bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12669: Identification of Novel Genetic Modifiers of LQT2 by Combining Patient Derived iPS Derived Cardiomyocytes and Exome Sequencing
Authors: Chai Sam , Wan Xiaoping , Ficker Eckhard , Ramirez-Navarro Angelina , Kaufman Elizabeth S , George Alfred L , Deschenes Isabelle
Published: April 2024

Background:
Long QT Syndrome Type 2 (LQT2) is caused by autosomal dominant loss-of-function in hERG, but often with incomplete penetrance. We investigated the mechanisms underlying genotype-phenotype discordance seen in a large LQT2 family by studying cardiac myocytes derived from induced pluripotent stem cells from affected and unaffected mutation-positive family members. We hypothesize that the presence of disease modifying genes contributes to this phenotype.

Methods:
Two family pairs displaying this genotype-phenotype discordance were studied. iPS cells were generated from skin biopsies and differentiated into ventricular cardiomyocytes (iPS-CM) that were studied electrophysiologically. Exome sequencing was also performed on the four subjects.

Results:
hERG R752W mutation-positive cardiomyocytes exhibited reduced I
Kr
compared to control cells. Further, cardiomyocytes from the affected individuals displayed prolonged action potentials as well as greater L-type calcium current (LTCC) compared to cells from control subjects and an unaffected mutation-positive family member. Whole exome sequencing identified two potential disease-modifying genes. The first is a single nucleotide variant (SNV) in KCNK17 encoding a 2-pore potassium channel. When expressed in Chinese Hamster Ovary cells, this variant potassium channel, which was found only in asymptomatic mutation-positive individuals, leads to increased current density compared to the nonvariant channel. The second SNV was identified in a Ras-like GTPase and was present exclusively in symptomatic mutation-positive individuals. Overexpression of this variant protein in iCells
©
resulted in a significant increase in LTCC.

Conclusion:
We have successfully recapitulated the genotype-phenotype discordance seen in a LQT2 family using patient-derived iPS-CMs. We postulate that the difference in the currents conferred by the 2-pore potassium channel variant could partially protect hERG R752W mutation-positive subjects by mitigating the severity of the hERG mutation. However, it appears that ultimately the inheritance of a SNV in a Ras-like GTPase in tandem with the primary mutation in hERG is the permutation that drives the complete disease phenotype.
Abstract 12677: Long-Term Survival of Patients With Left Bundle Branch Block who are Clinical or Echocardiographic Hypo-Responders to Cardiac Resynchronization Therapy
Authors: Vidula Himabindu , Kutyifa Valentina , McNitt Scott , Goldenberg Ilan , Solomon Scott , Moss Arthur J , Zareba Wojciech
Published: April 2024

Introduction:
Guidelines support cardiac resynchronization therapy with a defibrillator (CRT-D) in heart failure (HF) patients with left bundle branch block (LBBB). However, not all patients demonstrate clinical or echocardiographic (ECHO) response to CRT-D. We aimed to compare the long-term outcomes of clinical hypo-responders and ECHO hypo-responders with LBBB who were enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT).

Methods:
Five-hundred thirty-four patients with LBBB in the CRT-D arm were followed for 5.6 years (median). Clinical hypo-response was defined as presence of defibrillator treated ventricular arrhythmia or HF event in the first year after CRT-D implantation. ECHO hypo-response was defined as less than or equal to 35% reduction (median) in left ventricular end-systolic volume (LVESV) 1 year after CRT-D implantation; we also tested 15% and 25% reduction in LVESV.

Results:
Clinical and ECHO response was observed in 246 (46%) patients. Two-hundred twenty-six (42%) patients were ECHO hypo-responders and 62 (12%) patients were clinical hypo-responders. Fifty (9%) patients died during long-term follow-up. ECHO hypo-responders had an increased risk of all-cause mortality compared to clinical + ECHO responders (hazard ratio [HR] 3.02, 95% CI 1.45-6.31, p=0.003). Clinical hypo-responders had an increased risk of mortality compared to clinical + ECHO responders (HR 3.67, 95% CI 1.45-9.33, p=0.006), but not compared to ECHO hypo-responders. There was no significant difference between outcomes for clinical hypo-responders and ECHO hypo-responders when using an ECHO cutoff of 15% or 25% reduction in LVESV.

Conclusion:
During long-term follow-up, heart failure patients with LBBB who have clinical or echocardiographic hypo-response to CRT-D have comparable increased risk of mortality relative to patients who demonstrate good clinical and echocardiographic responses.
Abstract 12709: Dynamics of Flow-Responsive Kinase Cε Modulates Glycolytic Metabolites to Promote Vascular Repair
Authors: Beebe Tyler , Liem David , Yen Hilary , Kaboodrangi Amirhossein , Jen Nelson , Lee Juhyun , Fei Peng , Ping Peipei , Li Rongsong , Hsiai Tzung K
Published: April 2024

Hemodynamic shear stress has recently been reported to modulate vascular development and repair via canonical Wnt--catenin signaling pathway. It is recognized that protein Kinase C isoform epsilon (PKCε) signaling in mitochondria confers cardioprotection via VEGF and eNOS activation in response to ischemia/reperfusion injury. Here, we hypothesized that shear stress-responsive PKCε signaling modulates glycolytic metabolites to promote vascular repair. By performing a metabolomic analysis, both oscillatory (OSS: ±1 dynes·cm
-2
at 1 Hz) and pulsatile shear stress (PSS: 23 dynes·cm
-2
at 1 Hz) significantly increased endothelial glycolytic metabolites; namely, xylitol and dihydroxyacetone (
n
=6,
p
< 0.01 vs. control), but decreased gluconeogenic metabolites; namely, aspartic acid. Both OSS and PSS up-regulated PKCε mRNA and protein expression via VEGF receptor (n=3,
p
< 0.05); and constitutively active PKCε increased basal glycolysis and activity by the Seahorse assay (
n
=4,
p
<0.01 vs. dominant negative PKCε control), implicating that shear stress-responsive PKCε modulates glycolysis. To recapitulate in transgenic
Tg(flk1:GFP)
zebrafish embryos, we performed micro-injection of
GATA-1a
morpholino oligonucleotide (MO) at 1-4 cell stage to inhibit hematopoeisis, thus decreasing viscosity and fluid shear stress. In response to tail amputation,
GATA-1
MO impaired and delayed vascular repair compared with the control injection (
n
=20,
p
<0.01 vs. control) (
Figure 1
). Co-injection of PKCε mRNA with
GATA-1a
MO rescued tail repair (
n
=5,
p
<0.05). Overall, shear stress-responsive VEGFR- PKCε signaling modulates glycolytic metabolites to influence vascular repair. Thus, hemodynamic shear stress imparts both developmental and metabolic effects to promote vascular regeneration.

