bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18931: Integrative Genomics Analyses Identifies Shared Regulatory Networks for Cardiovascular Disease and Type 2 Diabetes Mellitus in American Women of Caucasian, African and Hispanic Ethnicities
Authors: Shu Le , Chan Kei Hang Katie , Liu Simin , Yang Xia
Published: July 2021

Cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) have many shared risk factors, suggesting that they have common pathophysiological mechanisms. Our recent analysis of genome wide association studies (GWAS) of both CVD and T2D in three ethnic populations revealed a number of biological pathways, such as extracellular matrix and focal adhesion, to be genetically associated with both diseases. Building on our prior work employing knowledge-driven pathways, we performed data-driven integrative genomics analyses using gene co-expression networks constructed from a multitude of tissue-specific transcriptome datasets in conjunction with GWAS for CVD, T2D, and a vascular disease phenotype (VD, representing combined CVD+T2D) in three different ethnic groups of 8155 African Americans, 3494 Hispanic Americans and 3697 Caucasian Americans participated in the national Women’s Health Initiative (WHI) study. We examined a total of 2674 coexpression networks and found that 24 modules were significantly enriched for GWAS signatures for all three disease end points (15 modules) or VD only (9 modules) across multiple cohorts at false discovery rate <5%. These modules were enriched for the previously identified pathways like focal adhesion. Further, top modules for all three diseases were enriched for genes involved in citrate cycle and G-protein coupled receptor signaling, whereas top modules for VD were related to amino acid metabolism and BMP signaling, indicating novel processes that are shared between CVD and T2D. To pinpoint key driver (KD) for these modules, we integrated Bayesian networks of adipose, brain, kidney, liver and muscle tissue, and identified highly significant KDs such as BCL6B in adipose, MALAT1 in brain, ZNF565 in kidney, GLS2 in liver and MYL2 in muscle. Among the top KDs, MALAT1, GLS2 and MYL2 have been previously implicated in CVD and T2D, whereas the others represented novel findings. In summary, by leveraging multi-ethnic GWAS data on CVD and T2D and data-driven transcriptional networks, we uncovered both known and novel regulatory mechanisms that appeared to be shared by the two vascular diseases. These network regulators revealed may serve as important targets for future experimental validation.
Abstract 19020: ABCG1 Regulates Pulmonary Surfactant Homeostasis and the Lung Microbiome
Authors: de Aguiar Vallim Thomas Q , Baldan Angel , Cheng Joan , Goulbourne Christopher , Org Elin , Lusis Aldons J , Tarling Elizabeth J
Published: July 2021

Chronic respiratory diseases are the 3rd leading cause of death, and individuals suffering from respiratory distress are at risk for cardiovascular complications. Changes in the commensal bacteria in the lung have been associated with the development of chronic lung conditions including asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis. The lung is a dynamic environment, constantly subject to influx of debris and microbes. The clearance of pathogens and adaptation to changes in commensal flora are mediated by innate and acquired immune responses that minimize inflammation and maintain pulmonary homeostasis. Surfactant proteins are essential for the structure and function of pulmonary surfactant, produced solely by pulmonary type 2 cells, and have their own intrinsic innate immune properties. The ATP Binding Cassette Transporter G1 (ABCG1) is highly expressed in pulmonary type 2 cells, alveolar macrophages and immune cells. We have recently demonstrated that ABCG1 regulates pulmonary B cell and natural antibody homeostasis. Here we show that mice lacking ABCG1 specifically in pulmonary type 2 cells have altered lamellar body and surfactant homeostasis. Additionally, we show that mice lacking ABCG1 have disturbances in the commensal bacteria that populate the lungs. Abcg1-/- mice may represent a novel model in which to study the interaction between pulmonary surfactant metabolism, pulmonary innate immune responses and the lung microbiome.
Abstract 19078: Early Predictors of Survival to Heart Transplantation in Patients With Amyloid Light-chain Cardiomyopathy
Authors: Steiner Johannes , Selby Van , Verkouw Karla , Svetlichnaya Jana , Defaria Yeh Doreen , De Marco Teresa , Semigran Marc
Published: July 2021

Background:
Amyloid cardiomyopathy progresses more rapidly and has different manifestations than more common cardiomyopathies. Nevertheless, survival of selected cardiac amyloid patients after orthotopic heart transplantation (OHT) followed by autologous stem cell transplant is similar to other restrictive cardiomyopathies. The importance of clinical presentation and pre-transplantation characteristics on outcome in patients with AL amyloid cardiomyopathy evaluated for heart transplantation is still not well defined.

Methods:
The impact of echocardiographic, hemodynamic, and clinical parameters on outcome in 46 patients evaluated for OHT and enrolled in the International Consortium for Cardiac Amyloid Transplant (iCCAT) database was studied. Cox proportional hazards models of time to death were used. End point was death after transplant evaluation censored at transplant.

Results:
The median age at the time of transplant evaluated was 57.6 (+/- 9.6) years, and the mean time from presentation to listing was 27 (+/- 26) days. 19 (41%) patients underwent OHT after an average wait time of 72 days. Univariate risk factors associated with death after initial evaluation were cardiac output (p=0.012), right ventricular stroke work index (p=0.033), left ventricular end diastolic dimension (p=0.024), left ventricular outflow tract velocity time integral (p=0.019), mean arterial pressures (p=0.005), NT pro-BNP (p=0.007), presence of pleural effusion (p=0.005), as well as elevated kappa and lambda serum free light chain concentrations (p=0.004). Whereas left ventricular ejection fraction did not correlate with death after evaluation, increased right ventricular wall thickness remained a strong mortality predictor in a multivariate model with light chain difference and cardiac output (HR 1.6 for every 1 mm increase in thickness, p=0.017).

