bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18108: Extreme Physical Activity Reverses Beneficial Vascular Effects of Moderate Physical Activity. Study in an Animal Model
Authors: Rubies Cira , Batlle Montserrat , Castillo Nadia , Dantas Ana P , Sitges Marta , Brugada Josep , Mont Lluís , Guasch Eduard
Published: July 2021

Introduction:
Moderate aerobic exercise reduces atherosclerotic burden. However, recent data show increased cardiovascular disease burden and mortality in the most trained individuals.

Aim:
To assess vascular remodeling after very high intensity training.

Methods:
Wistar rats underwent very high (INT, 60min 60cm/s, n=20) or moderate intensity (MOD, 45min 35cm/s, n=20) treadmill training for 16 weeks. Sedentary rats (SED n=20) served as controls. Morphologic analyses were performed in descending thoracic aorta and intramyocardial arteries. Aortic wall oxidative stress was quantified with dihydroethidium (DHE). In vivo functional remodeling was assessed in a hemodynamic study. Ex vivo vascular reactivity to acetilcholine (Ach), phenylephrine (Phe) and KCl was studied in intact- and denuded-endothelium conditions.

Results:
INT promoted increased aorta wall thickness, elastin fiber disorganization and disruptions in tunica media compared to MOD and SED. Lumen of intramyocardial arteries was narrower and tunica media was thicker in INT rats (Fig A). An in vivo hemodynamic study showed a higher pulse pressure in the INT group (Fig B), suggesting a stiffer aorta. MOD exercise improved ex vivo endothelial function by increasing Ach-mediated vasodilatation and reducing Phe vasoconstriction response; INT exercise did not provide further benefits (Fig C). Conversely, Phe response was increased in endothelium deanuded aorta of the INT group (Fig D); increased response to KCl in the INT group confirmed tunica media hypereactivity. DHE staining was increased in the tunica media of the INT group.

Conclusions:
While moderate exercise improves vascular function, high intensity exercise blunts it by increasing vascular wall thickness and stiffness, and by inducing tunica media hipereactivity. Oxidative stress likely mediates these effects. Our findings provide important insights into increased atherosclerotic burden in very high trained individuals.
Abstract 18111: Flecainide Exerts its Antiarrhythmic Action in CPVT Through Blockade of Neuronal Na+ channel-mediated Arrhythmogenic Diastolic Ca2+ Release
Authors: Radwanski Przemyslaw , Ho Hsiang-Ting , Knollmann Björn , Belevych Andriy , Györke Sándor
Published: July 2021

Background:
Flecaininde is an effective antiarrhythmic in management of CPVT. Its antiarrhythmic action has been attributed to direct effect on RyR2 and reduced cellular excitability through the inhibition of cardiac-type Na
+
channels. Recently we demonstrated that neuronal Na
+
channels (nNa
v
s) colocalize with the ryanodine receptors (RyR2) Ca
2+
release channels on the sarcoplasmic reticulum. Here we explore a novel mechanism that may contribute to the antiarrhythmic effect of flecainide, mainly uncoupling of aberrant Na
+
/Ca
2+
signaling through nNa
v
inhibition.

Methods:
To study the effects of flecainide on Ca
2+
signaling we used a murine model of cardiac calsequestrin-associated CPVT. We performed confocal microscopy in intact isolated ventricular myocytes to assess Ca
2+
handling and recorded late Na
+
current (I
Na
) during various pharmacological interventions. Surface electrocardiograms were performed during catecholamine challenge to monitor arrhythmic activity
in vivo
.

Results:
During catecholamine stimulation with isoproterenol (Iso; 100 nM) disruption of the cross-talk between nNa
v
s and RyR2 by nNa
v
blockade with 100nM tetrodotoxin (TTX) and riluzole (10μM) as well as flecainide (2.5μM) reduced Iso-promoted late I
Na
and DCR in isolated intact CPVT cardiomyocytes. To further examine the role of nNa
v
-mediated late I
Na
in genesis of DCR we augmented nNa
v
channel activity with β-Pompilidotoxin (β-PMTX, 40μM). Effects of β-PMTX in CPVT cardiomyocytes were reversed by nNa
v
blockade with TTX and riluzole as well as flecainide. This reduction in late I
Na
and DCR frequency with riluzole and flecainide in the presence of β-PMTX on cellular level translated to decreased ventricular arrhythmias in CPVT mice.

Conclusion:
These data suggest that disruption of nNa
v
-mediated late I
Na
can prevent arrhythmogenic DCR in CPVT. Importantly, the antiarrhythmic effects of flecainide can be attributed, at least in part, to its nNa
v
blocking properties.
Abstract 18116: Genetic Associations With Atherosclerotic Abdominal Aortic Calcification
Authors: Malhotra Rajeev , Mauer Andreas C , Yao Jie , Guo Xiuqing , Smith Albert V , Pechlivanis Sonali , Hwang Shih-Jen , Wang Judy , Lu Lingyi , Lino-Cardenas Christian , Shelton Georgia , O’Rourke Caitlin , Gupta Anjana , Campbell Catherine Y , Johnson Andrew D , Song Ci , Kälsch Hagen , Nöthen Markus M , Freedman Barry I , Bowden Donald W , Thanassoulis George , Lindsay Mark E , Bloch Donald B , Jöckel Karl-Heinz , Moebus Susanne , Erbel Raimund , Feitosa Mary , Gudnason Vilmundur , Post Wendy S , O’Donnell Christopher J
Published: July 2021

Background:
There is limited information regarding genetic contributions to atherosclerotic aortic calcification, an important predictor of cardiovascular disease.