Figure 1.
Tail repair in response to injection with
GATA-1
MO or rescue by co-injection with PKCε mRNA, dpf: days post-fertilization; dpa: days post-amputation.
Abstract 12780: Collagen Derived Matricryptin Robustly Promotes Angiogenesis Post-myocardial Infarction Reducing Cardiac Dysfunction
Authors: Neuhaus Madeleine , Shaver Patti R , Lust Robert M , de Castro Brás Lisandra E
Published: April 2024

Proteolytically released extracellular matrix (ECM) fragments - matricryptins - exert biological activities usually different from those of the full-length protein and play important roles in tissue healing and regeneration. Following myocardial infarction (MI), the native ECM is cleaved by proteases during remodeling of the left ventricle (LV) originating ECM-derived peptides. Previously, we identified a collagen matricryptin, p1158/59, that is naturally generated post-MI. This study aimed to identify the biological roles of this matricryptin. We isolated cardiac fibroblasts from mouse hearts and treated cells with 1 μM of p1158/59. HUVEC cells were used to assess p1158/59 effects in angiogenesis. A permanent occlusion model of MI was used to investigate the roles of p1158/59 in post-MI remodeling. Animals were treated with p1158/59 (950 μg/day/kg body weight) or saline for 7 days post-MI. In vitro, p1158/59 increased migration of cardiac fibroblasts and robustly induced formation of a network of 3-D capillary-like tubular structures in endothelial cells (~4-fold versus negative control, p<0.05). In vivo, mice treated with p1158/59 for 7 days post-MI showed enhanced expression of components of the basal membrane known to stimulate angiogenesis - Col4a1, Col4a2, and Lama1 (p<0.05 for all). By immunoblotting and immunohistochemistry we observed increased vessel numbers in both the remote and infarct regions of p1158/59 treated animals compared to those treated with saline (p<0.05). Increased angiogenesis in both remote and infarct regions may offer the necessary cardioprotection to mitigate the detrimental effects of hypoxia and resulting LV dysfunction post-MI. We used echocardiography to assess physiological effects. Animals treated with p1158/59 displayed preserved LV wall thickness, geometry, and contractility, resulting in reduced systolic dysfunction post-MI. Taken together, our data show that p1158/59 is a biologically active molecule with potent pro-angiogenic properties and strongly promote this matricryptin as a molecule of interest for treatment of adverse LV remodeling.
Abstract 12785: In Patients Supported by a Left Ventricular Assist Device, Bi-Ventricular Pacing does not Offer Hemodynamic Improvement over Right Ventricular Pacing
Authors: Inampudi Chakradhari , Johnson Frances , Tahir Rizwan , Tandon Rudhir , Iqbal Omer J , Emerenini Uzodinma , Giudici Michael C , Cotarlan Vlad
Published: April 2024

Hypothesis:
The benefit of biventricular (BiV) pacing in patients supported by a left ventricular assist device (LVAD) is unknown. This pilot study aimed to assess the acute hemodynamic effects of biventricular pacing compared to right ventricular (RV) pacing in patients supported by LVADs and to determine appropriate pacing rate.

Methods:
We studied 7 patients (age 65±7, 100% males) supported by Heartmate II (HM2) LVAD who underwent biventricular (BiV) pacemaker (PM) implant prior to LVAD. All patients underwent a ramp echo study for speed optimization prior to enrollment. Two patients were in sinus rhythm and 5 were in chronic atrial fibrillation (AF) and pacemaker dependent due to complete atrioventricular block (AVB).

Results:
A total of 42 complete sets of hemodynamics were obtained during BiV and RV pacing at various pacing rates ranging from 50 to 110 bpm. There were no significant differences in right atrial(RA) pressure, mean pulmonary artery(mPA) pressure, cardiac index(CI), PA saturation(PASat) and right ventricular stroke work index(RVSWI) between BiV and RV pacing (table). There was a trend for higher stroke volume index (SVI) and RVSWI at lower heart rates for each individual patient.

Conclusion:
BiV pacing does not appear to have any acute hemodynamic benefit compared to RV pacing in patients supported by HM2-LVAD. At lower heart rate, whether BiV or RV, may confer better RV efficiency.
Abstract 12826: Systolic Velocity of the Tricuspid Annulus Decreases After Pulmonary Thromboendarterectomy in Patients With Chronic Thromboembolic Pulmonary Hypertension
Authors: Wong Darrin , Yousefian Omid , Auger William , Dittrich Teri , Madani Michael , Daniels Lori , Raisinghani Ajit , DeMaria Anthony , Blanchard Daniel
Published: April 2024

Introduction:
Echocardiographic assessment of RV function is problematic. Systolic velocity of the tricuspid annulus (tS
m
) has been shown to correlate with RV ejection fraction. Furthermore, tS
m
is generally depressed in chronic pulmonary hypertension. We sought to evaluate RV systolic function in chronic thromboembolic pulmonary hypertension (CTEPH) using 2D speckle tracking before and after pulmonary thromboendarterectomy (PTE).

Hypothesis:
We hypothesized that tS
m
would increase after PTE.

Methods:
We measured tS
m
from 2D echocardiography using speckle tracking in 127 consecutive CTEPH patients (52 ± 14 years, 49% female) with adequate images pre- & post- PTE. tS
m
was measured 9.7 ± 17.3 days before and 11.3 ± 17.0 days after PTE using Epsilon Imaging EchoInsight software.

