2) Examine the association between the three types of coping strategies and physical and emotional health status outcomes; 3) Describe the mediating effect of coping strategies on the relationship between the reported symptom severity and subsequent physical and emotional health outcomes.

Conceptual framework:
This study is guided by the Stress and Coping model that consists of three components: antecedents of stress, coping strategies, and adaptational outcomes.

Methods:
This in-progress study uses a cross-sectional descriptive design examining associations and potential mediators. A total of 112 HF patients will be recruited online using
ResearchMatch
, a secure online tool that aims to match researchers with target participants, and in-person from cardiovascular clinics in Michigan. The inclusion criteria are: 1) HF diagnosis, 2) a New York Heart Association classification ≥ II; 3) aged over 18; 4) speak and read in English. The Brief COPE and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) will be used to measure coping strategies and health outcomes, respectively. A mediation model was proposed to illustrate the mechanism in which coping mediates the influence of symptom severity on health status outcomes.

Conclusion:
This study will provide insight into coping strategies utilized by HF patients and highlight the influence of demographics, disease duration, and symptom severity on coping.
Abstract 13218: CITED4 is Required for Exercise-Induced Cardiac Growth and Cardiomyogenesis in Mice
Authors: Trager Lena E , Kuznetsov Alexandra , Lyons Margaret , Iwamoto Yoshiko , Kitchen Robert , Lerchenmueller Carolin , Platt Colin , Guseh James S , Houstis Nicholas , Li Haobo , Rosenzweig Anthony
Published: April 2022

Introduction:
CITED4 (CBP/p300-interacting transactivators with E [glutamic acid]/D [aspartic acid]-rich-carboxylterminal domain 4) is a transcriptional regulator which limits pathologic remodeling after ischemic and pressure overload models of cardiac stress. It is also upregulated in the heart with exercise, an effective intervention which induces physiological hypertrophy and cardiomyogenesis in adult mice. We
hypothesized that CITED4 is required for exercise-induced cardiac growth and cardiomyogenesis.

Methods and Results:
Eight- to ten-week-old mice with cardiomyocyte-specific CITED4 knockout (C4KO) and littermate controls underwent 8 weeks of voluntary wheel running in comparison to sedentary controls. 5-Ethynyl-2′-deoxyuridine (EdU) was injected subcutaneously every two days for the first two weeks. There were no significant differences in cardiac size and function at baseline between C4KO and control mice. In control mice, running increased heart weight to tibial length ratio (HW/TL, 6.26±0.25 vs 7.37±0.75, p=0.01, n=5-9 per group), heart weight to body weight ratio (HW/BW, 4.08±0.40 vs 4.93±0.48, p=0.01), and cardiomyocyte (CM) size without affecting fractional shortening (FS), consistent with physiologic remodeling. There was also a nonsignificant trend to increased EdU+ CMs in the control exercised mice (2.96±2.34% vs 5.23±6.28%, p=0.44), suggestive of previously documented exercise-induced cardiomyogenesis. In contrast, running did not change HW/TL and CM size in C4KO mice (HW/TL, 6.44±0.48 vs 6.66±0.29, p=0.22, n= 0-13 per group) but reduced %FS (58.78±3.27 vs 53.67±4.59, p=0.03) and increased chamber size (LVIDs, 1.32±0.13 vs 1.50±0.17, p=0.032), suggesting maladaptive cardiac remodeling with exercise, confirming prior findings observed in a more extreme swim-exercise model. Rather than the expected increase, hearts from exercised C4KO mice had
fewer
EdU+ CMs compared to sedentary C4KO mice (3.76±2.60% vs 2.11±0.76%, p=0.05) and reduced expression of cell cycle genes Cdkn1b, Cyclin B1, Cdkn2a, and Ki-67.

Conclusions:
CITED4 is required for exercise-induced cardiomyogenesis, CM hypertrophy, and adaptive remodeling. CITED4 deficiency leads to maladaptive cardiac remodeling with physiologic stress.
Abstract 13229: Statins Improve Endothelial Function via Suppression of Epigenetics Driven-EndMT
Authors: Liu Chun , Chen Ian Y , Liu Yu , Shen Mengcheng , Ameen Mo , Sayed Nazish , Wu Joseph C
Published: April 2022

Introduction and Hypothesis:
Statins, a class of HMG-CoA reductase inhibitors that repress the mevalonate pathway, have been increasingly recognized to reduce cardiovascular risks in a pleiotropic manner independent of their lipid-lowering effects. Yet, the precise molecular mechanisms underlying their cardiovascular protection effects remain elusive. As an unlimited alternate source of human primary cells, we sought to use human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) to tackle this question.

