bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 183: Appropriate Prolongation of Therapeutic Hypothermia Reduces Myocardial Damage After Prolong Cardiac Arrest
Authors: Tsai Min-Shan , Huang Chien-Hua , Tsai Chia-Ying , Cheng Hsaio-Ju , Chang Wei-Tien , Chen Wen-Jone
Published: April 2024

Background:
Therapeutic hypothermia improves myocardial dysfunction and survival in cardiac arrest survivors. However, whether the duration of hypothermia should be prolonged in according to the duration of cardiac arrest to mitigate excess myocardial damage has not been clarified.

Hypothesis:
Appropriate prolongation of therapeutic hypothermia can mitigates excess myocardial damage after prolong cardiac arrest.

Methods:
The animals were equally randomized to NormoT(normothermia), 5H1, 5H2, 7H1, 7H2 and 7H4 groups. VF was induced and untreated for 5 minutes (NormoT, 5H1, 5H2) or 7 minutes (7H1, 7H2, 7H4), followed by 1 minutes of CPR, and then one electric shock of 5 J. Therapeutic hypothermia was initiated at simultaneously at the start of CPR with intravenous administration of 4°C saline and fan. After ROSC, hypothermia was maintained for 1hour (5H1, 7H1), 2 hours (5H2, 7H2) and 4 hours (7H4), respectively.

Results:
The plasma Troponin-I and FABP concentration at 2
nd
hour following ROSC was significantly lower in the 5H2 and 7H4 groups than in the other groups (except the 7H2 group) (Figure). At 4
th
hour after ROSC, The 5H2 and 7H4 groups showed less myocytolysis and apoptosis (Tunel staining) in the myocardium when compared with the other groups. Six out of 12 animals in both the 5H2 and 7H4 groups survived 72 hours after ROSC, whereas only 3 out of 12 animals in the 5H1 and 7H2 groups, and only 1 out of 12 animals in the 7H1 and NormoT groups. At the 72
nd
hour, the 5H2 and 7H4 groups showed less myocardial fibrosis when compared with the groups.

Conclusion:
Appropriate prolongation of therapeutic hypothermia can mitigates excess myocardial damage in prolong cardiac arrest.
Abstract 18304: Assessment of Age-Related Aortic Stiffness With Magnetic Resonance Imaging
Authors: Chirinos Julio , Shiva-Kumar Prithvi , Chandrashekhar Rahul , Desai Sanjal , Witschey Walter , Jain Snigdha , Saif Hassam , Haines Philip , Broderick Preston , Geraci Salvatore , Vakilipour Amin , Rawat Deepa , Ferrari Victor , Akers Scott
Published: April 2024

Background:
Several methods have emerged to assess aortic stiffness with magnetic resonance imaging (MRI). We aimed to compare 3 MRI methods to assess thoracic aortic stiffness as an index of arterial aging.[[Unable to Display Character:   ]]

Methods:
We studied 97 patients referred for a clinically-indicated cardiac MRI at 1.5 T. We assessed aortic stiffness via the following

Methods:
(1) Pulse wave velocity (PWV) measurements from the foot-to-foot transit-time (PWV-TT) of flow between the ascending and distal thoracic descending aorta, measured via in-plane MRI phase-contrast imaging; (2) PWV estimations via the flow-area method (PWV-QA), where local PWV is computed as the ratio between ascending aortic pulsate flow (assessed with through-plane phase-contrast imaging) and change in cross-sectional area (assessed with steady-state free precession cine imaging) during the reflection-free period of the cardiac cycle (early systole); (3) Ascending aortic distensibility, measured as the fractional aortic lumen area change (assessed with steady-state free precession imaging) divided by central pulse pressure (measured with carotid applanation tonometry).[[Unable to Display Character:   ]]

Results:
Semi-automated segmentation of aortic steady-state free precession cine images using active contour methods was feasible in 72.2% of cases, whereas transit-time estimations were feasible in all cases studied. Among cases with complete data,[[Unable to Display Character:   ]]coefficients of correlation (R) with age were as follows: 0.49 for PWV-TT, 0.43 for PWV-QA and 0.62 for aortic distensibility (all P<0.0001). However, after adjustment for distending pressure (mean arterial pressure), partial coefficients of correlation (R) with age were as follows: 0.39 for PWV-TT (P=0.001), 0.61 for PWV-QA (P<0.0001) and 0.56 for aortic distensibility (P<0.0001).

Conclusion:
Local ascending aortic distensibility or PWV assessments using the area-flow method appear to be more robust indicators of age-related large artery stiffening than the transit-time method based on in-plane phase-contrast aortic imaging. However, semi-automated aortic segmentation is not feasible in a significant proportion of cases, underscoring the need to develop more robust MRI methods to quantify aortic distension.
Abstract 18309: Outcomes of Single Versus Kissing Stenting Technique in Lateralized Complex Aortoiliac Bifurcation Lesion
Authors: Suh Yongsung , Ko Young-Guk , Shim Won-Heum , Shin Dong-Ho , Kim Jung-Sun , Kim Byeong-Keuk , Choi Donghoon , Hong Myeong-Ki , Jang Yangsoo
Published: April 2024

Backgrounds:
Kissing stenting technique has been frequently performed even in the cases of unilateral aortoiliac diseases in order to protect contralateral common iliac artery (CIA) with intermediate plaque burden. However, kissing stenting is associated with loss of access from contralateral side for future revascularization. We compared the outcomes of single versus kissing stenting technique in lateralized complex aortoiliac occlusive disease.

Methods:
From Jan. 2006 to Dec. 2012, we retrospectively enrolled 86 consecutive patients (73 males, 67±9 years) treated with a single stenting technique and 33 patients (29 males, 68±8 years) treated with a kissing stenting technique for lateralized complex aortoiliac bifurcation lesions. A lateralized complex aortoiliac bifurcation lesion was defined as a significant unilateral CIA ostial stenosis (>70%) combined with an intermediate (30~50%) stenosis of contralateral CIA.

