bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16795: A Trans-Ventricular Restraint to Reshape and Reduce the Left Ventricle Halts Chronic Adverse Remodeling in a Rodent Model of Ischemic Cardiomyopathy
Authors: Onohara Daisuke , Hernandez-Merlo Roberto , Corporan Daniella , Guyton Robert A , Padala Muralidhar
Published: April 2024

Introduction:
Elevated wall stress (WS) from chamber dilatation and wall thinning drive cause congestive heart failure(CHF) after a myocardial infarction(MI). Reducing WS by reshaping the left ventricle (LV) could decelerate or halt CHF progression, delaying need for ventricular assist devices or transplantation. In this study, we sought to investigate if a transventricular reshaping device (TRD -
Fig 1A,B
) can preserve cardiac function and inhibit adverse remodeling in a rodent model of chronic ischemic cardiomyopathy.

Hypothesis:
Reducing left ventricular WS and sphericity index (SI) can preserve cardiac function and inhibit adverse remodeling in ischemic cardiomyopathy.

Methods:
Rats (n=18) were induced with an MI by left coronary artery ligation. 3 weeks post-MI, TRD was implanted on a beating heart in 9 rats (MI+TRD) (
Fig 2A-C
) and no surgery in others (MI only).TRD was tightened with echo, for 25% reduction in end-diastolic diameter and in WS. All rats were survived for another 3 weeks, with echo at 0, 2, 4, 6 weeks post-MI, and invasive hemodynamics at termination. Tissue was snap frozen for RNA-seq analysis.

Results:
Cardiac dysfunction were confirmed in both groups prior to TRD implantation (%EF in MI+TRD: 77.4±1.2vs. 59.6±2.1; p<0.0001; %EF in MI: 74.7±1.8 vs. 57.0±3.3; p=0.0002 ). TRD implantation and tightening, reduced LVEDD from 8.7±0.2mm to 6.7±0.2mm (23% change, p <0.0001), reduced sphericity index from 0.74±0.04 to 0.54±0.05 (27% reduction, p<0.0001), and WS from 19.9±2.0 to 14.5±1.7 (27% decrease, p=0.0662) (
Fig 3A-B
). At termination, EDV and ESV were significantly reduced in MI+TRD compared to MI alone (EDV: 647.5±39.0μl vs 500.1±14.4μl; p=0.0032; 317.5±16.9 μl vs 218.1±14.7 μl; p=0.0021), indicating halted adverse remodeling with TRD (
Fig 4A-B
). Infarct border zone wall thickness was preserved in MI+TRD, but significantly reduced/thinned in MI (

Fig
5A

), containing infarct expansion. Pre-load adjusted LV dp/dt(max), was significantly higher in MI+TRD compared to MI only (

Fig 5B

).

Conclusions:
Reshaping and reducing the ischemic LV with the transventricular restraint, improves cardiac contractility, preserves ventricular wall thickness and inhibits infarct expansion in this chronic rodent model of cardiomyopathy.
Abstract 16806: Mechanisms of Sex Differences in Exercise Capacity
Authors: Oydanich Marko , Zhang Jie , Vatner Dorothey E , Vatner Stephen F
Published: April 2024

