bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9762: Brain Tumor Necrosis Factor-α Augments Sympathoexcitation and Left Ventricular Remodeling of Ischemia-induced Heart Failure via Dysfunction of Keap1/Nrf2-mediated Antioxidant in Brain Astrocyte
Authors: Kishi Takuya , Hirooka Yoshitaka , Sunagawa Kenji
Published: April 2024

[Backgrounds] We have demonstrated, in ischemic heart failure (HF), angiotensin II increases oxidative stress and induces apoptosis of brain astrocyte, sympathoexcitation and left ventricular (LV) remodeling. In astrocyte, the oxidant-sensing Keap1/NF-E2-related factor 2 (Nrf2) pathway mediates antioxidant function. Recent studies have indicated that brain proinflammatory cytokines also contribute to sympathoexcitation. The aim of the present study was to determine whether brain tumor necrosis factor (TNF)-α augments sympathoexcitation and LV remodeling caused by apoptosis of brain astrocyte in ischemia-induced HF, and if so, whether TNF-α impairs Keap1/Nrf2-mediated antioxidant function of brain astrocyte. [Methods and Results] We treated, for 4 weeks, Sprague-Dawley rats with HF (by coronary ligation) with a continuous intracerebroventricular infusion of angiotensin II type 1 receptor blocker (ARB), ARB+etanercept (ETN; TNF-a receptor blocker), vehicle (Veh) or sham. Urinary norepinephrine excretion (UNE; an index of sympathoexcitation), brain oxidative stress, and glial fibrillary acidic protein expression (GFAP; marker of astrocyte apoptosis) in the brain were significantly higher and LV end-systolic dimension (LVESD) were significantly larger in Veh than in sham (UNE; 2.3±0.3 μg/day vs. 1.1±0.2 μg/day, n=5 for each, p<0.05). Brain Nrf2 expression was significantly lower in Veh than in Sham (0.3±0.1 U vs. 1.0 U, value is expressed relative to that in sham, n=5 for each, p<0.05). In comparison to Veh, ARB lowered UNE (1.8±0.1 μg/day vs. 2.3±0.3 μg/day, n=5 for each, p<0.05), brain oxidative stress, GFAP expression, and LVESD. Furthermore, all of these beneficial effects were augmented in ARB+ETN to the similar levels in sham (UNE; 1.4±0.2 μg/day, n=5). Brain Nrf2 expression was significantly higher in ARB+ETN than in Veh (0.7±0.1 U vs. 0.3±0.1 U, value is expressed relative to that in sham, n=5 for each, p<0.05), although it was not different between in ARB and Veh. [Conclusion] Brain TNF-α augments angiotensin II-induced sympathoexcitation and LV remodeling of ischemia-induced HF via dysfunction of Keap1/Nrf2-mediated antioxidant in brain astrocyte.
Abstract 9857: Cardiac Function in an Extraordinarily Long-lived Rodent, the Naked Mole-rat
Authors: Grimes Kelly M , Chiao Ying Ann , Lindsey Merry L , Buffenstein Rochelle
Published: April 2024

Mechanisms underlying prolonged maintenance of cardiac function in long-lived species may differ from those involved in short-lived species. We assessed cardiac function in young (2-4 year old) male and female naked mole-rats (NMRs; Heterocephalus glaber) and compared these data to those of young (7-8 month old) male and female C57BL/6 mice to establish the use of the NMR for cardiac aging studies. NMRs have a maximum lifespan potential of 32 years (8-fold longer than mice) despite being comparably sized. Furthermore, NMRs maintain good health for at least 75% of their extremely long lifespan, equivalent to >80 year old humans. As such, NMRs provide us a unique opportunity to explore mechanisms that enable prolonged maintenance of cardiac function. Like humans NMRs have a lower than predicted heart rate for their body size. Interestingly, unlike in mice, isofluorane anesthesia had little depressive effect on NMR cardiac function, as heart rates stayed similar between anesthetized and unanesthetized NMRs. Echocardiography revealed significant differences between species (see table). While there were no species differences in average diastolic wall thickness, average systolic wall thickness was greater in mice compared to NMRs. Baseline fractional shortening (FS) was significantly lower in NMRs than in mice. Dobutamine stress echocardiography (3 μg/g body weight i.p.) elicited a greater increase in FS in NMRs than in mice, suggesting that NMRs have greater cardiac reserve. Doppler analysis of blood flow revealed that diastolic (E/A ratio) and systolic (aortic peak velocity) function were significantly different between species. The higher NMR E/A ratio is indicative of more pliable ventricle muscle and less reliance on atrial filling. The interspecies differences observed may indicate mechanisms employed by NMRs to prolong cardiac health into old age. Future studies will probe the existence of such mechanisms and investigate age-related cardiac changes in NMRs.
Abstract 9891: Usefulness of Transthoracic Echocardiography with Strain Analysis in Initial Assessment of Acute Chest Pain in Emergency Department
Authors: Lee Mirae , Chang Sung-A , Sohn Gwan-Hyeop , Park Sung-Ji , Choi Jin-Oh , Lee Sang-Cheol , Oh Jae K , Park Seung Woo
Published: April 2024

Background:
Conventional transthoracic echocardiography (TTE) is currently not recommended as an initial test to diagnose coronary artery disease (CAD) due to its insensitivity. Left ventricular (LV) strain was reported to be more sensitive than regional wall motion abnormality (RWMA). The aim of this study was to evaluate the usefulness of TTE including LV strain analysis in initial assessment of acute chest pain in emergency department (ED).

Methods:
Patients visiting ED with acute chest pain were included. Patients with ST elevation myocardial infarct (MI), hemodynamic instability, known CAD or cardiomyopathy, high probability of non-cardiac chest pain, and poor echocardiographic window were excluded. All the patients were initially assessed by an ED physician for pretest probability of CAD. TTE was performed including LV strain image and global and regional LV longitudinal stain (S
GL
and S
RL
) was analyzed online. S
RL
abnormality was defined as decreased S
RL
in at least 2 adjacent segments. Diagnosis of CAD (based on coronary angiography or CT angiography) and cardiac events (cardiac death, revascularization, MI, or recurrent ED visit due to chest pain) were reviewed at 1 month after ED visit.