Results:
Single stenting and kissing stenting was successfully performed in all patients without procedure-related major complications. However, in the single stenting group, bailout stenting in contralateral CIA was required in two (2.3%) cases due to unfavorable plaque shift. Median follow up duration of the single and the kissing stenting group was 24 (3~88) and 14 (3~82) months, respectively. The primary patency of the ipsilateral CIA in the single stenting group was 93.9% comparable with 94.9% in the kissing stent group (OR 0.823, 95% CI 0.157-4.298). Target lesion revascularization occurred in 5 (6%) cases of the single stenting group and in 2 (6.1%) cases of the kissing stenting group. Progression of the contralateral un-stented CIA requiring additional revascularization was observed in only 2 (2.4%) cases of the single stenting group during follow up.

Conclusions:
Single stenting technique in lateralized complex aortoiliac bifurcation lesion was relatively safe and showed comparable outcomes as the kissing stenting technique.
Abstract 18312: In vivo Selection of Ghrelin as a Powerful Cardioprotective Factor After Myocardial Infarction
Authors: Ruozi Giulia , Bortolotti Francesca , Falcione Antonella , Dal Ferro Matteo , Zentilin Lorena , Zacchigna Serena , Giacca Mauro
Published: April 2024

Introduction:
By applying an innovative selection procedure based on in vivo gene transfer of AAV libraries coding for the entire mouse secretome, we discovered that the neurohormone ghrelin exerts a powerful protective effect against skeletal muscle damage. In particular, an AAV9 expressing ghrelin protected muscle fibers from severe hind limb ischemia and promoted muscle regeneration.

Hypothesis:
Based on the established similarities between biology and functional regulation of cardiomyocytes and muscle cells, we wanted to assess the hypothesis that ghrelin was also an effective protective factor in a mouse model of myocardial infarction (MI).

Methods:
A group of CD1 mice (n=20 per group) underwent permanent left descendent coronary artery ligation and were immediately injected into the peri-infarcted area with 1x10^11 viral particles of an AAV9 vector expressing ghrelin or a control AAV9 empty vector. Cardiac function after MI was monitored by echocardiography, morphometric, histological and molecular analysis.

Results:
Cardiac gene delivery of AAV9-Ghrelin after MI determined a marked improvement of cardiac function (LVEF: 51±3% vs. 31±3% for AAV9-Ghrelin vs. AAV9-Control vector; LVFS: 26±1% vs. 15±2%) at day 90 after MI (p<0.001 in both cases), while significantly reducing infarct size (27±2 vs. 51±5%; p<0.001). The marked improvement in cardiac contractility was paralleled by a reduced apoptotic rate at early times after MI (31±5% vs 8±4%, p<0.005) and reduced inflammatory cells infiltration in the peri-infarctual region. Moreover, ghrelin counteracted the induction of markers of cardiac damage (in particular, miR21 and MMP-2) and prevented the deregulated expression of pathological left ventricle remodelling markers, such ad bMHC, BNP and others.

Conclusions:
In conclusion, these results demonstrate the efficacy of ghrelin as a powerful molecule conferring protection from skeletal muscle degeneration and providing benefit upon cardiac damage.
Abstract 18323: Positive Frequency-Dependent Effects of Highly Selective Kv1.5 Blockers (XEN-D0103 & MK-0448) in Right Atrial Trabeculae From Patients in Sinus Rhythm
Authors: Loose Simone , MÜller Judith , Wettwer Erich , El-Haou Said , Jackson Claire , Tang Raymond , Milnes James , Ravens Ursula , Ford John
Published: April 2024

Aim:
Despite promising effects of Kv1.5 blockers in experimental models of atrial fibrillation, limited data is available for man. Therefore we investigated two selective Kv1.5 channel blockers, XEN-D0103 and MK-0448, on atrial myocardium from patients in sinus rhythm (SR).

Method:
Kv1.5 currents were measured with in CHO cells expressing hKv1.5. Sharp microelectrodes were used to record action potentials (AP) at various stimulation frequencies (37°C) in right atrial trabeculae from consenting patients in SR.

Results:
Kv1.5 was activated by voltage-clamp steps from -80 to 0mV (900ms)at 0.2Hz (room temp). XEN-D0103 and MK-0448 inhibited Kv1.5 with IC50 of 25nM and 32nM resp.. Both compounds display >500-fold selectivity over hERG, Kv4.3, Nav1.5, Cav1.2, Kir2.1. The plateau phase of the atrial AP was elevated with XEN-D0103 and MK-0448 in a concentration-dependent manner. At 1Hz this effect was associated with shortening of APD90 and of effective refractory period (ERP) (see Table). At higher stimulation rates the APD90 and ERP shortening effects of XEN-D0103 and MK-0448 (3μM each) diminished and eventually converted to prolongation. With XEN-D0103, significant prolongation of APD90/ERP occurred at 3Hz and higher rates. In control, 10 out of 16 trabeculae followed stimulation at 5Hz, however, in the presence of XEN-D0103 10 out of 10, and with MK-0448 4 out of 6 preparations failed to capture stimulation.

Conclusion:
This is the first report of robust frequency dependence of selective Kv1.5 channel blockers in human atrial myocardium suggesting that these drugs are more effective at high than at low activation rates. Therefore, XEN-D0103 and MK-0448 should possess potential for suppressing episodes of rapid atrial excitation.