Conclusions:
Pleural involvement, high light chain burden, and right ventricular infiltration predicted death while awaiting a donor organ and may be markers of more systemic disease. Ultimately, this could affect transplant candidate selection and allocation strategies.
Abstract 19109: Low PCSK9 and LDL Cholesterol and Risk of Dementia, Parkinson’s Disease, and Epilepsy - A Mendelian Randomization Study
Authors: Benn Marianne , Nordestgaard Børge G , Frikke-Schmidt Ruth , Tybjærg-Hansen Anne
Published: July 2021

Introduction:
Low levels of low-density-lipoprotein cholesterol(LDL-C) due to statin use has been associated with reduced cognitive function. We aimed to assess whether low LDL-C due to genetic variation in the 3-hydroxy-3-methylglutaryl-CoA reductase(HMGCR; rs17238484) and proprotein convertase subtilisin kexin 9(PCSK9; rs11591147, rs148195424, rs562556, rs505151) genes, involved in LDL-C biosynthesis and metabolism, respectively, is associated with risk of Alzheimer’s dementia, vascular dementia, all dementia, Parkinson’s disease, and epilepsy in a general population off and on lipid lowering medication.

Methods:
We examined associations of plasma LDL-C with observational risk of disease; genetic variants with plasma LDL-C levels; and genetic variants and risk of disease as an indication of causality using a Mendelian randomization design in 92,068 participants off and 11,519 participants on lipid lowering medication from the Copenhagen General Population Study and the Copenhagen City Heart Study.

Results:
In observational analysis, risk of epilepsy was 98%(95% confidence interval: 32%-297%) higher in participants with an LDL-C <1.5mmol/L versus ≥3.0mmol/L. Low LDL-C was not associated with risk of Alzheimer’s dementia, vascular dementia, all dementia, and Parkinson’s disease. In causal genetic analyses, PCSK9 and HMGCR variants associated with 7.8% and 2.9% lower LDL-C. Genotypes were not associated with risk of Alzheimer’s dementia, vascular dementia, all dementia, Parkinson’s disease, or epilepsy.

Conclusions:
Using 103,587 individuals from the general population, we found that observationally low LDL-C level was associated with increased risk of epilepsy. Low LDL-C due to PCSK9 and HMGCR variants was not associated with Alzheimer’s dementia, vascular dementia, all dementia, Parkinson’s disease or epilepsy, and results does not support a causal role of low LDL-C in these diseases.
Abstract 19190: Effectiveness of Supervised Exercise Therapy for the Treatment of Intermittent Claudication in Real-world Clinical Practice
Authors: Rouwet Ellen , Weststrate Karin , Bons Lidia , Verhagen Hence , Hoeks Sanne
Published: July 2021

Introduction:
Guidelines recommend supervised exercise therapy (SET) as a first-line treatment for patients with intermittent claudication. In trials, SET has indeed been shown to be equally effective as endovascular revascularization in improving walking performance and quality of life. However, SET is an underutilized treatment and the effectiveness of a SET-first approach outside a trial setting is unknown.

Hypothesis:
We assessed the hypothesis that SET is an effective treatment for intermittent claudication in real-world clinical practice.

Methods:
In a single-center prospective cohort study, 204 patients with newly diagnosed intermittent claudication were referred to a physiotherapist for SET between August 2009 and December 2013. All patients underwent lower extremity CTA or MRA imaging. Significant stenosis was defined as ≥50% reduction in luminal diameter. Community-based SET was provided according to national guidelines. Freedom from endovascular or open surgical intervention at the last outpatient visit was considered as the primary outcome. Kaplan Meier estimate was used to determine freedom from intervention at 1 year.

Results:
Mean age was 70±10 years with 59% men and the common risk factors (77% hypertension, 31% diabetes, 46% smoking, 10% obesity) and comorbidities (32% and 23% history of ischemic heart or cerebrovascular disease, resp.). Median maximum walking distance on treadmill testing at baseline visit was 320 m (IQR 150-510 m). The majority (88%) of patients had significant femoropopliteal and/or crural disease. Only 4% had isolated aortoiliac and/or common femoral artery stenoses. Of the 204 referred patients, 84% followed the SET program. After 1 year follow up, 88% of patients were still free from endovascular or surgical intervention.

Conclusions:
In a real-world clinical setting, a SET-first approach is an effective treatment for intermittent claudication, preventing invasive treatment in most patients.
Abstract 19213: Epigenetically Reprogrammed Mesenchymal Stem Cells Improve Myocardial Remodeling and Cardiac Function After Myocardial Infarction by Modulating Post-infarct Inflammation and Neoangiogenesis
Authors: Kim Jin Jin , Park Eun-Hye , Park Hyo Eun , Kim Eunmin , Choi Young , Lee Kwan Yong , Lee Young Soo , Park Ha-Wook , Kim Tae-Hoon , Koh Yoon Seok , Seung Ki-Bae , Hwang Byung-Hee , Choo Eun Ho , Ihm Sang-Hyun , Chang Kiyuk
Published: July 2021

Background:
The efficacy of transplantation of default mesenchymal stem cells (MSCs) is controversial because of their limited plasticity and decreased function in elderly patients with myocardial infarction (MI). We investigated whether epigenetically reprogrammed-MSCs ameliorate myocardial remodeling in a mouse model of MI.

Methods:
Bone marrow-derived MSCs were sequentially treated with 5 mM/L of valproic acid and 100 nM/L of 5-azacytidine for 48 hours. Quantitative RT-PCR was performed to evaluate the effect of epigenetic modifiers on the gene expression of MSCs. 2 x 105 default MSCs, 2 x 105 epigenetically reprogrammed-MSCs, or phosphate-buffered saline were injected into peri-infarct zone immediately after ligating proximal portion of left anterior descending artery. On days 28 after MI, in vivo cardiac magnetic resonance (CMR) and harvest of heart tissue was sequentially performed.