Results:
Unexpectedly, tS
m
worsened after PTE (8.2 ± 3.5 to 5.4 ± 2.8 cm/sec [p=<0.0001]). Pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), and cardiac output (CO) all improved: 723 ± 258 to 246 ± 133 dyne-sec/cm
5
(p=<0.0001), 46 ± 12 to 24 ± 7 mm Hg (p=<0.0001), and 4.4 ± 1.3 to 5.6 ± 1.2 L/min (p=<0.0001) respectively after PTE (Table 2). Preoperatively, tS
m
correlated inversely with PVR (p=<0.0001) and mPAP (p=0.003) and directly with CO (p=0.0002) (Table 1). Postoperatively, tS
m
did not significantly correlate with PVR, mPAP, or CO.

Conclusions:
tS
m
correlates significantly with PVR, mPAP, and CO in patients referred for CTEPH. Early after PTE, however, tS
m
decreases by 34% and demonstrates no correlation with postoperative right heart catheterization data. In conclusion, tS
m
cannot be used to accurately predict RV function immediately following successful PTE.
Abstract 12837: Nondipper Pulse Rate Pattern is Associated With Cardiovascular Events, but Night Pulse Rate is Not: Japan Morning Surge Home Blood Pressure (J-HOP) Study
Authors: Ogoyama Yukako , Kabutoya Tomoyuki , Hoshide Satoshi , Negishi Keita , Kario Kazuomi
Published: April 2024

Introduction:
Nondipper patterns of pulse rate (PR) as well as blood pressure (BP) have been associated with cardiovascular events. High night PR is also associated cardiovascular events.

Hypothesis:
We assessed the hypothesis that a nondipper PR pattern was independently associated with cardiovascular events in patients with cardiovascular risk factors, adjusting for night pulse rate.

Methods:
Ambulatory BP monitoring was conducted at baseline in 1443 patients who had one or more cardiovascular risk factors. PR nondipping status was defined as (awake PR - sleep PR)/awake PR < 0.1.

Results:
The nondipper PR patients (N=339) were older (66.8±10.6 vs. 63.9±11.8, p<0.001) and had a higher night PR (65.5±9.6 vs. 58.9±7.3/min, p<0.001) than the dipper PR patients (N=1104). The mean follow-up period was 60±30 months; in that time 50 patients (4.5%) in the dipper PR group and 34 patients (10.0%) in the nondipper PR group suffered primary endpoints (log rank 22.2, p<0.001). On the Cox proportional hazards model including age, gender and night systolic blood pressure, nondipper PR was an independent predictor of cardiovascular event (hazard ratio 2.38, 95% confidence interval 1.51-3.74, p<0.001), but night PR was not (p=0.50). We analyzed four groups according to BP and PR dipping status, the combination of nondipper BP and nondipper PR constituted a higher risk of cardiovascular events and stroke than the sum of the other three combination risks (Log rank= 39.2, p<0.001, figure). When we added the nondipper BP pattern in the model, nondipper PR remained an independent predictor of cardiovascular events (hazard ratio 2.29, 95% confidence interval 1.50-3.51, p<0.001). After excluding patients who took beta blockers (N=1003), nondipper PR was an independent predictor of cardiovascular events (hazard ratio 2.16, 95% confidence interval 1.22-3.82, p=0.008).

Conclusions:
The nondipper PR pattern was associated with cardiovascular events, but night pulse rate was not.
Abstract 12890: Relaxin Reverses Profibrotic and Inflammatory Atrial Remodeling in a Human Tachyarrhythmia Model
Authors: Bukowska Alicja , Bornfleth Philipp , Kutschka Ingo , Goette Andreas
Published: April 2024

Introduction:
Atrial fibrosis is a critical substrate in the initiation and maintenance of atrial fibrillation (AF). Deposition of atrial collagen has been well documented in patients with AF. The accumulation of collagens results from transcriptional activation of collagens genes in the response to bioactive peptides, cytokines and oxidative stress. The present study addresses the therapeutic potential of relaxin in human atrial tissue.

Hypothesis:
Relaxin reverses atrial remodeling in tachyarrhythmia.

Methods:
Right atrial appendages were obtained from 28 patients undergoing heart surgery for coronary artery bypass graft or mitral/aortic valve replacement. Tissue samples were sliced into 350μm and cultivated for up to 24h in the presence of relaxin in the concentration range from 10nM to 1μM (n=15). To resemble AF, the tissue slices were stimulated in the electrical field at 4 Hz (vs.0.6 Hz) up to 24h without and with the presence of 0.1 μM (n=6), or 1 μM (n=7) relaxin. Then, atrial tissue was examined at the transcriptional and protein level.

Results:
Relaxin diminished the transcriptional expression of molecules associated with atrial fibrosis like: collagen 3 (0.1μM: 0.83±0.06; 1μM: 0.68±0.07; p<0.01), CTGF, TGF-ß1, and TGFßR2. Moreover, relaxin reduced basal expression of inflammatory molecules like ICAM-1 and IL-8. To assess the therapeutic potential of relaxin in tachyarrhythmia, tissue slices were exposed to electrical field. Relaxin prevented the pacing-dependent increase in the expression of collagen3 (0.1μM: 1.2±0.2; 1μM: 1.0±0.2; p<0.05 vs 4Hz: 2.2±0.4) CTGF (0.1μM: 1.1±0.2; 1μM: 1.2±0.2; p<0.05 vs 4Hz: 2.2±0.3), TGF-ß1 (0.1μM: 1.1±0.2; 1μM: 0.9±0.1; p<0.05 vs 4Hz: 2.2±0.4). Similarly effects achieved relaxin on the expression of inflammatory molecules. Of note, relaxin prevented the pacing-dependent activation of NF-κB transcription factor and MAP kinases. However, relaxin did not influence the pacing-induced phosphorylation of SMAD2.