Table:
Frequency-dependent effects of the Kv1.5 blockers XEN-D0103 and MK-0448 in human right atrial trabeculae. Differences between pre-drug controls and values after 1 hour of drug superfusion (means ± SEM).
Abstract 18333: Tdag51 Deficiency Protects Against Aortic Vascular Calcification by Attenuating Smooth Muscle Cell Death and Osteoblastic Trans-Differentiation
Authors: Al-Bondokji Imtisal , Ingram Alistair , Krepinsky Joan , Austin Richard
Published: April 2024

Vascular Calcification (VC), a severe complication increasing the risk of cardiovascular (CV) mortality and morbidity in ageing, diabetic and chronic renal failure patients. VC occurs as vascular smooth muscle cells (VSMC) differentiate into osteoblast- like cells or undergoing apoptosis, resulting in arterial stiffness, elevated pulse pressure (PP) and left ventricular hypertrophy. Yet, molecular mechanisms modulating VSMC differentiation and viability are unclear. Our previous findings demonstrate that T-cell death associated gene 51 (TDAG51, pleckstrin homology-like domain family member) deficiency protects against atherosclerotic lesions. This study provides evidence that TDAG51 contributes to VC by regulating osteogenic transcription factor RUNX2 expression and VSMC survival. To study aortic calcification (AC), male C57Bl/6 wild-type (TDAG51+/+) and TDAG51 deficient (TDAG51-/-) mice were injected subcutaneously with Vitamin D3 (VD3, 50,000 IU/kg) or vehicle (0.9% Saline) for 10 days, an established model of VC. AC was assessed by plasma Pi and Ca2+ levels and aortic valve, thoracic and abdominal aorta segments stained with von Kossa. Osteogenic differentiation and TDAG51 levels were assessed by immunoblot, qRT-PCR and immunohistochemistry. TDAG51-/- mice are protected against osteogenic differentiation in aortic artery. Hallmark features of VC including elastinolysis, collagen deposition and RUNX2 expression were significantly reduced in TDAG51-/- mice compared to control. TDAG51-/- mice maintained PP levels. Microarray analysis revealed ENPP1 (inhibitor of VC) was increased 15-fold in cultured TDAG51-/- aortic smc. The results were verified by qRT-PCR and immunoblots showing elevated ENPP1 expression in TDAG51-/- in presence or absence of VD3 compared to control. Also plasma pyrophosphate remained elevated in TDAG51-/- mice in presence of VD3, indicating increased endogenous ENPP1 activity. ENPP1 transient knockdown in TDAG51-/- vsmc lead to VC, elevated RUNX2, alkaline phosphatase activity and apoptosis. Our data demonstrate TDAG51 is a novel and key promoter of VC by regulating RUNX2 and ENPP1 levels in VC. TDAG51 loss confers protection against VC, apoptosis and PP elevation thereby reducing CV injury risk.
Abstract 18337: Comparison of the Distribution and Predictive Value of Framingham Risk Factors and Coronary Artery Calcium for Major Coronary Events Between Asian (South Korean) and Framingham Cohorts
Authors: Chun Eun Ju , Onuma Oyere K , Pencina Karol , Massaro Joseph M , O’Donnell Christopher J , Hoffmann Udo
Published: April 2024

Background:
Coronary artery calcium (CAC) predicts major adverse cardiovascular events (MACE) beyond Framingham risk factors (RF) across multiple ethnic groups within the United States. However, its value in other, non-US populations is unknown.

Methods:
We prospectively obtained data on RF and MACE in asymptomatic adults from the registry-based ESCORT Study (4502 Koreans) and the population-based Framingham Heart Study (FHS, 3141 Whites), who underwent computed tomography to assess CAC. The primary composite endpoint of MACE included CV death, acute myocardial infarction and unstable angina with revascularization. We compared association of traditional RF and CAC with MACE in the two cohorts using multivariate Cox proportional hazard regression analysis, examining CAC both as a categorical variable using established cut-points and as a continuous variable using log 2 [CAC + 1]. We tested for interaction between ethnicity and CAC categories.

Results:
Over median 55 (ESCORT) or 60 (FHS) month follow-up, there were 95 MACE (ESCORT=45, FHS=50). ESCORT participants had greater prevalence of smoking, diabetes and hypertension (p<0.001 all) and greater 10-year Framingham risk score (11.4% vs 8.2%). In contrast, mean CAC prevalence and score were significantly lower in ESCORT (21.9%, 25.3 Agatston units, AU) vs FHS (41.5%, 99.9 AU). In ESCORT, more RF (age, male sex, systolic BP, HDL_C, diabetes) were predictive of MACE vs FHS (age only.) After adjustment for standard RF, doubling of CAC score (1-unit increase in log 2 [CAC + 1]) resulted in a 40% increase in risk of MACE in each cohort. Low CAC (1-100) was a significant predictor of MACE only in ESCORT but not in FHS (interaction p-value = 0.099.)

Conclusion:
There were significant differences in the burden and distribution of RF and CAC between Asian (South Korean) and white US (FHS) cohorts . CAC is a strong predictor of MACE in both cohorts, however lower CAC scores have greater predictive value in the Korean cohort.
Abstract 18375: Cardioprotection by Cardiosphere-Derived Cells Administered 20 Min After Reperfusion in Rats: Reductions of Infarct Size, Apoptosis, and Macrophage Infiltration, Accompanied by Improved Function
Authors: de Couto Geoffrey , Tseliou Eleni , Kanazawa Hideaki , Marbán Linda , Marbán Eduardo
Published: April 2024

Introduction:
Cardiosphere-Derived Cells (CDCs) have been shown to reduce scar size following an established myocardial infarction (CADUCEUS Trial). It is currently unknown whether CDCs confer acute cardioprotection following ischemic injury. Here we test the hypothesis that intracoronary infusion of CDCs following ischemia/reperfusion (I/R) injury reduces cardiomyocyte stress, and protects against cardiac dysfunction and infarct expansion.

Methods & Results:
Wistar-Kyoto rats (aged 8-12 weeks) underwent 45 minutes of ischemia and 20 minutes of reperfusion. Animals were then randomly allocated to either CDC or placebo groups and treated with 5x105 CDCs or PBS, respectively. Two days following I-R injury, CDC-treated rats revealed a reduction in percent infarct mass relative to PBS-treated controls (6.3% vs. 13.6%, p<0.01 n=5/group). These findings were accompanied with reduced programmed cell death within the infarct zone at day 2 (cleaved caspase 3, TUNEL positivity; p<0.05), and improved cardiac function at day 14 (EF: 45% vs. 62% p<0.01). While no difference was observed in peripherally circulating inflammatory cells, a reduction in CD68+ macrophages (Mϕ) was found within the myocardium of CDC-treated animals (23% vs. 18%, p<0.05; n=4/group). In vitro co-culture of CDCs with TNF-α-stimulated Mϕ cells attenuated the expression of IL-6, while concomitantly elevating IL-10, Tgfb1, and Arg1, gene expression profile within Mϕ cells (p<0.05).

