bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 19183: Insulin Resistance Develops after the Onset of Heart Failure in Dogs
Authors: Velez Mauricio , Ramesh Gupta , Sunkara Bipin , Lanfear David E , Sabbah Hani N
Published: April 2024

Background:
Heart failure (HF) is a condition associated with increased plasma norepinephrine levels. Norepinephrine is known to affect glucose homeostasis by decreasing insulin sensitivity. We have previously reported an increase in plasma norepinephrine levels in coronary microembolization-induced HF dogs. However, the status of plasma insulin and glucose levels is unknown in large animal models of HF. In the present study, we examined insulin and glucose levels in fasted plasma from dogs before and after the onset of HF.

Methods:
12 healthy mongrel dogs weighing 20-30 kg underwent serial coronary microembolization to produce HF. Embolization was performed every 1-2 weeks until angiographic left ventricular ejection fraction (LVEF) was <35%. All procedures were performed during cardiac catheterization, under general anesthesia and sterile conditions. Fasted plasma was collected before and after inducing HF and was stored at -80
o
C. Insulin and glucose levels were determined using commercially available ELISA kits for insulin and colorimetric assay kits for glucose, and expressed in microunits/mL and mg/dL, respectively. Homeostasis assessment model for insulin resistance (HOMA-IR) ([fasting insulin in microunits/mL * fasting glucose in mg/dL] * 0.5551/22.5) was calculated in all dogs at baseline and after inducing HF. Data were analyzed using paired t-tests.

Results:
Baseline LVEF was > 55% in all dogs. Once HF was established, mean LVEF was 31 ± 1%. Baseline mean fasting blood glucose and fasting plasma insulin were 84 ± 17 mg/dL and 9.7 ± 3.6 microunits/mL, respectively. Once HF was established, fasting blood glucose rose to 161 ± 44 mg/dL (p<0.0001) and fasting plasma insulin increased to 16.5 ± 4.0 microunits/mL (p=0.0008). HOMA-IR score increased from 2.0 ± 0.8 at baseline to 6.7 ± 3.0 with HF (p=0.0002).

Conclusions:
Hyperglycemia, hyperinsulinemia and insulin resistance develop after the onset of heart failure due to coronary microembolization in dogs consistent with observations previously reported in patients with chronic HF. This large animal model of HF can serve as a useful tool in exploring the underlying causes and consequences of insulin resistance in the setting of chronic HF.
Abstract 19194: Cardiac MRI and Electrophysiology Study Can Risk Stratify Patients with Ventricular Tachycardia and Structurally Normal Heart
Authors: Mathuria Nilesh , Michowitz Yoav , Moriarty John , Tung Roderick , Buch Eric , Bradfield Jason , Fujimura Osamu , Boyle Noel , Mandapati Ravi , Finn J. Paul , Cheng Jie , Shivkumar Kalyanam
Published: April 2024

Introduction
The role of MR imaging in risk stratification of patients with ventricular tachycardia (VT) and structurally normal heart is not well defined.

Methods
From 2005-2010, patients who presented with sustained VT or frequent nonsustained VT without echocardiographic evidence of structural heart disease were reviewed. All patients had a normal ejection fraction and no angiographic evidence of coronary artery disease. Patients received cardiac MRI and electrophysiology study (EPS) as part of their evaluation and long term outcomes were assessed.

Results
Thirty-two pts were evaluated for VT or nonsustained VT despite structurally normal hearts and underwent cardiac MRI with delayed gadolinium hyperenhancement (DHE) protocol to assess for scar prior to EPS. Fifteen had outflow tract VT (OTVT) morphology and eighteen presented with “non idiopathic” VT (not compatible with OTVT or fascicular VT). All 15 patients with OTVT morphology had a normal MRI and only the clinical VT was induced during EPS. Of the 18 patients with “non idiopathic” VT morphology, four patients had evidence of delayed enhancement on MRI (3 basal inferior/inferolateral LV, 1 basal to mid anterior LV). 3/4 with DHE had multiple VT (mean 2.25) induced during EPS. One patient had normal MRI yet multiple VT induced during EPS. All other patients had a negative MRI and EPS. During mean followup of 32+/-29 months, 2/4 patients (50%) with DHE on MRI, had recurrent VT requiring either ICD therapy or cardioversion. Additionally, the patient with multiple VT induced during EPS and normal MRI, also had recurrent VT at 7 months requiring cardioversion. The remaining 13 patients with non idiopathic VT morphology but normal MRI and EPS have not had recurrence. No deaths have occurred in any patient. All patients with outflow tract VT had normal MRI and have been managed medically or with ablation without reccurrence.

Conclusions
Cardiac MRI and EPS can help risk stratify patients with “non idiopathic” VT and structurally normal heart. Abnormal findings on MRI and EPS may identify a subgroup of patients who may be at higher risk for recurrent arrhythmic events.
Abstract 19201: Unseeded Engineered Valve Leaflets Retain Function and Remodel After Implant in Sheep Right Pulmonary Outflow Tract
Authors: Bayoumi Ahmed S , D'Amore Antonio , Aikawa Elena , Amoroso Nicholas , New Sophie E , Cubberley Alexander , Chen Peter , Shapero Kayle , Padera Robert F , Schoen Frederick J , Wagner William R , Sacks Michael S , Mayer John E
Published: April 2024