Methods:
We treated iPSC-ECs with or without statins in both baseline and prodiabetic conditions, and evaluated their biological functions specifically at the transcriptional and epigenetic levels using an array of state-of-the-art technologies, such as transcriptome profiling, ChIP-seq, ATAC-seq, and CRISPR interference (CRISPRi).

Results:
We observed that, compared to vehicles, statins significantly improved endothelial functions in both baseline and prodiabetic conditions in iPSC-ECs. Mechanistically, statins could reduce chromatin accessibility at TEAD elements and ultimately at endothelial-to-mesenchymal transition (EndMT)-regulating genes in a yes-associated protein (YAP)-dependent manner. Interestingly, inhibition of geranylgeranyltransferase I (GGTase I), a mevalonate pathway intermediate, was able to block YAP nuclear translocation and thereby YAP activity by suppressing RhoA signaling. Based on these observations, we further confirmed that inhibition of any component of the GGTase-RhoA-YAP/TEAD signaling axis using either genetic or pharmacological approaches was effective to rescue EndMT-associated endothelial dysfunction, especially under prodiabetic conditions.

Conclusions:
Taken together, our study identifies a novel protective role of statins in endothelial dysfunction by epigenetically repressing EndMT, and proposes that GGTase, RhoA, and YAP inhibitors may be tested as potential therapeutic candidates in addition to statins to prevent or treat endothelial dysfunction-associated cardiovascular diseases.
Abstract 13231: Semaphorin3F Reduces Atherosclerosis by Decreasing Endothelial Activation and Barrier Permeability and Smooth Muscle Cell Migration
Authors: Singaraja Roshni R , Rattanasopa Chutima , Castano Mayan David , Ghosh Sujoy
Published: April 2022

Coronary artery disease (CAD) remains a leading cause of death worldwide. To identify genes causally linked to CAD, we previously conducted large-scale genetic analyses, and identified an association between genes in the semaphorin pathway and CAD. Expression profiling in human atherosclerosis-relevant cell types and atherosclerotic plaques identified semaphorin3F (SEMA3F) as a possible candidate causally linked to atherosclerosis. Administration of SEMA3F reduced aortic lesion area in western-type diet-fed
Ldlr
-/-
mice (Control: 12.1±1.4; SEMA3F: 8.1±0.8, % lesion area/total aortic sinus area, p=0.02). In contrast, neointimal formation was increased in
Sema3f
-/-
mice with partial carotid artery ligation (
WT
: 22.8±2.8;
Sema3f
-/-
: 39.2±4.0; % intimal area/total vessel area, p=0.004). Additionally, SEMA3F administration increased re-endothelialization and reduced restenosis in
Ldlr
-/-
mice that underwent carotid endothelial denudation (Control: 53.3±3.5; SEMA3F: 21.4±3.1; % intimal plaque area/vessel area, p=0.0006). Monocyte adhesion to aortic vascular endothelial cells (VECs) from
Sema3f
-/-
mice was elevated, driven by increased NF-κB activation and increased expression of its target adhesion molecules, VCAM1 and ICAM1, in VECs. Monocyte transmigration through VECs from
Sema3f
-/-
mice was also increased, likely due to increased membrane permeability, assessed by
in-vivo
intravital two-photon microscopy. The increased membrane permeability was modulated in part by decreased mTOR phosphorylation that in turn suppressed vascular endothelial cadherin protein expression. SEMA3F increased thick actomyosin filaments and elicited larger focal adhesions in VECs, suggesting decreased migration. In line with this, SEMA3F inhibited vascular smooth muscle cell (VSMC) migration and maintained the contractile phenotype of VSMCs, which was mediated by the Rho pathway. SEMA3F is causally atheroprotective in models of atherosclerosis and restenosis, mediated, in part, through the modulation of vascular endothelial cell permeability and adhesion molecule expression, and vascular smooth muscle cell migration and phenotype switching.
Abstract 13232: Prokineticin as a Biomarker of Cardiotoxicity in Cancer Patients
Authors: Nebigil Canan G , AUDEBRAND Anaïs , Cardinale Daniela
Published: April 2022