Conclusions:
Collectively, these data demonstrate that intracoronary infusion of CDCs following I/R produce acute cardioprotection, and confer prolonged myocardial integrity. Furthermore, CDCs reduce infarct expansion at 2 days and improve cardiac function at 14 days. The cardioprotective effects of CDCs involve a reduction in infiltrating, cytotoxic Mϕ cells.
Abstract 18382: Stromal Cell Derived Factor-1Alpha Promotes C-kit+ Cardiac Stem/Progenitor Cell Quiescence Through Casein Kinase1Alpha and GSK3beta
Authors: Dimova Neviana , Wysoczynski Marcin , Rokosh Gregg
Published: April 2024

A population of c-kit
+
cardiac stem/progenitor cells (CPSC) has been identified in the heart and shown to contribute to myocardial regeneration after infarction. Previously, we have shown the chemokine, stromal cell derived factor 1α (SDF1) is necessary for the myocardial response to infarction where chronic AMD3100 infusion exacerbated MI. Notably, AMD3100 increased CSPC proliferation.

The effect of SDF1 on CSPC proliferation was further investigated in primary cultures of magnetically sorted c-kit
+

CSPCs. SDF1 facilitated CSPC quiescenc by blocking cell cycle progression at the G0 to G1 transition. SDF1 decreased casein kinase 1α (CK1α) consequently attenuating β-catenin phosphorylation, destabilization, and degradation. Increased levels of β-catenin with SDF1 were effective, increasing TCF/LEF reporter activity. SDF downregulation of CK1α was dependent on proteasomal degradation and decreased mRNA expression. CK1α siRNA knockdown verified SDF1-dependent CSPC quiescence requires CK1α downregulation and stablilization of β-catenin. Conversely, β-catenin knockdown increased CSPC proliferation.

SDF1 also increased GSK3β Y216 phosphorylation responsible for increased activity. SDF1 mediated CK1α downregulation and increase in GSK3β activity affected cell cycle by downregulation of Bmi1, increased cyclin D1 phosphorylation, and decreased cyclin D1 levels.

In conclusion, SDF1 exerts a quiescent effect on resident c-kit
+

CSPCs by decreasing CK1α levels, increasing GSK3β activity, stabilizing β-catenin, and affecting regulation of the cell cycle through Bmi1 and cyclin D1. SDF1 dependent quiescence is an important factor in stem and progenitor cell preservation under basal conditions, however, with stress or injury in which SDF1 is elevated, quiescence may limit expansion and contribution to myocardial regeneration.
Abstract 18391: Cardiac Magnetic Resonance Imaging for the Functional Assessment of Normal Bioprosthetic Mitral Valves: A Comparison Against in vitro Flow Transducer and Doppler Echocardiography Measurements
Authors: Maragiannis Dimitrios , Jackson Matthew S , Igo Stephen R , Chin Karen , Autry Kyle , Ghosn Mohamad , Shah Dipan , Little Stephen H
Published: April 2024

Introduction:
Few studies have evaluated the accuracy of Cardiac Magnetic Resonance (CMR) imaging for the functional assessment of bioprosthetic mitral valves (BMV). This study aimed to compare CMR measurements of flow volume and orifice area against in vitro flow transducer and Doppler Echo measurements.

Methods:
A previously described pulsatile, MRI compatible flow loop was used to generate diastolic flow volumes (DFV) across BMVs (sizes 27, 29, and 31 mm) within a “cardiac” imaging chamber. The imaging chamber was placed within a 1.5 Tesla MRI scanner (Siemens) under DFVs of 70, 90 and 110 ml/beat at 70 bpm. Steady state free precession sequences were used to assess BMV morphology and motion. 2D Phase contrast (PC) pulse sequences were used to assess trans-valvular velocity and mean stroke volume. Anatomic orifice area (AOA) and the effective orifice area (PC-EOA) were measured by 2 independent observers. A 1-5MHz ultrasound probe (iE33, Philips) was used to evaluate trans-valvular inflow velocity and Doppler-EOA.

Results:
For bioprosthetic valves, PC-CMR techniques accurately measure forward stroke volume across the range of predefined reference flow volumes (N=10; r=0.99, p<0.001, mean difference 3.5±3.4 ml/beat). PC-CMR peak velocity showed good correlation with Doppler derived values (r=0.91, p<0.001, mean difference -14.5±14.1 cm/s). CMR-derived AOA and PC-EOA correlated well with each other (r=0.87, p<0.05, mean difference 0.04±0.1 cm2). However, CMR-derived AOA and PC-EOA correlated poorly with Doppler derived EOA (r=0.6, p=0.0067, mean difference 0.9±0.17 cm2).

Conclusion:
PC-CMR is a promising modality for determining DFVs and assessing velocity through competent BMVs directly at the valve itself. This is inherently different than the normal clinical MRI practice of inferring valvular flow volumes from indirect measurements of aortic flow and ventricular dimension changes.This method could prove useful for regurgitant flow measurement.
Abstract 18401: The Immunoregulatory Cytokine FGL2 is Associated With Functional Impairment in Patients With Heart Failure
Authors: Chruscinski Andrzej , Greig Douglas , Alba Carolina , Rao Vivek , Levy Gary , Ross Heather
Published: April 2024

Introduction:
Chronic heart failure is a condition that is characterized by immune activation and release of pro-inflammatory cytokines, which are associated with worsening functional class. Fibrinogen-like protein 2 (FGL2) is a novel immunoregulatory protein that is involved in innate and adaptive immune responses. A connection between plasma FGL2 levels and heart failure has not been previously reported.

Objective:
To determine if there is an association between plasma FGL2 levels and functional impairment in heart failure.