Current materials for heart valve replacement and repair are limited by the inability to grow or remodel. Tissue engineered valves offer the potential to overcome these disadvantages by creating living structures, but is limited by the availability of biocompatible scaffold materials with desirable biomechanical properties. We assessed the in vivo performance of a novel scaffold poly(carbonate urethane) urea (PCUU), fabricated by electrospinning and implanted in the pulmonary outflow tract of sheep. PCUU was electrospun into elastomeric sheets of thickness ranging from 120-180 μm. Using cardiopulmonary bypass we replaced the native anterior pulmonary leaflet with an acellular PCUU leaflet. Valve function was evaluated by epicardial echocardiography at implant and explant at weeks 1 (n=3), 3 (n=3), 6 (n=3) and 16 (n=3). Histological, immunohistochemical, molecular imaging analyses and multi-photon imaging were performed on the explanted leaflets. Echocardiography demonstrated mobile functioning leaflets, with zero to mild pulmonary regurgitation. Molecular imaging showed increased levels of proteolytic activity and macrophage accumulation. Histology showed persistence of scaffold material up to 16 weeks with cellular infiltration throughout the leaflet. Picrosirius red revealed mature collagen deposition along the arterial surface of the construct at 6 and 16 weeks. These findings were corroborated by multi-photon analysis showing highly aligned collagen fibers across the leaflets. Both surfaces of the engineered leaflets were consistently covered with CD31 positive cells. The majority of cells expressed α-SMA and MMP2. CD45 positive cells, suggesting hematogenous origin, were found throughout the leaflet. These results suggest that: 1) PCUU can be a suitable polymer for valve bioengineering; 2) cell pre-seeding may not be required for tissue formation or remodeling for a functional engineered valve; 3) host cells seem to populate the leaflet either by migration from adjacent tissue or by attachment from circulating blood; 4) mature matrix orientation and increased proteolytic activity suggests active tissue remodeling. Longer term implants and the role of scaffold pre-seeding will require further study.
Abstract 19209: Ectonucleoside Triphosphate Diphosphohydrolase-1 (cd39) Attenuates Expression f of P-Selectin Glycoprotein Ligand-1 in Hypoxic Raw Cells via Hif-1α
Authors: Liao Hui , Baek Amy E , Pinsky David J
Published: April 2024

CD39 is a transmembrane enzyme that phosphohydrolyzes ATP and ADP to AMP. CD39 inhibits platelet reactivity and inflammation and thus limits platelet accumulation and leukocyte transmigration to sites of inflammation or injury. P-selectin glycoprotein ligand-1 (PSGL-1) is a mucin-like glycoprotein on the surface of leukocytes which binds with high affinity to P-selectin, to promote tethering and rolling adhesion of leukocytes to activated endothelial cells and platelets. As this leads to increased leukocyte migration to sites of inflammation or injury, we hypothesized that CD39 may regulate PSGL-1 expression on leukocytes under hypoxic conditions. Murine RAW macrophages transfected with a CD39 overexpression construct (CD39Tx) or a pcDNA3.1 vector (VTx) as control were incubated in hypoxia (0.5% O2) or nomoxia. Subsequent flow cytometry showed 35% more cells expressed PSGL-1 after 6 hours of exposure to hypoxia (H) on VTx cells compared to normoxic (N) VTx control (p < 0.0001). The number of cells expressing PSGL-1 was reduced by 14% in H CD39Tx cells compared with H VTx cells (p = 0.0061). Western blotting showed PSGL-1 antigen expression increased 4.9, 7.0 and 3.9 fold after 2, 6, and 16 hours of hypoxia in VTx cells, respectively, compared to N VTx controls; and PSGL-1 antigen was also attenuated 19%, 30%, and 28% respectively in H CD39Tx cells compared with H VTx cells. Quantitative real-time PCR results showed that PSGL-1 mRNA expression increased by 2.1 fold in 6 hours H VTX cells compared with N VTx cells (p < 0.0001) and decreased 40% in H CD39Tx cells compared with H VTx control (p < 0.0001). The PSGL-1 promoter region contains 3 HIF-1α response elements (HRE). The activity of PSGL-1 promoter increased by 1.9-fold in 6 hours H VTx cells compared with N VTx controls (p < 0.0001) and decreased by 61% in H CD39Tx cells compared with H VTx controls (p < 0.0001). HIF-1α protein expression was also reduced in nuclear protein samples of H CD39Tx cells compared to H VTx cells. These data identify CD39 as a critical regulator of macrophage PSGL-1 expression, acting through the HIF-1alpha pathway to squelch inflammatory cell trafficking under hypoxic/ischemic conditions.
Abstract 19216: Optical Magnetic Twist Cytometry to Study the Effects of Desmin Cytoskeleton Modifications in an in vitro Model of Cardiac Hypertrophy
Authors: Agnetti Giulio , An Steven , Halperin Kuhns Victoria , Tomaselli Gordon F , Van Eyk Jennifer E
Published: April 2024

Background:
Desmin is the major protein component of the intermediate filaments (IF) cytoskeleton in the cardiac myocyte. Desmin phosphorylation modulates IF lattice formation and correlates with disease in canine and human models of heart failure (HF). In order to investigate the contribution of desmin phosphorylation to cell biophysics as a potential mechanism of contractile dysfunction and HF we employed optical magnetic twist cytometry (OMTC) to measure the elastic and frictional properties of cultured neonatal rat ventricular myocytes (NRVMs), under both basal conditions and after hypertrophy was induced by endothelin-1 (ET). We also characterized desmin phosphorylation by tandem mass spectrometry (MS2) and identified glycogen synthase kinase 3 (GSK3) as a modulator of desmin phosphorylation.

Methods and Results:
Freshly isolated NRVMs were incubated with RGD-coated magnetic beads, which avidly bind to the integrin receptors, localized at focal adhesions. The beads integrate with the cytoskeleton and can be magnetized and twisted using magnetic fields to measure cell stiffness and friction. In NRVMs, ET treatment alone (10 nM, 48 hrs) induced a 23%±3.0SE (n≥230, p=0.008) increase in cell stiffness in the presence of the contraction uncoupler heptanol (2 mM). Depolymerization of the other cytoskeleton components (microfilaments and microtubules) with selective inhibitors (cytochalasin D and colchicine, respectively, both 10μ M, 5min) was also achieved. Finally, we confirmed desmin phosphorylation at Ser-27 in NRVMs by MS2 and identified a mediator of desmin phosphorylation by phos-tag gels combined with a GSK3-specific inhibitor (BIO, 2μ M).