Results:
Epigenetic modification of MSCs induced gene expression of anti-inflammatory markers such as transforming growth factor-β, indoleamine 2,3-dioxygenase. Fibroblast growth factor-β increased 37.5% and myocyte-specific enhancer factor 2C increased 36.8% at the mRNA level. Transplantation of modified-MSCs showed improved ejection fraction on CMR. In histopathologic analysis, infarct size was significantly decreased in modified-MSCs transplanted mice (p=0.002). When assessing capillary density of peri-infarct zone, larger number of CD31+ staining vascular structures was observed in modified-MSCs transplanted mice. Immunofluorescence stain showed marked increase of CD4+CD25+Foxp3+ regulatory T cells as well as CD68+MR+ M2 macrophage and decrease of CD68+iNOs+ M1 macrophage in modified-MSCs transplanted mice.

Conclusions:
Transplantation of epigenetically reprogrammed-MSCs significantly improves cardiac function by modulating post-infarct inflammation and neoangiogenesis in a preclinical model of AMI.
Abstract 19228: Cost-effectiveness of the CardioMems Implantable Pulmonary Artery Pressure Monitoring System in Patients With Chronic Heart Failure
Authors: Sandhu Alexander T , Goldhaber-Fiebert Jeremy D , Turakhia Mintu P , Kaiser Daniel W , Heidenreich Paul A
Published: July 2021

Background:
For management of heart failure, the value of the CardioMems device remains uncertain. We assessed the cost-effectiveness of the CardioMems device.

Methods:
We developed a Markov model to determine quality-adjusted life-years (QALYs), cost, and cost-effectiveness of patients with heart failure receiving CardioMems implantation compared to those with routine care. In the main case analysis, we modeled the intervention in the CHAMPION trial cohort, which included patients with NYHA Class III heart failure with a heart failure hospitalization within the past twelve months. We also performed subgroup analyses of patients with preserved ejection fraction or reduced ejection fraction, and a scenario analysis of a second cohort of patients from the CHARM trials with a previous heart failure hospitalization. We obtained event rates and utilities from published trial data; we used costs from literature estimates and Medicare payment data. The main case analysis was calibrated to the hospitalization and survival rates of the CHAMPION trial.

Results:
In the CHAMPION trial main case analysis, CardioMems reduced lifetime hospitalizations (2.37 versus 3.27), increased months of survival (67 versus 62), increased QALYs (2.66 versus 2.38) and increased costs ($171,132 versus $154,084), yielding a cost of $59,520 per QALY gained or $40,301 per life-year gained. The cost per QALY gained was $71,964 in patients with reduced ejection fraction compared to $34,899 in those with preserved ejection fraction. In less ill patients from the CHARM trials, which included patients with NYHA Class II heart failure, the device cost increased to $110,565 per QALY gained. If the device cost decreased from $17,500 in the main case analysis to $15,000, the intervention would cost less than $50,000 per QALY gained. The duration of effectiveness was initially assumed to be lifelong; if less than 29 months, CardioMems would cost more than $150,000 per QALY gained.

Conclusion:
The CardioMems device is cost-effective in populations similar to the CHAMPION trial, with a cost of less than $100,000 per QALY gained, if durability of device effectiveness is sustained. Post-marketing surveillance data on the device’s durability will further clarify its value.
Abstract 19252: Ideal Cardiovascular Health and Employee Productivity
Authors: Driver Steven , Panjwani Anita , Spring Bonnie , Lloyd-Jones Donald M , Allen Norrina
Published: July 2021

Introduction:
The AHA has defined ideal cardiovascular health (CVH) as the simultaneous presence of 4 optimal health behaviors (not smoking, eating a healthy diet, meeting physical activity goals, and maintaining a healthy weight) and 3 optimal health factors (lower blood pressure, blood sugar, and cholesterol). An association between ideal CVH and employee productivity has not yet been established.

Objectives:
In this study, we sought to investigate whether employees with high CVH are more productive than employees with moderate or low CVH.

Methods:
In fiscal year 2015, an academic medical center offered health risk appraisal surveys (HRAs) to its 6,500 employees. Completion rates have been >90% to date (n=6,144). Ideal, intermediate, and poor levels for each of the 7 components listed above were calculated from HRA responses according to standard AHA definitions and assigned values of 2, 1, and 0 respectively. An overall CVH score was calculated for each respondent from the sum of individual component scores with a range of 0-14 (low 0-7 points, moderate 8-10, and high 11-14). Productivity was measured by responses related to missed work days due to illness (absenteeism) and days employees came to work but did not feel at their best (presenteeism). In this cross-sectional analysis, we used logistic regression to compare productivity responses between employees with high, moderate, and low CVH adjusting for race and sex (age was unavailable due to employee privacy concerns).

Results:
Overall, 35% of employees were in high CVH, 58% moderate, and 6% low. The odds of missing at least one workday due to illness during a two-week period were 67% lower among employees with high CVH compared to employees with low CVH (adjusted OR 0.33; 95% CI, 0.20-0.56). The odds of reporting that physical or emotional health problems made it difficult to concentrate on work at least half the time were 85% lower among employees with high CVH compared with low CVH (adjusted OR 0.15; 95% CI, 0.07-0.33).

Conclusions:
Self-reported higher CVH was strongly associated with better employee productivity as measured by fewer sick days and better concentration at work. These results support the notion that helping employees stay healthy may represent a valuable near-term strategy for employers.
Abstract 19258: Altered Redox State Impairs the Functional Competence of Skeletal Muscle Pericytes in Patients With Complicated Type 2 Diabetes
Authors: Vono Rosa , Gargioli Cesare , Sangalli Elena , Maselli Davide , Gotti Ambra , Losa Sergio , Spinetti Gaia , Madeddu Paolo
Published: July 2021

Introduction:
Type 2 diabetes mellitus (T2D) in association with critical limb ischemia (CLI) is detrimental to skeletal muscle function and metabolism and compromises muscle intrinsic regenerative ability.