Many anticancer drugs are highly effective for cancer treatments. However, they triggerclinically significant cardiovascular morbidity and in some case mortality. Recently,experimental data support an important protective role of prokineticin-2, a cytokine, againstanthracycline-mediated cardiovascular toxicity. The aim of this study was to examine thelevels of plasma prokineticins (PROK1 and PROK2), and clinically used cardiac biomarkers(Troponin-T, Brain Natriuretic peptide) to assess possible correlations of these cytokines withrisk and severity of cardiotoxicity of cancer treatments. 200 patients with different type oftumor (mostly breast cancer, and ovarian cancer, urinarybladder cancer or other types oftumors), were enrolled. They were scheduled for cancer treatments including anthracyclinesalone, monoclonal antibody-based tyrosine kinase inhibitors TKI alone, a combination ofanthracyclines and TKI, and a combination of both anticancer agents and taxanes. Theexclusion criteria were previous anticancer treatments and cardiovascular pathologies suchashypertension, cardiomyopathy, coronary artery disease, life threatening arrhythmias, andongoing cardiovascular treatments. High-sensitive troponin I (TNI), BNP, PROK1 and PROK2were assessed in the plasma and cardiac systolic function (left ventricular ejection fraction,LVEF) were assessed by ECHO atbaseline and at 3, 6, 12 months after the completion of theoncology treatments. 42/142 patients (33%) showed an increase in TNI during or soon afterthe completion of cancer therapy. All patients (except for2) with an elevated TNI received acardioprotective therapy with enalapril. LVEF gradually and significantly decreased frombaseline during the observational period (P<0.001). This was associated with increased levelsof TNI levels during and soon after cancer treatments. BNP levels remained unaltered. PROK1levels (N=63) had slightly, but not significant increased. PROK2 levels significantly increased(N=63) from baseline. This pilot study confirmed the role of TNI in predicting chemotherapy-mediated cardiotoxicity, and identified for the first time PROK2 as potential biomarker thatmay help to identify patients more prone to develop cardiotoxicity.
Abstract 13234: Impact of Sex on Outcomes After Cardiac Surgery: A Systematic Review and Meta-Analysis
Authors: Dixon Lauren K , Di Tommaso Ettorino , Dimagli Arnaldo , Sinha Shubhra , Sandhu Manraj , angelini gianni , Umberto Benedetto
Published: April 2022

Introduction:
Despite advances in cardiac surgery, there is evidence from observational studies which suggests that females have poorer post-operative outcomes than males. This study is the first to review sex related outcomes following both coronary artery bypass graft (CABG) and valve surgery with or without combined CABG.

Hypothesis:
Females have worse outcomes following cardiac surgery than males.

Methods:
We identified 30 primary research articles reporting either short-term mortality (in-hospital/30 day), long-term mortality, post-operative stroke, sternal wound infection and post-operative myocardial infarction (MI) in both sexes following CABG and valve surgery with or without combined CABG Reported adjusted odds/hazard ratio were pooled using an inverse variance model.

Results:
Females were at higher risk of short-term mortality (odds ratio (OR) 1.40; 95% confidence interval (CI) 1.32-1.49; I
2
=79%) and post-operative stroke (OR 1.2; CI 1.07-1.34; I
2
=90%) when compared to males. There was no increased risk in long-term mortality (OR 1.04; 95% CI: 0.93-1.16; I
2
=82%), post-operative MI (OR 1.22; 95%CI: 0.89-1.67; I
2
=60%) or deep sternal wound infection (OR 0.92; 95%CI: 0.65-1.03, I
2
=87%). No evidence of publication bias or small study effect was found.

Conclusions:
Females are at a greater risk of short-term mortality and post-operative stroke than males following CABG and valve surgery with or without combined CABG. However long-term mortality is equivalent in both sexes.
Abstract 13243: Integrin Linked Kinase Expression in Human Valvular Endothelial Cells Plays a Protective Role in Calcific Aortic Valve Disease
Authors: Sanchez Sandra , Reventun Paula , Castro Mercedes , Cook-Calvete Alberto , Benito Lucía , Hernandez Navarro Ignacio , Lopez Menedez Jose , Zaragoza Carlos , Saura Marta
Published: April 2022

Introduction:
Calcific aortic valve disease (CAVD) is the most common valvular heart disease in the aging population. CAVD is a highly active ossification process originated in valvular interstitial cells which differentiate towards an osteoblastic phenotype. However, the role of valvular endothelial cells in CAVD has not been fully explored. We previously demonstrated that ILK expression in vascular endothelium plays an essential cardioprotective role.

Hypothesis:
Endothelial ILK plays a protective role in human valvular endothelial cells osteogenesis.

Methods and Results:
Human aortic valves were obtained from 52 patients with calcific aortic stenosis compared with 16 non-calcified aortic valves and ILK levels were analyzed. Our study showed a significant relationship between the degree of AV calcification and decreased ILK expression detected by IHQ and qPCR (p< 0,013). Moreover, decreased ILK expression correlated with BMP2 and Runx2, two markers of valvular calcification (p<0.01). Human valvular endothelial cells (hVECs) isolated from non-calcified controls display the ability to calcify when cultured in pro-calcifiying conditions and ILK levels were unaffected by the pro-calcifiying conditions. However, silencing ILK expression in hVECs resulted in decreased NO production, increased expression of calcific disease markers Runx2, BMP2, and osteopontin. ILK silencing in hVECs induced calcium deposition, determined by alizarin red staining, when cultured in pro-calcifiying conditions. Thus, our results suggest that decreased ILK expression could promote endothelial to osteogenic phenotype transition. Restoring nitric oxide levels by DETA-NONOate treatment in ILK silenced hVEC was able to reverse those effects partially.