Conclusion:
OMTC was employed for the first time, to our knowledge, in NRVMs inaugurating the application of a powerful biophysical tool to the investigation of a well established in vitro model for cardiac hypertrophy. Desmin cytoskeleton was also monitored and a new signaling pathway for its phosphorylation identified which was associated with increased cell stiffness.
Abstract 19228: Lack of Uncoupling Protein 2 (UCP2) Reduces Mitochondrial Calcium Uptake from the Endoplasmic Reticulum (ER), Triggering Mitochondrial Suppression and Pulmonary Hypertension (PHT)
Authors: Dromparis Peter , Paulin Roxane , Sutendra Gopinath , Michelakis Evangelos D
Published: April 2024

A metabolic shift from glucose oxidation to glycolysis due to suppressed mitochondrial function contributes to the hyperproliferation and resistance to apoptosis in resistance pulmonary arteries (PA) in PHT. Disruption of the ER-mitochondria unit, which can result from many PHT-triggers including hypoxia, prevents the transfer of ER Ca2+ to mitochondria, reducing the activity of Ca2+-sensitive mitochondrial enzymes and causing mitochondrial suppression. Emerging links between PHT and insulin resistance suggest a global metabolic dysfunction. The mitochondrial protein UCP2 is implicated in the uptake of ER-derived Ca2+ and loss-of-function UCP2 polymorphisms are associated with insulin resistance/obesity. We hypothesized that reduced UCP2-mediated mitochondrial Ca2+ uptake suppresses mitochondrial function and causes PHT. UCP2 is expressed in PA smooth muscle cells (PASMCs) from wild-type (WT), but not knockout (KO) mice. KO-PASMCs had lower mitochondrial Ca2+ levels than WT-PASMCs, at baseline and during histamine-stimulated ER Ca2+ release (FRET-imaging), despite intact ER-mitochondrial morphology (electron microscopy). In keeping with reduced mitochondrial Ca2+, KO-PASMCs had mitochondrial hyperpolarization, lower activity of Ca2+-sensitive mitochondrial enzymes, reduced mitochondrial reactive oxygen species and resistance to apoptosis. UCP2 KO-mice (which have an apparently normal phenotype) had a modest, but significant elevation in mean PA pressure (catheterization; 26±2 vs. 19±1 mmHg), total pulmonary resistance (1.37±.14 vs. 0.89±0.07 mmHg ml-1 min), %medial thickness, PASMC proliferation (% Ki67-positive), and resistance PA muscularization (n=6, p<0.05 for all). Chronic Hypoxia increased PA pressure in WT-mice to the level of the normoxic UCP2 KO-mice. However the UCP2 KO-mice were resistant to further exacerbation of PHT in vivo or hypoxia-induced PASMC changes in vitro. Since in hypoxia-induced PHT the ER-mitochondria unit is disrupted, the loss of UCP2 does not have additional effects. We conclude that lack of UCP2 causes mitochondrial suppression in PASMC and predisposes to PHT. UCP2 polymorphisms may predispose to PHT and potentially underlie the unexplained systemic metabolic abnormalities in PHT.
Abstract 19234: A Short Term Premorbid High Fat Diet Disrupts Cardiac Leptin Signaling, Impairs Glucose Metabolism and Increases Morbidity and Mortality with Myocardial Infarction
Authors: McGaffin Kenneth , Yester Keith , Witham William
Published: April 2024

Introduction
A habitual high fat diet (HFD) contributes to obesity, and increases morbidity in cardiovascular disease (CVD), whereas the effects of a short-term HFD on CVD outcomes are unknown. This study was performed to test the hypothesis that a short term premorbid HFD disrupts cardiac leptin signaling, impairs glucose metabolism and exacerbates morbidity and mortality with myocardial infarction (MI).

Methods/Results
Lean, 12 week old male C57BL/6 mice were provided either a HFD (60% fat calories; n=24) or regular chow (RC) (16% fat calories; n=24) for 7 days. Equal number of mice from each dietary group were then randomly assigned to experimental MI or sham procedure, and maintained on RC until study completion at 7 days. Echocardiography and cardiac catheterization were performed on all surviving mice, and hearts were examined for biochemical and histologic measures of cardiac injury, and oxidative metabolism. Results are presented as mean ±
SEM
with statistical comparisons by t-test, or log-rank Mantel-Cox test (for survival). Groups of sham mice were not significantly different from each other in any measured outcome. However, with MI, a HFD increased mortality (41 vs 19%), cardiac dysfunction (fractional shortening 23±1 vs 29±1% and ejection fraction 24±2 vs 36±2%), and cardiac dilation (end diastolic dimension 4.6±0.1 vs 3.9±0.1mm and volume 56.6±1.3 vs 44.3±2.5uL); all p<0.05. A HFD also increased post-MI cardiac TUNEL positive cells (11.3±0.5 vs 4.1±0.3%; p<0.05) and oxidative stress by thiobarbituric reactive substances (6.8±0.2 vs 4.2±0.3 nMol/ml malondialdehyde equivalents; p<0.05). These worse indices of cardiac injury were associated with a 89±3% reduction in cardiac ObR expression, and a corresponding 86±17% reduction in signal transducer and activator of transcription-3 activation by Western blot (both p<0.05). Finally, post-MI decreases in pyruvate dehydrogenase activity (65±12%), glut4 mRNA (83±2%) and glucose oxidation (69±11%) were seen in hearts from premorbid HFD mice, whereas a 88±9% increase in fatty acid oxidation occurred (all p<0.05).

Conclusions
These data suggest that a short-term premorbid HFD impairs cardiac leptin signaling and glucose metabolism, and exacerbates morbidity and mortality outcomes in MI.
Abstract 19245: Time Trends of Echocardiography Measures of LV Function in a Cohort of Women with Breast Cancer Treated with Anthracyclines, Taxanes and Trastuzumab
Authors: Tan Timothy C , Sawaya Heloisa , Sebag Igal A , Cohen Victor , Martin Randolph P , Picard Michael H , Passeri Jonathan J , Kuter Irene , Scherrer-Crosbie Marielle
Published: April 2024

Background:

The cardiotoxicity that occurs during treatment by anthracyclines and trastuzumab used for cancer therapy is well recognized. However, the time trend of the decrease in cardiac function is unknown. In particular, the decrease in left ventricular ejection fraction (LVEF) seen with trastuzumab is thought to be transient although there is controversy on this reversibility.