Methods:
We conducted a genome-wide association study (GWAS) meta-analysis with subsequent replication analysis to define single nucleotide polymorphisms (SNPs) associated with abdominal (AAC) or thoracic aortic calcification (TAC). AAC and TAC were quantified using multi-detector computed tomography. SNPs were assayed by Illumina or Affymetrix arrays and imputation at the cohort level was performed using data from the 1000 Genomes project.

Results:
9417 individuals of European descent from four cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) consortium were included in the AAC discovery analysis and 8422 individuals from five cohorts in the TAC discovery analysis. SNPs achieving genome-wide significance were tested for replication in four additional cohorts with Hispanic-American (HA) and African-American (AA) participants. Two regions contained SNPs associated at a genome-wide level for AAC (p<5.0x10
-8
, Table), the
HDAC9
(chromosome 7, 6 SNPs) and
RAP1GAP
(chromosome 1, 2 SNPs) genetic loci. All six
HDAC9
SNPs were associated with AAC in HA. Among these, rs2107595 was associated with AAC both in HA (p=2.8x10
-6
) and in AA (p=0.01). SNPs in
RAP1GAP
were not associated with AAC in the replication analysis. No SNPs were associated with TAC at the genome-wide threshold. SNPs in the
HDAC9
locus were associated with other forms of calcification (coronary artery calcification) as well as clinically apparent coronary heart disease (p<0.05). Conclusions: SNPs in the
HDAC9
locus are associated with the presence of AAC in participants of European descent. This association was replicated in other ethnic groups in the United States. These findings suggest a novel role for
HDAC9
in the development of abdominal aortic calcification.
Abstract 18159: A Functional Variant for Atrial Fibrillation Affects PITX2c Expression by Interacting With TFAP2a
Authors: Ye Jiangchuan , Tucker Nathan R , Dolmatova Elena , Ellinor Patrick T
Published: July 2021

Background:
To date, 17 loci associated with atrial fibrillation (AF) have been identified, and there are 4 regions at 4q25 around
PITX2
gene strongly associated with AF. However, the functional variants at all known AF loci remain elusive.

Methods and Results:
Among the 4 AF loci at 4q25, we focused on one associated region of ~84 kb extending from Chr4: 111,520,926 to 111,604,727 that includes the
PITX2
gene itself (defined as all SNPs with r
2
> 0.6 from the sentinel SNP rs1448818). To identify potential functional variants
,
we analyzed DNase hypersensitivity, histone modification and mammalian conservation from ENCODE and Roadmap Epigenomics Project. Additionally, cap analysis of gene expression (CAGE) data was also investigated. We identified 13 candidate regions, 5 of which showed enhancer activity in zebrafish skeletal muscle and heart. Using luciferase assays in a mouse atrial cell line (HL-1), we then identified one SNP (rs2595104) in which the T risk allele was associated with 31% decreased activity compared to the G non-risk allele (p = 0.007). rs2595104 lies ~10 kb upstream of
PITX2c
transcriptional start site and is in high linkage disequilibrium (LD) (r
2
= 0.67) with rs1448818.
In silico
investigation of rs2595104 using UniPROBE and HaploReg database revealed differential binding of each allele to activating enhancer binding protein 2 alpha (TFAP2a). Electrophoretic mobility shift assays showed that TFAP2a bound robustly to the non-risk G allele at rs2595104 but not to the risk T allele. Chromatin immunopricipitation followed by allele-specific qPCR in human embryonic stem cell-derived cardiomyocytes (hESC-CM) further suggested that TFAP2a was preferentially recruited to the non-risk G allele at rs2595104 in an AF-relevant cell type. hESC-CMs with homozygous deletion of rs2595104-containing enhancer using CRSPR-Cas9 expressed less PITX2c (35 ± 6%, p = 0.036), compared to the wild-type hESC-CMs. Finally, mutating the G allele at rs2595104 to T allele by CRSPR-Cas9 led to 21% reduction in PITX2c level in hESC-CMs (p = 0.027).

Conclusion:
We have found that the AF-associated SNP rs2595104 alters PITX2c expression via interaction with TFAP2a. Such a pathway may ultimately contribute to AF susceptibility at the
PITX2
locus.
Abstract 18171: HCN Channel Distribution in the Human Sinoatrial Node and Latent Atrial Pacemakers
(Best of Basic Science Abstract)
Authors: Li Ning , Csepe Thomas A , Hansen Brian J , Dobrzynski Halina , Higgins Robert S , Kilic Ahmet , Mohler Peter J , Janssen Paul M , Rosen Michael R , Biesiadecki Brandon J , Fedorov Vadim V
Published: July 2021

Background:
The hyperpolarization-activated current,
I
f
, plays an important role in cardiac pacemaker cells. However, the distribution and expression of HCN isoforms in the human SAN and latent atrial pacemaker clusters is unknown.

Methods:
Human atria and entire SAN complexes were isolated from failing (n=5) and non-failing (n=9) human hearts cardioplegically-arrested in the operating room. Three dimensional intramural SAN structure was identified as the fibrotic compact region around the SAN artery with Connexin43-negative pacemaker cardiomyocytes visualized in Masson’s trichrome and immunostained cryosections. Pure SAN tissue was precisely isolated from the frozen SAN cryo blocks using a 16G biopsy needle (Figure). Atrial tissues from different locations were fresh frozen in liquid nitrogen. Immunoblot and immunostaining were used to study the expression pattern of HCN isoforms.

Results:
Three HCN isoform proteins were detected in the atria and SAN (Figure). HCN1 was predominantly distributed in all the human SAN with a 125.1±40.2 (n=12) expression ratio of SAN to right atrial free wall (RAFW). HCN2 and HCN4 expression levels were higher in SAN than atria with ratios of 6.1±0.9 and 4.6±0.6 (n=12), respectively. HCN2 expression but not HCN1/4 in the latent atrial pacemakers from the right atrioventricular ring (RR) area was significantly higher than in RAFW, with the band density ratio of RR/RAFW= 2.4±0.4 (n=12).