Results:
Overall 104 patients were analyzed. CAD was diagnosed in 24% (n=25) and cardiac event was detected in 25% (n=26) of patients.Diagnostic accuracy for CAD was higher when using S
RL
with cut-off value of -13% (sensitivity of 89%, specificity of 77%, NPV = 92%, PPV = 70%) than when using RWMA (sensitivity of 62%, specificity of 88%, NPV = 80%, PPV = 76%). S
RL
showed better diagnostic performance for CAD than S
GL
, and pretest probability (Figure). Predictive value of S
RL
for cardiac events was also highest in those of S
GL
, RWMA, and pretest probability (Figure).

Conclusion:
LV strain echocardiography can diagnose the CAD and predict future events with high accuracy. TTE including strain analysis can be used as an initial diagnostic tool in evaluation of acute chest pain in ED.
Abstract 9929: Novel Mutations Identified by Whole Exome Sequencing in Families With Congenital Heart Disease
Authors: Manickaraj Ashok Kumar , Buske Orion , Brudno Michael , Mital Seema
Published: April 2024

Congenital heart disease (CHD) is a complex disorder with multifactorial etiology and high heritability. We used whole exome sequencing to identify novel variants associated with familial CHD.

Methods:
CHD patients were enrolled in a prospective biobank registry (n=2800). Whole exome sequencing was performed in 12 affected members with LV outflow tract defects and 7 non-affected members from 5 families using Illumina Hi-Seq 2000, and Agilent SureSelect Human All Exon v.2 Kit for sequence capture.

Results:
Sequence alignment to the reference human genome (GRCh37/hg19) identified over 48K single nucleotide variants (SNVs) and indels (average 820 novel coding variants per individual). SNVs were called using SOAP tools and SIFT, Polyphen and Mutation Taster algorithms were used to predict pathogenicity. Affected and unaffected members were compared using the dominant model to identify novel CHD-associated variants. We identified 216 novel SNVs that segregated within affected members (not seen in unaffected members). These included 82 potentially pathogenic variants on 69 genes expressed in the heart and/or vasculature. Of these, 51 were inherited and 31 were de novo. Novel inherited variants in two genes on the Eph (ephrin) family receptor interacting proteins segregated within 4 affected members from 2 families. Eph receptors form the largest subfamily of receptor tyrosine kinases that are components of cell adhesion, migration, and signalling pathways and are involved in organ development. Additional inherited and de novo variants are being further characterized to determine if they are related to cardiac developmental pathways.

Conclusions:
Next-generation sequencing can detect novel variants on susceptibility genes that identify new pathways involved in CHD causation. Replication in additional CHD families and candidate gene resequencing will help validate the association of observed variants with CHD.
Abstract 9959: An Intensive Lifestyle Modification Program Reduces the Number of Component Factors in Subjects With Metabolic Syndrome
Authors: Chan Sammy , Hardwick Emma , McQueen Kay , Naruki-Van Velzen Minetaro , Kam Cindy , Burns Susanne , Bondy Gregory , Walker Minette , Frohlich Jiri , Ignaszewski Andrew
Published: April 2024

The prevalence of obesity is increasing. Among subjects with obesity, those with metabolic syndrome represent a high risk subset for development of cardiovascular disease. We initiated an intensive lifestyle modification program targeting subjects with Metabolic Syndrome. The program is based on an expanded chronic care model with a multidisciplinary team. The program duration is 18 months with initial active 12 months of intervention and 6 months of passive follow up afterwards. In the intervention phase there are prescribed individual counselling and group visits and exercise sessions. The central themes of the program are collaborative goal setting between subjects and care team, stress management, motivation enhancement for behaviour change, self management support and prevention of relapse. We have previously reported the aggregate results. We now report results pertaining to individual changes. Paired data after the one year intervention phase were available for 346 subjects (age 55±10y, female 59%); 37 subjects (age 55±10y, female 51%) who registered but did not participate in the program (≤ 4 sessions) formed the control group. We determined the number of metabolic syndrome components (IDF 2006 worldwide definition) for each subjects at entry into program and at 1 year. At one year, majority of subjects who actively participated in the program (53% active, 38% control, Table) had at least one less Metabolic Syndrome criteria whereas majority of control subjects has same number of Metabolic Syndrome criteria (36% active, 54% control, Table). Chi square analysis showed a significant difference between active and control groups in the proportion of subjects who had less, same or more number of Metabolic Syndrome criteria from entry to one year (Chi-square=6.85, df 2, p=0.038). We conclude that a multidisciplinary intensive lifestyle modification program can significantly reduce the number of Metabolic Syndrome criteria in obese community living subjects.
Abstract 9991: The Product of Blood Hemoglobin and Regional Brain Oxygen Saturation is a Simple and Excellent Predictor for a Short-term Neurological Outcome in Patients with Post Cardiac Arrest Syndrome
Authors: Hayashida Kei , Suzuki Masaru , Shiroshita-Takeshita Akiko , Ito Noritoshi , Nishiyama Kei , Arimoto Hideki , Unoki Takashi , Orita Tomohiko , Murai Akira , Endo Tomoyuki , Watanabe Tomorou , Anan Hideaki , Hatada Tsuyoshi , Mizobuchi Masanori , Yasuda Hideto , Nishi Yutaro , Hori Shingo
Published: April 2024

BACKGROUND:
It has been suggested that brain tissue oxygenation (rSO2) and blood hemoglobin (Hb) at hospital arrival are independently crucial for a prognosis in post cardiac arrest syndrome (PCAS). Although it has been reported that rSO2 correlates with Hb in perioperative patients, this correlation has not been demonstrated during CPR. The product of Hb and rSO2 might represent tissue oxy-Hb level, theoretically. Therefore, it was speculated that the product during CPR predicts neurological outcome in PCAS. AIM: To investigate the relationship between the product of Hb and rSO2 on hospital arrival and good neurological outcome at 30 days in PCAS patients.