Conclusions:
Relaxin reverses atrial remodeling in a human tachyarrhythmia model. We demonstrated that relaxin abolishes the expression of pro-fibrotic and pro-inflammatory and prevents via NF-kB inhibition the pacing-dependent pro-fibrotic and pro-inflammatory responses.
Abstract 12925: The Neuro-Mechanical Unloading for Acute Myocardial Infarction Strikingly Reduces the Infarct Size and Prevents Heart Failure in the Long Term
(Best of Basic Science Abstract)
Authors: Saku Keita , Arimura Takahiro , Kakino Takamori , Tohyama Takeshi , Nishikawa Takuya , Akashi Takuya , Murayama Yoshinori , Sakamoto Takafumi , Kishi Takuya , Ide Tomomi , Sunagawa Kenji
Published: April 2024

Introduction:
Although widespread practice of early coronary intervention has reduced the acute phase mortality in myocardial infarct (MI), the late development of heart failure remains increasing at an alarming rate. Left ventricular (LV) assist device (VAD) unloads the heart, thereby decreases oxygen consumption. Vagal nerve stimulation (VNS) exerts a powerful anti-infarct effects.

Hypothesis:
We hypothesized that the combination of short term VAD (mechanical unloading) and VNS (neural unloading) for the ischemia/reperfusion (IR) model would prevent the late development of heart failure.

Methods:
In 24 dogs, we occluded the left anterior descending coronary artery for 180min and then reperfused. We unloaded LV with transvascular VAD (Impella®). We administrated transvascular VNS with a pacing catheter in the superior vena cava (10Hz). The neuro-mechanical unloading started at 90min after the onset of ischemia and ended at 60min after reperfusion. We allocated dogs into 4 groups, IR (n=7), VAD (n=6), VNS (n=4) and VAD+VNS (n=5) and compared the infarct size and cardiac function one month after IR.

Results:
LVAD+VNS normalized LV end-systolic elastance (IR: 6.1±3.3, VAD: 8.1±1.3, VNS: 10.6±4.5, VAD+VNS: 14.9±2.8 mmHg/ml, p<0.05) and maximally lowered LV end-diastolic pressure (EDP) (16.8±6.4, 6.4±1.5, 5.3±3.1, 3.7±0.4 mmHg, p<0.05). NT-proBNP paralleled the changes in LVEDP (3712±1141, 1728±348, 1507±511, 1059±397 mmHg, p<0.05), supporting nearly normalized cardiac function. VAD+VNS strikingly reduced the infarct size by more than 70% (p<0.05, Figure).

Conclusions:
The combination of short term VAD and VNS prior to reperfusion markedly reduces the infarct size and prevents the late development of heart failure. The fact that we can deliver both VAD and VNS transvascularly indicates that the neuro-mechanical unloading therapy is clinically applicable and would improve the long term survival in post-MI patients with coronary intervention.
Abstract 13111: Cardiac Determinants of Right Ventricular Pressure-Flow Response to Exercise in Heart Failure: A Non-Invasive Approach Combining Cardiopulmonary Exercise Testing and Exercise-Echocardiography
Authors: Generati Greta , Bandera Francesco , Pellegrino Marta , Carbone Francesco , Labate Valentina , Alfonzetti Eleonora , Guazzi Marco
Published: April 2024

Background:
The pulmonary pressure (PAP) over cardiac output (CO) exercise response has been proposed as expression of right ventricular (RV) to pulmonary circulation (PC) coupling. The functional implications and cardiac phenotype of PAP/CO slope in heart failure (HF) have never been investigated. Aim: To define the functional and cardiac characteristics related to an unfavorable RV-PC coupling in HFrEF.

Methods:
87 HFrEF patients (mean age 65±11 y, male 70%, mean LVEF 33±9%) underwent a maximal CPET (incremental ramp protocol) combined with exercise-echo. MeanPAP/CO slope is calculated as the slope between the exercise increase in mean PAP and CO.

Results:
Population was divided into 2 groups according to mPAP/CO slope: Group A (n=27) slope <3.5 mmHg/L*min and B (n= 60) slope≥3.5 mmHg/L*min. Patients with abnormal response (Group B) exhibited a worse functional capacity (lower maximal workload and peak oxygen consumption) and ventilatory efficiency (steeper VE/VCO2). Group B had also worse LV remodeling and higher prevalence of dynamic severe mitral regurgitation (MR), associated with elevated pulmonary arterial pressure (systolic PAP) and an impaired rest and peak CO. The best linear regression model identified age, gender, LV EDVi and rest and peak severe MR as main cardiac determinants of mPAP/CO slope. Conclusions: In HFrEF population, an unfavorable pulmonary pressure to cardiac output exercise response, or steeper mPAP/CO slope, is associated with advanced eccentric LV remodeling and dynamic severe MR, overall resembling the most unfavorable functional phenotype.
Abstract 13390: Nitrite Ameliorates Sepsis-Induced Myocardial Dysfunction via Mitochondrial Protection
Authors: Kawaguchi Ryoichi , Hirata Naoyuki , Yoshikawa Yusuke , Chaki Tomohiro , Yamakage Michiaki
Published: April 2024

Introduction:
Mitochondrial impairment plays an important role in septic myocardial dysfunction. Several studies have shown that nitrite can ameliorate myocardial ischemia-reperfusion injury via mitochondrial protection. However, the effect of nitrite on septic myocardium has not been investigated in detail.

Hypothesis:
Nitrite therapy will improve cardiac contractility via mitochondrial function in a murine model of polymicrobial sepsis.

Methods:
Sepsis was induced in Wistar rats by cecal ligation and puncture (CLP). After CLP, we administered saline (NS group, n=8) or saline with nitrite (Nit group, n=8) subcutaneously. No procedure was performed in the control group. First, to determine the most effective dose of nitrite in septic rats, we administered different doses of nitrite (0.1, 0.3, 1, 3, 10 mg/kg) and examined cardiac function in an isolated heart experiment after 8 hours. The most effective dose of nitrite (1 mg/kg) was used in subsequent experiments. For an in vitro study, hearts were removed and cardiac mitochondria were isolated by differential centrifugation. We measured mitochondrial oxygen consumption and determined the respiratory control ratio (RCR). We also assessed protein expression by ELISA and immunoblotting.