Methods:
Seventy-four heart failure patients with NYHA FC I-IV, standard medical treatment, mean age 55 ± 11 years, mean ejection fraction of 29% ± 10%, and 23% females were included. Functional impairment was assessed by determination of peak VO2. Plasma levels of FGL2 and CRP were determined using ELISA in HF patients and healthy controls. We compared peak VO2 according to tertiles of FGL2 using ANOVA (tertile 1<39.7, tertile 2=39.7 to 63.2, and tertile 3>63.2 ng/ml). Correlations were assessed using Pearson’s correlation. We performed a multiple linear regression analysis to investigate the association between peak VO2 and FGL2 adjusting for variables of clinical significance and/or statistical significance. Results are provided as mean ± SD.

Results:
The plasma levels of FGL2 were significantly higher in HF patients compared with controls (58.6 ± 41.2 versus 32.4 ± 14.7 ng/ml, respectively, p<0.001). 28% of the patients had an ischemic cardiomyopathy, 34% had hypertension, and 18% had diabetes. In HF patients, the mean peak VO2 was 16.9 ± 5.0, 14.2 ± 4.9, and 12.7 ± 3.8 ml/kg/min in the 1
st
, 2
nd
and 3
rd
tertile of FGL2, respectively (p= 0.012). FGL2 was negatively correlated with peak VO2 (r= -0.271, p=0.026) and positively correlated with CRP (r= 0.314, p=0.011). In the adjusted regression model, FGL2 was independently associated with peak VO2 (adjusted beta estimated=-0.031, test statistic=5.77, p=0.016).

Conclusion:
In heart failure patients, higher levels of plasma FGL2 were associated with a greater degree of functional impairment as measured by peak VO2. These results suggest that immune activation as measured by FGL2 is associated with the severity of heart failure.
Abstract 18420: Angiotensin II Infusion Provokes Remodeling of the Aortic Valve Tissue in Mice: A Model for Early Non-Calcified Stage of Aortic Sclerosis
Authors: Poggio Paolo , Branchetti Emanuela , Grau Juan B , Bavaria Joseph E , Gorman Robert C , Ferrari Giovanni
Published: April 2024

Objective:
Asymptomatic aortic valve (AV) sclerosis, characterized by thickening of the cusps with accumulation of reactive oxygen species (ROS) and ECM remodeling, is a hallmark of several cardiovascular conditions. Despite its high prevalence, there is a lacking of reliable animal models for early non-calcified stages of aortic sclerosis. Our preliminary data show that infusion of Angiotensin II in mice receiving a Western diet augments atherosclerosis and causes formation of aortic aneurysms (AA). Although AV disease and atherosclerosis are independent dysfunctions, early stages of these conditions share many similarities. We tested, in vivo, whether Ang II infusion would induce changes in aortic valve microstructure.

Methods:
Male wild type mice were fed with Western diet and infused with saline (n=5), or Ang II (1 mg/kg/min) (n=15) for 28 days. Echocardiographic and immunohistological analysis were performed on each animal to test AV thickness, ROS accumulation and ECM remodeling.

Results:
We reported the development of aortic aneurysms in 54% of the experimental group compared to the controls, independent from changes in blood pressure (FIG 1A). Interestingly, microdissection analysis of the aortic valve of all mice receiving Ang II show increased cusp thickness (FIG 1B) when compared to saline infused mice (p<0.01). Histological and protein quantification analysis also revealed increased ROS (nitrotyrosine staining) in mice cusps (FIG 1C) and ECM remodeling without affecting the mechanical proprieties of the valve.

Conclusion:
Here we conclude that our animal model mimics the tissue remodeling of the aortic cusps with increased thickness and accumulation of reactive oxygen species as seen in human pathological samples of aortic sclerosis.

FIG 1. Ang II infusion and AV thickness. (A) Example of Ang II-induced AA, TTE and AA expansion (B) Representative images of H&E of AV cusp ± Ang II with cusp’s thickness (B) Nitrotyrosine staining and quantification.
Abstract 18426: The Role of /SUMO-1 in Cardiac Oxidative Stress and Hypertrophy
Authors: Lee Ahyoung , Jeong Dongtak , Mitsuyama Shinichi , Kho Changwon , Hajjar Roger J
Published: April 2024

Background:
Small ubiquitin-like modifier type 1 (SUMO-1) has been shown to have a critical role in the dysfunction of the cardiac isoform of the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) in the setting of heart failure. In cardiac hypertrophy the role of SUMO-1 has not been defined and our study’s goals were to examine the effects of modulating SUMO-1 on the hypertrophic response in vitro and in vivo and to examine whether oxidative stress (during cardiac hypertrophy) is abrogated by SUMO-1 gene transfer.

Results:
In mice undergoing trans-aortic constriction (TAC), SUMO-1 levels increased slightly during the compensated stage of hypertrophy and then dropped sharply following the transition to heart failure. In isolated cardiomyocytes, SUMO-1 gene transfer inhibited hypertrophic responses in the presence of phenylephrine. AAV9 (adeno-associated vector type 9) gene transfer of SUMO-1 prevented the heart from hypertrophying following TAC and prevented the development of left ventricular dysfunction. Furthermore, SUMO-1 gene transfer blocked the negative effects of H2O2 on SERCA2a activity in cardiac myocytes, while in vivo indices of oxidative stress were decreased by SUMO-1 in cardiac hypertrophy and heart failure.

Conclusion:
The results of this study indicate that post-translational modifications of SERCA2a caused by the toxic environment of the hypertrophied and failing myocardium can be prevented by the expression of SUMO-1.
Abstract 18427: Impact of Medication on Quantification of Plasma MicroRNAs in Patients With Cardiovascular Disease
Authors: Kaudewitz Dorothee , Lee Regent , Willeit Peter , Zampetaki Anna , Morton Allison C , Warner Tim D , Storey Robert F , Channon Keith , Mayr Manuel
Published: April 2024

Background:
MicroRNAs are small non-coding RNAs that are detectable in the blood. Circulating levels of microRNAs have been measured in various epidemiological studies, but the effects of medication are unclear. To address these uncertainties, we assessed how plasma microRNAs change in response to platelet inhibition and heparin administration. We also correlated plasma levels of microRNAs with existing markers of platelet activation.