The current policy for NIH grants involves rigor, which not only includes adequate statistics, but also examination of both males and females. The reason for the priority to examine sex differences is because male rodents have been used almost exclusively in pre-clinical studies, which allows for biases to arise. Accordingly, the goal of this investigation was to determine sex differences in exercise capacity in mice and the mechanisms mediating these differences. C57 female wild-type (WT) mice (5 months old) exhibited greater, p<0.05, maximal exercise capacity for running distance (469 ± 24 m; n=7) than age-matched male WT mice (337 ± 14 m; n=8) as well as a 21% improvement in work to exhaustion. The first goal was to look at the effect of physical factors, such as weight and muscle mass, on exercise capacity. When matched for weight females still out-performed males in both running distance (541 ± 21 vs. 456 ± 18m, p<0.05; n=10/group) and demonstrated an 18% improvement in work to exhaustion. Similar outcomes were observed when matching for hind-limb muscle mass. The second goal was to study the effects of estrogen on exercise capacity. After ovariectomy (OVX), female mice no longer demonstrated enhanced exercise compared with males. Conversely, chronic administration of estrogen to male mice improved capacity in running distance and work to exhaustion by 35% after 4 weeks of treatment. Next, we investigated nitric oxide (NO), a downstream target of estrogen, a mechanism which has not been examined previously for mediating sex differences in exercise capacity. Total NO synthase (NOS) activity was higher in female mice compared with male mice (207 ± 14 U/mg vs. 138 ± 4 U/mg, p<0.05), but was no longer different after OVX. Furthermore, males chronically treated with estrogen exhibited a 47% increase in NOS activity. NO blockade with L-NAME eliminated the enhanced exercise capacity observed in both females and males treated with estrogen. Thus, as expected, estrogen is a key mechanism mediating the enhanced exercise capacity in female mice. However, this investigation also demonstrated another, novel key mechanism, increased nitric oxide activity.
Abstract 16811: Concomitant Fetal Heart and Brain Mri in Congenital Heart Disease Mouse Models With Sub-Nyquist Acquisition
Authors: Wu Yijen L , Christodoulou Anthony G , Lo Cecilia
Published: April 2024

Introduction:
Congenital heart disease (CHD) patients suffer higher incidences of neurocognitive impairment. An unanswered clinical question is whether the poor neurodevelopmental outcome in CHD is driven by hemodynamic perturbations arising from the structural heart defects or primarily driven by patient intrinsic/genetic factors. In order to simultaneously evaluate genetic factors, structural heart defects and brain development in CHD mutant mouse models, we have developed a fast MRI methodology for simultaneously imaging fetal mouse hearts and brains.

Methods:
The specific challenge for fetal mouse MRI is to overcome motion artifacts arising from multiple fetuses and maternal abdominal and respiratory motion. We performed 4D MRI
in utero
using a hybrid compressed sensing and low-rank imaging method. The two key features of this fetal MRI approach are (1) the ability to express incoherent fetal and maternal motion with reduced degrees of freedom; and (2) a sub-Nyquist sparse sampling scheme to accelerate acquisition and increase temporal resolution. This allows assessments of anatomical structures and the hemodynamic function and its relationship with the developing fetal brain.

Results:
4D MRI was performed
in utero
of a pregnant female mouse on embryonic day E16.5. Outlier respiratory states were automatically identified and removed before image reconstruction. After reconstruction, the image closest to the median image was automatically extracted for analysis. The boundary of each individual yolk sac is indicated by yellow dotted lines, with embryos numbered from E1 to E8. This isotropic 3D data set can be re-oriented according to each embryo’s body axis. FigA shows the sagittal orientation of embryo #2 to highlight brain structures. FigB shows the coronal view of the embryo #7 to highlight stomach, liver, and both kidneys. Placenta can be clearly seen as well (Fig.C).

Conclusion:
Our fetal MRI can be used to evaluate congenital heart and brain defects.
Abstract 16816: 1-Year Outcomes From the Low Risk Transcatheter Aortic Valve Replacement (LRT) Study
Authors: Waksman Ron , Rogers Toby , Asch Federico , Gordon Paul , Goncalves John , Levitt Robert , Parikh Puja , Butzel David , Hanna Nicholas , Torguson Rebecca , Garcia-Garcia Hector , Corso Paul
Published: April 2024

Introduction:
Transcatheter aortic valve replacement (TAVR) is now standard of care for patients with symptomatic severe aortic stenosis who are extreme, high or intermediate risk for surgical aortic valve replacement (SAVR). However, safety and effectiveness of TAVR in low risk patients remains untested.

Hypothesis:
To test the safety and effectiveness of TAVR in low risk patients.

Methods:
The Low Risk TAVR (LRT) trial was the first FDA-approved Investigational Device Exemption (IDE) trial to enroll in the United States (US). This investigator-led trial was a prospective, multicenter, unblinded, non-randomized, feasibility study at 11 centers in the US. Subjects determined to be low risk by the enrolling center multidisciplinary Heart Team and by an independent Case Review Committee underwent TAVR using a commercially available balloon-expandable or self-expandable TAVR device. All imaging studies were analyzed by an independent Core Lab and endpoints were adjudicated by an independent Clinical Events Committee using Valve Academic Research Consortium (VARC 2) definitions.