Results:
In the isolated heart experiment, left ventricular developed pressure in the Nit group (dose of 1 mg/kg) was significantly higher than that in the NS group (Fig. 1). Although RCR in the NS group was significantly decreased compared to that in control group, RCR in the Nit group was preserved (Fig. 2). Myocardial nitrotyrosine levels were comparable in the NS group and the Nit group. In the Nit group, Akt phosphorylation was preserved and activation of NF-κB was inhibited.

Conclusions:
Nitrite therapy preserved mitochondrial oxidative phosphorylation in the septic myocardium and improved contractility. Nitrite affects the stress response signaling pathway and may be novel treatment for septic myocardial dysfunction.
Abstract 13398: Impact of CREST on Carotid Artery Stenting and CEA Utilization in the Dallas/Fort Worth Area
Authors: McCurdy Robert M
Published: April 2024

Introduction:
Carotid endarterectomy (CEA) is a safe and effective way to reduce the ischemic stroke risk in patients with both symptomatic and asymptomatic carotid stenosis. Following the North American Symptomatic Carotid Endarterectomy Trial and the Asymptomatic Carotid Atherosclerosis Study in the early 1990s, the number of CEAs performed annually surged. An alternative to this procedure is carotid angioplasty and stenting, which was introduced in 1994. In May 2010, the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) compared the overall effectiveness of carotid artery stenting (CAS) versus CEA. CREST is currently considered the definitive study demonstrating the therapeutic equivalence of CEA and CAS. The goal of our study is to compare the incidence of CEA before and after the CREST study in the Dallas-Fort Worth (DFW) area. We hypothesize that the number of CAS procedures has increased since the CREST study. This is the first report to determine the effect of CREST on CAS utilization.

Methods:
Consecutive cases of intervention for carotid artery stenosis were reviewed before and after CREST using data from the DFW Hospital Council from 7/1/07-7/1/13. The primary endpoint of the study was the number of CEA and CAS performed during Pre-CREST (7/1/07-6/30/10) and Post-CREST (7/1/10-7/1/13).

Results:
A total of 12021 interventions on patients with carotid stenosis were identified. Pre-CREST there were 4575 CEA and 1060 CAS performed. Post-CREST there were 5250 CEA and 1136 CAS performed. The adjusted p-value comparing the likelihood of undergoing CAS between the two study periods was 0.305.

Conclusions:
In contrast to previous carotid treatment trials the CREST study has not impacted the utilization CAS in the DFW area. Possible reasons for this include the higher rate of stroke with CAS compared with CEA in CREST, the CMS restrictions on re-imbursement for CAS compared with CEA, limitations in the physician workforce performing CAS, and non-malleable referral patterns that favor the status quo for these two procedures.
Abstract 13406: The Novel Biased Apelin Receptor Agonist MM07 Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension
Authors: Yang Peiran , Crosby Alexi , Buonincontri Guido , Maguire Janet J , Kuc Rhoda E , Sawiak Stephen J , Morrell Nicholas W , Davenport Anthony P
Published: April 2024

Introduction:
Apelin, a ligand of the G protein-coupled apelin receptor, is a vasodilator and a positive cardiac inotrope. Apelin expression is reduced in pulmonary arterial hypertension (PAH) and administration is reported to be beneficial in animal models of PAH. A synthetic biased apelin receptor agonist (MM07) that preferentially activates G protein-dependent signalling could be used to reduce the detrimental cardiac hypertrophy that contributes to heart failure whilst retaining the beneficial actions of apelin. The effect of MM07 has not been tested in an animal model of PAH.

Hypothesis:
We hypothesised that MM07 would attenuate PAH pathogenesis in the rat model of monocrotaline (MCT)-induced PAH.

Methods:
Male Sprague Dawley rats (187±2g) were randomly assigned to receive MCT (60mg/kg body weight) or saline subcutaneously on day 0. From day 1, animals in both groups were given daily intraperitoneal injections of either MM07 (1mg/kg body weight) or saline for 20 days. On day 21, the animals were anaesthetized and right ventricular systolic pressure (RVSP) was measured as a surrogate of pulmonary arterial pressure. Subsequently, hearts were dissected and the weight ratio of right ventricle compared to left ventricle and septum (RV/(LV+S)) was determined as an indicator of right ventricular hypertrophy. Data between groups were compared using one-way ANOVA with Tukey’s post-test.

Results:
Compared to saline control, as expected, the MCT group showed elevated RVSP (19.8±2.0mmHg, n=4 vs 45.8±8.4mmHg, n=5, p≤0.01) and RV/(LV+S) (0.22±0.01 vs 0.41±0.02, p≤0.001). Compared to the MCT group both parameters were significantly reduced in MCT-injected rats treated with MM07 (RVSP 28.8±2.7mmHg p≤0.05; RV/(LV+S) 0.29±0.01, p≤0.001, n=6). MM07 alone (n=4) did not alter right ventricular parameters (RVSP 20.6±1.2mmHg, p≥0.05; RV/(LV+S) 0.23±0.01, p≥0.05) in control animals.

Conclusions:
In this proof principle study we have shown for the first time that a biased apelin receptor agonist, MM07, significantly attenuated the development of PAH in an animal model. The predicted additional benefit of a G protein-biased agonist used chronically for PAH is less receptor desensitisation and cardiac remodelling that are mediated via β-arrestin pathways.
Abstract 13492: Increasing Endothelial Insulin Sensitivity Rescues Vascular Function and Repair in Systemic Insulin Resistance by Restoring Nitric Oxide Bioavailability and Improving Endothelial Cell Migration
Authors: Sengupta Anshuman , Yuldasheva Nadira , Viswambharan Hema , Galloway Stacey , Mughal Romana , Mercer Ben , Ali Noman , Walker Andrew , Aziz Amir , Smith Jessica , Skromna Anna , Makava Natallia , Kearney Mark , Cubbon Richard
Published: April 2024

Introduction:
Insulin resistance is independently associated with vascular disease. Insulin receptor haploinsufficient (IRKO) mice are hypertensive and exhibit endothelial dysfunction and impaired vascular repair despite normal glucoregulation. We hypothesise that endothelial insulin signalling is crucial for vascular function and that selectively restoring endothelial cell (EC) insulin signalling may rescue these vascular derangements.