Conclusions:
This is the first study to conduct precise molecular mapping of the human SAN by isolating pure pacemaker SAN tissue. HCN1 was almost exclusively expressed in SAN and may play a critical role in determining the leading pacemaker in human SAN. Even HCN2 and HCN4 expression is higher in the SAN than RAFW, these isoforms are less SAN-specific than HCN1. SAN and latent atrial pacemakers have different HCN expression patterns, suggesting the utility of HCN isoform specific blockers to selectively modify sinus rhythm or atrial ectopic rhythms.
Abstract 18182: Phosphodiesterase 10A Regulates Vascular Inflammation and Pathogenesis of Abdominal Aortic Aneurysms
Authors: Cai Yujun , Cai Yujun , Yan Chen , Guzman Raul J
Published: July 2021

Rationale:
Abdominal aortic aneurysms (AAA) are characterized by aortic enlargement and underlying weakness of the vessel wall. Experimental and clinical evidence suggests that vascular inflammation is a central trigger of AAA formation. Phosphodiesterases (PDEs), known regulators of cyclic nucleotide signaling, play a critical role in vascular inflammation.

Objective:
In this study, we sought to determine the role and function of PDE10A in vascular inflammation and AAA formation.

Methods and Results:
Extensive evidence suggests that angiotensin II (Ang II) signaling plays an important causative role in AAA formation. Therefore, Real-time PCR array for all 22 known PDE genes was performed in control and Ang II-treated VSMCs. We observed that PDE10A elicited the highest levels of induction by Ang II among all PDEs. Moreover, we found that PDE10A was dramatically upreguated in the Ang II-infused AAA mouse model and in human AAA specimens. PDE10A was primarily expressed in medial VSMCs and infiltrating macrophages in AAA. More importantly, deficiency of PDE10A or PDE10A inhibition significantly attenuated AAA formation in vivo. In cultured VSMCs, knockdown of PDE10A with specific siRNA and inhibition of PDE10A by papaverine markedly suppressed Ang II-induced vascular cell adhesion molecule 1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and MMP2 expression. Deficiency of PDE10A also blocked lipopolysaccharide (LPS)-induced TNF-α, MCP-1, and MMP9 expression in peritoneal macrophages isolated from PDE10A knockout mice. Further mechanistic studies revealed that histone deacetylase 5 (HDAC5) plays an important role in PDE10A-regulated vascular inflammation via cAMP-dependent protein kinase (PKA).

Conclusions:
These findings demonstrate that PDE10A is an important regulator of vascular inflammation and AAA development. They further provide evidence for PDE10A as a potential therapeutic target for aortic aneurysms and other vascular diseases.
Abstract 18200: Intracoronary Delivery of Bioabsorbable Alginate Matrix (IK-5001) Ameliorates Adverse Post-infarction Left Ventricular Remodeling and Improves Left Ventricular Function in a Porcine Model of Reperfused Myocardial Infarction
Authors: Santos-Gallego Carlos G , Picatoste Belén , Njerve Ida U , Ishikawa Kiyotake , Aguero Jaime , Vahl Torsten , Hammoudi Nadjib , Sanz Javier , Narula Jagat , Hajjar Roger J , Meglasson Martin D , Fuster Valentin , Badimon Juan J
Published: July 2021

Background:
Adverse cardiac remodeling after MI is associated with excessive degradation of the extracellular matrix (ECM). IK-5001 is a low viscosity injectable solution that provides the polysaccharide alginate. After intracoronary injection into the MI area it undergoes phase transition forming a hydrogel which can support the ECM. We hypothesized that administration of alginate post-MI would provide a temporary scaffold and attenuate adverse LV remodeling.

Methods:
Acute MI was induced in 16 pigs by balloon occlusion of the proximal LAD for 2 hours. Animals randomly received intracoronary alginate or saline 4 days post-MI. LV function and remodeling were evaluated with cardiac MRI, 3D-echo and pressure-volume loops at 1 and 2 months post-MI. Histology and Western blot analysis were performed after 2 months.

Results:
Both groups had similar LVEF and infarct size 4 days post-MI. Coronary angiography immediately after alginate injection showed no impairment in coronary flow. However, 2 months post-MI, alginate-treated pigs exhibited reduced LV remodeling compared with controls demonstrated by reduced LV end-systolic volume, LV mass and sphericity (Table). Alginate-treated pigs had less cardiomyocyte hypertrophy and decreased interstitial fibrosis. Consistent with this, chronic activation of Akt and ERK was reduced. Alginate pigs also showed lower plasma levels of BNP and aldosterone. Interestingly, after 2 months, alginate pigs showed better systolic LV function: higher LVEF, better contractile reserve with dobutamine, and higher dP/dt.

Conclusions:
Intracoronary administration of alginate ameliorates adverse post-MI LV remodeling at the anatomical, histological and molecular level, and mitigates neurohormonal activation in a porcine model of MI. Alginate also improves systolic LV function. Intracoronary injection of alginate represents an exciting novel treatment option to reduce post-MI remodeling that merits assessment in clinical studies.
Abstract 18205: Successful Implementation of a Tele-visit Multidisciplinary Program
Authors: Bhatt Ami , Sossong Sarah , Stefanescu Ada , Schwamm Lee H
Published: July 2021

Objectives:
To design, implement and assess a patient and physician centered virtual visit program.

Methods:
Patients within the Cardiology and Neurology departments were enrolled in a real-time videoconferencing virtual visits program between April 1st 2014 and June 3rd 2015. Surveys were sent to patients who had at least one virtual visit between in the first 8 months to assess response to the use of the system and satisfaction, including the Consumer Assessment of Healthcare Providers and Systems survey (CAHPS).