Hypothesis:
Assess whether T2D+CLI negatively impact on muscular regenerative cells such as muscle pericytes (MPs) functional properties.

Methods:
Skeletal muscle biopsies were obtained under ethical approval at occasion of osteosarcoma diagnosis (H-MPs, n=8 ) or major amputation (T2D+CLI-MPs, n=11). MPs were characterized by flow cytometry (CD90, CD44, and Alkaline Phosphatase-AP), immunofluorescence (PDGFR-β, α-SMA, CD146, and NG2) and immunicytochemistry (AP). MP proliferation (BrdU assay), migration (scratch assay), apoptosis (caspase assay), myogenic differentiation (myosine heavy chain-MyHC staining), HUVECs tubulogenesis (Matrigel) and ROS production (MitoSox-Red) were assessed in vitro in at least n=3 donors per group. Molecular analysis were performed by RT-PCR.

Results:
Both H-MPs and T2D+CLI-MPs expressed typical pericyte markers, but T2D+CLI-MPs proliferated slowly (0.16±0.06 vs. 1.98±0.46 vs. H-MPs) and differentiated less into MyHC positive fibres (4.78±0.34 vs. 16.15±5.032 vs. H-MPs) while migration and apoptosis were not modified. The addition of T2D+CLI-MPs or their conditioned media to HUVECs impaired endothelial tubulization on Matrigel (respectively 10.40±1.39 vs. 13.73±0.64, and 11.88±1.04 vs. 16±1.4, vs. HUVECs alone). Furthermore ROS content increased in T2D+CLI-MPs (3.70±0.45 vs. 0.57±0.24, vs. H-MPs) and was associated with a down-regulation of SOD-1 (0.53±0.11 vs. 1.03±0.11) and catalase (0.41±0.1 vs. 0.97±0.2 vs. H-MPs) and an up-regulation of p66Shc (2.84±0.6 vs. 0.81±0.02 vs. H-MPs). Antioxidant treatment with N-acetylcysteine reverted altered proliferation (1.55±0.06 vs. 1.21±0.02) and antiangiogenic effect (13.63±1.00 vs. 7.367±0.75) compared to untreated counterparts. For all experiments significance was p<0.05.

Conclusions:
T2D+CLI hampers MPs biological functions relevant to muscular repair. Reversion of T2D+CLI-MPs alterations by antioxidant treatment suggests possible therapeutic targets for attenuation of peripheral complications.
Abstract 19260: Predictive Value of Circulating Biomarkers of Collagen Metabolism Following Catheter Ablation of Atrial Fibrillation
Authors: Pérez-Castellanos Alberto , Atienza Felipe , López Begoña , Ormaetxe José Miguel , Martínez-Alday Jesús Daniel , Arias Miguel Ángel , Pachón Marta , Arcocha María Fe , Arenal Ángel , Díez Javier , Fernández-Avilés Francisco
Published: July 2021

Introduction:
Myocardial fibrosis plays an important role in the pathogenesis of atrial fibrillation (AF). However, catheter ablation may eliminate AF sources but also increases fibrosis. We aimed to assess the predictive value of circulating biomarkers of collagen metabolism following AF catheter ablation.

Methods:
Serum levels (ELISA) of biomarkers of collagen metabolism were analyzed in patients undergoing AF ablation (62 paroxysmal, 67 persistent) at baseline and 12 months after ablation. Biomarkers levels in 20 patients in sinus rhythm were also evaluated to establish the normal values.

Results:
Before ablation, there was a direct linear correlation between PICP (carboxy-terminal propeptide of procollagen type I) levels and left atrial diameter for the overall sample (p=0.006). PICP levels at baseline were lower in paroxysmal AF patients with vs. without AF recurrences following ablation (68.30 ± 9.66μg/l vs 90.72 ± 3.78μg/l; p=0.017). At 12 months following ablation of paroxysmal patients, PICP levels significantly increased only in patients with AF recurrences (21.74μg/l vs -0.12 μg/l, Figure). There were no significant changes in biomarkers levels in persistent AF patients at baseline or during follow-up.

Conclusions:
Progressive increase of PICP levels following catheter ablation of AF is related with arrhythmia recurrence in paroxysmal AF patients. This result suggests that ablation may increase collagen turnover in non-responders paroxysmal AF patients.
Abstract 19335: Rescue of Cardiac Function Lost Due to Congenital Defect in Proteasome Heterogeneity
Authors: Trogisch Felix , Koser Franziska , Jungmann Andreas , Müller Oliver , Hecker Markus , Drews Oliver
Published: July 2021

The ubiquitin-proteasome system is a major regulator of protein homeostasis in health and disease by targeted proteolysis. Recent findings show that the heterogeneity of proteasome complexes is dynamically altered via elevated incorporation of non-essential proteasome subunits in the pathogenesis of cardiac remodeling. However, the impact of this regulatory event on cardiac remodeling is not known. Therefore, aim of the study was to determine the influence of the non-essential proteasome subunit Lmp2 on cardiac remodeling induced by chronic catecholamine exposure. Wild-type mice subjected to 30mg/kg isoproterenol for 7 days developed cardiac hypertrophy with increased cardiac function (fractional shortening/FS: +18% vs. pre-treatment). In hearts of these mice, Lmp2 showed increased abundance and incorporation in proteasome complexes. Adult mice lacking Lmp2 congenitally seem phenotypically indistinguishable from wild-types, but developed exacerbated cardiac hypertrophy with decreased cardiac function (FS: -27% vs. wt) upon continuous isoproterenol stimulation. Myocardial transfer of the gene encoding Lmp2 via adeno-associated virus in adult mice resulted in the expression of its processed form comparable to wild-type levels with no obvious phenotypic effects under unstimulated conditions. Upon catecholamine challenge, increasing levels of processed Lmp2 were detected in hypertrophied hearts, suggesting induced functional incorporation in proteasome complexes similar to observations previously made in wild-type animals. Re-expression of Lmp2 reduced the extent of cardiac remodeling in mice congenitally lacking this subunit and rescued cardiac function at least in part (FS: +13% vs. treated virus control). In conclusion, the study demonstrates for the first time that induced expression of the non-essential proteasome subunit Lmp2 is a regulatory mechanism of targeted proteolysis, which mitigates cardiac remodeling and contributes to maintaining cardiac function.
Abstract 19348: Efficacy of Cryoballoon Pulmonary Vein Isolation in Patients With Persistent Atrial Fibrillation
Authors: Guhl Emily , Siddoway Donald , Adelstein Evan , Saba Samir , Voigt Andrew , Jain Sandeep K
Published: July 2021