METHODS:
The database of the J-POP registry (multicenter observational study) has prospectively enrolled 764 OHCA patients. Of these, 193 PCAS patients admitted to the wards after ROSC were included in this study. Hb and rSO2 were obtained during resuscitation within 3 min after hospital arrival. The neurological outcome was evaluated by CPC at 30 days, and CPC1 and 2 were defined as favorable neurological outcome. RESULTS: Among 193 PCAS patients, 27 presented favorable outcome (14%) and median [IQR] of Hb and rSO2 were 12.0g/dL [10.4-13.8] and 35% [15-55]. The favorable outcome group showed higher Hb (13.8+/-2.5 vs. 11.7+/-2.7, p<0.001) and rSO2 (58.6 +/- 20.5 vs. 30.6+/-21.0, p<0.001) compared to the unfavorable group. The ROC analysis revealed the product of Hb and rSO2 significantly predicted the favorable outcome (AUC, 0.861; optimal cut-off point, 411; sensitivity, 0.917; specificity, 0.709). When divided into 4 groups by quartile of the product of Hb and rSO2 level, the ratio of patients with favorable outcome was 4.2% in the first quartile (Q1, the product<182), 4.2% in Q2 (183-257), 16.6% in Q3 (258-627), and 75.0% in Q4 (>628), respectively (chi-square test: p<0.001).

CONCLUSIONS:
The product of blood Hb and rSO2 level during resuscitation is a simple and excellent predictor for a 30-day neurological outcome in patients with PCAS.
Abstract 18030: Electrophysiological Effects of Efferent and Afferent Right and Left Vagal Nerve Stimulation on Regional Ventricular Myocardial Repolarization
Authors: Yamakawa Kentaro , So Eileen L , Hoang Jonathan , Makkar Nupur , Ajijola Olujimi A , Zhou Wei , Mahajan Aman , Shivkumar Kalyanam , Vaseghi Marmar
Published: April 2024

BACKGROUND:
Vagal nerve stimulation (VNS) is thought to be cardioprotective and decreases ventricular arrhythmias. Regional ventricular electrophysiological differences of left and right and afferent vs. efferent VNS are unclear. The purpose of this study was to evaluate effects of right vs. left and afferent vs. efferent VNS on ventricular repolarization.

METHODS:
In 8 pigs, the heart, bilateral cervical vagus nerves, and stellate ganglia were exposed. A 56 electrode sock was placed on the ventricles and used to record activation recovery interval (ARI), a marker of action potential duration. ARIs were obtained at baseline and during intact left and right VNS. Further, ARIs were analyzed with afferent (proximal end) or efferent (distal end) VNS under 3 conditions: 1) contralateral vagus intact 2) bilateral vagal transection and 3) bilateral vagal nerve transection plus stellectomy. A Millar conductance catheter was used to record hemodynamics.

RESULTS:
Intact and efferent left and right VNS decreased heart rate, blood pressure, and dp/dt, P<0.05 for all parameters. Intact and efferent VNS increased ARI by 49±20 ms (right intact), 45±16 ms (left intact), 46±15 ms (right efferent), and 36±8 ms (left efferent), P<0.05 for all conditions vs. baseline. No significant regional differences in ARI were found with efferent VNS. Transection of the contralateral vagus nerve did not alter the effects of ipsilateral efferent VNS (403±36 ms vs. 396±31 ms, P=NS). Afferent VNS had no significant influence on ventricular ARI, with contralateral vagus nerve intact (from 365±27 ms to 373±28 ms, P=NS) or transected (from 354±25 ms to 346±27 ms, P=NS). Stellectomy reduced the impact of efferent VNS (412±26 ms pre vs. 382±25 ms post stellectomy, P<0.05).

CONCLUSIONS:
Unlike left and right sympathetic innervation, epicardial vagal innervation is uniform without significant regional differences. Effects of efferent VNS are diminished by sympathectomy. Afferent VNS had no impact on ARI.
Abstract 18031: Identification of Novel Determinants Towards Endothelial Differentiation Using a Heterokaryon Approach
Authors: Wong Wing Tak , Sayed Nazish , Cooke John P
Published: April 2024

For directed differentiation of embryonic stem cells (ESCs) to endothelial cells (ECs), we need more information regarding the genes that are activated or suppressed, and their temporal order of activation, during EC specification. Accordingly, we sought to use heterokaryons (the stable fusion product of two different cell types) to identify critical determinants of EC differentiation. The premise is that cytoplasmic factors in the EC that maintain its phenotype will act on the ESC nucleus in the heterokaryon to reprogram it toward EC lineage. Using murine specific probes, or RNAseq, we will identify key genes that are modulated during early EC determination. Accordingly, we employed murine ESC labelled by transduction with retroviruses encoding GFP, and human ECs labelled with CellTracker Red, and induced heterokaryon formation using sendai virus-enveloped protein. Multi-nucleated heterokaryons were generated, which contained punctate murine nuclei and diffusely staining human nuclei. The dual-stained heterokaryons were sorted from the unfused cells and homokaryons by FACS. The extent and timing of differentiation of the murine ESCs within the heterokaryons were examined by probing for EC specific genes (KDR, CD144, vWF and CD31) and ES pluripotency markers (Nanog, Sox2 and Oct4) using murine specific primers. Intriguingly, heterokaryons appear to recapitulate ontogeny, in that early mesodermal genes (eg. KDR) are upregulated in murine ESC at 6h, whereas more EC-specific genes are not upregulated until later (eg. vWF at 24h). Data from RNAseq studies further confirmed the major transcriptional factors and regulators and identified some novel factors for endothelial differentiation. These novel genes will be confirmed using gain- and loss- of function studies of ESCs undergoing differentiation. These studies shall provide new knowledge regarding the hierarchy of genes regulating differentiation to the EC lineage and thus provide insight into vascular development, and ultimately new therapeutic avenues for vascular regeneration.
Abstract 18059: Utility of Infarct Edge Homogenization in Controlling Ventricular Tachycardia in Patients With Underlying Ischemic Heart Disease
Authors: Mulpuru Siva K , Mcleod Christopher J , Monahan Kristi H , Friedman Paul A , Packer Douglas L
Published: April 2024

Introduction:
Point source ablation may be effective in eliminating stable ventricular tachycardia (VT), where actual mapping and ablation are possible. Ablating patients with unstable VT is more complicated and may require aggressive intervention. While small linear lesions have been utilized, the actual utility of longer linear homogenization for eliminating ventricular arrhythmias has not been examined.