Results:
A total of 200 subjects with symptomatic severe aortic stenosis were enrolled. Interim short-term results have been reported previously. Mean age was 74.6±5.7 years, and mean Society of Thoracic Surgeons (STS) score was 1.9±0.5%. There was no mortality or disabling stroke at 30 days. The permanent pacemaker implantation rate was 4.8% at 30 days. No patients had ≥moderate paravalvular leak at 30 days. We will present 6-month and 1-year clinical outcomes and echocardiographic findings at the American Heart Association 2018 Scientific Sessions.

Conclusions:
LRT was the first FDA-approved prospective multicenter clinical trial of TAVR in low risk patients in the US. Interim short-term results demonstrated excellent safety and effectiveness at 30-days. We will present the 6-month and 1-year clinical outcomes and echocardiographic findings at the American Heart Association 2018 Scientific Sessions.
Abstract 16817: Single Anti Platelet Agent vs. Dual Anti Platelet Agents in Patients Undergoing Percutaneous Coronary Intervention: A Tertiary Care Center Experience
Authors: Arora Shilpkumar , Khan Safi U , Dave Mihir , Sattur Sudhakar
Published: April 2024

Introduction:
Data on P2Y12 inhibitor (single agent) use in percutaneous coronary intervention (PCI) is sparse.

Hypothesis:
Long term outcomes in patients undergoing PCI with only P2Y12 inhibitors vs. dual antiplatelet therapy (DAPT).

Methods:
We used PCI registry of Guthrie clinic system from the year 2001 to 2012. We identified patients discharged only on P2Y12 inhibitors (Plavix, Ticagrelor, Prasugrel) due to aspirin allergy. We created propensity score using patient demographics (age, gender), risk factors (hypertension, diabetes, hyperlipidemia etc.), medications detail (statin, B blocker etc.) and catheterization detail (vessel involved, type of stent and culprit vessel etc.) for patients discharged only on P2Y12 inhibitors vs DAPT. Propensity score match (1:100) analysis was conducted using greedy’s method for adjusting confounders. The primary outcome was MACE(myocardial infarction(MI), stroke, death, coronary artery occlusion) up to 8 years and secondary outcomes were death and recurrent myocardial infarction(MI) up to 8 years. Sensitivity analysis was done using Cox-proportional hazard regression.

Results:
7742 patients with successful intervention were identified during the study period. Out of which, 43(0.65%) had aspirin allergy and received only P2Y12 inhibitor. Hyperlipidemia (78.8%), hypertension (72.8%), obesity (48.7%) and diabetes (31.6%) were most common risk factors. >90% patients were on optimum medical treatment. 59% of patients received drug-eluting stent/s and 17.5% patients underwent multivessel PCI. Right coronary artery(37.6%) and left anterior descending artery(35.8%) were commonest culprit vessels. Median follow up period was 1828 days (~ 5 years). After adjusting with propensity score match, primary outcome (HR:1.73, 95% CI: 1.17-2.67, p-0.005) and secondary outcomes (MI: HR: 2.46, 95% CI:1.28-4.51, p-0.005), (death: HR:1.85, 95% CI:1.09-2.23, p-0.023) were higher in patients discharged only on P2Y12 inhibitors. Sensitivity analysis showed similar results.

Conclusions:
Only P2Y12 inhibitor was inferior to DAPT in patients undergoing PCI. Future clinical trials will be needed to reinforce our findings.
Abstract 16845: Functional Regulation of Native Coronary Kv1 Channels by Pyridine Nucleotides
Authors: Dwenger Marc M , Wohl Zachary B , Bhatnagar Aruni , Nystoriak Matthew A
Published: April 2024

Introduction:
Recent studies indicate that vasodilation and enhanced blood flow to the heart following increases in myocardial O
2
demand are mediated by voltage-gated Kv1 channels in coronary smooth muscle cells (CVSM). Periods of high O
2
demand alter the intracellular pyridine nucleotide (PN) redox (e.g., elevated NADH:NAD
+
), which, in heterologous systems, differentially modulates the gating properties of Kv1 channels by binding to intracellular Kvβ subunits.