Introduction:
Cryoballoon pulmonary vein isolation (PVI) has emerged as an alternative to radiofrequency PVI for the treatment of paroxysmal atrial fibrillation (AF). The optimal ablation strategy for patients with persistent AF is unclear, as data on Cryoballoon PVI alone are limited.

Methods:
We analyzed a prospective registry of consecutive patients with persistent AF who underwent Cryoballoon PVI at a single center between 2011 and 2014. Patients were assessed for AF recurrence (including any atrial arrhythmia) after a 3 month blanking period at 6 months, 1 year, 2 years, and as needed for symptoms post PVI. Recurrence was based on typical symptoms or ECG/ event monitor evidence of AF. Kaplan-Meier analysis was used to estimate AF-free survival.

Results:
The 69 patients who underwent Cryoballoon PVI were aged 59 ± 8 years, 86% male, 54% HTN, had a CHADS2-VASC score 1.6 ± 1.2, and had a LA dimension 4.5 ± 0.6 cm. The AF recurrence-free rate at 1-year post-procedure was 59%. Overall, AF-free survival was 50% at the mean follow-up of 607 days. In comparing patients with persistent AF duration <1 year vs. >1 year, there was a trend toward greater AF recurrence-free rates in the <1 year group (66% vs 55%, p=0.09)

Conclusions:
Cryoballoon PVI appears to be an effective initial strategy in treating persistent AF, with an AF recurrence-free rate of 59% at 1 year.
Abstract 19355: Assessment of Myocardial Capillary Rarefaction Using Intracoronary Wave Intensity Analysis: A Validation in Cardiac Allograft Patients With Resultant Prognostic Insights
Authors: Broyd Chris J , Hernández-Pérez Francisco , Echavarria-Pinto Mauro , Quirós-Carretero Alicia , García-Pavía Pablo , Salas Clara , Jiménez-Quevedo Pilar , Gonzalo Nieves , Nuñez-Gil Ivan , Ibañez Borja , Alonso-Pulpón Luis , Fernández-Ortiz Antonio , Davies Justin , Segovia Javier , Escaned Javier
Published: July 2021

Introduction:
A decrease in capillary density (capillary rarefaction) is the predominant mechanism of microcirculatory dysfunction in certain heart conditions. Measuring capillary rarefaction with coronary flow reserve (CFR) or resistance measurements is hampered by the frequent presence of arteriolar remodelling. We investigated the potential of wave intensity analysis (WIA) to ascertain the presence of capillary rarefaction using transplant vasculopathy as a clinical model of microcirculatory disease. The prognostic implications of WIA-assessed capillary density in predicting cardiac allograft vasculopathy (CAV) was then also investigated.

Methods:
52 patients with unobstructed coronary arteries underwent combined LAD pressure and flow measurements at rest and with intracoronary adenosine. CFR, hyperaemic microvascular resistance, coronary resistance index, coronary conductance (IHDVPS) and WIA were calculated. Simultaneous right ventricular biopsies were obtained and analysed for capillary density in 17 patients. All patients were then followed up with 1-3 yearly screening angiography and IVUS.

Results:
All patients were in sinus rhythm with normal LV function. A statistically significant relationship with capillary density was noted with CFR (r=0.52, p=0.048) and the backward decompression wave (BDW) (r=-0.65, p<0.01) the latter of which was maintained with multiple regression analysis (p=0.02). Over a mean follow-up of 9.3 ± 5.2 years, the BDW was able to predict outcome in terms of CAV-events (-7.1 vs -4.5 x10
3
Wm
-2
s
-1
, p=0.04) as well as the development (7.9 vs 4.8 x10
3
Wm
-2
s
-1
, p=0.01) and severity (p=0.04) of angiographic CAV. There was a strong trend towards prediction of angiographic CAV disease with IHDVPS (1.7 vs 1.1 cm/s/mmHg, p=0.08) but no other relationships were noted with prognosis and microvascular indices.

Conclusions:
WIA is an excellent tool for assessing capillary rarefaction and provides a more focused insight into this domain of the microcirculation than other contemporary measures of microcirculatory function. In cardiac transplant patients, it is able to document the early histological changes of CAV and can predict CAV-related outcome as well as its angiographic presence and severity.
Abstract 19360: Potassium Infusion at the Onset of CPR Prevents Mitochondrial Impairment After Prolonged VF Arrest
Authors: Bartos Jason A , Matsuura Timothy R , Tsangaris Adamantios , Chandra Shekar Kadambari , McKnite Scott H , Rees Jennifer N , Yannopoulos Demetris
Published: July 2021

Introduction:
Potassium-based cardioplegia has been used for decades in cardiac surgery to preserve cardiac tissue while inducing cardiac standstill. Recent studies have also shown that animals can be successfully resuscitated after infusion of potassium at the beginning of cardiopulmonary resuscitation (CPR). This study tested the hypothesis that infusion of potassium at the onset of CPR prevents mitochondrial impairment caused by reperfusion injury after prolonged cardiac arrest.