Conclusions:
Collectively, our results point to a crucial role of ILK in maintaining human valve endothelial cell function preventing valvular calcification.
Abstract 13250: Factors Associated With Improvement of Left Ventricular Function After Catheter Ablation for Atrial Fibrillation in Patients With Heart Failure
Authors: França Marcos Roberto Q , Nascimento Bruno R , Miranda Reynaldo C , Silva Gustavo A , França Anna Terra , Moreira Henrique B , Fontes Vitor F , Ribeiro Antonio L , Carmo Andre A
Published: April 2022

Introduction:
Catheter ablation is a well-established therapy for atrial fibrillation (AF), and studies have shown positive outcomes in patients with heart failure (HF). We aimed to evaluate the impact of AF ablation on echocardiographic and clinical parameters in patients with HF in Brazil, and to assess factors associated with improvement of the left ventricular ejection fraction (LVEF).

Methods:
Consecutive patients diagnosed with HF and LVEF <50%, who underwent successful radiofrequency AF ablation in 5 high-volume institutions, were prospectively included. All patients underwent standard transthoracic echocardiography before the procedure and during clinical follow-up, and the analysis by the examiner was considered. The primary outcome was LVEF normalization (LVEF ≥50%) at follow-up. Clinical, echocardiographic, and procedure-related variables associated with the primary outcome were assessed by univariate logistic regression. P-value <0.05 was considered significant.

Results:
From 2018 to 2020, 44 patients were included, being 28 (64%) males, mean age 66±11 years. Of these, 12 were in NYHA functional class 3/4, 35 had persistent AF, and only 3 had previous ablations. Mean pre-procedural LVEF was 38±7%, with 13 (30%) having LVEF<35%. Complications occurred in only 2 patients, with 1 case of arterial pseudoaneurysm. In the 8.0±7.6 month follow-up, there was a substantial improvement of the LVEF to 53±14% (p<0.001), and 27 (61%) achieved the primary outcome of LVEF normalization. Thirty patients (68%) had LVEF improvement of ≥10%, only 5 remained in NYHA class 3/4, and recurrent AF occurred in 11 (25%). Predictors of LVEF normalization were: pre-ablation LVEF (OR: 1.32, 95%CI 1.13-1.54, p=0.001), baseline left atrial diameter (OR: 0.87, 95%CI 0.77-0.98, p=0.02), baseline NYHA functional class 1/2 (OR: 5.11, 95%CI 1.29-21.28, p=0.025) and the absence of indication of spironolactone (OR: 5.60, 95%CI 1.20-26.14). There were 3 deaths, and none of them had LVEF improvement in follow-up echo.

Conclusion:
AF ablation in patients with HF resulted in remarkable echocardiographic and functional improvement, with low complication rates. Less clinical severity and less morpho-functional impairment were associated with LVEF normalization.
Abstract 13263: Sex Differences in Outcomes After Cardiac Surgery: Insights From a National Database
Authors: Dixon Lauren , Dimagli Arnaldo , Di Tommaso Ettorino , Sinha Shubhra , Sandhu Manraj , angelini gianni , Benedetto Umberto
Published: April 2022

Introduction:
Female sex is considered an independent risk factor for mortality and morbidity following cardiac surgery. This study is the first to review the UK national database to compare outcomes following surgical revascularisation and valvular cardiac procedures between females and males.

Hypothesis:
Females have worse outcomes following cardiac surgery than males.

Methods:
Using data from National Adult Cardiac Surgery Audit (NACSA), we identified all elective and urgent, isolated coronary artery by-pass grafting (CABG), aortic valve replacement (AVR) and mitral valve replacement/repair (MVR) procedures from 2010-2018. We compared baseline data, operative data and outcomes of mortality, stroke, renal failure, deep sternal wound infection, return to theatre for bleeding and length of hospital stay. Multivariable logistical/linear regression models were used to assess relationships between sex and our outcomes, adjusting for baseline characteristics.