Methods:
Therefore, the results of 86 patients undergoing VT ablation at Mayo Clinic were examined. 42 had underlying ischemic heart disease with an EF of 33.5 ± 16.8 had VT with a cycle length of 326 ± 165 ms, and had 2.5± 1.6 episodes of VT in the preceding three months. 32 required shocks for that tachycardia.

Results:
Of these, 21 patients (16 male, 5 female Age 67±18) underwent detailed linear ablation at the scar margin in an effort to homogenize that region. This was drawn into the infarct scar by decreasing the upper voltage boundary to 2.0. In these patients, 18 showed elimination of clinical VT. In addition, 12 showed a decrease in VT from 10 ± 8.7 episodes down to 2.5 ± 1.2 episodes of actual ventricular arrhythmias. The shock requirement decreased from 8.6 ±4.7 to 1.5 ±2.7. These patients had 7 ± 3.5 different VTs at the time of ablation. These data suggest not only a decrease the occurrence of VT, but an improved control of the arrhythmia as manifested by decreased frequency of episodes and a decrease in shock. This suggests a straightforward alternative to point source ablation or to the requirement of detailed LAVA intervention.

Conclusion:
Linear infarct edge homogenization is a straightforward means of ablating ventricular tachycardia’s, even when unstable. This approach may be simpler than seen with LAVA interventions.
Abstract 18096: Novel Role of Caveolin-1 in Endothelial Function by Regulating Extracellular SOD Activity and Cu Transporter ATP7A Function
Authors: Varadarajan Sudhahar , Okur Mustafa N , O’Bryan John P , Minshall Richard D , McKinney Ronald D , Ushio-Fukai Masuko , Fukai Tohru
Published: April 2024

Caveolin (Cav)-enriched lipid raft (C/LR) microdomains play an important role for regulating insulin signaling and endothelial function; however underlying mechanisms is incompletely understood. Vascular extracellular superoxide dismutase (ecSOD), a secretory copper (Cu) enzyme synthesized from vascular smooth muscle cells (VSMCs), preserves nitric oxide (NO)-mediated endothelial function by reducing extracellular superoxide anion (O2•-) levels. We previously demonstrated that Cu transporter ATP7A is required for full activity of ecSOD and that both ecSOD and ATP7A are found in C/LR. However, the functional significance of ATP7A-ecSOD pathway in insulin signaling and C/LR remains unknown. Here we show that in organoid culture of mouse aorta, insulin stimulation increases ecSOD specific activity (47%) and ATP7A expression. In cultured VSMCs, insulin stimulation promotes ATP7A translocation to the C/LR (1.7 fold) where ecSOD is activated by ATP7A through their binding. Furthermore, insulin stimulation promotes ATP7A association with Cav1 as shown by immunofluorescence and co-immunoprecipitation assay. Specific activity of ecSOD, but not Cu/Zn SOD, is significantly decreased (60%) in aorta of Cav1 knockout (KO) mice, indicating that Cav1 or C/LR is required for full ecSOD activity. Of note, ATP7A expression is decreased in aorta from Cav1 KO mice or Cav1-depleted VSMCs with siRNA, which is due to enhanced ATP7A ubiquitination. These results suggest that Cav1 binding to ATP7A at C/LR protects ATP7A from proteosomal degradation, thereby increasing ecSOD activity. Functionally, NO-dependent vasorelaxation induced by acetylcholine, but not NO-independent relaxation induced by sodium nitroprusside, is impaired in mesenteric arteries of Cav1 KO mice vs. wild type mice (P<0.05), which is associated with overproduction of O2•- in the vessels and rescued by gene transfer of ecSOD. In summary, Cav1 plays an essential role for insulin-induced full ecSOD activation by regulating ATP7A translocation and expression. Our studies will provide novel insights into the Cav1-ATP7A-ecSOD axis as a potential therapeutic target for promoting endothelial function against oxidative stress-dependent cardiovascular and metabolic diseases.
Abstract 18105: Genetic Deletion of IL-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Failure
Authors: Cheng Guangming , Girgis Magdy , Davani Arash , Yang Yanjuan , Elias Harold , Chen Lei , Hauptman Jeryl , Vincent Robert J , Dawn Buddhadeb
Published: April 2024

Increasing evidence indicates a role of proinflammatory cytokines in the pathogenesis of myocardial hypertrophy and failure. Chronic interleukin-6 (IL-6) stimulation leads to LV hypertrophy and dysfunction, and deletion of IL-6 reduces LV hypertrophy after angiotensin II infusion. In this study, we tested the hypothesis that genetic deletion of IL-6 would ameliorate pressure overload-induced myocardial hypertrophy and failure. We performed transverse aortic constriction (TAC) in IL-6 knockout (IL6 KO) mice and wild-type (WT) C57BL/6J mice (control) to induce pressure overload. Cardiac structure and function were assessed by serial echocardiography prior to and until 42 days after TAC. Pressure overload induced progressive LV hypertrophy, remodeling, and dysfunction in WT control mice compared with baseline (BSL) (Figure). At 6 wks after TAC, these adverse effects of pressure overload were significantly attenuated in IL6 KO mice, as evidenced by smaller LV mass and greater LV EF compared with controls (Figure). We conclude that genetic deletion of IL-6 attenuates LV remodeling and dysfunction induced by pressure overload. These data suggest a possible therapeutic potential of IL-6 inhibition to ameliorate LV hypertrophy and dysfunction in patients with systemic hypertension.
Abstract 18164: The Effect of Sex Chromosomes on Myocardial Ischemia/Reperfusiong Injury
Authors: Li Jingyuan , McClusky Rebecca , Chen Xuqi , Arnold Arthur P. , Eghbali Mansoureh
Published: April 2024

Introduction:
Sex differences in susceptibility to ischemia/reperfusion(I/R) injury have been demonstrated both in basic and clinical settings. Female hearts show better functional recovery after I/R injury compared with males. Most of these sex differences in I/R settings have been attributed to sex hormones. Here we used two unique mouse models (four core genotypes mice and XY* mice) to investigate the role of sex chromosomes on cardiac I/R injury.