Hypothesis:
Elevated levels of reduced PNs increase Kv1 channel activity in CVSM via the Kvβ complex.

Methods:
We performed patch clamp electrophysiology on CVSM freshly isolated from the left anterior descending coronary arteries (1
st
and 2
nd
order) of wild type and Kvβ2-null (Kvβ2
-/-
) mice. In the conventional whole cell configuration, we measured outward K
+
current density and the voltage-dependence of activation and inactivation (V
0.5, act,
V
0.5,inact
, respectively) in the absence and presence of extracellular lactate or pyruvate (10 mM), which alter intracellular PN levels. In inside-out membrane patches, we measured the open probability (nPo) of single K
+
-permeable channels that are sensitive to the Kv1 channel inhibitors 4-aminopyridine (4-AP; 1 mM) and psora-4 (500 nM), in the absence and presence of NADH (1 mM).

Results:
Treatment of wild type CVSM with lactate to elevate [NADH]
I
significantly increased whole cell Kv current density and shifted V
0.5, act
to more negative membrane potentials (n=4, P<0.05). This response was effectively reversed upon increasing [NAD
+
]
i
by treatment with pyruvate. Recordings performed in the inside-out configuration revealed K
+
currents that were sensitive to inhibition by psora-4 and 4-AP and had a unitary conductance of 70.2 ± 2.4 pS. Perfusion with a bath solution that contained 1 mM NADH lead to a significant increase (~2-fold) in the nPo of 4-AP-sensitive channels (n=25-30 cells, P<0.05). However, this effect was largely attenuated in membrane patches from Kvβ2
-/-
CVSM.

Conclusions:
Native Kv1 channels in CVSM are functionally regulated by the intracellular NADH:NAD
+
ratio via their auxiliary Kvβ subunit complex.
Abstract 16855: Endothelial Dysfunction Through MAPK Signaling in Cardiac Hypertrophy and Failure
Authors: Papangeli Irinna , Park Saejeong , Clapham Katharine R , Adachi Takaomi , Hu Jianqiang , Chun Hyung J
Published: April 2024

Heart failure (HF) is the most frequent cause of hospitalization in people over 65 years. Endothelial dysfunction correlates with worse outcomes in HF, and although it has been observed in both preserved (HFpEF) and reduced (HFrEF) ejection fraction patient populations, it has been intensely studied predominantly in the latter group, due to challenges in diagnosis, limited human tissue samples and lack of animal models of HFpEF.

Here, we present a novel mouse model of endothelial dysfunction caused by loss of the Mitogen Activated Protein Kinase (MAPK) Erk5, which develops cardiac hypertrophy and a HFpEF phenotype. Tamoxifen inducible endothelial specific deletion of Erk5 (Erk5
ECKO
) is lethal within 25 days. Serial echocardiograms showed that Erk5
ECKO
mice develop dramatic left ventricle hypertrophy, characterized by increased heart/body weight ratios, increased cardiomyocyte size and extended fibrosis. The ejection fraction was remarkably preserved, while blood pressure was unaffected. Erk5
ECKO
mice presented with increased expression of HF biomarkers and fibrotic genes, as well as increased proliferation of cardiac endothelial cells. Knockdown of ERK5 in endothelial cells resulted in dysregulation of multiple homeostatic genes, including decreased phosphorylation and subsequent degradation of YAP, a pro-proliferative Hippo pathway effector. Increased protein levels of Yap were identified both in Erk5
ECKO
mouse hearts and in a subset of human HF left ventricle samples. Finally, using tamoxifen inducible, endothelial specific knockout mice of both Erk5 and Yap we show that endothelial loss of Yap improves left ventricle hypertrophy and normalizes HF biomarker expression in Erk5
ECKO
mice.