Aim:

To determine the trends of LVEF, strain and strain rate after treatment by anthracyclines, taxanes and trastuzumab in a cohort of women with breast cancer that had been serially followed during their treatment.

Methods:

Follow up echocardiograms (TTEs) were performed in 25 women >18 years of age with first time breast cancer treated with anthracyclines and trastuzumab, 26.4±11.1 months after the end of the cancer treatment. These women had undergone serial TTEs before and during the duration of the treatment (15 months). LVEF was calculated using a modified Simpson’s biplane method. Global peak systolic longitudinal strain and strain rate were calculated by averaging the values of peak systolic strain and strain rate in the basal, mid-wall and apical segments of the 4- and 2- chamber views.

Results:

LVEF, strain and strain rate decreased during the study period (p<0.05 for all 3 parameters) and did not improve after 24 months of treatment completion. Of the three parameters, strain appeared to be most sensitive for the detection of cardiac dysfunction since it demonstrated a significant decrease within the 3 first months of treatment.

Conclusion:

Impairment in cardiac function from chemotherapy appears to be persistent even at 26.4±11.1 months post treatment suggestive of long term underlying cardiac damage. These results highlight the potential value of echocardiography in detecting sub-acute cardiac pathology and may help guide cardiac treatment in cancer survivors.
Abstract 19251: Identification of Conducting Channels by Delayed Enhanced Cardiac Magnetic Resonance Imaging
Authors: Mesubi Olurotimi , Jeudy Jean , Ego-Osuala Kelechi , Purtilo Jim , Ament Dawn , Etienne-Mesubi Martine , See Vincent , Saliaris Anastasios , Shorofsky Stephen , Dickfeld Timm-Michael
Published: April 2024

Objective:
Delayed enhanced cardiac magnetic resonance imaging (DE-CMRI) is able to define a heterogeneous zone of fibrotic tissue and surviving myocytes, known as ‘gray zone’ (GZ). Studies suggest that the GZ is related to ventricular tachycardia (VT) slow conducting channels (CC). There are established algorithms for GZ characterization. We evaluated the correlation of DE-CMRI defined CC and VT electroanatomic maps (EAM).

Methods:
Preprocedural DE-CMRI for scar evaluation and electrophysiology study were done in 14 male patients with ischemic (10) and non-ischemic (4) cardiomyopathy and VT. GZ was assessed on contiguous two-dimensional (2D) short axis DE-CMRI slices and reconstructed three-dimensional (3D) models. The reconstructed scar models were integrated in a clinical mapping system and compared to EAM. GZ were defined based on previously described signal intensity (SI) thresholds; full-width half maximum (FWHM), n-standard deviation (NSD) using 2-3SD thresholds and ‘Roes’ (≥ 35% - 50% of peak SI as GZ, and > 50% of peak SI as core).

Results:
CMRI and scar detection was possible in all patients including 64% of the patients with ICDs. Software analysis allowed detection and reconstruction of scar core and GZ on all 2D- and 3D-CMRI image series. Scar core and GZ were detected with all 3 algorithms. There was more scar core by NSD (NSD vs. Roes vs FWHM, 27±11g vs. 17±8g vs 17±8g, p < 0.01 ) but more GZ by FWHM (NSD vs. Roes vs. FWHM, 5±2g vs. 8±3g vs 12±7g, p < 0.01 ). CC were detected by CMRI in 50% (NSD), 64% (Roes) and 64% (FWHM) of patients. Compared to 12 CC seen on EAM, there were 17 CC seen by FWHM and Roes and 11 CC by the NSD method. There were 14 successful ablation sites in 12 patients with 2 (14%) located in EAM defined CC compared with 18% (FWHM and Roes) and 9% (NSD) in CMRI defined CC. Above 80% of the ablation sites were located in GZ areas on DE-CMRI for all algorithms (91%, 82% and 91% for NSD, Roes and FWHM).

Conclusion:
CMRI defined GZ/channels can be detected by established algorithms and compared with EAM. The FWHM has the highest GZ mass and FWHM/Roes visualize more CC. More than 80% of successful ablation sites are located in direct vicinity of the GZ. This may enable a more refined analysis of the MRI scar substrate with important features for the successful ablation sites.
Abstract 19252: Onset Scenarios of Paroxysmal Atrial Fibrillation in Patients with Ischemic Stroke
Authors: Bonnemeier Hendrik , Kurtz Franziska , Sandrock Sarah , Demming Thomas
Published: April 2024

The characterization of onset scenarios of paroxysmal atrial fibrillation (pAF) has recently gained prominence to determine various underlying arrhythmogenic trigger mechanisms. It is hypothesized that there might be specific onset scenarios of pAF in patients with ischemic stroke, however, onset scenarios of pAF have not yet been systematically analysed in a broad patient population without pacemaker indication and especially those patients after ischemic stroke.