Methods:
We used two unique mouse models of “four core genotypes” (FCG) (XX mice with ovaries or testes and XY mice with ovaries and testes) and XY* (mice with one X chromosome (XO or XY) or with two X chromosomes (XX or XXY). All mice were gonadectomized at day75 and used 30 days after gonadectomy to eliminate the effects of gonadal hormones. Isolated hearts were subjected to 30 min global normothermic ischemia followed by 60 min reperfusion to measure heart function and infarct size. There were 4-7 mice per group. Two way ANOVA was used for statistical analysis. P<0.05 was considered statistically significant. Values are expressed as mean± SE.

Results:
In both FCG and XY* models, the cardiac function was similar among all groups before ischemia. However postischemic function of XX mice was significantly lower than XY, irrespective of gonadal sex (recovery of rate pressure product (RPP): 31.2±5.7% in XX females and 44.7±8.8% in XX males vs. 56.6±5.8% in XY females and 67.2±10.1% in XY males, p<0.01). Infarct size was also markedly larger in XX mice than XY (52.4±4.7% in female-XX and 49.4±7.6% in male-XX vs. 33.2±5.6% in female-XY and 30.5±5.5% in male-XY, p<0.05). In XY* mice, functional recovery of mice with two copies of the X chromosome was significantly lower than mice with a single copy(recovery of RPP=34.0±10.3% XX females and 28.0±12.1% in XXY males vs. 60.3±13.5% in XO females and 60.5±13.8% in XO males, p<0.05). Infarct size was also markedly larger in mice with two X chromosomes (41.4±8.9% in XX females and 46.3±9.5% in XXY males) than mice with one X chromosome (23.7±3.9% in XO females and 26.6±6.9% in XO males, p<0.05).

Conclusion:
Irrespective of gonadal sex, the number of X chromosomes in gonadectomized mice plays a key role in susceptibility to myocardial I/R injury regardless of the presence or absence of the Y chromosome.
Abstract 18211: Reducing the 30-Day Readmission Rate of Heart Failure Patients Through Home Telemonitoring
Authors: Donofrio Kathryn , Braun Lynne T
Published: April 2024

Background:
Heart failure (HF) is the number one reason for hospitalization, and over 25% of hospitalized HF patients are readmitted within 30-days. Many HF readmissions are preventable with improved care coordination, better symptom management, and adherence to medications and diet. In 2012, Centers for Medicare and Medicaid Services (CMS) began to financially penalize hospitals for excess HF readmissions costing facilities significant funds.

OBJECTIVE:
To determine the impact of a nurse-based home telemonitoring program on 30-day all-cause readmission rate of HF patients and the cost effectiveness of this program.

METHODS:
This was a quasi-experiment comparing 40 HF patients at high risk for readmission who were given a nurse-based telemonitoring program, with an 80-patient usual care (UC) group. Telemonitoring (TM) patients received two home visits by a nurse consisting of HF education and use of home telemonitoring equipment. TM patients transmitted vital signs, weight and pulse oximetry daily for 3 months. Data was reviewed by a nurse who contacted the patient if a significant change or trend emerged, as well as contacting the physician for an appropriate course of action. Baseline characteristics and readmission rates were compared between TM and UC groups using independent t-test and two-sample t-test between proportions.

RESULTS:
Baseline characteristics were similar between groups except for a lower ejection fraction in the TM group (UC 46% vs TM 38%; p=0.005). All-cause 30-day readmission rate for the TM group was 12.5% compared with 27.5% for the UC group (p=0.039); HF 30-day readmission rate for the TM group was 2.5% versus 10% for the UC group (p=0.052). Program financial analysis indicates a first year cost of $35,000 for the one-time purchase of 10 monitors with variable cost of roughly $400/patient. Total cost of the program approached $51,000 however the CMS penalty for excess HF readmission is nearly $183,500 for 2013.

CONCLUSION:
This study shows that home telemonitoring can significantly reduce 30-day readmission rates in HF patients. Additionally, the decrease in HF readmissions reduces the CMS penalty by approximately $118,400 showing that home telemonitoring can be a cost effective way to transition patients from hospital to home.
Abstract 18253: Hematocrit Level is Associated With Subclinical Vascular Inflammation in a Middle-Aged Brazilian Population
Authors: Ali Shozab S , Oni Ebenezer , Karim Adil , Maziak Wasim , Blaha Michael J , Martin Seth S , Feldman Theodore , Agatston Arthur A , Blumenthal Roger S , Carvalho Jose A , Conceicao Raquel D , Meneghelo Romeu S , Santos Raul D , Nasir Khurram
Published: April 2024

BACKGROUND:
Hematocrit (Hct) has been inconsistently reported to be a risk marker of cardiovascular morbidity and mortality. Previous studies have shown some association between Hct and cardiovascular risk, however, its association with subclinical disease is not clear. We aimed to investigate whether Hct is related to subclinical vascular inflammation in a middle-aged population.

METHODS:
We evaluated 6,437 healthy Brazilian subjects (43±10 years, 79% males) without clinical coronary heart disease between November 2008 and July 2010. A C-reactive protein (CRP) ≥ 3mg/dl was used as a marker for vascular inflammation and Hct was divided into quartiles. Anemia was defined as a hematocrit <36% in women and <39% in men.