Methods:
After 15 minutes of untreated ventricular fibrillation (VF), 18 pigs were randomized to receive control saline, 50 mEq potassium (low-dose), or 100 mEq potassium (high-dose) via central venous catheter at the initiation of CPR. All animals received mechanical CPR with active compression/decompression, an impedance threshold device, and epinephrine per standard AHA protocols. Cardiac tissue was harvested after 4 minutes of CPR without defibrillation. Primary endpoints included mitochondrial respiratory control index (RCI) and mitochondrial calcium retention capacity (CRC). Secondary endpoints included the hemodynamic assessment.

Results:
Infusion of potassium at the onset of CPR had no effect on hemodynamics including coronary perfusion pressure (25 vs. 28, p=0.7 for Control and low-dose KCl, respectively). Despite similar hemodynamics, potassium infusion improved RCI comparing control to low-dose KCl infusion using both complex I (4.3 vs. 6.1, p=0.01) and complex II (2.4 vs. 3.3, p=0.003) substrates. High-dose KCl did not provide additional respiration benefit. Potassium infusion also increased CRC. With complex I substrates, high-dose KCl enhanced CRC compared to controls [1361 vs. 1040, (in nmol), p=0.008, respectively]. Low-dose KCl increased CRC with complex II (1337 vs. 1597, p=0.02, for control and low-dose KCl, respectively) while high-dose KCl did not provide additional benefit.

Conclusions:
Potassium infusion at the initiation of CPR prevents reperfusion-induced mitochondrial damage. This improvement was independent of the perfusion pressure achieved during CPR. Improvement of mitochondrial function and stability is observed within the first four minutes of CPR providing an improved substrate for establishing ROSC.
Abstract 19403: Deterioration of Cardiac Performance and Dysfunction of Sympathetic Activity Affects Respiratory Instability in Chronic Heart Failure: Non-invasive and Simple Quantitative Assessment of Respiratory Stability
Authors: Domae Keitaro , Miyagawa Shigeru , Fukushima Satsuki , Nakamura Teruya , Yoshikawa Yasushi , Saito Shunsuke , Yoshioka Daisuke , Sakata Yasushi , Yamada Kenji , Toda Koichi , Asanoi Hidetsugu , Sawa Yoshiki
Published: July 2021

Background:
Cardiac sympathetic activity, in general assessed by 123I-meta-iodobenzylguanidine cardiac scintigraphy (mIBG-s), has been shown to be a critical indicator to predict morbidity and mortality associated with chronic heart failure (HF). We herein hypothesized that nocturnal respiratory stability, which has been suggested to be impaired by autonomic dysfunction, may be correlated with sympathetic nerve activity in advanced HF. To test this hypothesis, we developed respiratory stability index (RSI), which is calculated by computer-based non-invasive measurements.

Methods:
Fifteen patients with chronic HF under intensive medical treatments including maximized beta-blocker therapy were enrolled. All patients echocardiographically displayed their ejection fraction (EF) less than 35%. Nocturnal respiratory signals were serially collected by the under-pillow sensor to evaluate the respiratory spectrum during asleep. RSI was calculated from average of the reciprocal of the standard deviation of respiratory spectral ranges (Figure).

Results:
RSI was successfully and reproducibly evaluated in all cohorts with an average value being 44±21. mIBG-s-based values to indicate sympathetic activity, such as heart-to-mediastinum ratio (HMR) or wash-out rate, showed abnormality in all cohorts. Of note, the RSI was strongly correlated with HMR (ρ=0.83, p<0.01) or wash-out rate (ρ=-0.87, p<0.01). In addition, RSI was significantly correlated with standard indicator of HF such as plasma brain natriuretic peptide level (ρ=-0.59, p<0.05), EF (ρ=0.73, p<0.05) or pulmonary capillary wedge pressure assessed by right heart catheter study (ρ=-0.70, p<0.05).

Conclusions:
RSI showed a significant correlation with degree of autonomic dysfunction assessed by mIBG-s in advanced HF of chronic stage. This non-invasive method might enable serial evaluation to predict cardiac events even in patients on home healthcare, though further validation is required.
Abstract 19440: Reintervention Rates Following Balloon Aortic Valvuloplasty versus Surgical Valve Repair in Isolated Congenital Aortic Valve Stenosis - A Meta-analysis
Authors: Saung May T , McCracken Courtney , Sachdeva Ritu , Petit Christopher J
Published: July 2021

Introduction:
The optimal treatment for congenital aortic stenosis (AS) is debated despite decades of experience with both balloon aortic valvuloplasty (BAV) and surgical aortic valve repair (SAV). While BAV has been the mainstay of therapy for AS, recent single-center reports suggest optimal results following SAV.

Hypothesis:
We propose that reintervention rates following SAV and BAV are equivalent.

Methods:
We queried Medline, EMBASE and Web of Science for eligible studies using the keywords: “congenital aortic stenosis”, “balloon valvotomy”, “aortic valve stenosis surgery” and “treatment outcome or reintervention”. Studies were excluded when cohort size was <20 pts, when follow-up was < 2.5 yrs from primary intervention, and when primary indication was not AS (e.g. SAV in the setting of aortic valve regurgitation (AR)). Outcomes analyzed included death, reintervention and moderate or severe AR. Analysis was performed using Comprehensive Meta Analysis v3 using random effects models.

Results:
A total of 20 studies were included in our meta-analysis: SAV alone (n=3), BAV alone (n=12), and both (n=5). The mean age at BAV was 3.1 years (range, 4 days - 7 years) with a mean follow-up duration of 6.8 years, while mean age at SAV was 2.8 years (range, 14.2 days - 7.1 years) with a mean follow-up duration of 9.1 years. Mortality rates following BAV and SAV were 12.3% (95% CI: 7.7 - 19.1) and 10.2% (95% CI: 7.0 - 14.5), respectively (p=0.27). Reintervention following initial procedure for treatment of AS was higher following BAV (35.7% [95% CI: 29 - 43.1]) compared to SAV (25.2% [95% CI: 19.9 - 31.3])(p=0.012). Long-term and mid-term follow-up in these studies showed moderate to severe AR was present in 24.1% and 28.1% of BAV and SAV patients, respectively.