Methods and Results:
From a total of 20.546 consecutive ambulatory 24-hour-Holter-ECG-recordings, 668 episodes of pAF (lasting > 1 minute) were identified in 343 patients without previous stroke (155 females; 71±10years) and 35 pAF episodes in 20 patients after ischemic stroke (8 females; 67±15 years). The dominant portion of episodes of pAF was preceded by atrial ectopy [single atrial premature beats (APB), blocked APB, multiple APB, short atrial runs, short-long-short sequences] or heart rate alterations [bradycardia, tachycardia, sudden rate drop, ventricular premature beats (VPB)]. Almost one third of all pAF episodes were not preceded by either ectopy or heart rate alterations (i.e. sudden-onset pAF). There were no significant differences between patients with or without stroke regarding the distribution of pAF-onset patterns. Mean RR-interval during sinus-rhythm tended to be higher in patients after ischemic stroke (866±184ms vs 845±190ms; p=0.1)

Conclusion:
There are no significant differences regarding specific onset-scenarios of pAF patients after ischemic stroke and in patients without stroke. Interestingly, patients with stroke tended to have lower heart rates during sinus rhythm.
Abstract 19309: What is the Impact of Transcatheter Aortic Valve Implantation on Patients' Profile and on Outcomes of Aortic Valve Surgery Programs? A Multi-Institutional Appraisal
Authors: D'Onofrio Augusto , Alfieri Ottavio , Alamanni Francesco , Fusari Melissa , Tarzia Vincenzo , Rizzoli Giulio , Gerosa Gino
Published: April 2024

Objective:
Aim of this retrospective multicenter study was to assess how the introduction of transcatheter aortic valve implantation (TAVI) influenced the characteristics and the outcomes of patients undergoing aortic valve procedures.

Methods:
We analyzed data from 1395 patients who underwent isolated surgical aortic valve replacement (SAVR) or TAVI in 3 centers with a high-volume TAVI program. We considered two different time periods: “Pre-TAVI”, 395 patients (28.3%) operated on before the introduction of TAVI and “Post-TAVI”, 1000 patients (71.7%) operated on after the introduction of TAVI into clinical practice. We evaluated patients’ age, preoperative risk stratification (logistic Euroscore) and hospital mortality according to time periods and to the procedure performed.

Results:
“Post-TAVI” patients were older (78.2±7.8 vs 76.8±6.7 years; p=0.002) and with a significantly higher risk profile (Logistic Euroscore: 17.8±14.7% vs 9.1±9.2%; p<0.001) when compared to “Pre-TAVI” patients. However, hospital mortality was not significantly different between groups (“Pre-TAVI”: 8 patients, 2% vs “Post-TAVI”: 34 patients, 3.4%; p=0.17). Out of the 1000 “Post-TAVI” period patients, 605 (60.5%) underwent TAVI and 395 (39.5%) underwent SAVR. Patients undergoing TAVI were older (79.9±7.1 vs 75.5±9.2 years; p<0.001) and had a higher Euroscore (22.9±15.3% vs 9.7±9.3%) than “Post-TAVI” SAVR patients but their hospital mortality was similar (24 patients, 3.9% vs 10 patients, 2.5%; p=0.22). Preoperative risk stratification was similar between “Pre-TAVI” and “Post-TAVI” SAVR patients (9.1±9.2% vs 9.7±9.3%; p=0.26). Furthermore, we did not find significant differences in the overall hospital mortality between SAVR and TAVI patients: 18 patients, 2.3% vs 24 patients, 3.9%, p=0.08.

Conclusions:
The development of TAVI has determined an increase of preoperative risk profile of patients scheduled for aortic valve procedures (SAVR or TAVI) without increasing hospital mortality. TAVI patients were older and with higher Euroscore than SAVR patients but hospital mortality was similar. Therefore these data justify the introduction of TAVI into routine practice since it allows treatment of high risk patients without an adverse impact on mortality.
Abstract 19325: Genetic Ablation of the P2y2 Nucleotide Receptor Reduces Atherosclerosis in Mice
Authors: Seye Cheikh , Qian Shaomin
Published: April 2024

Objective:
We have shown that nucleotide binding to P2Y2 receptor induces endothelial activation via enhanced VCAM-1 expression leading to intimal recruitment of monocyte/macrophage. Here, we sought to determine whether genetic ablation of P2Y2 receptor affects the development of atherosclerosis.

Methods and Results:
Western blot and immumofluorescence analysis revealed that P2Y2 receptor deficiency in ApoE mice is accompanied by a sharp reduction in basal VCAM-1 expression levels. To analyze the consequence of P2Y2 receptor deficiency in endothelial function, we examined transmigration of monocytes isolated from the peripheral blood of wt or P2Y2R
−/−
mice across
wt
or P2Y2R
−/−
endothelial monolayers in response to monocyte chemoattractant protein-1. Absence of P2Y
2
R in endothelial cells significantly impaired monocyte transmigration. Remarkably, loss of P2Y2 receptor in monocytes did not significantly impair transmigration in the presence (transendothelial) or absence (chemotaxis) of P2Y2R
+/+
endothelial monolayers, suggesting that endothelial P2Y2R is relatively more important than monocytic P2Y
2
R in regulating monocyte motility. The absence of P2Y
2
R did not significantly change the plasma cholesterol or triglyceride levels; however, lipid deposition in the lesion, as demonstrated by Oil Red O–positive region, was decreased by 47% in the aortic preparation from ApoE−/−/P2Y2R+/+

mice. Notably, P2Y2R deficiency in ApoE−/− resulted in a 52% reduction in the area of aortic sinus lesion as compared to ApoE
−/−
mice. Consistent with reduced lesion size, decreased macrophage content was observed in the sinus aortic lesions of ApoE−/−/P2Y
2
R

−/− mice. Staining for SMC showed that most of the SMCs were in the intimal area close to the lumen. The staining showed a 36% decrease in ApoE−/−/P2Y
2
R

−/− when compared with ApoE
−/−
/P2Y2R
+/+
mice. Staining with Sirius red showed that the interstitial collagen content of the lesions of ApoE
−/−
/P2Y2R
+/+
mice was 2-fold higher than in ApoE−/−/P2Y2R

−/−mice.