Results:
There were 131 virtual visits in Cardiology and 419 visits in Neurology. The great majority of patients (83%) responded that they would definitely recommend a virtual visit to family or friends. Patients found the platform easy to use, with 74% of patients easily installing the product. Despite 42.5% reporting at least one technical problem, the overall patient satisfaction was high based on the CAHPS measures (Figure 1), and more than half of patients said they would even be willing to pay an up to $50 copay if needed for such visits. More than half of patients and providers felt that the quality of the visit was the same as in the office. While 45% of Cardiology patients felt the same during a virtual visit as in the office, 45% felt a stronger connection in person. Most providers felt virtual visits were either more efficient (38.5%) or just as long as office visits (50%), while 90% of patients thoughts their clinicians spent just as much time with them. Only 23.2% of patients overall however felt that a telephone call could definitely have addressed the same issue, emphasizing the value of the video conferencing platform.

Conclusion:
Virtual visits are well received by patients and providers, and considered by both to be efficient and useful. Implementing a virtual visit program with a design approach to assess and respond promptly to user feedback has encouraged adoption and holds promise for increasing the scale and integration into models of care delivery.
Abstract 18226: Fibrinolysis Before Percutaneous Coronary Intervention Reduces the Rate of Cardiogenic Shock in Patients Presenting Within 3 Hours After Symptom Onset
Authors: Vanhaverbeke Maarten , Sinnaeve Peter , Van de Werf Frans , Janssens Luc
Published: July 2021

Introduction:
Primary percutaneous coronary intervention (PCI) has become the standard of care for the treatment of ST-elevation myocardial infarction (STEMI) when it can be performed within 90 to 120 minutes after first medical contact. Whether fibrinolysis given before the intervention reduces the incidence of cardiogenic shock is not known.

Methods:
We identified randomized trials of fibrinolysis pre-PCI versus primary PCI in STEMI and assessed the incidence of cardiogenic shock in both groups. The Mantel-Haenszel method was used to calculate the weighted relative risk and the Chi-square test to determine the overall effect.

Results:
The results of the STREAM, FINESSE, WEST, ASSENT-4 PCI and CAPTIM trials were included. The first four trials investigated facilitated or pharmaco-invasive PCI with full or half dose fibrinolysis. In CAPTIM, fibrinolysis was compared to primary PCI and the majority of patients in the fibrinolysis group underwent PCI. In total 3097 patients were randomized to the fibrinolysis pre-PCI group and 3088 to the primary PCI group. The incidence of cardiogenic shock was not different between both groups (4.8% vs. 5.7% respectively,
p
=0.12). This result is largely driven by the ASSENT-4 PCI trial. In a subgroup analysis of patients presenting within 3 hours after symptom onset, the incidence of cardiogenic shock was significantly lower in patients receiving fibrinolysis pre-PCI (4.1% vs. 6.5%,
p
=0.002). However, administration of a fibrinolytic agent pre-PCI increased the risk of major bleeding (5.6% vs. 3.7%,
p
=0.004) and was not associated with an early mortality reduction (5.1% vs. 4.8%,
p
=0.29).

Conclusion:
Our analysis suggests that in STEMI patients presenting within 3 hours after symptom onset, early reperfusion with a fibrinolytic agent before PCI reduces the risk of cardiogenic shock when compared with primary PCI alone, at the cost of an increased risk of bleeding. Whether such a strategy improves long-term survival is not known.
Abstract 18237: Non-invasive Three Dimensional Imaging of Ventricular Arrhythmias: In-procedure Simultaneous Mapping of Ventricular Tachycardia and Premature Ventricular Complexes
Authors: Yu Long , Pogwizd Steve , McElderry Hugh T , Yang Ting , He Bin
Published: July 2021

Introduction:
Noninvasive activation imaging and the identification of initiation sites or reentrant circuits are highly desirable for aiding catheter ablative treatment of ventricular arrhythmia. While approaches are being developed to image epicardial potential, Cardiac Electrical Sparse Imaging (CESI), a 3-dimensional noninvasive activation imaging technique offers insight into intramural activation. In this study, we report the first clinical study of the CESI technique with in-procedure simultaneous mapping of Ventricular Tachycardia (VT) and Premature Ventricular Complexes (PVCs).

Methods:
Body surface potential maps (BSPMs) were recorded using 170±9 electrodes in 4 patients (2 males, 2 females, age 53±5) with VT and/or PVC in the EP lab simultaneously with CARTO mapping and ablation. CT or MRI images were obtained for individualized volume conductor modeling. Activation sequences were estimated using CESI upon the 40 isolated PVC or VT beats induced by programmed stimulation or isoproterenol infusion. Imaging results were compared with CARTO map and ablation sites/outcomes.

Results:
Good concordance was observed between the imaged results and the EP study. A Correlation Coefficient of 0.76±0.04 and Relative Error of 0.22±0.05 were found between the imaged activation sequences and the Local Activation Time maps from CARTO. The imaged initiation sites well co-localized with the ablation outcomes with Localization Error of 8±1.3mm from the last ablation site and 3.3±1.7mm from the nearest ablation site.

Conclusions:
We demonstrate for the first time that the beat-to-beat 3D activation imaging technique CESI can be applied clinically with simultaneous mapping in the EP lab. The noninvasive imaging results are in good agreement with the EP study and catheter ablation outcome. The promising results suggest CESI warrants further investigation and has the potential to become a clinically useful technology guiding ablation procedures in patients.
Abstract 18258: High-intensity Interval Training Improves Aerobic Capacity and Metabolic Risk Factors in Older Adults: A Randomized Controlled Trial
Authors: Hwang Chueh-Lung , Yoo Jeung-Ki , Kim Han-Kyul , Hwang Moon-Hyon , Handberg Eileen M , Christou Demetra D
Published: July 2021

Introduction:
Aging is associated with increased cardiovascular disease risk including reduced aerobic capacity and increased metabolic risk factors. Aerobic exercise training improves the risk for cardiovascular disease. The optimal exercise regimen for older adults, however, remains unknown. We tested the hypothesis that high-intensity interval training (HIIT) would be more effective than isocaloric moderate-intensity continuous training (MICT) in improving aerobic capacity and metabolic risks factors in older adults.