Methods:
Transgenic mice with Tie-2-driven human IR expression in the endothelium (HIRECO) were bred with IRKO, providing HIRECOxIRKO (HxI) offspring. Metabolic assessment included glucose and insulin tolerance tests, ELISA for plasma insulin concentration and non-invasive blood pressure measurement. Femoral artery injury was performed with angioplasty wires; repair was quantified in Evans Blue-perfused vessels at day 4. Circulating endothelial progenitor cells (EPC) were counted using FACS and cultured from blood. Explanted aortic rings were exposed to phenylephrine (PE) before and after incubation with the NOS inhibitor L-NMMA in organ baths to assess vasomotor function. Boyden chamber assays were used to assess migration of cultured lung ECs to VEGF. Data are expressed as mean(SE) and compared using t-tests;*=p<0.05.

Results:
HxI and IRKO had similar glucocompetence and basal insulin [0.8(0.1)ng/mL vs 0.7(0.2);p=0.8]. Systolic BP was lower in HxI [97(2)mmHg vs 106(3)*]. Vascular repair was improved in HxI [57(4)% vs 46(2)%*]. There was no recovery in EPC numbers by FACS [99(10) vs 105(15);p=0.74], nor in culture [0.4(0.1)/HPF vs 0.4(0.2);p=0.99]. HxI aortic rings showed less PE-induced constriction than IRKO [EC50 8.9(0.8)x10
7
nM vs 6.3(0.9)x10
7
*], with greater NO bioavailability [Post-L-NMMA PE EC50 4.1(0.8)x10
7
nM vs IRKO 6.1(1.8)x10
7
*]. ECs from HxI showed greater net migration to VEGF [6.3(1.3) vs 1.9(1.2)*].

Conclusion:
HIRECOxIRKO show rescue of vascular function despite global insulin resistance. This is not associated with improved glucoregulation or EPC abundance; rather, it may relate to increased NO availability and enhanced EC migration. Our data support endothelial insulin sensitisation as a potential therapeutic target for vascular dysfunction in insulin resistance.
Abstract 13556: Elderly Patients Receiving Durable LVAD Support: Insights and Outcomes
Authors: Shah Palak , Pagani Francis D , Desai Shashank S , Rongione Anthony , Maltais Simon , Haglund Nicholas A , Dunlay Shannon M , Aaronson Keith D , Stulak John M , Davis Mary Beth , Salerno Christoper , Cowger Jennifer A
Published: April 2024

Introduction:
Age ≥ 70 is used to exclude patients from cardiac transplantation. Elderly patients may be offered left ventricular assist device (LVAD) therapy as an alternative. It remains poorly defined how they respond to LVAD support.

Hypothesis:
Elderly patients have LVAD outcomes that are non-inferior to younger patients.

Methods:
Data on 1,149 continuous-flow LVAD recipients from May 2004 to May 2015 was pooled from the Mechanical Circulatory Support Research Network (MCSRN). Groups were assigned based on Age ≥ 70 (n = 163) and < 70 (n = 986).

Results:
Patients age ≥ 70 were more likely to be male (91%), have an ischemic cardiomyopathy (71%), atrial fibrillation (41%), hypertension (66%), diabetes (38%) and prior sternotomy (45%). Older patients also had a lower BMI and higher creatinine, 26.7 ± 0.4 v. 29.9 ± 0.5 and 1.46 ± 0.04 v. 1.35 ± 0.02, p < 0.05. The hazard ratio for mortality was highest in elderly patients in the early post-operative period and stabilized over time with no long-term differences in survival, p = 0.18, Figure 1a. Elderly patients had equivalent rates of device thrombosis and stroke, p = 0.47 and 0.44, Figures 1b-c. Survival free of gastrointestinal bleeding (GIB) at 1-year was 58% in elderly patients compared to 69% in younger patients, Figure 1d, p < 0.01. Multivariate cox regression revealed that age ≥ 70 was not a significant predictor of mortality (HR 0.93, 95% CI 0.69 - 1.25, p = 0.62), but pre-operative creatinine (HR 1.54, 95% CI 1.28 - 1.86, p < 0.01) and bilirubin (HR 1.2, 95% CI 1.03 - 1.4, p = 0.02) were. When age was considered a continuous variable, the HR was 1.2 (95% CI 1.07 - 1.3 per 10y, p < 0.01).

Conclusions:
Elderly patients, age ≥ 70, have equivalent long-term survival after LVAD implantation with similar rates of device thrombosis and stroke. Rates of GIB were higher in the elderly and this finding warrants caution when choosing anti-coagulation protocols in the elderly. Overall age ≥ 70 does not portend a poorer survival after LVAD implant.
Abstract 13639: Time to Extubation May Indicate Quality of Care Following Neonatal Cardiac Surgery
Authors: Blinder Joshua , Thiagarajan Ravi , Williams Kathryn , Nathan Meena , Mayer John , Kulik Thomas
Published: April 2024

Background:
Most neonates survive cardiac surgery, but assessing quality of care is challenging. We aimed to determine: a) minimum time to extubation (TTE) assuming “perfect” care (i.e. no complications and adequate repair) and b) how potentially avoidable events influence TTE.

Methods:
Neonates <30 days old undergoing RACHS-1 classifiable surgery from 1/09-1/13 were reviewed using existing data. Technical performance score (TPS) measures adequacy of repair using imaging and clinical criteria prior to hospital discharge: class 1 (trivial/no residua), class 2(minor residua) and class 3 (major residua/re-intervention). Minimum TTE was determined for RACHS-1 class 2, 3-4 and 5-6. Classes 3 and 4 were collapsed as TTE was similar and 5-6 due to too few class 5 pts. Multiple linear regression was used to identify the variables associated with TTE days.