Conclusion:
These observations suggest that genetic ablation of P2Y
2
R

significantly decreases both macrophage accumulation and interstitial fibrosis but also reduces smooth muscle cell content of sinus aortic lesions.
Abstract 19326: Microrna Regulating Protein Bicc1 Causes Dilated Cardiomyopathy Through Modulation of Polycystin-2
Authors: Yagi Hisato , Liu Xiaoqin , Chatterjee Bishwanath , Li You , Srinivasan Ashok , Kim Adrew , Farkas Deborah , Francis Richard , Ho Jacqueline , Tobita Kimimasa , Lo Cecilia W
Published: April 2024

An ENU-induced mutation in the RNA binding protein Bicc1 was recovered in a mutant named Destro. Destro exhibits complex congenital cardiovascular defects (CHD) associated with heterotaxy, with some mutants also exhibiting kidney, biliary ductal and pancreatic cysts. The mutation was identified by whole genome sequencing as Bicc1c.606+2T>C, which caused an 18 amino acid in-frame deletion in the K homology domain required for RNA recognition. Previous studies showed Bicc1 mutations can cause polycystic kidney disease (PKD) via its role in regulating microRNA-17 (miR-17) activity, and the altered expression of polycystin-2 (Pkd2), a known miR-17 target. Destro mutants without CHD or laterality defects are postnatal viable, but die prematurely at 4-5 months of age with severe runting, even in the absence of PKD. Transthoracic echocardiography showed cardiac function in such animals declined markedly with age. This was associated with increase in LV chamber size/body weight ratio and the elevated expression of heart failure markers such as Nppa, Nppb, and osteopontin. As Pkd2 was recently shown to interact with ryanodine receptor, RyR2 to modulate Ca(2+) signaling in cardiomyocytes, we propose Bicc1 mutation can cause cardiomyopathy independent of defects associated with the kidney. Consistent with this hypothesis, we noted all homozygous Bicc1 mutants surviving to adulthood succumb to heart failure associated with dilated cardiomyopathy, but yet show no evidence of PKD. Overall, these findings indicate a novel role for the RNA binding protein Bicc1 in cardiac pathology involving dilated cardiomyopathy. Experiments are underway to examine the role of microRNA regulation of Pkd2 on cardiac pathology in the Bicc1 mutants. Based on these observations, we suggest patients with PKD may have additional risk for cardiomyopathy of an independent etiology from any underlying kidney disease.
Abstract 19343: Chemical Chaperone Mediated Inhibition of Activating Transcription Factor 6 (ATF6) is a Novel Therapy in Pulmonary Arterial Hypertension (PAH)
Authors: Dromparis Peter , Paulin Roxane , Stenson Trevor H , Haromy Alois , Sutendra Gopinath , Michelakis Evangelos D
Published: April 2024

The high mortality associated with PAH is in part, due to the poorly understood pathogenesis. Endoplasmic reticulum (ER)-stress is a potential commonality among many molecular triggers of PAH, including mutations, viruses, inflammation and hypoxia. The ER forms a functional unit with the mitochondria (the ER-mito unit), allowing for exchange of Ca2+. Recently, we showed that ER-mito unit disruption was critical in PAH pathogenesis. In pulmonary artery smooth muscle cells (PASMCs), ER-stress activated the transcription factor ATF6, increased levels of the ER protein Nogo, disrupted the ER-mito unit, and resulted in the apoptosis-resistance that is central to pulmonary vascular remodeling in PAH. Chemical chaperones including the FDA-approved 4-phenylbutyrate (PBA) attenuate ER-stress and have been studied in metabolic diseases and cancer. We hypothesized that attenuation of ER stress-induced ATF6 activation with PBA will prevent the disruption of the ER-mito unit and prevent/reverse PAH. Hypoxic mice or monocrotaline-injected rats were treated with PBA in their drinking water (~500mg/kg/day) in prevention (days 0-28) and reversal (days 14-28) protocols. Mechanistic studies were performed in lungs and PASMCs exposed to hypoxia. PBA decreases ATF6 activation (nuclear localization, luciferase, target gene (Nogo/GRP78) expression) and normalizes mitochondrial function (mitochondrial-Ca2+, membrane potential, reactive oxygen species). Both in vivo and in vitro, PBA suppresses proliferation (Ki67) and induces apoptosis (TUNEL). Treated mice had less pulmonary artery remodeling, improved hemodynamics, decreased right ventricular hypertrophy and better functional capacity compared to vehicle-treated controls (see table; data presented as mean±SEM). Treated rats responded similarly. Chemical chaperones improve PAH by inhibiting ATF6 activation, a pathway compatible with several PAH-triggers that induce ER-stress.
Abstract 19390: Sirtuin 1 Modulates Cardiac Sodium Channels in vivo
Authors: Dai Shengchuan , Kumar Ajay , Islam Zahid , lewarchik christopher , Naqvi Asma , Irani Kaikobad , London Barry
Published: April 2024

The rapid upstroke in phase 0 of the cardiac action potential is the result of the inward sodium current (I
Na
) carried by the cardiac voltage-gated sodium channel Na
v
1.5 (SCN5A). We recently reported that the overexpression of Silent Information Regulator 1 (Sirtuin 1, SIRT1), an NAD
+
dependent protein deacetylase, deacetylated SCN5A, increased its cell surface expression, and increased I
Na
in HEK-293 cells and rat neonatal cardiac myocytes. Overexpression of a dominant negative SIRT1 construct decreased SCN5A cell surface expression and I
Na
. The role of acetylation of SCN5A and its regulation by SIRT1 has not been shown in vivo, however. We engineered cardiac specific Sirt1 knockout (cSirt1KO) mice by breeding Sirt1
flox/flox
with α-MHC-cre mice on a C57BL-6 background. cSirt1KO compared to littermate Sirt1
flox/flox
mice showed much less expression of Sirt1 mRNA (12±6%, n=3) and protein in the heart but not in the kidney, and Scn5a immunoprecipitated from cardiac membrane fractions of the cSirt1KO mice showed an ∼2-fold increase in acetylation (Figure A). At 3 months of age, EKGs from anesthetized cSirt1KO compared to littermate Sirt1
flox/flox
mice showed PR prolongation (43±3 ms, n=4, vs. 37±2 ms, n=5; p<0.02) and telemetry from ambulatory cSirt1KO mice showed high degree heart block not seen in the controls (Figure B). Thus, our results show that Scn5a is acetylated in vivo in the mouse, that the degree of acetylation is regulated by cardiac-specific expression of Sirt1, and that decreases in Sirt1 lead to conduction disease similar to those seen in Scn5a
+/-
mice. These findings raise the possibility that pharmacological manipulation of Sirt1 may provide a means to modulate cardiac I
Na
and arrhythmias.
Abstract 19396: Diuretic Use Guided by a Wireless Implanted Pulmonary Artery Pressure Monitoring System in NYHA Class III Heart Failure Patients: Observations from the CHAMPION Trial
Authors: Costanzo Maria Rosa , Adamson Philip B , Abraham William T , Jeffries Bradley , Neville Susan , Cowart Pam , Henderson John , Jadav Jay S
Published: April 2024