Methods and Results:
92 microRNAs were assessed in a dose-escalation study with aspirin and prasugrel in healthy volunteers (n=11). Plasma levels of platelet microRNAs, such as miR-223, miR-191 and others decreased on platelet inhibition. Findings were confirmed by individual TaqMan qPCR assays and validated in an independent cohort of patients with symptomatic carotid stenosis (n=33).

In a cohort of patients on dual anti-platelet therapy 30 days post myocardial infarction (n=129), plasma levels of most platelet microRNAs were positively correlated to the VASP assay. Levels of miR-126 were also significantly associated with results from the VerifyNow P2Y12 aggregation assay. No association was observed with optical aggregometry with arachidonic acid or ADP.

When platelet-poor plasma was collected at different time points from patients undergoing PCI (n=20) or diagnostic angiography with (n=7) and without (n=10) heparin administration, heparin was found to have pronounced effects on the assessment of the exogenous C. elegans spike-in control (decrease by >3 cycles), which disappeared six hours after the heparin bolus. Normalisation of individual microRNAs with the average cycle threshold value of all microRNAs provided a suitable alternative to normalization with exogenous C. elegans spike-in control in this setting.

Conclusions:
Our studies provide evidence for a correlation of plasma microRNAs with commonly used methods in platelet testing. They also highlight that microRNA levels are sensitive to medication, in particular antiplatelet and anticoagulation therapy. This has to be taken into account when designing studies to investigate the relation of circulating microRNAs to cardiovascular disease.
Abstract 18452: IKca Current Contributes to Ventricular Repolarization During Chronic, Not Short-term, Heart Failure
Authors: Bonilla Ingrid M , Long Victor P , Wright Patrick , Mowrey Kent , Green Jeanne , Vargas-Pinto Pedro A , Mohler Peter J , Carnes Cynthia A
Published: April 2024

Heart failure (HF) is a chronic disease that develops over months to years. In HF, ventricular repolarization is prolonged. We tested the hypothesis that I
KCa
modulates repolarization only when ventricular repolarization reserve is reduced as occurs in chronic HF, but not short term HF.

Methods:
A tachypacing - induced HF canine model was used, and LV midwall myocytes were isolated from 1 and 4 month HF groups, and compared to normal controls. Action potential duration at 50 (APD50) and 90% (APD90) repolarization was measured before and after the application of 100nM apamin (I
KCa
blocker, n=5-9 per group). Adjacent tissue (n=4 per group) was collected to measure the proteins encoding cardiac I
KCa
(SK2 and SK3).

Results:
One and 4 month HF had similar severity of HF (LVFS: 19.00 ± 1.36 vs. 15.9 ± 2.45, respectively P=NS). APD50 or APD90 in 1 month HF was no different from controls. 4 Mo HF resulted in a significant (P<0.05) APD90 prolongation compared to both control and 1 Mo HF groups, consistent with reduced repolarization reserve. Apamin significantly increased (P<0.05) APD50 and APD90 only in the 4 Mo HF group. Similarly proarrhythmic repolarization instability (beat-to-beat variability) was evident after apamin in the 4 month, but not the 1 month HF group (p<0.05).

SK2 expression was unchanged between groups; SK3 was increased ~ 4 fold in both 1 month and 4 month HF group (P<0.05 vs control).

Conclusions:
Changes in SK protein expression do not fully explain I
KCa
-induced repolarization modulation. Rather, I
KCa
inhibition prolongs repolarization only when repolarization reserve is decreased, as occurs in chronic HF. The safety of targeting I
KCa
in chronic HF needs to be carefully evaluated as I
KCa
inhibition may increase susceptibility to ventricular arrhythmias.
Abstract 18458: Cardiac Magnetic Resonance T1 Mapping Identifies Diffuse Ventricular Fibrosis in Patients With Atrial Fibrillation Undergoing First and Repeat Catheter Ablation
Authors: Yousuf Omair , Beinart Roy , Khurram Irfan M , Liu Songtao , Bluemke David A , DeWire Jane , Zimmerman Stefan , Calkins Hugh , Nazarian Saman
Published: April 2024

Background:
Left ventricular (LV) T1 mapping by cardiac magnetic resonance (CMR) imaging may quantitatively identify diffuse LV fibrosis in patients with atrial fibrillation (AF). An inverse relationship between T1 relaxation times after gadolinium and degree of LV fibrosis is hypothesized. The primary aim of this study was to compare LV T1 times amongst healthy volunteers, patients undergoing first time catheter ablation for AF, and patients undergoing repeat ablation for recurrent AF.

Methods:
CMR imaging at 1.5-Tesla was performed in patients with symptomatic AF before ablation and in healthy volunteers. A modified Look-Locker inversion-recovery (MOLLI) sequence (11 images within 17 heartbeats) was acquired in the vertical long axis plane 12 min after gadolinium chelate (0.20 mmol/kg). T1 measurements were obtained from the inferoposterior LV myocardial wall.

Results:
51 patients (64% males, median age 55 years, inter-quartile range [IQR] 51-65 years) (53% prior to first ablation, 47% prior to repeat ablation) and in 16 healthy volunteers (31% males, median age 26 years, IQR 23-30 years) were evaluated. The median LV T1 relaxation time was lower in patients with AF undergoing first ablation (454ms, IQR 412-474ms) and recurrent ablation (431ms, IQR 412-464ms) compared to healthy volunteers (595ms, IQR 566-606ms, P<0.001) [Figure]. In an ordered logistic regression model, T1 time remained associated (p=0.044) with participant status (control, prior to first ablation, prior to repeat ablation) as the dependent variable, after adjusting for age, gender, BMI, and DM.