Methods:
Thirty eight sedentary older adults (age 65±1.0 yrs; mean±SE), free of cardiovascular disease, were randomly assigned to HIIT (n=13), MICT (n=13) or non-exercise control group (n=12). HIIT consisted of cycling at alternating intensities of 90 and 70% maximal heart rate for 40 minutes while MICT consisted of cycling at 70% maximal heart rate for 47 minutes. HIIT and MICT were performed on Airdyne bicycles, 4 days/week for 8 weeks, under supervision. Aerobic capacity was assessed by peak oxygen consumption during an incremental treadmill test. Metabolic risk factors included fasting lipid profile, glucose, insulin, and insulin resistance (homeostasis model assessment; HOMA-IR). Body composition was assessed using dual-energy x-ray absorptiometry. All measures were obtained at baseline and following the intervention.

Results:
Peak oxygen consumption increased by 2.8 ml/kg/min (23.0±1.6 vs. 25.7±1.5, pre- vs. post-intervention;
P
<0.05) in HIIT, but did not change in MICT and control group (26.0±1.5 vs. 26.2±1.4 and 23.5±1.4 vs. 24.0±1.4, respectively;
P
>0.05). Insulin and HOMA-IR improved only in HIIT (-1.9±0.6μU/ml and -0.42±0.16,
P
<0.05; respectively) and these changes were negatively associated with the change in peak oxygen consumption (r=-0.37,
P
<0.05 for both). Overall, lipids, body weight, body fat, and fat-free mass did not change in response to the intervention in any of the groups (P>0.05).

Conclusions:
HIIT but not MICT improves aerobic capacity and glucose control in healthy older adults without affecting lipids or body composition.
Abstract 18343: B-type Natriuretic Peptide (BNP) Levels Correlate With Indices of Left Ventricular Function and Predict Outcomes Following Transcatheter Aortic Valve Implantation (TAVI): A Cardiovascular Magnetic Resonance Imaging Study
Authors: Lindsay Alistair C , Kanyal Ritesh , Sawhney Paramvir , Broadhurst Helen , Harron Katie , Mohiaddin Raad , Duncan Alison , Di Mario Carlo , Davies Simon W , Moat Neil
Published: July 2021

Background:
High levels of B-type natriuretic peptide (BNP) have been shown to predict outcomes following transcatheter aortic valve implantation (TAVI). However, the relationship between pre-procedural BNP levels and magnetic resonance imaging (MRI) parameters of cardiac function has not previously been described in patients with severe aortic stenosis undergoing TAVI.

Methods:
108 patients underwent cardiac MRI and had measurements of BNP taken prior to TAVI. MRI was performed using a 1.5T scanner; steady-state free precession sequences were used for aortic valve planimetry and to assess ventricular volumes and mass. Gadolinium enhancement was assessed after injection of 0.1 mmol/kg of gadolinium contrast agent. Semi-automated image analysis was performed by two specialist reviewers blinded to patient treatment.

Results:
The mean age of the population studied was 79 years (IQR 74-85); mean follow-up was 805 days (IQR 368-1025). The mean BNP level was 698 ng/l (range 14-6048); univariate linear regression showed significant relationships between BNP and left ventricular (LV) ejection fraction (p<0.0001), end diastolic volume (p=0.001), end systolic volume (p<0.0001), and indexed mass (p=0.012). Median BNP levels were lower in patients who survived than in those who died (287ng/l vs. 560ng/l; p=0.099); ROC curve analysis found a BNP level of >170ng/l to be the optimal cutoff for the prediction of all-cause mortality. Survival curve analysis showed a significantly increased risk of all-cause mortality in patients with BNP>170ng/l and MRI LV ejection fraction <50% (Hazard ratio 5.72, p=0.015; Figure).

Conclusions:
In patients with severe aortic stenosis undergoing TAVI, BNP levels are closely correlated with LV function, indexed LV mass, and both end-systolic and end-diastolic volumes, as measured by MRI. Patients with BNP>170ng/l and MRI LV ejection fraction<50% are at significantly higher risk of death following TAVI.
Abstract 18374: Targeted Sequencing and Massively Parallel Reporter Assay Identify the Functional Variation Underlying the 4q25 Locus for Atrial Fibrillation
Authors: Tucker Nathan R , Ye Jiangchuan , Lin Honghuang , McLellan Michael A , Benjamin Emelia J , Lunetta Kathryn L , Mikkelsen Tarjei S , Lubitz Steven A , Ellinor Patrick T
Published: July 2021

Introduction:
Genome-wide association studies have identified 14 independent loci for atrial fibrillation (AF). The 4q25 locus upstream of the left-right asymmetry gene
PITX2
is, by far, the strongest association signal for AF. However, as with most GWAS loci, the functional variants are noncoding, presumed to be regulatory, and remain unknown. We therefore sought to rapidly identify the functional variants at an AF locus by combining high throughput sequencing and massively parallel reporter assays.