Conclusions:
Notwithstanding publication bias, both survival rates and development of late AR following BAV and SAV are similar. However, reintervention rates are significantly higher following BAV compared to SAV.
Abstract 19443: Riociguat for the Treatment of Raynaud’s Phenomenon: A Single-dose, Double-blind, Randomised, Placebo-controlled Cross-over Study (DIGIT)
Authors: Huntgeburth Michael , Kieβling Johannes , Weimann Gerrit , Kiepsel Verena , Saleh Soundos , Hunzelmann Nicolas , Rosenkranz Stephan
Published: July 2021

Background:
Raynaud’s phenomenon (RP) is a digital ischemia caused by vasoconstriction in the digital blood vessels. Triggers of RP include cold and stress. Medical therapy for RP is unsatisfactory, with many patients not responding to treatment. Here we investigated the safety, efficacy and pharmacokinetics of riociguat, a soluble guanylate cyclase stimulator, in patients with RP.

Methods:
Patients who had primary RP or secondary RP associated with systemic sclerosis (SSc), and a symptom duration of ≥1 year, were randomized to receive a single oral dose of riociguat 2 mg or placebo. Digital blood flow (DBF) in the right index finger was determined by Laser Speckle Contrast Analysis at room temperature (RT) and after 5 minutes of cold water exposure (CWE), both at baseline and 2 hours after study drug administration.

Results:
In the patients valid for evaluation (n=20), treatment with riociguat led to an increase in DBF versus baseline of 40.6% at RT and 15.1% after CWE. Based on predefined criteria, patients were considered responders if the placebo-corrected DBF after CWE increased by ≥10% versus baseline at 2 hours after drug intake. This was the case in 12/20 (60%) patients. The highest response rates were seen in patients with primary RP and limited cutaneous SSc, whereas patients with RP associated with diffuse cutaneous SSc responded less well. In responders, riociguat led to an increase in DBF versus baseline of 135.7% at RT and 38.9% after CWE. Riociguat Cmax (SD) 2 hours after drug intake was 76 (1.5) μg/ml, which is in the range previously seen in healthy volunteers and patients with pulmonary hypertension. Comparable Cmax values were observed in responders (81 [1.5] μg/ml) and non-responders (71 [1.6] μg/ml). AEs were reported in 5 patients receiving riociguat (headache, n=4; dyspepsia, n=1) and 1 patient receiving placebo (malaise). No serious AEs were reported.

Conclusions:
In this small pilot study, riociguat was well tolerated in patients with primary and secondary RP, and improved DBF versus placebo in 60% of patients after cold exposure.
Abstract 19446: Role of miR-181 Family in the Heart: A Tale of Two Intracellular Compartments
Authors: Das Samarjit , Kohr Mark J , Dunkerly Brittany , Bedja Djahida , Kent Oliver A , Leung Anthony K , Henao-Mejia Jorge , Flavell Richard A , Steenbergen Charles
Published: July 2021

Recent reports suggest that mi(cro)RNAs, non-coding RNAs, can regulate numerous human genes. miRNAs play an important role in physiologic and pathologic processes of cardiovascular health. We identified a nuclear encoded miRNA (miR-181c) that translocates into mitochondria to regulate a mitochondrial gene, and ultimately affects mitochondrial function. To investigate how miR-181c leads to cardiac injury, we designed miR-181-sponges, RNA molecules with ten repeated complimentary miR-181 “seed” sequences, and generated a set of stable-H9c2 cells by transfecting either a scrambled- or the miR-181-sponge-sequences. Sponge-H9c2 showed a significant decrease in ROS production and reduced basal mitochondrial respiration, and significant protection against Doxorubicin-induced oxidative stress. However, chronic down-regulation of the entire miR-181 family also stimulates PTEN expression, and thus the sponge decreased PI3K signaling. Thus, protection against Doxorubicin is enhanced when we treated sponge-H9c2 with siRNA against PTEN. We hypothesize that miR-181a/b targets PTEN in the cytosol and miR-181c targets mt-COX1 in the mitochondria. To extend this finding, miR-181a/b-/- and miR-181c/d-/- mice were used. miR-181a/b-/- shows a significant decrease in cardiac function at baseline compared to both miR-181c/d-/- and WT groups. Basal mitochondrial ROS production was significantly decreased in miR-181c/d-/- compare to WT or miR-181a/b-/-. Using both Electron Microscopy and light-scattering at 540 nm by isolated heart mitochondria, we found that the mitochondria are smaller in the miR-181c/d-/- , and genomic DNA-qPCR showed the number of mitochondria was markedly higher in the miR-181c/d-/- heart compared to the WT or 181a/b-/- groups. miR-181c/d-/- showed a significant decrease, while miR-181a/b-/- showed a significant increase in infarct size compared to WT, when the hearts were challenged with ischemia-reperfusion injury. Taken together, the miR-181 family regulates important signaling pathways in oxidative stress, notably with detrimental results by targeting mt-COX1 (miR-181c), or with protection by targeting PTEN (miR-181a/b).
Abstract 19447: Correlation of Early Echocardiographic Right Ventricular Dimension and MRI Right Ventricular Volumes Late After Tetralogy of Fallot Repair
Authors: Hussain Sara , Al-Radi Osman , Pondorfer Prisca , Grosse-Wortmann Lars , Mertens Luc , Van Arsdell Glen
Published: July 2021

Introduction:
Right Ventricular End-Diastolic Volume indexed (RVEDVi) obtained by MRI is an accurate measure of RV size and a marker for secondary complications. Echo RV measurements are used early in life after TOF repair for practical reasons. We sought to examine the correlation between early echo Right Ventricular End-Diastolic Dimension z-score (RVEDDz) and MRI RVEDVi at 15 years post-repair. The relationship between these parameters and repair technique is investigated.