Our findings provide critical mechanistic knowledge on the role of endothelial dysfunction in HFpEF, downstream of impaired MAPK signaling, while setting forth new biomarkers and therapeutic candidates for diseases involving endothelial dysfunction.
Abstract 16859: Prevalence of Mechanical Complications and Associated Mortality in Patients With ST-Segment Elevation Myocardial Infarction (STEMI) Treated With Thrombolysis (TT) Compared to Primary-PCI (P-PCI): A Nationwide Study Using National Inpatient Sample (NIS)
Authors: Shrivastav Rishi , Pati Prateeth , Perimbeti Stuthi , Tamis-holland Jacqueline
Published: April 2024

Introduction:
Papillary muscle rupture (PMR), ventricular septal rupture (VSR) and cardiac free wall rupture (FWR), are dreaded complications of STEMI and are associated with increased morbidity and mortality. In multiple previous small to intermediate sized studies, TT as compared to P-PCI was associated with an increase in these mechanical complications. However, large scale observational studies are lacking.

Methods:
Adult admissions with a primary diagnosis of STEMI between 1999 and 2014 were extracted from the NIS using the ICD-9 code 410.x, except 410.7x (NSTEMI). ICD-9-CM procedure codes 36.01 to 36.07, 36.09, 00.66 and 99.10 were used to stratify the extracted data into patients who underwent P-PCI (Time-to procedure function was used to filter PCI performed within first 24 hours of presentation) and those treated with TT. The incidence of PMR (ICD-9 Code 429.6) and VSR (ICD-9 Code 429.71), VSR (ICD-9 Code 429.71) and FWR (ICD-9 Code 429.79) within 30 days of hospitalization were compared between these two groups. We performed multivariate analysis using Cox Proportional Hazard Regression to control for confounders and determine the hazard of all three complications in patients who had undergone P-PCI vs TT, and the relative mortality of these complications by reperfusion strategy.

Results:
Of the weighted 2,534,019 admissions for STEMIs, 1,335,711 (52.71%) underwent P-PCI whereas 125,009 (4.93%) were treated with TT. Among these, 748 (0.02%) developed PMR, 3122 (0.12%) developed VSR, and 4850 (0.19%) developed FWR. The adjusted hazard for a complication according to reperfusion modality, and the mortality by treatment are depicted below in Table 1.

Conclusions:
As compared with P-PCI, patient who were treated with TT had a higher risk of mechanical complications, including PMR, VSR and FWR, and a higher mortality associated with each of these complications.
Abstract 16870: Dickkopf-Related Protein 1, a Wingless-Regulatory Molecule, Identifies Maladaptive Left Ventricular Remodeling in Aortic Stenosis
Authors: Leungsuwan Kanjit , Shahid Abdullah , Tirrell Julie , Rammohan Harish R , Scribani Melissa , Jenkins Paul , Hyink Deborah , Klotman Paul , Hutter Randolph , Katz Daniel
Published: April 2024

Introduction:
Aortic stenosis (AS) may lead to left ventricular (LV) dysfunction with inadequate LV remodeling or may result in excessive LV hypertrophy. We hypothesized that circulatory Dickkopf-related protein 1 (DKK-1) as experimental regulator of myocardial repair could identify patients with a maladaptive LV response to AS. Maladaptive response may be defined by inadequate remodeling resulting in LV dysfunction or excessive hypertrophy.

Methods:
There were 53 adult patients demonstrated to have AS by echocardiogram or cardiac MRI completed between Jan 1st, 2016 and Dec 31st, 2017. Study patients were compared with 239 patients without AS. Patient and imaging data were collected. DKK-1 level was measured using Human DKK-1 quantikine ELISA kit. Values of DKK-1 were skewed, so non-parametric tests were used to determine the associations between DKK-1 and LV and AS parameters in echocardiography and cardiac MRI. Spearman’s Rank Order Correlation, Wilcoxon Rank Sum Test, and analysis of variance (ANOVA) were used to assess associations.

Results:
Among the 53 patients with AS, 29 (54.7%) were mild, 6 (11.3%) were moderate, and 18 (34%) were severe as per standard imaging criteria. In the study group, 32 (60.4%) were male, 21 (39.6%) were female, with a mean age of 72.2 years (range 47-90). In patients with AS, the median DKK-1 was 427.57 pg/mL, mean LV ejection fraction was 48.07%, mean LV mass was 147.5 g, and mean LV mass index was 69.1 g/m
2
. There was a statistically significant inverse correlation between DKK-1 and LV ejection fraction (correlation coefficient -0.28, p<0.05) only in patients with AS. There was an inverse trend of a correlation between DKK-1 and LV mass and mass index (correlation coefficient -0.3 and -0.23, respectively). There was no association between the severity of AS (aortic valve area, maximum velocity, or mean pressure gradient) and the level of DKK-1.