Results:
Females, compared to males, had a greater odds of experiencing 30-day mortality in each procedure (CABG OR 1.76, CI 1.47-2.09, p<0.001; AVR OR 1.59, CI 1.27-1.99, p<0.001; MVR OR 1.37, CI 1.09-1.71, p=0.006). After CABG, females also experienced increased need for post-operative dialysis (OR 1.31, CI 1.12-1.52, p<0.001), deep sternal wound infections (OR 1.43, CI 1.11-1.83, p=0.005) and length of stay (Beta 1.2, CI 1.0-1.4, p<0.001) compared to males. Female sex was protective against returning to theatre for post-operative bleeding following CABG (OR 0.76, CI 0.65-0.87, p<0.001) and AVR (OR 0.72, CI 0.61-0.84, p<0.001).

Conclusions:
Despite advances in cardiac surgery, females in the UK have an increased risk of short-term mortality after cardiac surgery compared to males. This highlights the need to focus on the understanding of the causes behind these disparities and therefore implementation of strategies to improve this.
Abstract 13264: Gender-Based Risk Prediction for 1-year Readmission Among Younger Women Hospitalized for Acute Myocardial Infarction
Authors: Arakaki Andrew J , Raparelli Valeria , Murphy Terrence , Tsang Sui , DONOFRIO Gail , Wood Malissa , Xie Catherine F , Pilote Louise , Dreyer Rachel P
Published: April 2022

Background:
Younger women (≤55 years) are at higher risk for readmission within one-year of hospitalization following acute myocardial infarction (AMI) compared to similarly aged men, yet there are no gender-specific risk prediction models for this population. Prior research suggests that gender-related factors more comprehensively explain sex-based differences in readmission risk. The objective was to develop and validate a risk prediction model of 1-year post-AMI readmission in young women considering demographic, clinical, and gender-related factors.

Methods:
We used data from women enrolled in the VIRGO study (n =2,007), a prospective observational study of young patients aged ≤55 years hospitalized with AMI in the US. Data were obtained from patient interviews, medical record abstraction, and adjudicated hospitalization records. Bayesian Model Averaging was used for model selection in a derivation cohort of 1338 women and subsequently validated in the remaining 669 women.

Results:
Within 1-year post-AMI, 684 (34.1%) women were readmitted at least once with a majority of readmissions due to cardiac causes (57.5%). The final model contained 9 predictors: experiencing any in-hospital complications, physical health at baseline (SF-12), disease-specific quality of life (Seattle Angina Questionnaire), diabetes, history of congestive heart failure, low income (≤30,000 USD), depression, length of hospital stay, and employment status
(Figure)
. Of the 9 predictors, 5 were gender-related. The model was well calibrated (calibration plots) and exhibited modest discrimination (C statistic=0.66 in development and validation cohorts).

Conclusions:
Younger women with diabetes, depression, history of congestive heart failure, and longer hospital stays were more likely to be readmitted. While clinical factors were the strongest predictors of readmission within 1-year among younger women with AMI, gender-related variables were important complements.
Abstract 13277: Deep Learning Networks Trained on Routine Echocardiography Images Provide Expert Level Prognostication in Patients With Pulmonary Hypertension: A Study on 408 Patients From an Expert Centre
Authors: Benesch Vidal Maria Luisa , Kempny Aleksander , Li Wei , Dimopoulos Konstantinos , Wort John , Gatzoulis Michael A , Diller Gerhard
Published: April 2022

Background:
Pulmonary arterial hypertension (PAH) is a progressive disease with high morbidity and mortality. Assessing PAH prognosis is paramount for guiding therapy and transthoracic echocardiography (TTE) remains the mainstay of regular assessment. We hypothesized that deep learning networks (DL) could provide essential prognostic information of comparable quality as a comprehensive expert assessment.

Methods:
All PAH pts. with routine TTE between 2005 and 2018 were included. A combination of U-Net DL-frameworks was developed to automatically segment cardiac chambers and extract geometric information throughout the cardiac cycle (see
Figure
). The prognostic value of chamber dimensions and functional parameters for all-cause mortality was assessed using Cox proportional-hazard analyses.

Results:
Overall, 408 PAH patients (median age 59 years, 74% female; 34% idiopathic PAH, 66% associated PAH) were included. Over a median follow-up of 0.6 years , 196 patients died. On univariable Cox analysis automatically determined right atrial area, right ventricular (RV) area, RV fractional area change, RV inflow diameter, RV length, left ventricular (LV) eccentricity index (p<0.001 for all) were significantly related to mortality. On multivariable analysis DL-based RV fractional area change (HR 0.97/%, p=0.004), right atrial area (HR 1.03/cm
2
, p=0.01) and LV longitudinal diameter (HR 0.92/cm, p=0.02) emerged as independent predictors of outcome. The prognostic value of all EDL parameters was non-inferior to traditional measures obtained by expert echocardiographers (p>0.05 for all concordance-C comparisons).