Conclusion:
Post-gadolinium ventricular T1 mapping identifies diffuse LV fibrosis in AF patients undergoing first and repeat catheter ablation. Lower T1 times were observed in patients who had prior ablation attempts, suggesting greater LV fibrosis in those with recurrent AF. Further studies will be needed to determine changes in T1 time after restoration of sinus rhythm with catheter ablation.
Abstract 18490: The Use of a Personalized Gene Expression Score in Women Presenting to Primary Care With Symptoms of Suspected Obstructive Coronary Artery Disease Improves Clinical Decision Making Around Non-Invasive Diagnostic Testing: Gender-Specific Results From the IMPACT-PCP (Investigation of a Molecular Personalized Coronary Gene Expression Test on Primary Care Practice Pattern) Trial
Authors: Herman Lee , Froelich James , Kanelos Dino , St Amant Robert , Yau May , Rhees Brian , Monane Mark , McPherson John
Published: April 2024

Introduction:
Better methods are needed to evaluate symptomatic patients with suspected obstructive coronary artery disease (CAD), particularly among women as current methods overestimate disease prevalence. A previously validated blood-based diagnostic test with a negative predictive value of 96% among patients with low gene expression score (GES ≤ 15) uses expression levels of 23 genes to determine the likelihood of a patient having at least one vessel with ≥50% coronary artery stenosis. Use of a GES early in the diagnostic work-up for obstructive CAD may impact quality and efficiency of care.

Hypothesis:
In this gender-based analysis, we hypothesized that GES results would lead to a change in the clinician’s diagnostic assessment of women presenting with symptoms suggestive of obstructive CAD.

Methods:
The IMPACT-PCP Trial (
NCT01594411
) evaluated 251 consecutive patients with no prior history of CAD who presented to nine primary care clinicians for evaluation of chest pain and related symptoms and underwent GES testing. The clinicians outlined their diagnostic strategy before and after GES results were known. The primary outcome was the decision change in the diagnostic strategy pre/post GES testing as measured by regression modeling. In this pre-specified secondary analysis, we focused on the assessment of women in this prospective cohort.

Results:
There were 140 women (56%) eligible for analysis, with mean age 59 years (SD± 13). Mean GES was 11 (SD± 9), with 76% (n=107) of women patient with low GES. Following GES, a change in the evaluation plan was noted in 83 patients (59% observed vs 10% expected change, p<0.001). More patients had a decreased (n=69, 49%) vs increased (n=14, 10%) intensity of testing (p<0.001). In particular, 96% (66/69) of patients with decreased testing had low GES (≤ 15), while 93% (13/14) of patients with increased testing had elevated GES. There has been one MACE event reported (judged as not related to CAD status by the clinician) over 30 days of follow-up.

Conclusions:
The GES showed clinical utility in the evaluation of suspected obstructive CAD by affecting clinical decision making among primary care practitioners and was associated with an overall relevant reduction in diagnostic test utilization among women with low GES.
Abstract 18505: Determination of Non Invasive Cardiac Output by Electrical Cardiometry Technique in Acute Hemorrhagic Shock Model
Authors: Shih Renata L , Garcia-Pereira Fernando , Estrada Amara , Badugu Shrini , Johnson Jacob , Conner Bobbi , Udassi Jai , Pablo Luisito , Bandt Carsten , Shih Andre
Published: April 2024

Introduction:
The non-invasive continuous determination of stroke volume (SV) in hypovolemic shock would be advantageous in pediatric intensive care. Electrical Cardiometry (EC) detects changes in thoracic bio-impedance and electrical conductivity of aortic blood flow allowing subsequent calculation of SV volumetric variables of preload, such as total end-diastolic volume index (TFC). The objective of this study was to evaluate the accuracy of EC when compared to trans esophageal echocardiogram (TEE) in hemorrhagic shock model.

Hypothesis:
SV calculated by EC would be similar to TEE in acute hemorrhagic shock model.

Methods:
Nine 3 month old pigglets (~25 Kg) were anesthetized and instrumented to measure heart rate, mean arterial pressure (MAP), SV. SV was measured using EC and TEE using Modified Simpson techniques. After baseline, celiac artery was transectected and ~ 50% of the blood volume was removed (hemorrhagic state), colloid infusion was administered at 10 mls/kg once MAP reached 35 mmHg (resuscitation state). TEE and EC was used to determine SV and TFC at baseline, hemorrhagic and resuscitation state. After evaluation of atrium and ventricular function the cardiologist also submitted a subjective score (0-50points) for pre-load (TPL) at the same time points. Where 0 is poor pre load and 50 is excessive pre load. SV and TPL vs TFC agreement was determined by Blant Altman.

Results:
Agreement was determined using Bland Altman analysis. 64 comparisons were made. SV correlation (r2= 0.74) was good between the 2 methods with a mean difference (bias) and precision of -0.8 and 0.85, respectively. TFC correlated well with TPL with bias 1.5 and limits of agreement -36 to 33%.

Conclusions:
EC technique is a viable method for measuring cardiac output in patients with acute hemorrhagic shock.
Abstract 18534: TAT-Protein Blockade of PTEN After Cardiac Ischemia is Highly Protective
Authors: Zhu Xiangdong , Shao Zuohui , Wang Huashan , Li Jing , Meliton Angelo , Chen Sy-Jou , Li Changqing , Leff Alan R , Vanden Hoek Terry L
Published: April 2024

Introduction:
Cooling protects against cardiac ischemia/reperfusion (I/R) injury by enhancing PI3K/Akt/NOS signaling. PI3K/Akt signaling depends on binding by its regulatory subunit p85 to the catalytic subunit p110 or the inhibitory phosphatase PTEN. We studied novel TAT-p85 fusion proteins that selectively inhibit these competing p85 interactions. We hypothesized that TAT fused p85 lacking the PTEN binding site (TAT-ΔPTEN p85) would enhance Akt phosphorylation to afford cardioprotection in a heart cell model of I/R. Conversely, TAT fused p85 lacking the p110 binding site (TAT-Δp110p85) would abrogate protection. To further test TAT fusion proteins for the I/R injury of mouse cardiac arrest (CA), we studied whether a TAT-fused PTEN C-terminal 9 amino acid (TAT-PTEN9c) PTEN inhibitor would activate Akt in critical organs and improve survival.