Conclusions:
In conclusion, DKK-1 might be a predictor of a maladaptive response in AS patients. In patients with elevated DKK-1 level, there is an associated diminished myocardial repair and LV dysfunction. In patients with low DKK-1 level there is a trend towards the development of accentuated LV hypertrophy. Our findings support further prospective clinical investigations of DKK-1 and other Wnt-regulatory molecules in patients with AS in the future.
Abstract 16872: Characterization of Pediatric Patients With Syndromic Anomalies Listed for Heart Transplant: Waitlist and Post-Heart Transplant Outcomes
Authors: Wilkens Sarah J , Priest James R , Kaufman Beth , Barkoff Lynsey M , Rosenthal David N , Hollander Seth A
Published: April 2024

Introduction:
We sought to describe the prevalence, characteristics and outcomes of pediatric patients with a syndromic anomaly (SA) who were accepted for listing for heart transplant (HT).

Methods:
This is a single center retrospective review of pediatric patients listed for heart transplantation after January 1, 2009 at our center. Patients were analyzed based on the presence of any underlying syndrome, which was heterogeneous and included chromosomal anomalies, skeletal myopathies, connective tissue disorders, mitochondrial disease and other systemic disorders. Waitlist and post-heart transplant outcomes were compared to those without SA.

Results:
A total of 243 patients were listed for (HT), of whom 21 patients (9%) had an associated SA (Table 1). Of those, 15 (71%) survived to transplant, 3 (14%) died while on the waitlist, 1 (5%) improved and was removed from the waitlist, and 2 (10%) patients are currently listed. Waitlist survival was not different between those with/without an associated syndrome (p = 1.0). Among those who survived to HT, there was no difference in median listing days (70 vs. 90 days, p=0.8), survival to hospital discharge [14 (93%) vs 150 (95%), p = 0.6], post-HT intubation days (2 vs 2 days, p = 0.6), or post-HT hospital length of stay (18 vs 18 days, p = 0.8). Overall survival was equivalent between groups post-HT, with a median follow-up time of 3.3 years (p = 0.7).

Conclusions:
A syndromic anomaly was present in 9% of pediatric patients waitlisted for heart transplant, but was not associated with an increased waitlist mortality, post-heart transplant hospital morbidity or long-term survival. If children with a syndromic anomaly were decided to be suitable candidates for heart transplant listing, they appear to have similar waitlist times and post-heart transplant survival as non-syndromic children.
Abstract 16883: Ablation of Slc26a6 Protects the Heart From Ischemia/Reperfusion Injuries
Authors: Thai Phung , Ren Lu , Ledford Hannah A , Sirish Padmini , Ngo Richard Q , Timofeyev Valeriy , Li Yang , Zhou Xiaotian , Jian Zhong , Chen-Izu Ye , Chiamvimonvat Nipavan , Zhang Xiao-dong
Published: April 2024

Introduction:
Ischemic heart disease is the most common type of heart disease, accompanied by a major decline in local myocardial pH, resulting in abnormal cardiac function. However, the mechanisms of pH regulation and the homeostasis of H
+
neutralizing buffers, such as HCO
3
-
and Cl
-
in cardiomyocytes remain incompletely understood. We have recently identified a key molecule, Slc26a6, in mouse and human hearts, which mediates electrogenic Cl
-
/HCO
3
-
exchange and plays key roles in the regulation of cardiac pH
i
, excitability and contractility. Because Slc26a6 is an acid loader in cardiomyocytes, we hypothesize that ablation of Slc26a6 may protect the heart from ischemia/reperfusion (I/R) injury.