Introduction:
Optimal diuretic dosing strategies for the treatment of chronic heart failure (HF) have not been established. The range of effective diuretic doses varies widely from patient to patient and within patient from time to time. Knowledge of wirelessly measured Pulmonary Artery Pressure (w-PAP) can provide immediate feedback on treatment response and thus may help identify an optimal diuretic strategy.

Methods:
Retrospective analysis of CHAMPION trial data to determine if adjustments of diuretic therapy in response to w-PAP are associated with reduced HF hospitalization rates.

Results:
In the CHAMPION trial 270 patients were assigned to w-PAP and 280 to usual care (UC). At baseline w-PAP and UC groups were similar in percentage of patients receiving diuretics (91.9% and 94.2%) and diuretics doses. Over a 6 month follow up period loop diuretics were more frequently adjusted in the w-PAP than in the UC group (1267 vs. 498 times; p<0.0001). In the w-PAP group 629 diuretic adjustments (49.8%) in 155 patients (57.4%) resulted from detection of increases in PAP and 107 diuretic changes (75.4%) in 46 patients (17%) occurred after detection of declining PAP. Compared to baseline, 6 months daily loop diuretic dose increased from 96.8 mg to 122.7 mg in the w-PAP group and 98.0 mg to 112.4 in the UC group. Despite more frequent diuretic adjustments in the w-PAP than in the UC group, mean daily loop diuretic dose
changes
were similar between groups (25.9 mg vs. 14.3 mg; p=0.1214). The 89 w-PAP patients with increased loop diuretic dose had a lower rate of HF hospitalizations than the 68 UC patients with similarly increased diuretic doses (0.32 vs. 0.70; p= 0.0014. In contrast HF hospitalization rates were similar in the 134 w-PAP and 173 UC patients without diuretic dose change (0.28 vs.0.27).

Conclusions:
Utilization of w-PAP permits physicians to effectively increase and decrease diuretic doses and reduce HF hospitalizations rates. Such adjustments in diuretic doses without knowledge of w-PAP are associated with a high 6-month rate of HF hospitalizations.
Abstract 194: ST Changes on Continuous Telemetry Monitoring Before In-Hospital Cardiac Arrests
Authors: Do Duc H , Hayase Justin , Kim Sunghan , Hu Xiao , Boyle Noel G
Published: April 2024

Introduction:

In-hospital cardiac arrests (CA) remain a significant problem in the United States, affecting up to 750,000 patients annually. No more than 30% survive to discharge - this has improved little in the past 25 years, and is unlikely to improve further without major changes in treatment or better identification of at risk patients. Hence, there is significant interest in predicting impending CA to allow for intervention and possibly improve survival. In this retrospective study, we examine the characteristics of ST changes prior to CA to evaluate their utility in predicting CA.

Methods:

We evaluated all “Code Blue” events at UCLA Ronald Reagan Medical Center, a 520 bed tertiary care hospital, from April 2010 to April 2012. Inclusion criteria were: age ≥ 18, actual cardiac arrest, continuous telemetry data available for at least 3 hours immediately prior to CA. Up to 24 hours of telemetry data prior to CA was obtained and analyzed for each case. The arrhythmic mode and likely underlying cause, and presence/absence/duration of ST changes prior to CA were assessed for each case.

Results:

Of 65 cases meeting inclusion criteria, 19(29%) had progressive ST changes leading up to CA. The most likely cause was respiratory failure in 5(26%), multiorgan failure in 7(37%), acute cardiac failure (pulmonary embolism or myocardial infarction) in 5(26%), metabolic acidosis in 1(5%), and hemorrhagic shock in 1(5%). The arrhythmic mode of CA was pulseless electrical activity in 14(73%), bradycardic in 4(21%) and torsade de pointes in 1(5%). ST changes were detectable on telemetry monitoring in 6(32%) more than 60 minutes prior to CA, in an additional 6(32%) between 10 and 60 minutes prior to CA, and only in the last 10 minutes in a further 6(32%).

Conclusions:

ST changes leading up to CA occurred in one third of cases in this small series, mainly in PEA and bradycardic arrests. These were associated with multiple underlying medical conditions that may lead to cardiac hypoperfusion such as multiorgan failure on pressors, severe hypoxia, pulmonary embolism and myocardial infarction. In about two thirds of the cases in which ST changes were detectable, they were evident more than 10 minutes prior to onset of arrest, which may allow sufficient time for rapid intervention to prevent CA.
Abstract 19411: Inter-Atrial Regional Adipose Burden in Relation To Metabolic Abnormalities as a Novel Clinical Marker for Left Atrial Remodeling in Preserved Ejection Fraction Heart Failure
Authors: Hung Chung-Lieh , Yun Chun-Ho , Lai Yau-Huei , Kuo Jen-Yuan , Wu Yih-Jer , Liu Chuan-Chuan , Yeh Hung-I
Published: April 2024

Background:
Excessive visceral adipose tissue, a marker of abnormal metabolic process, has recently been shown to exert effects on cardiac struture and function. However, data regarding regional fat burden on left atrial (LA) mechanics and contractile function in subjects with heart failure and preserved ejection fraction (HFpEF) remained elusive.