RESULTS:
Mean±SD Hct was 43±4%. Overall, one third (31%) had elevated hs-CRP and 5% were anemic. The prevalence of elevated hs-CRP was significantly lower across Hct quartiles (1
st
=35%, 2
nd
=31%, 3
rd
=29%, 4
th
=29%, p=0.001). In addition, those with anemia were more likely to have a higher CRP level compared to those with normal Hct (36% vs. 31%, p=0.06). As shown in table below, even after controlling for confounding variables higher Hct levels were 29-35% less likely to have elevated hs-CRP levels. In fully adjusted model, presence of anemia was associated with 1.31 fold (95% CI 1.02-1.68) likelihood of elevated CRP.

CONCLUSIONS:
In our study, individuals with anemia and lower Hct were more likely to have higher burden of subclinical inflammation; however, causality cannot be proved due to cross-sectional nature of the study. Further prospective studies are needed to fully understand the interactions of maintaining an optimal Hct.
Abstract 18260: Apolipoprotein A-I Mimetic Peptide, 4F Targets Lipoxygenases via miR193-3p Induction to Rescue Severe Pulmonary Hypertension
Authors: Sharma Salil , Wong Gabe , Umar Soban , Meriwether David , Navab Mohamad , Reddy Srinivasa T , Eghbali Mansoureh
Published: April 2024

Background:
Pulmonary hypertension (PH) causes increase in pulmonary arterial pressure causing right ventricular (RV) hypertrophy and RV failure (RVF). We have shown that apolipoprotein A-I mimetic peptide 4F rescues advanced PH and decreases circulating levels of oxidized fatty acids [hydroxyoctadecadienoic acids (HODEs) and hydroxyeicosatetraenoic acids(HETEs)] in the MCT rat-model of PH. Here, we show that 4F rescues PH in rats and mice by inducing miR-193-3p (miR193), which regulates the enzymes responsible for the production of HETEs and HODEs.

Methods and results:
PH was induced in rats by monocrotaline (MCT, 60mg/kg,s.c. single injection) or in mice by hypoxia (O
2
≤10%) for 21 days. 4F daily therapy or intratracheal instillation of miR193 were started after the establishment of PH in both models (4F: 50mg/kg/day, s.c. from day 21-30 in MCT model and day 14-21 in hypoxia model; miR193 (20nM) at days 16, 21 and 26 in MCT model or at days 14 and 18 in hypoxia model). RV pressure (RVP) was measured by direct catheterization. Rats developed PH 21 days after MCT (RVP=67.12±1 in PH vs. 29.8±1mmHg in the ctrl group) which progressed to RVF by day 30 (RVP=74±1, p<0.05 vs ctrl). 4F therapy rescued PH in both models (MCT model: RVP=46±3 mmHg, p<0.05 vs PH and RVF; Hypoxia model: RVP=22±3.8 mmHg vs 36.91±5.74 in PH and 20.93±2.52 in ctrl normoxic mice). MicroRNA microarray and qPCR showed a ~3 fold downregulation of miR193 in PH that was normalized to ctrl levels by 4F treatment in both models. OE of miR193 (20nM) resulted in ~2.5 fold gain of miR193 in the lung tissue and rescued preexisting PH as the RVPs were significantly lower than PH group in both models (38.2±5.5 mmHg in MCT-rat and ~25.3±0.97mmHg in hypoxic-mice). MiR193 therapy reversed increased arteriolar muscularization in PH. In vivo gain of miR193 suppressed transcription of lipooxygenases ALOX5, ALOX12 and ALOX15. In vitro treatment of human Pulmonary Arterial SMCs (hPASMC) with HETEs and HODEs suppressed miR193 levels in the absence of 4F. Lastly, miR193 OE decreased hPASMCs proliferation in the presence of serum or 12-HETE (100ng/ml) by >2 folds (p<0.05 vs ctrl) whereas miR193 KD increased proliferation.

Conclusion:
4F rescues preexisting severe PH in rats and mice by inducing miR193 and targeting lipoxygenases.
Abstract 18267: The Economic Impact of Healthcare Associated Infections in Cardiac Surgery
Authors: Greco Giampaolo , Shi Wei , Michler Robert , Blackstone Eugene , Kron Irving L , Moquete Ellen , Woo Joseph Y , Moskowitz Alan J , Thourani Vinod , Gillinov A. Marc , Gelijns Annetine C , Argenziano Michael , Alexander John H , Perrault Louis P , Lee Albert , Burks Sandra G , O’Gara Patrick T , Bagiella Emilia , Hohmann Samuel F , Gardner Timothy J
Published: April 2024

Background:
Healthcare-associated infections (HAIs) are the most common non-cardiac complication after cardiac surgery, and are associated with increased morbidity, mortality and resource use. Despite being the focus of quality improvement efforts, there is little information about their economic impact. This prospective cohort study examines the incremental costs associated with HAIs within 65 days of cardiac surgery.

Methods:
Clinical data on major and minor infections (CDC/NHSN definitions) from 9 academic centers were merged with related financial data routinely collected by the University Health Consortium. Incremental length of stay (LOS) and cost attributable to HAIs were estimated using generalized linear models, adjusting for patient demographics, clinical history, baseline labs and surgery type.

Results:
The most common procedures in 4313 cardiac surgery patients were isolated valve (31%), isolated CABG (29%), and CABG/valve (12%), with a mean age 64±13 years. During the index hospitalization, 3% of patients experienced major infections, including pneumonia, sepsis, C. Difficile and surgical site infections. The most common minor infection was UTI, which occurred in 2% of patients. The adjusted average incremental cost due to major infection was nearly $50,000 (table), with the additional ICU stay increasing the index hospitalization cost by $1094/day during the first 2 weeks after surgery. Patients with major index HAIs were nearly twice as likely to be readmitted as those without. Overall, there were 855 readmissions; 19 % due to HAIs, costing on average nearly twice as much as non-HAI related readmissions.