Methods:
We generated I/R model using wild type (WT) and Slc26a6 knockout (

Slc26a6
-/-

) mice. Multidisciplinary
in vivo
and
in vitro
approaches were used, including echocardiography, electrophysiology, hemodynamic monitoring, electrocardiography (ECG), and histochemistry. In addition, cellular experiments were performed to test the Cl
-
/HCO
3
-
exchange currents, Ca
2+
transient, sarcoplasmic reticulum Ca
2+
load, and sarcomere shortening.

Results:
ECG recordings were performed during the I/R surgery to monitor the I/R injury. 24 hours after reperfusion, troponin I level was lower in

Slc26a6
-/-

I/R mice relative to WT I/R mice, suggesting less cardiac injuries in

Slc26a6
-/-

mice. This was validated 4 weeks after I/R.

Slc26a6
-/-

I/R mice showed better systolic and diastolic function than WT I/R mice, assessed by echocardiography and hemodynamics monitoring. Moreover, histological analyses revealed lower collagen formation and smaller infarct size in

Slc26a6
-/-

compared to WT mice.
In vitro
analyses of sarcomere shortening, Ca
2+
transients, and sarcoplasmic reticulum Ca
2+
load of the cardiomyocytes from infarct zone corroborated the
in vivo
findings, showing more preserved cellular function in

Slc26a6
-/-

compared to WT mice.

Conclusion:
Ablation of
Slc26a6
is cardioprotective in a murine model of I/R, which may result from the elevated pH
i
and the reduction of acidification during I/R. Our findings suggest critical roles of Slc26a6 in I/R injury. Slc26a6 may represent a novel therapeutic target for cardioprotection in ischemia through pH regulation.
Abstract 16889: A Novel Single-Chain Enzyme Complex With Triple-Catalytic Activities Controlling the Metabolism of Arachidonic Acid Toward the Anti-Bleeding Thromboxane A
2
Biosynthesis
Authors: Li Yan , Li Qunying , Ling Qinglan , Chen Chang , Ruan Ke-He
Published: April 2024

Background:
One of the most common bleeding emergencies in interventional cardiology and surgical procedures is caused by the use of nonsteroidal anti-inflammatory drugs (NSAIDs), which strongly inhibit enzymatic biosynthesis of thromboxane A
2
(TXA
2
).

Objectives:
We want to investigate an effective approach to overcome such NSAIDs-mediated severe bleeding emergencies.

Methods:
In this study, according to structure-based enzymatic design, we have created a novel single-chain hybrid enzyme complex (SCHEC), COX-1-10-aa-TXAS, by linking the C-terminus of cyclooxygenase-1 (COX-1) to the N-terminus of the TXA
2
synthase (TXAS) through a 10-residue amino acid linker.

Results and conclusions:
The recombinant COX-1-10aa-TXAS could not only maintain full activities of the parent enzymes, but also more effectively pass COX-1-derived intermediate prostaglandin (PG) H
2
to the active site of TXAS. This results in rapidly redirecting the cellular metabolism of arachidonic acid (AA) toward TXA
2
; meanwhile, reducing PGH
2
being passed to other prostanoid synthases, such as prostaglandin-I and prostaglandin-E synthases (PGIS, PGES), which compete with TXAS to isomerize PGH
2
into bleeding mediators, prostacyclin (PGI
2
) and prostaglandin E
2
(PGE
2
). With these multiple effects, the novel COX-1-10aa-TXAS demonstrated a strong anti-bleeding ability to treat normal bleeding, aspirin-resulted TXA
2
-deficient bleeding, as well as PGI
2
-mediated bleeding
in vitro
and
in vivo
. Therefore, this novel SCHEC has a great potential to be developed into a biological anti-bleeding reagent to deal with acute and severe bleeding situations.
Abstract 16895: Lrp1, an Endocytic Vesicle Trafficking Protein, is Associated With Congenital Heart Diseases - Through a "non-Autonomous" Action
Authors: Lin Jiuann-Huey I , Jha Anupma , McCleary Jaccob , Feinstein Timothy , Lo Cecilia
Published: April 2024

Backgrounds:
Congenital heart diseases affect nearly 1% of neonates per year in the United States and are the leading cause of neonatal death. Despite a strong indication of genetic contribution to congenital heart diseases, the developmental processes and genetic components are poorly understood. From the large-scale forward genetic screen using inbred mice chemically mutagenized with ethyl-nitrosourea (ENU), a novel finding of endocytic trafficking gene mutations, including Lrp1, were recovered as causing congenital heart disease phenotypes. Endocytosis plays roles in modulating cell signaling by regulating the trafficking of the internalized endocytic vesicles to different endosomal compartments, some destined for fusion with lysosomes and degradation while others are recycled to the surface by recycling endosomes. Mutations in these genes causes a spectrum of congenital heart disease comprising of outflow tract abnormalities and alignment defects.