Conclusions:
The current study demonstrates for the first-time the utility of ensemble-based DL algorithms to assess prognosis of PAH based on a large tertiary centre dataset. Due to the automated process, these DL algorithms can ultimately serve as online based decision-making tools and the performance is comparable to expert investigators.
Abstract 13286: Ryanodine Receptor Inhibition Prevents Sudden Cardiac Death by Preserving Cardiac Repolarization Reserve in Stressed Arrhythmogenic Hearts
Authors: Joshi Pooja , KANURI BABUNAGESWARARAO , Crocker Jeffrey S , Byon Sonia Y , DeMazumder Deeptankar , Knollmann Bjorn C , Dey Swati
Published: April 2022

Introduction:
Current therapies for preventing sudden cardiac death (SCD) are limited. Prior studies have shown that cardiac stress-induced ryanodine receptor (RyR2) hyperactivity increases sarcoplasmic calcium leak, leading to ventricular tachyarrythmias (VT) and SCD. We hypothesized that inhibition of RyR2 with dantrolene sodium (DS) reduces Ca
2+
leak and mitigates VT and SCD risk in pressure-overloaded arrhythmogenic hearts.

Methods:
We used an established guinea pig model that uniquely recapitulates key features of human SCD, including a high incidence of spontaneous VT in freely ambulating animals, randomized to placebo vs. DS treatment. We performed
in vivo
(e.g., VT/SCD incidence, ECG heart rate and QT variability, echocardiographic measures of cardiac function) and
ex vivo
(e.g., pressure-volume, electrophysiology) studies. We performed intention to treat analysis for 4-week VT-free survival.

Results:
About half the animals receiving placebo had SCD by 4 weeks. By contrast, dantrolene treatment reduced SCD incidence by 50%. Compared to placebo, dantrolene treatment preserved chronotropic competency during transient β-adrenergic challenge, and improved heart rate variability (SDNN: 11±1.1 vs 17±2.8 ms, p<0.05), reduced QT variability (0.52±0.13 vs 0.19±0.08 (log, ms, p<0.05), and improved cardiac function (fractional shortening: 26±1.9 vs 45±4.5 %, p<0.05). In perfused excised hearts, dantrolene treatment mitigated VT (induced by isoproterenol or burst pacing).

Conclusion:
Inhibition of RyR2 hyperactivity by dantrolene treatment prevents VT and SCD by increasing cardiac repolarization reserve. Dantrolene also improved overall cardiac electromechanical function in stressed arrhythmogenic hearts. Targeted inhibition of RyR2 hyperactivity may be an effective therapeutic strategy for preventing VT and SCD.
Abstract 13287: Sex Differences in the Impact of Parental Obesity on Offspring Cardiac SIRT3 Expression, Mitochondrial Efficiency and Diastolic Function Early in Life
Authors: da Silva Alexandre A , Omoto Ana C , Dai Xuemei , Moak Sydney P , Li Xuan , Wang Zhen , Mouton Alan J , Hall John E , Docarmo Jussara M
Published: April 2022

Introduction:
Previous studies suggest that the perinatal environment can profoundly impact long-term metabolic health of the offspring.

Hypothesis:
We tested the hypothesis that parental (paternal + maternal) obesity impairs cardiac function in the offspring early in life.

Methods:
Within 1-3 days after weaning, offspring from obese rats fed a high fat diet (HFD-Offs) and age-matched offspring from lean rats (ND-Offs) were submitted to echocardiography and cardiac catheterization for assessment of pressure-volume relationships. Then, hearts were digested and isolated cardiomyocytes were used to determine contractile function, calcium transients, proteins related to calcium signaling, and mitochondrial bioenergetics.

Results:
Female and male HFD-Offs were heavier (72±2 and 61±4 vs 57±2 and 49 ±1 g), hyperglycemic (112±8 and 115±12 vs 92±10 and 96±8 mg/dL), with higher plasma insulin and leptin concentrations compared to female and male ND-Offs respectively. Compared to male ND-Offs controls, male HFD-Offs exhibited similar systolic function but impaired diastolic function as indicated by increased isovolumetric relaxation time (IVRT, 22±1 vs. 17±1 ms), the ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E’) (E/E’ ratio, 29±2 vs. 23±1) and Tau (5.7±0.2 vs. 4.8±0.2 ms). The impaired diastolic function was associated with reduced resting free Ca
2+
levels and phospholamban protein expression, increased activated matrix metalloproteinase 2 and reduced sirtuin 3 (SIRT3) protein expression, mitochondrial ATP reserve and ATP-linked respiration. We found no differences in diastolic function or SIRT3 expression levels in female HFD-Offs and ND-Offs.