Conclusions:
In an era that emphasizes early discharge and the need to avert preventable readmissions, this study shows that both are heavily influenced by infection rates and that the costs of HAIs in cardiac surgery are substantial. These data provide critical insights about the potential economic impact of infection prevention programs.
Abstract 18277: Bioadhesive and Biodegradable Hyaluronic Acid-Serum Hydrogel Promotes Cardiac Regeneration
Authors: Chan Angel T , Vakrou Styliani , Woldemichael Kirubel , Afzal Junaid , Rittenbach Andrew , Lin Xiaoping , Brown Sophia , Wahl Richard , O’Rourke Brian , Abraham Theodore P , Tsui Benjamin M , Steenbergen Charles J , Elisseeff Jennifer H , Abraham M. R
Published: April 2024

Cellular cardiomyoplasty is limited by low levels of engraftment due to cell egress from injection site and death due to anoikis/necrosis.

We hypothesized that tissue-engineered scaffolds that promote rapid cell adhesion would promote transplanted cell engraftment.

We custom-designed stem cell niches, examined encapsulated stem cell viability, proliferation and
18
FDG uptake. Acute cardiac retention was measured by cut/count after transplantation of
18
FDG labeled rat cardiosphere derived cells (CDCs), in vivo transplanted cell bioenergetics by dual isotope SPECT/CT imaging of Na-Iodide symporter
+
CDCs (after
99m
Tc-pertechnetate administration), and chronic engraftment by bioluminescence imaging (BLI) of luciferase
+
CDCs; LV function was assessed by echocardiography.

Crosslinking of N-hydroxysuccinimide-derivatized hyaluronic acid with autologous serum yielded bioadhesive, biodegradable hydrogels (HA:Ser) that promoted survival and proliferation of mouse embryonic stem cells, human mesenchymal stem cells, and CDCs (viability: 99%, 93%, and 95%; proliferation: 759%, 126%, and 322%, respectively at d7; n=3,
p<
0.05). I
n vitro
18
FDG uptake revealed rapid depression (0.13±0.01%ID/μg DNA) following trypsinization and prompt restoration by encapsulation in hydrogels (0.36±0.04%ID/μg DNA; n=4,
p<
0.05); in vivo
99m
Tc uptake of encapsulated CDCs at 1hr was 2.4fold higher than transplantation of suspended CDCs. Hydrogels boosted acute cell retention following intra-myocardial transplantation (hydrogel: 92±3%; suspended cells: 15±5%), in vivo BLI revealed CDC proliferation (20%increase) in hydrogels and cell loss (99% decrease; n=3,
p
<0.05) in the suspended cell group. Echocardiogram revealed increased in LVEF of 0.69±1.9% in control, 10.33±2.1% in epicardial HA:Ser and 12.9±4.1% in intra-myocardial HA:Ser (n=7,
p
<0.05) at d28 compared to d1 post-MI. Hydrogels also induced 5fold higher angiogenesis than controls.

In conclusion, HA:Ser hydrogels can be injected intramyocardially or applied epicardially as patches to beating hearts. These hydrogels induce rapid stem cell attachment, acute retention, in vivo proliferation and improve cardiac function following myocardial infarction.
Abstract 18278: Anabolic-Androgenic Steroid Use is Associated With Systolic and Diastolic Left Ventricular Dysfunction
Authors: Weiner Rory B , Isaacs Stephanie K , Hutter Adolph M , Kanayama Gen , Hudson James I , Picard Michael H , Pope Harrison G , Baggish Aaron L
Published: April 2024

Background:
Illicit anabolic-androgenic steroid (AAS) abuse is a worldwide public health problem. While several small recent human studies suggest that AAS abuse leads to left ventricular (LV) dysfunction, this association remains incompletely explored. We therefore examined LV function in long-term AAS users (≥2 years of lifetime AAS) and age-matched, non-user comparison men.

Methods:
All participants underwent a structured clinical interview to obtain a detailed medical history, prior use of AAS and other illicit drugs, and exercise exposure followed by standard 2-dimensional transthoracic echocardiography. LV systolic function was assessed by LV ejection fraction (bi-plane method) and LV diastolic function was assessed using early LV relaxation velocity (E’). Groups were compared by linear regression with adjustment for traditional cardiovascular risk factors and lifetime use of other drugs.

Results:
We evaluated 33 weightlifting current AAS users (mean [SD] age 44.0 [5.7] years), 18 weightlifting prior AAS users with > 3 months of abstinence (42.4 [4.2] years), 19 non-AAS-using weightlifters (43.2 [5.2] years), and 18 non-AAS-using non-weightlifting men (42.4 [5.2] years). Current AAS users had significantly lower LV ejection fractions than non-AAS-using weightlifters and non-weightlifting men (Table). Similarly, current AAS users showed impaired diastolic function compared to non-AAS-using weightlifters and non-weightlifting men (Table). Of note,
prior
AAS users showed no significant difference from the two non-AAS comparison groups, and were significantly better than current users on both indices of LV function.

Conclusions:
Current AAS use is associated with statistically and clinically significant impairment of LV function. Although further confirmatory study is required, these findings suggest that AAS-induced LV dysfunction is a serious but potentially reversible pathology that regresses with AAS abstinence.
Abstract 18355: Human S100/calgranulin Accelerates Calcific Valve Disease and Promotes Cardiac Hypertrophy in Chronic Kidney Disease in a RAGE-Dependent Manner
Authors: Yan Ling , Mathew Liby , Chellan Bijoy , Gardner Brandon , Earley Judy , Puri Tipu S , Hofmann Bowman Marion A
Published: April 2024

Purpose:
Serum S100A12 and FGF 23 are biomarker for cardiovascular mortality in patients with chronic kidney disease (CKD). We test the hypothesis that S100/calgranulin accelerates cardiovascular disease in CKD.

Methods:
Human S100/calgranulin is expressed using a bacterial artificial chromosome containing genes and regulatory elements for S1008/9 and S100A12 (60kb) in C57BL6/J mouse (hBAC-S100). CKD was induced in hBAC-S100 mice and in wild type (WT) littermate mice by surgical ligation of the ureters. The heart and aorta were analyzed after 10 weeks of CKD.