Methods:
Totally studied 48 heart failure patients with preserved left ventricular ejection fraction (HFpEF) from heart failure (HF) outpatient clinics. Another 58 hypertensives and 26 normal volunteers were recruited from health evaluation center at the same time of patients enrollment. Myocardial deformation imaging from all directions, cardiac twist and left atrial (LA) strain analyzed. Global epicardial (EAT), thoracic peri-aortic (TAT) adipose tissue and regional inter-atrial fat burden (IAF, in thickness) were quantified by multi-detector Computed Tomography (MDCT) (Sensation 16, Siemens Medical Solutions, Forchheim, Germany) off-line analysis (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA). Metabolic risk scoring (MS) was calculated by NCEP ATP III score.

Results:
Compared to hypertensives and normal group, patients with HFpEF tended to have higher LV mass index and LA diameter though similar LVEF (all p<0.05) observed. In addition, EAT, TAT and IAF all correlated with MS (trend p<0.05), and were all significantly higher in HFpEF group (ANOVA p<0.05), which were accompanied by significantly reduced LV deformation from all three directions and cardiac twist as well as lower LA strain (all p<0.05). In a multivariate model adjusting for age, gender, body mass index, blood pressure, MS and LV mass, for each increased standard deviation of IAF were independently associated with reduced LA strain (ß coef: -0.35, p=0.018).

Conclusions:
Fat pad surrounding inter-atrial region in relation to metabolic abnormalities may influence left atrial mechanical function in terms of atrial deformation. Our data suggested that such excessive regional adipose burden may partly play a role in the pathogenesis of early stage heart failure.
Abstract 19434: Early Ischemic Preconditioning Requires Akt- and PKA-Mediated Activation of eNOS via Serine
1176
Phosphorylation
Authors: Yang Changjun , Talukder M.A. Hassan , Varadharaj Saradhadevi , Velayutham Murugesan , Zweier Jay L
Published: April 2024

Aims:

The role of endothelial nitric oxide synthase (eNOS)/NO signaling is well-documented in late preconditioning or postconditioning; however, the role of eNOS and its activation in early IPC remains controversial and poorly defined. This study investigates the role of eNOS in early IPC and what signaling pathways and molecular interactions regulate eNOS activation during early IPC.

Methods and Results:

Rat hearts were subjected to 30-min global ischemia and reperfusion (I/R) with or without IPC (3 cycles 5-min I and 5-min R) in the presence or absence of the NOS inhibitor, L-NAME, PI
3
K inhibitor, LY294002/LY, or PKA inhibitor, H89, during IPC induction. IPC improved postischemic contractile function and reduced infarction compared to I/R with this abrogated by NOS inhibition. eNOS
Ser1176
, Akt
Ser473
, and PKA
Thr197
phosphorylation was increased following IPC. I/R decreased eNOS
Ser1176
phosphorylation, while IPC increased it. Mass spectroscopy confirmed eNOS
Ser1176
phosphorylation and quantative western blots showed that ∼24 % modification of eNOS
Ser1176
was present following induction of early IPC. Immunoprecipitation demonstrated eNOS, Akt and PKA complexation. Immunohistology showed that IPC induced Akt and PKA phosphorylation in cardiomyocytes and endothelial cells. With eNOS activation, IPC increased NO production as measured by EPR spin trapping and fluorescence microscopy. LY or H89 not only greatly decreased Akt
Ser473
or PKA
Thr197
phosphorylation, respectively; but also abolished IPC-induced preservation of eNOS and eNOS
Ser1176
phosphorylation as well as subsequent cardioprotection.

Conclusion:

Thus, Akt- and PKA-mediated eNOS activation, with phosphorylation near the C-terminus, is critical for early IPC-induced cardioprotection with eNOS-derived NO serving a critical role.
Abstract 19448: Ventricular Arrhythmias in Patients Following Continuous Flow Left Ventricular Assist Device Implantation
Authors: Garan Arthur R , Morrison Kerry , Letarte Laurie , Vazquez Jesus , Dano Drew , Colombo Paolo , Yuzefpolskaya Melana , Te-Frey Rosie , Takayama Hiroo , Naka Yoshifumi , Morrow John , Garan Hasan , Jorde Ulrich P , Uriel Nir
Published: April 2024

Background:
Sustained ventricular arrhythmias (VA) (i.e. VT or VF) are common following continuous flow LVAD (CF-LVAD) implantation. Reports of VAs in this population have been retrospective, included short-term VADs, or focused predominantly on pulsatile flow devices.

Objective:
In this study we aim to evaluate the prevalence and predictors of VAs in CF-LVAD patients, their clinical impact, and the need for ICDs in those patients.

Methods:
All patients with CF-LVADs and an ICD presenting to our institution were enrolled and followed prospectively. The primary end-point was a composite of hemodynamically significant VA (causing hypotension, worsening CHF, or end-organ dysfunction) or admission as a result of VA. At subsequent hospitalizations or clinic visits, patients’ ICDs were interrogated to identify new VAs.

Results:
Sixty-nine patients were enrolled. Follow up totaled 64.5 CF-LVAD-patient years. Sixty-five (94.2%) were men, 34 (49.3%) had ischemic cardiomyopathy, and average age was 62.9 + 11.9 years. Six (8.7%) had undergone catheter ablation for VT prior to surgery, 19 (27.5%) had experienced a VA 90 days prior to surgery, and 27 (39.1%) were taking an anti-arrhythmic drug at enrollment. Excluding VAs occurring within 30 days of surgery, 19 (27.5%) patients had 85 VAs for an event rate of 1.3 VAs/patient year. Twelve patients (17.4%) met the primary end-point. Predictors of the primary end-point were VAs occurring prior to surgery and use of anti-arrhythmic drug. There was a trend towards significance for ischemic cardiomyopathy and prior VT ablation.

Conclusions:
Despite the support provided by CF-LVADs, VAs carry significant morbidity and pose risk for end organ damage and recurrent hospitalization. VAs pre-operatively and anti-arrhythmic use were associated with VA-related morbidities post-operatively. These patients may require more aggressive anti-arrhythmic therapies following surgery and ICDs continue to play a crucial role in their care.