Results:
601 neonates underwent surgery, 58% were male, median age (IQR) was 5.6 (3.6, 9.4) days, median (IQR) BSA was 0.21 (0.19, 0.22) m
2
; 27% had single ventricle palliation. STS defined-preop factors occurred in 35% (e.g. preop ventilation, genetic anomalies, shock, need for CPR, and sepsis) while postop complications in 72%. 95% of patients with class 3 TPS and 67% of pts with class 1-2 TPS had postoperative complications (p<0.001). Preop (p=0.015) and postop (p<0.001) complications, RACHS-1 class (p<0.001) and class 3 TPS (p<0.001) were associated with increased TTE. Table 1 indicates that with class 3 TPS, preop factors and postop complications, TTE increases across each RACHS-1 class, with the lowest TTE occurring in patients with an class 1 or 2 TPS and no preop factors or postop complications.

Conclusion:
Class 3 (major residua/re-intervention) surgical performance, preop factors and postop complications affect TTE. Recognizing that not all postop complications are avoidable, TTE may be a surrogate measurement of the quality of care.
Abstract 13657: Induced Hypothermia Improves a Novel Array of Metabolic Outcomes After Mouse Hemorrhagic Shock
Authors: Li Jing , Wang Huashan , Lee Chunpei , Costakis James , Zhu Xiangdong , Vanden Hoek Terry L
Published: April 2024

Introduction:
Hemorrhagic shock results in myocardial dysfunction which involves impaired aerobic metabolism leading to energy depletion (ATP and NAD) and lactate production. Prior studies demonstrated that hypothermia (TH) protects heart against HS injury and is associated with decreased metabolic activity and energy demand. We hypothesized that TH protection is result of preservation of energy substrates in tissues via reduced release into blood.

Methods:
Mice underwent arterial bleed (2.25 ml/100 g over 10 min) and were randomized to normothermia (NT, 37 ± 0.5 °C) and hypothermia (TH, 33 ± 0.5 °C) groups. MAP was then maintained at 35 ± 5 mmHg for 90 min. Resuscitation was initiated by reinfusion of shed blood plus L-lactate Ringer’s solution. TH was induced at 30 min of shock and maintained for 2 h. Hearts were collected at Sham, shock 5, 15, 30 and 90 min (S5, S15, S30 and S90 respectively), and the end of resuscitation (R180). Tissue and blood ATP, NAD, the inflammatory markers PBEF and tissue sorbitol were measured. Tissue content of ATP, NAD and the NAD synthesizing enzyme nicotinamide phosphoribosyltransferase (Nampt) were also measured.

Results:
Compared to NT, TH improved survival (33% vs. 83%, p < 0.5). In the NT group, ATP, NAD and Nampt were released into blood during shock with resuscitation, with significant attenuation by TH. In contrast, tissue levels of ATP and NAD were significantly higher than blood and were reduced during shock, with restoration to baseline levels in mice that survived to R180. Tissue sorbitol concentrations were increased during shock, were reduced by hypothermia and returned to baseline levels at R180 in mice that survived.

Conclusions:
Hemorrhagic shock resulted in rapid depletion of ATP and NAD, an effect attenuated by TH, as measured by increased release from muscle tissue into blood. This work identifies a novel array of metabolic markers potentially important to hemorrhagic shock outcome.
Abstract 13658: The Clinical Impact of Diabetes Mellitus on Outcome After Transcatheter Aortic Valve Replacement
Authors: Abramowitz Yigal , Jilaihawi Hasan , Chakravarty Tarun , Kashif Mohammad , Maeno Yoshio , Kazuno Yoshio , Takahashi Nobuyuki , Kawamori Hiroyuki , Cox Justin , Sharma Rahul P , Cheng Wen , Makkar Raj R
Published: April 2024

Background:
DM adversely affects morbidity and mortality for cardiovascular diseases and procedures. DM has been independently associated with increased morbidity and mortality after surgical aortic valve replacement. There is limited data on the impact of DM on the prognosis of patients with severe aortic stenosis that undergo TAVR. In a sub-study of the PARTNER trial, 1-year mortality was significantly higher in patients without DM compared to patients with diabetes, although multivariable analysis was not performed. We aimed to evaluate the clinical characteristics and the early and midterm outcomes after TAVR according to DM status.

Methods & Results:
We examined 802 consecutive patients that underwent TAVR: 548 patients without DM, 177 patients with orally treated DM and 77 with insulin treated DM. Patients with DM were younger (mean age 80±8.4 vs. 82.9±8.8; p<0.01), had higher BMI (29±6.8 vs. 25.8±5; p<0.01), had higher incidence of CAD (70.9% vs. 61.5%; p=0.01) and lower incidence of frailty (28% vs. 37.6%; 0=0.01). Device success, postprocedural perivalvular leak and 30-days mortality and major complications rates were similar between groups (Table). In a Cox multivariable regression analysis including age, BMI, CAD and frailty, DM was associated with decreased overall survival. This was driven by increased overall mortality of the insulin treated DM subgroup (Figure).

Conclusions:
DM does not significantly affect short term mortality or rates of complications in patients who underwent TAVR. Insulin treated DM, but not orally treated DM, is independently associated with death at midterm follow up and should be included into future TAVR dedicated scores.
Abstract 13691: Extracorporeal Cardiopulmonary Resuscitation for Nonshockable Rhythms
Authors: Kagawa Eisuke , Dote Keigo , Kato Masaya , Sasaki Shota , Kihara Yasuki
Published: April 2024

Introduction:
In cardiac arrest patients, patients with shockable rhythms have more favorable outcomes than those with non-shockable rhythms. Recently, alternative cardiopulmonary resuscitation (CPR) using extracorporeal membrane oxygenation (ECMO) has shown the potential to improve the outcomes of patients who are unresponsive to conventional CPR.

Hypothesis:
We assessed the hypothesis that initial shockable rhythms are associated with improved outcomes in extracorporeal CPR (ECPR) using ECMO.