Methods:
A TAT-Δp110 p85 plasmid was constructed with nucleotide deletions at amino acids 478-513. The TAT-ΔPTEN p85 plasmid deleted amino acids 1-313. TAT-PTEN9c was synthesized by Anaspec. Cardiomyocytes were isolated from 1-2-day old C57BL6/J mice and exposed to up to 90 min ischemic arrest with 3 h reperfusion (I/R). Cell viability was evaluated by propidium iodide uptake and p-Akt was measured by Western blot. C57BL6 mice were subjected to an established potassium-induced CA protocol. TAT-PTEN9c (7.8 mg/kg) was given IV after return of spontaneous circulation (ROSC) (n=10) and the 2nd dose for another 5 mice was given at 60 min after ROSC.

Results:
TAT-Δp110 p85 increased cell death from 44.6 +/- 2.7% to 92.5 +/- 3.4%, while TAT-ΔPTEN p85 decreased cell death caused by I/R from 47.8 +/- 1.4% to 11.9 +/- 5.3%. 30 mice were randomized to either saline or TAT-PTEN9c post-ROSC. TAT fusion proteins could be seen within heart and brain tissues within 2 minutes of IV infusion. The survival rate was significantly increased in TAT-PTEN9c treated mice compared with that of saline treated mice at 2 hrs (14/15, 93% vs. 9/15, 60%, P < 0.05) and at 4 hrs (10/15, 67% vs. 6/15, 40%, P < 0.05) after ROSC.

Conclusions:
TAT fusion protein inhibition of PTEN during cardiac I/R and after cardiac arrest appear to be promising strategies for enhancing Akt activation and survival.
Abstract 18586: GPD1-L Inhibits the Cardiac Sodium Channel Nav1.5 by decreasing SIRTUIN1 Activity
Authors: Lewarchik Christopher M , Viswanathan Prakash C , Madhusudanan Mohan , Kerchner Laurie J , Shah Pranav , Nilles Kathleen M , Navqi Asma , Zhu Xiaodong , Agrawal Vineet , Mehdi Haider , Kim Yong-Rae , Irani Kaikobad , London Barry
Published: April 2024

GPD1-L is a cytosolic protein that catalyzes the reduction of dihydroxyacetone phosphate + NADH into glycerol 3-phosphate + NAD+. Mutations in GPD1-L have been linked to Brugada syndrome and sudden infant death syndrome. GPD1-L regulates the cardiac Na+ channel Nav1.5 but the mechanism is not fully understood. We have recently shown that SIRTUIN1 (SIRT1), a NAD+ dependent deacetylase, increases Na+ current (INa) by deacetylating Nav1.5 and increasing cell surface expression. We therefore tested the hypothesis that GPD1-L mutations alter Nav1.5 activity and INa through a SIRT1-dependent mechanism, and that GPD1L’s catalytic function is an essential component of this regulation. Whole cell patch clamp studies in HEK cells demonstrated that a decrease of GPD1-L expression by siRNA knockdown or catalytic function by mutagenesis increases INa, while overexpression of the A280V Brugada syndrome GPD1-L mutation decreased INa. Moreover, catalytic deficient GPD1-L increased and A280V GPD1-L decreased cell surface expression of Nav1.5. Co-immunoprecipitation studies showed that GPD1-L binds to SIRT1 (Figure A). In addition, catalytically inactive GPD1-L increased and A280V GPD1-L decreased SIRT1deacetylase activity (Figure B). In summary, our evidence supports the hypothesis that GPD1-L functions as a negative regulator of the cardiac Na channel Nav1.5 by interacting with SIRT1 and diminishing its activity; the A280V GPD1-L mutation enhances that inhibition, leading to Brugada syndrome.
Abstract 18612: Normal c-Myb Activity is Critical for Both Vessel-Resident and Bone Marrow-Derived Cell Responses to Arterial Remodeling Following Injury
Authors: Shikatani Eric A , Momen Abdul , Li Cedric C , Husain Mansoor
Published: April 2024

Background:
The c-myb proto-oncogene regulates the proliferation of adult vascular smooth muscle cells (VSMCs) and the differentiation of VSMCs from a specific embryonic stem cell-derived hematogenic progenitor cell population. It remains unknown if c-myb has a critical role in the proliferation or potential (trans)differentiation of bone marrow (BM)-derived vs. vessel resident cells in intimal hyperplasia following wire denudation carotid artery injury (CI). We used a mouse harboring a non-lethal point mutation in c-myb resulting in a hypomorphic (h) allele of c-myb with defective c-Myb activity. Previously, we showed that hypomorphic (h/h) mice on a C57BL6 background have decreased neointimal hyperplasia versus wild-type (wt) mice following CI. While BM transplantation (BMT) of h/h BM into wt recipients (h/h→wt) inhibited neointimal hyperplasia compared to injured wt→h/h mice, the role of c-myb in vessel resident cells remained unclear. Also, as many strain-specific differences exist in BM-derived cells, h/h mice were backcrossed 10 generations into a FVB/N background to study injury response.

Methods and results:
Reciprocal BMTs were performed in 5 wk old mice, which were allowed to reconstitute for 7 wks before CI. Injured arteries from wt→wt mice had greater intima formation than h/h→wt mice (19,222±2,622 vs. 8,080±1337 μm2; p<0.0001; N= 7/group), with no differences observed in uninjured BMT controls. However, reconstitution of h/h mice with WT BM had no effect on neointimal proliferation compared to h/h→h/h mice (14,519±486 vs. 13,437±1,175 μm2; p=NS; N= 7/group). To examine cell integration and (trans)differentiation of BM-derived cells, we generated h/h and wt mice with eGFP expression. When subjected to CI, eGFPxh/h mice show decreased neointimal hyperplasia consistent with non-eGFPxh/h mice. Wire injured 10-12wk old FVB/N h/h mice had reduced intima area (30,251±2,306 μm2 vs. 57,059±9,336 μm2; p=0.11) and I/M ratio (0.53±.010 vs 1.19±0.12; p=0.049) versus FVB/N wt mice (N=3/group).

Conclusions:
Effects of defective c-myb activity do not appear to be strain specific. Our data suggest that c-myb has a critical role in regulating neointimal hyperplasia in both vessel resident and BM-derived cell populations.