Methods:
185 TOF patients were repaired at our institution from 1996-2002. Repair techniques were: annulus preservation (AP=124), trans-annular patch (TAP=56), and Pulmonary valve replacement (n=5, patients excluded). Data was reviewed for outcomes, echo studies, and MRI reports. A linear ordinary least square model demonstrated the relationship between early RVEDDz and late RVEDVi (n=57) . Longitudinal analysis with mixed effects model was performed on 783 serial echocardiograms (n=146) to demonstrate the effect of technique on RVEDDz progression.

Results:
RVEDDz at 1-5 years post-repair was a significant predicator for late RVEDVi (p=0.0016). A change in RVEDDz from 0-3 predicted an increase in RVEDVi of 28 mL. TAP repair was an independent predictor of a larger RVEDVi (p=0.0011). TAP was associated with more RV dilation throughout follow-up (0.37 RVEDDz higher every 5 years, p<0.0001). TAP patients had larger late RV volumes for the same early RVEDDz as those with AP repair (Fig. 1). The same findings were demonstrated in a sub-analysis of anatomically matched patients who could have had either TAP or AP based on surgeon choice.

Conclusion:
These results from a single institution support the use of RVEDDz by echo as an early maker for late MRI RV volumes in TOF. Early identification of high risk patients may influence decisions around follow-up and re-interventions. Larger population studies are needed to confirm these findings and the effects of technique on long-term RV health.

Fig 1.
Abstract 19478: Endothelial and Cardiomyocyte -derived C-type Natriuretic Peptide Coordinate Heart Structure and Function
Authors: Moyes Amie J , Chu Sandy M , Baliga Reshma S , Hobbs Adrian J
Published: July 2021

Background:
Endothelium-derived C-type natriuretic peptide (CNP) plays a key vascular homeostatic role governing vascular tone, blood pressure, leukocyte flux, platelet reactivity and the integrity of the vessel wall. However, relatively little is known about physiological role(s) for endogenous CNP in regulating cardiac structure and function. Herein, we have utilised novel mouse strains with endothelium or cardiomyocyte -specific deletion of CNP to determine if the peptide modulates heart function under basal conditions and during cardiac stress.

Methods:
Blood pressure and ECG were assessed by radiotelemetry. A Langendorff heart model was used to study coronary vascular reactivity and ischemia-reperfusion (I/R) injury ex vivo. Echocardiography was performed to determine cardiac function at baseline and following pressure overload (trans-aortic constriction; 6 weeks) -induced left ventricular hypertrophy/heart failure.

Results:
Hearts from endothelium-specific CNP knockout (ecCNP KO) mice exhibited smaller reductions in coronary perfusion pressure (CPP) compared to wildtype (WT) littermates in response to the vasodilators bradykinin (ΔCPP: WT=31.7±2.7%, KO=21.1±2.9%, n=8, p<0.05) and acetylcholine (ΔCPP: WT=36.4±4.4%, KO=18.5±3.8%, n=6, p<0.05). Shear-stress induced coronary dilatation (i.e. reactive hyperaemia) was also blunted in ecCNP KO hearts (AUC: WT=2804±280 [a.u.], KO=1493±280 [a.u.], n=8, p<0.05). Under basal conditions the heart rate (BPM: WT=605±5, KO 579±4, n=5, p<0.001) and contractility (QA interval; WT=13.7±0.1ms, KO=14.8±0.1ms, n=5, p<0.001) were significantly reduced in cardiomyocyte-specific CNP (cmCNP) KO mice compared to WT. Myocardial infarct size was larger in cmCNP KO following I/R injury ex vivo (Infarct size: WT=14.1±6.3%, KO=21.8±1.8 %, n=6, p<0.05). Furthermore, cmCNP KO mice exhibited greater cardiac dysfunction following pressure-overload (e.g. fractional shortening: WT=34.4±0.9%, KO=30.5±1.4%, n=8, p<0.05).

Conclusion:
These data suggest that CNP of endothelial and cardiomyocyte origin preserves cardiac function and morphology via the regulation of coronary vascular tone, heart rate, and myocardial contractility/hypertrophy.
Abstract 19529: Risk of Sudden Cardiac Arrest According to the Month of STEMI Occurrence: The e-MUST Study
Authors: Karam Nicole , Tafflet Muriel , Bataille Sophie , Marijon Eloi , empana Jean Philippe , Spaulding Christian , Lambert Yves , jouven Xavier
Published: July 2021

STEMI mortality decreased drastically during the last decades, and out-of-hospital sudden cardiac arrest (SCA) has become its main cause of death. The risk of SCA according to the month of STEMI occurrence has not been assessed. Hypothesis: The risk of SCA varies according to the month of STEMI occurrence.

Methods:
Data were taken from a prospective pre-hospital study (e-MUST study) on STEMI patients managed by emergency medical services in Paris and its suburbs between January 2006 and December 2010. In this area, emergency calls are routed to the closest dispatch center and regulated by physicians who send an ambulance with a physician on board in case of suspected acute myocardial infarction. Pre-hospital EKGs are obtained for all patients and those presenting STEMI are included in the study. We assessed and compared the rate of SCA according to the month of STEMI occurrence.

Results:
Among the 8112 STEMI patients enrolled (mean age (SD) 61.6years (14.3), 78% males), 452 patients (5.6%) developed out-of-hospital SCA. We observed significant temporal changes in the rate of SCA per STEMI over the year. The peak rate of SCA per STEMI occurred in June (8.7%), while the lowest rate was in December (3.45%) (Figure). Conclusions: The risk of SCA varies significantly according to the month of STEMI occurrence, with STEMI occurring in June being at the highest risk for SCA while those occurring in December have the lowest risk. A better understanding of the pathophysiological mechanisms of this difference is needed to eventually reduce the risk of out-of-hospital SCA after STEMI diagnosis.