Methods and Results:
We sequenced a ~750kb region encompassing the
PITX2
locus in 462 individuals with early-onset AF from the MGH AF Study and 464 referents from the Framingham Heart Study. The SNP most significantly associated with AF in our sequenced sample was rs2129983, which is 140kb from
PITX2
(OR=2.43,
P
=8.9X10
-16
). rs2129983 is approximately 1.7kb from the most significantly associated SNP in a prior AF GWAS, rs6817105 (r
2
=0.52). From the targeted sequencing analysis, we identified 262 SNVs with a MAF >0.5% within a genomic region bounded by SNPs with an r2 greater than 0.4 with the top variant. To identify functional variants, we then utilized a massively parallel reporter assay (MPRA) in order to measure enhancer activity at each SNP across the entire AF locus. In both HL-1 and C2C12 myoblasts, MPRA identified many distinct SNP regions with differential enhancer activity. Using AF-association status as a standard, we were able to identify a series of variants that have both differential activity in either cell line tested and also a high level of association (rs17042076, rs4469143). Mechanistically, these functional SNPs are predicted to alter transcription factor binding.

Conclusions:
We have comprehensively identified the AF-associated variation at 4q25 and determined which of these variants are functional through differential enhancer activity. Here, in addition to identifying the causative variation for AF at 4q25, we provide a generalizable pathway for translating this work to other loci, a method that could expedite the identification of causative genetic variants at other disease loci.
Abstract 18412: Lactate Dehydrogenase Trends Predict Left Ventricular Assist Device Thrombosis
Authors: Hurst Thomas , Ehrlinger John , Rajeswaran Jeevanantham , Thuita Lucy , Smedira Nicholas , Moazami Nader , Blackstone Eugene , Starling Randall C
Published: July 2021

Introduction:
Recent analyses have demonstrated an increasing risk of HeartMate II (HMII) left ventricular assist device (LVAD) thrombosis than previously reported. Elevation of serum lactate dehydrogenase (LDH), a biomarker of hemolysis secondary to thrombosis, parallels the overall pattern of HMII thrombosis.

Hypotheses: We hypothesized that longitudinal trends of LDH could predict HMII thrombosis.

Methods:
From 10/2004 through 9/2014, 350 HMII devices were implanted in 323 patients at a single center. Of these, patients on 339 devices had at least 1 postop LDH value through 9/2014 (7,996 total measurements). A 2-step joint model combining longitudinal biomarker data and pump thrombosis events was generated to assess the impact of changing LDH on the risk of thrombosis. Device-specific LDH values were first estimated using Multivariate Boosted Trees to reduce measurement error and produce unbiased regression estimates. Estimated LDH values were then used as a time-varying covariate function in a multiphase hazard model to analyze time to thrombosis.

Results:
Thirty-five HMII pumps (10%) had either confirmed (18 HMIIs) or suspected (17 HMIIs) thrombosis, with 15 (43%) occurring within 3 months of implant. LDH was associated with pump thrombosis occurring both early and late after implant (P<.0001 for both phases). The model demonstrated increased probability of HMII thrombosis as LDH trended upward, with steep changes in thrombosis probability paralleling similar trajectories in LDH. Two individual patient probaliities are graphed in the figure.

Conclusions:
Longitudinal trends in surveillance LDH for patients on HMII support is useful for dynamic prediction of pump thrombosis, both early after implant and late. Incorporating upward and downward trends in LDH provides a dynamically updated model of LVAD thrombosis risk that may eventually be a tool for LVAD clinical management.
Abstract 18424: Elective Cardiac Arrest in Isolated Aortic Valve Surgery: Comparison of Blood-cardioplegia versus HTK-Bretschneider Solution in 7005 Consecutive Patients
Authors: Hoyer Alexandro A , Lehmann Sven , Oberbach Andreas , Merk Denis A , Feder Stefan , vonAspern Konstantin , Etz Christian D , Bakhtiary Farhad , Misfeld Martin , Mohr Friedrich W
Published: July 2021

Introduction:
Assessing the impact of HTK-Bretschneider solution versus blood-cardioplegia on short- and long-term outcome after isolated aortic valve replacement (AVR).

Hypothesis:
HTK-Bretschneider is not inferior to Blood-cardioplegia for isolated aortic valve replacement.

Methods:
Screening of our institutional database revealed 7290 consecutive patients who underwent AVR between 11/1994 and 06/2015. In the majority of patients (n=5998; 83%) antegrade infusion of htk-bretschneider solution (custodiol®) was used for elective cardiac arrest (Group A). Intermittent cold blood-cardioplegia was chosen in 1007 patients (14%; Group B). All preoperative risk-factors were considered for risk-factor analysis influencing outcome.

Results:
Early mortality was equal between the subgroups (p=0.22). Postoperative complications like pacemaker implantation (p=0.01) or low cardiac output were more likely to occur in group B (p=0.02). Overall long term survival was inferior for patients receiving elective cardiac arrest with cold blood cardioplegia (p<0.001). Cox-regression identified age (HR: 1.063 ; p<0.001), end stage renal disease (ESDR; HR:4.8; p<0.001), history of PCI (HR: 1.3; p=0.03), active infective endocarditis (AIE; HR: 2.1; p<0.001), neurological dysfunction (HR: 1.4; p=0.02), low ejection fraction (EF<30%; HR: 2.5; p<0.001), prior cardiac surgery (HR:1,5; p=0.02) and emergent surgical intervention (HR: 2.5; p<0.001) being highly associated with long term survival and occurring more frequently in group B. Artificial low-risk and high-risk groups showed no differences in longevity depending on cardioplegic solutions (p=0.35).

Conclusions:
Blood-cardioplegia for elective cardiac arrest seems to be preferred when complex aortic valve surgery is expected. However, HTK-Bretschneider solution yields equivalent longevity to blood-cardioplegia, even after surgery demanding extended cross-clamp times.
Abstract 18427: Low Left Ventricular Ejection Fraction and β-blocker Use Before Admission is Associated With In-hospital Cardiac Complications in Patients With Takotsubo Cardiomyopathy
Authors: Kato Ken , Saito Yuichi , Sakai Yoshiaki , Ishibashi Iwao , Yamamoto Masashi , Himi Toshiharu , Fujimoto Yoshihide , Kobayashi Yoshio
Published: July 2021

Introduction:
The prognosis of patients with takotsubo cardiomyopathy (TC) is thought to be relatively favorable. However, serious cardiac complications during hospitalization occur in some patients. There is little information about risk factors associated with in-hospital cardiac complications in patients with TC.