Conclusions:
These results indicate that male and female offspring from obese parents have metabolic abnormalities early in life (1-3 days after weaning) and that male, but not female, Offs from obese parents have impaired diastolic dysfunction and reductions in cardiac SIRT3, resting free Ca
+2
levels and mitochondrial bioenergetics. (R01 DK121411, NHLBI-PO1HL51971, NIGMS P20GM104357 and U54GM115428)
Abstract 13303: Identification of Critical Six Transcriptional Factors for Reprogramming of Mouse Adipose-Derived Regenerative Cells Toward Cardiomyocytes and Its Therapeutic Effect
Authors: Narita Shingo , Unno Kazumasa , Shibata Rei , Kondo Kazuhisa , Shimizu Yuuki , kato katsuhiro , Fujikawa Yusuke , Murohara Toyoaki
Published: April 2022

Background:
Adipose-derived regenerative cells (ADRCs) are promising stem cells for regenerative medicine that are easy to harvest from adipose tissues and can expand
in vitro
. While ADRCs can differentiate into mesodermal lineage cells including adipocytes, osteocytes, and chondrocytes, little is known about differentiating adult ADRCs into mature cardiomyocytes.

Objective:
The aim of this study was to explore how to differentiate adult mouse ADRCs into cardiomyocytes efficiently and test their effect on the myocardial infarction mouse model
in vivo
.

Method and Results:
We performed differential expression analysis to identify transcriptional factors which were upregulated in developing mice heart (E11.5) compared with ADRCs. We systemically screened the combinations of the required transcription factors in ADRCs derived from αMHC-EGFP reporter mice. Here, we identified the following six genes;
Baf60c
,
Gata4
,
Gata6
,
Klf15
,
Mef2a
,
Myocd
, not more or less, as the best combination to efficiently induce αMHC in ADRCs. Fluorescence-activated cell sorting analysis showed that 3.0±0.61% (n=3) ADRCs were positive for αMHC after introducing these six factors. In addition, quantitative PCR demonstrated that several other marker genes of mature cardiomyocytes, including
Actc1
,
Tnnt2
,
Ttn
,
Fhod3
, were confirmed to be upregulated by six factors. Immunocytochemical staining showed that most of the induced ADRCs had fibrous conformation of sarcomeric α-actin. Moreover, the gene expression pattern of the cells showed upregulation of genes associated with cardiac muscle cell differentiation. Finally, injection of the induced ADRCs into acute myocardial infarction lesions
in vivo
resulted in the improvement of survival rate (p=0.028, n=32), fractional shortening (p=0.012, n=7, 15), and the reduction of infarction scar area compared to the injection of ADRCs without induction (p=0.029, n=7). The induced ADRCs could survive
in situ
and continued to express the cardiac troponin T protein for four weeks after injection.

Conclusions:
The combination of six transcriptional factors could induce cardiomyocyte-like gene expression patterns on adult ADRCs. The induced ADRCs could have a therapeutic effect on an experimental ischemic heart model
in vivo
.
Abstract 13309: Differences in Clinical Characteristics and Hospitalizations Between Midrange, Reduced and Preserved Heart Failure
Authors: Wheeler Nathan , Dharmavaram Naga , Rajput Furqan , Hess Timothy , Baber Aurangzeb , Raza Farhan , Dhingra Ravi
Published: April 2022

Introduction:
Distinct pathophysiologic differences exist among heart failure (HF) patients depending on baseline left ventricular ejection fraction (LVEF) and degree of LVEF recovery to medical therapy; however, differences in clinical outcomes among these patients remain unclear.

Hypothesis:
We hypothesized that patients with HF and mid-range EF (HFmrEF) would have lower all cause and HF hospitalizations compared to HFpEF and HFrEF patients.

Methods:
We identified 9,428 patients between 2009-2018 with ICD diagnosis of HF with a baseline and 1-year follow-up echocardiogram. We created 9 subgroups based on initial and follow-up ejection fraction (LVEF defined as preserved >50%; midrange 40-50% and reduced <40%). All-cause and HF hospitalizations crude incidence rates and length of stay were calculated as per patient follow-up year.

Results:
A total of 424 HFmrEF patients who maintained mid-range ejection fraction at follow-up were included in our analysis. HFmrEF patients were less likely to have pulmonary hypertension and more likely to have ischemic cardiomyopathy, coronary artery disease, hyperlipidemia compared to HFrEF and HFpEF (P <0.001). There were 47832 total and 18594 HF hospitalizations with a mean follow-up time of 3.89 years. Patients with HFmrEF who stay mid-range had the lowest number of total (0.97 per follow-up year, P<0.001) and HF hospitalizations (0.43, P<0.001) when compared to all other groups. HFmrEF who stay mid-range also had the lowest length of stay during both total and HF hospitalizations (2.85 and 1.91, P<0.001).