Methods:
Patients who were treated with ECPR were enrolled in this study. Patients were divided into 2 groups according to the whether the initial recorded rhythms were shockable (shockable group) or not (nonshockable group). Baseline characteristics and 90-day survival were assessed. We constructed 90-day survival curves using the Kaplan-Meier method. A P < 0.05 was defined as statistically significant.

Results:
The study patients in the shockable and nonshockable groups were similar in terms of age, witnessed to arrest, bystander initiated CPR, collapse to CPR, collapse to initiation of ECMO. Patients in the shockable group were more likely than those in the nonshockable group to undergo immediate coronary angiography (91% vs. 66%, P < 0.001), subsequent coronary revascularization (55% vs. 37%, P = 0.02), and targeted temperature management (56% vs. 49%, P = 0.37). The rates of return of spontaneous heart-beat (88% vs. 91%, P = 0.58) and weaning from ECMO (48% vs. 40%, P = 0.25) were similar between groups. The 90-day survival curves are shown in the figure. Cox proportional hazard regression suggested that the initial shockable rhythm was not an independent predictors of 90-day survival.

Conclusions:
Unlike in conventional CPR, the initial nonshockable rhythm is not necessarily associated with an adverse outcome. However, none of the patients with an initial asystole rhythm survived up to 90 days.
Abstract 13712: Serum HDL Cholesterol Decreases in Microrna-33b Knock-in Mice for an Intron of Sterol Regulatory Element-binding Factor 1 (Srebf1)
Authors: Horie Takahiro , Nishino Tomohiro , Baba Osamu , Kuwabara Yasuhide , Nakao Tetsushi , Nishiga Masataka , Usami Shunsuke , Izuhara Masayasu , Nakazeki Fumiko , Ide Yuya , Koyama Satoshi , Sowa Naoya , Nakashima Yasuhiro , Hakuno Daihiko , Kimura Takeshi , Ono Koh
Published: April 2024

Background:
MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports, including ours, indicated that miR-33 (miR-33a) located within the intron of sterol regulatory element-binding factor (SREBF) 2 controls cholesterol homeostasis. Primates, but not rodents, express a second miR-33 gene (miR-33b) from an intron of SREBF1. To address miR-33b function in vivo, we developed humanized mice, in which a miR-33b transgene is inserted within a Srebf1 intron.

Methods:
The human miR-33b sequence was introduced into intron 16 of mouse Srebf1 because miR-33b is located in intron 16 of human SREBF1 and there are high homologies in exons 16 and 17 between human and mouse. The expression of serum miRNA was normalized with cel-miR-39 as a spike-in control.

Results:
We successfully established miR-33b knock-in (KI) mice with C57BL/6 background and this miR-33b KI strategy did not alter Srebf1 intron 16 splicing, which was confirmed by RT-PCR and sequencing. An LXR agonist T0901317, which induces Srebf1 expression, enhanced miR-33b expression in primary hepatocytes and the liver of miR-33 KI mice. The protein levels of known miR-33a target genes, such as ABCA1, ABCG1, and SREBP-1, were reduced compared with those in wild-type mice. Peritoneal macrophages from the miR-33b KI mice had a reduced cholesterol efflux capacity via apoA-I and HDL-C. Serum HDL-C levels were reduced by almost 35% in miR-33b KI mice. HPLC elution analysis showed that the decreased HDL-C levels were mainly composed of very large-, large-, medium sized HDL-C, which was compatible with the previous results of miR-33a deficient mice. Next, we measured miR-33b levels in serum of human. The expressions of miR-33b-3p were inversely correlated with serum HDL-C levels (P=0.025, R=0.336).

Conclusions:
miR-33b KI mice for an intron of Srebf1 showed reduced HDL-C level and serum miR-33b-3p levels were inversely correlated with HDL-C levels in human. These results indicate that miR-33b can be a potential target for raising HDL-C and may account for lower HDL-C levels in humans than those in mice. These mice will aid in elucidating the roles of miR-33s and screening of the drugs that can alter miR-33s levels and activities.
Abstract 13754: Scar Burden and Left Ventricular Dyssynchrony on Myocardial Perfusion Imaging as Predictors of Antitachycardia Pacing Responsiveness in the Treatment of Ventricular Tachycardia
Authors: Manola Akrivi , Duvall William L , Giedrimiene Dalia , Ahlberg Alan W , Shekar Chandana , Kluger Jeffrey
Published: April 2024

Background:
Antitachycardia pacing (ATP) is the primary treatment for sustained ventricular tachycardia (VT), resulting in a reduction in ICD shocks. Patients who fail ATP have increased mortality compared to ATP responders. Myocardial scarring by cMR and left ventricular dysynchrony (LVD) by nuclear imaging are associated with a higher risk for VT. We hypothesized that scar and dyssynchrony can predict response to ATP.

Methods:
We identified 119 patients with sustained VT from 2008-2012, who received ICD therapy with preprogrammed ATP delivery and had a single photon emission computed tomography (SPECT) myocardial perfusion study. Semi-quantitative visual scoring with a 17-segment model was used and the summed stress, rest and difference scores were calculated to measure abnormal myocardium, scar and ischemia. LVD was measured in gated studies (n=59), using the established phase analysis (PA) methodology. Phase standard deviation (PSD) and histogram bandwidth (HBW) were compared between groups using chi-square analysis.

Results:
Of 119 patients (105 men, mean age: 75.8±18.2y), 82 (68%) had successful ATP. Normal myocardial perfusion was more commonly found in ATP-responders (10.5% vs. 19.8%, p=0.29). There was no difference in the presence of ischemia between the two groups. Phase SD (13.5±6.2 vs. 9.0±5.4, p=0.009) and HBW (54.5±27.1 vs. 37.9±25.2, p = 0.03) were significantly higher among ATP responders. In both a univariate and multivariate logistic regression analysis phase SD (OR, 95% CI: 1.85, 1.09-3.15, p=0.02) was an independent predictor of ATP success.

Conclusions:
LV dyssynchrony but not scar burden was associated with ATP responsiveness. These results are hypothesis generating for a role of LV dyssynchrony in the prediction of ATP responsiveness.