Results:
S100A12 protein is expressed in myeloid cells and in serum of hBAC-S100 mice (25ng/ml serum), and increased further in response to CKD. hBAC-S100 mice with CKD developed diastolic dysfunction, ectopic cardiac calcification, hypertrophy and fibrosis measured by in-vivo echocardiography, heart weight, histology and gene expression of ANP, β-MHC, TGF-β, CTGF, and Col 1a1. Serum FGF23 was equally increased in WT/CKD and hBAC-S100/CKD compared to sham operated animals. However, intra cardiac expression of FGF23 mRNA (6 fold) and protein (2 fold) was increased only in hBAC-S100, and co-localizes to osteoblast-like cells nearby calcified fibrous tissue of the aortic and mitral valve. However, cultured cardiac fibroblasts (and VSMC) in response to calcification- inducing medium containing 10mM glycerophosphate and 10nM dexamethasone up regulate ALP, BMP-2, and MGP, but reduced FGF23 mRNA by 90%. This suggests that FGF23-positive osteoblast like cells in the heart of hBAC-S100 might stem from cells other than fibroblasts. hBAC-S100 mice lacking RAGE, the endogenous receptor for S100A12, showed attenuation of ectopic cardiac calcification, LVH, diastolic dysfunction and cardiac FGF23 expression when subjected to CKD, and the cardiac phenotype was similar to WT mice with CKD. Furthermore, aortic valve calcification develops spontaneously in 10-12-month old hBAC/S100 mice, indicating that CKD accelerates this process in hBAC/S100 mice, but is not required.

Conclusion:
Myeloid-derived S100/calgranulin promotes calcific valve disease in a RAGE dependent manner, possibly by selective enrichment of FGF23-positive osteoblast like cells not stemming from cardiac fibroblasts.
Abstract 18373: Arterial Stiffness (Pulse Wave Velocity) is Higher in Single Ventricle Patients With Reconstructed Aortas as Compared to Those Without: A Cardiac Magnetic Resonance Phase Contrast Study
Authors: Fogel Mark A , Li Christine , Keller Marc , Harris Matthew , Whitehead Kevin
Published: April 2024

Background:
Pulse wave velocity (PWV) is a measure of arterial stiffness and has been associated in adults with cardiovascular risk for morbidity and mortality including the association with atherosclerosis. Single ventricle patients who undergo an aortic to pulmonary anastomosis via the Norwood procedure have non-compliant patch material inserted into the vessel, possibly affecting PWV. The purpose of this study is to determine if PWV in these patients differs from single ventricle patients who did not undergo aortic reconstruction.

Methods:
We retrospectively reviewed 40 single ventricle pts from 2012 to the present, matched for age, who underwent cardiac magnetic resonance anatomic imaging and phase contrast evaluations at the neoartic valve (AoV) and the descending aorta at the level of the diaphragm (DAo). 20 had undergone Norwood reconstruction (recon) of the aorta while 20 had not (Nl). PWV was calculated as the distance from the AoV to the DAo, traced on the candycane view of the aorta, divided by the difference in time to reach 50% peak flow on the flow-time diagrams between AoV and DAo. See images below. Significance was a P < 0.05.

Results:
PWV in Recon were significantly higher than in Nl (3.9 +/- 1.7 m/s vs 3.0 +/- 1 m/s, P=0.01). There was no statistically significant difference in ages (4.1 +/- 4.2 vs 5.1 +/- 5.7 years), body surface area (0.61 +/- 0.3 vs 0.7 +/- 0.4 meter2) or cardiac index (4.9 +/- 1.5 vs 5.2 +/- 1.7 liters/minute/meter2) between Recon and Nl respectively.

Conclusion:
PWV in single ventricle patients undergoing the Norwood procedure with resulting recon is higher than single ventricle patients who do not. This implies a higher arterial stiffness and may pose an additional cardiovascular risk as the patient grows; future studies should monitor PWV in these patients for clinical outcome. Other biomaterials may potentially be used in the future to moderate PWV if clinical outcome is adversely affected.
Abstract 18389: Apamin Sensitive Current (IKCa ) Modulates Ventricular (but Not Atrial) Repolarization in Human Heart Failure
Authors: Bonilla Ingrid M , Long Victor P , Wright Patrick , Janssen Paul M , Binkley Philip , Mohler Peter J , Carnes Cynthia A
Published: April 2024

Altered myocyte electrophysiology in heart failure contributes to cardiac arrhythmias. In chronic human heart failure atrial repolarization is shortened while ventricular repolarization is prolonged. The calcium activated potassium (I
KCa
) current has been suggested as a novel atrial-selective pharmacologic target to modulate repolarization and arrhythmogenesis. We hypothesized that chamber-specific differences in I
KCa
current contribute to HF-induced repolarization changes.

Methods:
End-stage failing hearts obtained at the time of transplant were used to isolate left ventricular (LV) midwall and left atrial appendage (LAA) myocytes. Action potential durations (APDs) were recorded at 0.5, 1 and 2 Hz before and after the application of 100nM apamin, an I
KCa
blocker.

Results:
In LAA cells, apamin had no effect on APD50 or APD90 and no cellular arrhythmias (i.e. early afterdepolarizations, EADs) were observed. In the ventricular cells, apamin resulted in significant prolongation of the APD50 (p<0.05) and APD90 (p<0.05) at all rates; there was also a 40% increase in EADs, consistent with proarrhythmic potential.

Conclusions:
In end-stage human HF, I
KCa
modulates LV repolarization and I
KCa
inhibition induces cellular arrhythmias. I
KCa
does not appear to modulate LAA myocyte electrophysiology in end-stage HF; our results do not support I
KCa
as a pharmacologic target for AF associated with heart failure. Potential explanations for the chamber-specific effects we observed include differential HF-induced alterations in APD, channel expression or calcium cycling. Thus, we suggest that inhibition of I
KCa
as a pharmacologic strategy in HF may be detrimental, as it may favor the initiation of triggered ventricular arrhythmias.