Hypothesis:
We assessed the hypothesis that severe left ventricular (LV) dysfunction is associated with in-hospital cardiac complications in patients with TC.

Methods:
A total of 154 consecutive patients with TC based on Mayo criteria were enrolled. Coronary angiography and left ventriculography were performed in all patients and absence of obstructive coronary disease explaining the left ventricular contraction abnormality was confirmed. In-hospital cardiac complications were defined as cardiogenic shock, pulmonary edema, sustained ventricular tachycardia or ventricular fibrillation, complete atrioventricular block, thromboembolism, cardiac rupture, and cardiac death. Multivariate logistic regression analysis was performed to predict in-hospital cardiac complications.

Results:
In-hospital cardiac complications were observed in 61 patients (40%). There were 25 patients with cardiogenic shock (16%) and 44 patients with pulmonary edema (29%). Sustained ventricular tachycardia or ventricular fibrillation, complete atrioventricular block, and thromboembolism were noted in 10 (7%), 4 (3%) and 4 patients (3%), respectively. Four cardiac deaths (3%) were observed. Of these, one patient died of cardiac rupture. Multivariate logistic regression analysis identified systolic blood pressure (odds ratio=0.97, 95% CI=0.95-0.98, p <0.01), LV ejection fraction (odds ratio=0.95, 95% CI=0.91-0.98, p <0.01), and β-blocker use before admission (odds ratio=8.72, 95%CI=1.00-194.2, p =0.049) as independent predictors of cardiac complications during hospitalization.

Conclusion:
Low systolic blood pressure and low LV ejection fraction are independent predictors of in-hospital cardiac complications in patients with TC. Furthermore, β-blocker use before admission is associated with worse outcomes during hospitalization.
Abstract 18465: Real World Comparison of Major Bleeding Risk Among Non-valvular Atrial Fibrillation Patients Newly Initiated on Warfarin versus Apixaban 5mg BID, Dabigatran 150 mg BID, or Rivaroxaban 20 mg QD
Authors: Kamble Shital , Pan Xianying , Phatak Hemant , Kawabata Hugh , Masseria Cristina , Mardekian Jack , Bruno Amanda , Lip Gregory Y
Published: July 2021

Aim:
Limited data are available on the real-world safety of non-vitamin K antagonist oral anticoagulants (NOACs). The study purpose was to compare the first major bleeding event risk among non valvular atrial fibrillation patients (NVAF) patients newly initiated on dose-adjusted warfarin versus apixaban 5mg BID, dabigatran 150mg BID, or rivaroxaban 20 mg QD.

Methods:
Retrospective cohort study was conducted using MarketScan® commercial & Medicare supplemental database from 01/2012 to 12/2013. NVAF patients 18+ years with ≥1 year baseline and newly prescribed oral anticoagulant from 01/01/2013 to 12/31/2013 were included. Major bleeding was defined as bleeding requiring hospitalization on the index drug during the supply duration or within 30 days after the last supply day of the last prescription. A Cox proportional hazards model was used to estimate the hazard ratios (HR) of major bleeding adjusted for age, sex, baseline comorbidities and comedications.

Results:
Among 26,604 patients, 2,057 (7.73%) were newly initiated on apixaban 5mg, 3,768 (14.16%) on dabigatran 150mg, 8,066 (30.32%) on rivaroxaban 20mg and 12,713 (47.79%) on warfarin. Patients initiating warfarin (72.5±11.9 yrs) and apixaban 5mg (67.0±11.4 yrs) were older as compared to rivaroxaban 20mg (65.2±11.4 yrs) and dabigatran 150mg (65.4±11.5 yrs). Patients initiating warfarin had higher CHA
2
DS
2-
VASc score (3.22±1.65) and Charlson comorbidity index score (2.37±2.33) (P <0.0001 across all treatments) as compared to those initiating NOACs. After adjusting for baseline characteristics, patients newly initiated on apixaban 5mg BID had significantly lower risk of major bleeding (HR: 0.53, 95% CI: 0.29-0.97, P=0.0399) as compared to those initiated on warfarin (Table).

Conclusion:
Among newly anticoagulated NVAF patients in the real world setting, as compared to dose adjusted warfarin, only patients initiating on apixaban 5mg BID were associated with significantly lower risk of major bleeding.
Abstract 18506: Right Ventricular and Pulmonary Vascular Reserve in Heart Failure With Preserved Ejection Fraction: An Exercise Cardiac Magnetic Resonance Study
Authors: Petit Thibault , Claessen Guido , La Gerche Andre , Vanhaverbeke Maarten , Trenson Sander , Willems Rik , Van Cleemput Johan , Droogné Walter , Bogaert Jan , Claus Piet , Delcroix Marion , Heidbuchel Hein , Janssens Stefan
Published: July 2021

Introduction:
Right ventricular dysfunction (RVD) is a marker of adverse outcome in HFpEF patients. While RVD in HFpEF has been demonstrated using dobutamine stress and invasive hemodynamic studies, detailed assessment of RV and pulmonary vascular (PV) function using simultaneous exercise cardiac MRI and invasive hemodynamic measurements has never been performed.