Conclusions:
Patients who have mid-range ejection fraction at diagnosis and at follow-up had lower all cause and HF hospitalizations and shorter length of stay when compared to HFrEF, recovered EF, and HFpEF patients. Further research is needed to determine the proper management of this group.
Abstract 13310: Early Percutaneous Coronary Intervention: Risks and Outcomes in Patients With Cancer
Authors: Scarpone Marialuisa , Bergami Maria , Cenko Edina , Vasiljevic Zorana , Zdravkovic Marija , vavlukis Marija , Kedev Sasko , Milicic Davor , Manfrini Olivia , Bugiardini Raffaele
Published: April 2022

Background:
Patients with malignancies may have a high pro-thrombotic status as well as a high risk of hemorrhagic events either due to the tumor or its treatment.For this reason, these patients have always been excluded from randomized clinical trial on percutaneous coronary intervention (PCI).

Aim:
To investigate the safety of PCI in patients with malignancies admitted for an AMI.

Methods and Results:
Retrospective analysis on an international European ACS registry. Primary endpoint: 30-day mortality. Secondary endpoint: periprocedural-complications. There were 273 patients (35% women) with AMI and malignancies. Colon (19%), prostate (14%), breast (13%), lung (8%) and blood (8%) malignancies were the most frequents type of cancer. Women and men had similar age (68 ±11.5 vs 69.1 ±11.5, p=ns). STEMI was in 56% of patients (with no significant gender difference: 51% men vs 65% women, p=0.09). PCI was performed in 64% of patients (with primary PCI in 75% of STEMI). The rate of complications during cardiac catheterization and intervention was 6.5% (2.1% distal embolization, 2.1% no-reflow, 0.7% acute closure, 0.7% dissection, 0.7% perforation, none major bleeding). Nobody among patients that had cardiac catheterization and intervention complications died during hospital stay. In-hospital mortality was 5.9%. The group of patients treated with PCI had a significantly lower rate of death then that of those treated non invasively (1.7% vs 13.1%, p<0.00001). Factors associated with lower probability to receive cardiac catheterization were older age (OR 0.94, 95% CI 0.92-0.97) and absence of typical chest pain at admission (OR: 0.38; 95%CI:0.18-0.81), but the type of malignancy and gender were not. On multivariable model, age (OR 1.1, 95%CI 1.03-1.17) and PCI (OR 0.16 95%CI, 0.04-0.59) were independently associated with the risk of death for ACS (increased and decreased risk, respectively).

Conclusion:
These preliminary data from real word support the safety use of PCI in patients with malignancies and ACS, which have always been excluded from randomized clinical trial.
Abstract 13317: Optimization of Left Ventricular Assist Device Therapy: A Combined in vitro and in silico Strategy to Reduce Thromboembolic Adverse Events via Evidence-Based Surgical Configuration and Medical Management
Authors: Aliseda Alberto , Chivukula Venkat Keshav , Chassagne Fanette , Li Song , Beckman Jennifer , Mahr Claudius
Published: April 2022

Introduction:
Left Ventricular Assist Devices are growing in frequency and importance in the treatment of medical-refractory heart failure. The incidence of thromboembolic events is a principal cause of mortality and morbidity for these patients, despite third generation pumps greatly reducing in-pump thrombosis.

Hypothesis:
To understand this problem, we hypothesize that LVAD-induced hemodynamics precondition platelets to activate and aggregate, leading to incipient thrombus formation which may propagate throughout the circulation, explaining the high incidence of thromboembolic events in the absence of in-pump thrombosis.

Methods:
A combined computational and in vitro modeling approach is used to simulate blood flow in the left ventricle, LVAD inflow cannula, outflow graft and aortic arch, with the goal of understanding the role of LVAD therapy in hemodynamics.

Results:
A systematic optimization of surgical parameters (inflow cannula angle, inflow cannula insertion depth, outflow graft anastomosis angle, outflow graft diameter) and medical management (LVAD speed, blood pressure, aortic valve opening frequency) based on Lagrangian metrics confirmed that the thrombogenicity of LVAD therapy can be potentially be significantly reduced. These metrics allow for quantitative comparisons of device management. Guidelines of optimum ranges of therapy configurations, and definition of “high risk” surgical configurations to avoid have been proposed.

Conclusions:
Reducing thrombogenicity and improving hemocompatibility is the next frontier in durable LVAD therapy for advanced heart failure. Risk-benefit analysis of many surgical configurations and medical management strategies can be quantitatively analyzed. Systematic analysis can serve as the rationale for future clinical trials that will optimize patient outcomes and reduce complications.