Methods
In a prospective study, we performed CPET to determine maximal power output (Pmax) in patients with HFpEF (n=11, age 73±9 years) and in healthy controls (n=8, age 53±7 years). We also investigated asymptomatic subjects with echocardiographic evidence of LV concentric remodeling (LVCR) and impaired relaxation (n=4, age 63±7 years). All participants then performed a three-stage supine bicycle exercise test during real-time CMR imaging (at 25%, 50% and 66% of Pmax) with continuous recording of pulmonary arterial pressures using fluid-filled catheters. We determined the ratio of mPAP relative to cardiac output (mPAP/CO slope) as a measure of PV reserve and the change in RV end-systolic pressure volume ratio (dRVESPR) as a measure for RV contractile reserve.

Results
At rest, there was no difference in LV or RV ejection fraction (EF) between HFpEF patients and controls (p=NS). However, during exercise, HFpEF patients showed a decline in RVEF (-3.9±1.7%), contrasting with a marked increase in RVEF in the control group (+12.49±2.33%, p<0.001 for interaction workload*group, figure 1A). HFpEF patients had a greater mPAP/CO slope (p<0.001, figure 1B) and a significantly lower dRVESPVR (p<0.001) than controls. Interestingly, asymptomatic subjects with LVCR showed an intermediate response to exercise (figure 1A-B).

Conclusion
In patients with HFpEF, RV functional reserve and pulmonary pressure-flow relationships are markedly impaired. These data suggest an important role for cardiac exercise MRI in phenotyping heart failure patients and guiding RV or pulmonary vasculature targeted therapy.
Abstract 18557: Cardiovascular Risk Factor Trajectories From Childhood to Adulthood and Depression in Middle Age: The Bogalusa Heart Study
Authors: Stuchlik Patrick , Allen Norrina , Harville Emily , Chen Wei , Bazzano Lydia
Published: July 2021

Introduction:
It is well known that depression and heart disease are closely linked. However, it remains unclear whether changes in cardiovascular (CV) risk factors over time may be related to depression. Few studies have examined the long term patterns of CV risk factors in relation to depression in middle age.

Hypothesis:
The trajectories of cardiovascular risk factors are associated with depression and depressive symptoms.

Methods:
We examined data from the Bogalusa Heart Study, a long-term community-based observational study of a biracial cohort, with first measurements in childhood in 1976. Men and women who completed the CES-D in 2010 with at least two childhood and two adult CV measurements (n=913) were included. Age, systolic blood pressure, antihypertensive treatment status, smoking status, total and HDL cholesterol, were used to calculate standardized 10-year Framingham CV risk scores at each follow-up. CES-D scores were categorized using established cut points (<8, 8-15, >15). Discrete mixture modeling was employed to identify trajectory groupings of CV risk. The association between CV risk score trajectory and CES-D were determined using multivariable logistic regression adjusted for smoking, education, physical activity, and BMI in 2010.

Results:
Mean (±SD) age was 43.06±4.48 years, 57.9% were female, and 31.7% were black race. 27.7% of participants were current smokers in 2010. Mean (±SD) BMI was 30.97±7.73. We identified three CV risk patterns: stable (63.8%), slightly elevated (28.8%), and increasingly elevated (7.5%). Relative to stable CV risk, the multivariable adjusted odds ratio of higher CES-D categorization, i.e. more depressed, for slightly elevated was 1.49 (95% CI, 1.08-2.06), and for increasingly elevated, 1.53 (95% CI, 0.90-2.59). Smokers had increased odds of higher CES-D categorization over nonsmokers (OR=2.16, 95% CI 1.58-2.95). One-unit increases of BMI were associated with 1.02 times greater odds of higher CES-D categorization (95% CI, 1.01-1.04).

Conclusions:
Trajectories of cardiovascular risk from childhood through adulthood are associated with depression in middle age. Individuals with elevated or increasing cardiovascular risk profiles may benefit from depression screening in early middle age.
Abstract 18599: Clinical Assessment of Hemodynamic Profiles Predict Readmission and Mortality in Diastolic Heart Failure Patients
Authors: Siddiqui Mohammed , Pamboukian Salpy V , Tallaj Jose A , Falola Michael , Mazimba Sula
Published: July 2021

Background:
Reducing 30 day readmission rates for patients with heart failure (HF) has been a recent focus of lowering health care expenditures. Hemodynamic profiles (HP) have been associated with clinical outcomes in chronic systolic HF. The relationship of HP to outcomes in acute decompensated diastolic HF (DHF) has not been defined.

Methods:
This case-control study of 1892 DHF patients discharged alive from an academic hospital between 2002-2012 with left ventricular function greater or equal to 45% were categorized into 4 groups: Profile A, no evidence of congestion and hypoperfusion (dry-warm); Profile B, congestion with adequate perfusion (wet-warm); Profile C, congestion with hypoperfusion (wet-cold); and Profile L, hypoperfusion without congestion (dry-cold). All cause readmissions at 30 days and 1 year and mortality at 30 days and 1 year were examined. Statistical analysis using multivariable Cox Proportional hazard model was performed adjusting for demographic, clinical, care and hospital characteristics.

Results:
Of the 1892 patients, 1196 (63%) were females; mean age was 68 (±14) years. There were 724(38%), 1000 (53%), 88(5%) and 80 (4%) patients in the hemodynamic profiles A, B, C and L respectively. Profiles B and C were associated with an increased risk for 30-day all-cause HF readmission compared to profiles A and L: Hazard ratio (HR) [1.38 (95% C.I 1.17-1.61)], [1.39 (95% C.I 1.18-1.62)] for B and C profiles respectively. Profiles C and L were associated with increased mortality at 1 year: HR [1.46 (95% CI 1.06-1.89)] and [1.31 (95% CI 1.01-1.64)] for A and L profiles respectively (Table).

Conclusions:
Clinical assessment of HP can help identify DHF patients at increased risk of readmission and mortality, similar to systolic heart failure patients.