Methods and Results:
The LRP1 [line 1554(MGI 96828)] mutant mouse line recovered from a forward genetic screen results from a missense (C4232R) mutation in the region encoding the epidermal growth factor (EGF) repeat domain of LRP1. The mutants exhibit a spectrum of septation and outflow tract defects including endocardial cushion defects, double outlet of right ventricle with normal related great arteries as well as DORV with D-malposition of great arteries (Taussig-Bing anomalies). Mouse embryonic fibroblasts (MEF) from LRP1
m/m
mutants demonstrated decreased cell-surface expression and increased retention in the endosomes. Migration assay of MEF demonstrated decreased migration of LRP1
m/m
compared with control with normal Golgi orientation. The decreasing migration LRP1
m/m
also observed in the endocardial cushion tissue from E9.5-10.5 embryos. Different cell lineages crucial to cardiac development with tissue-specific genetic manipulations were used to define the roles of the LRP1 pathway in these three fields of cells during outflow tract development and septation. Cardiac neural crest cell (Wnt1-Cre) knockout of LRP1 recapitulate LRP1
m/m
cardiac phenotypes as well as Nkx2.5/Tie2-cre double knockout of LRP1. RNA expression profile suggests Notch pathway and integrin pathway are associated with LRP1 during cardiac development.

Conclusions:
We provide the first evidence of endocytic vesicle trafficking pathway associated with the development of congenital heart diseases with malalignment/septation and outflow tract defects
Abstract 16896: Risk Factors and Outcomes of Acute Limb Ischemia in Infants With Congenital Heart Disease
Authors: Swendiman Robert A , Quatromoni Jon G , Quarshie Willian , Griffis Heather , Damrauer Scott M , Naim Maryam Y
Published: April 2024

Introduction:
Acute limb ischemia (ALI) has been observed in infants with congenital heart disease (CHD). However, little is known about the demographics, clinical characteristics, and outcomes amongst these patients.

Hypothesis:
Infants with CHD with ALI are at significantly increased risk for adverse outcomes.

Methods:
We performed a retrospective cohort study of infants (<1 year of age) admissions for CHD using the 2003-2012 KID databases from the Healthcare Cost and Utilization Project. ALI and associated risk factors, treatments, and outcomes were defined using ICD-9 codes. Survey weights were utilized to estimate U.S. population-based estimates. Chi-square tests were used to compare groups. P < 0.05 indicated statistical significance.

Results:
We identified 368,398 observations of infants with CHD in the combined KID data, yielding an estimated average of 134,866 infant admissions per year for CHD in the U.S. Of these, 0.18% were diagnosed with ALI. The development of ALI was significantly associated with male sex (p = 0.0003) and single-ventricle CHD (p < 0.0001). Arterial line placement (RR 1.9 [1.67, 2.23]), cardiac catheterization (RR 14.7 [12.88, 16.87]), extracorporeal membrane oxygenation (RR 6.0 [5.24, 6.86]), and cardiac surgery (RR 8.5 [7.46, 9.73]) each increased the risk of ALI (p < 0.0001 for all). At least one of these procedures occurred in 73% of admissions with ALI as compared to 25% in admissions without ALI (p < 0.0001). Therapy for ALI (other than anticoagulation) varied, with a total of 174 admissions (18.1%) undergoing thrombolysis (4.0%), endovascular (4.0%), or an open surgical (9.3%) procedure. Admissions with ALI had a longer median length of stay (25.8 vs. 6.1 days, (p < 0.0001), and greater mortality (11.1% vs. 3.4%, p < 0.0001).

Conclusions:
Risk of ALI in infant visits with CHD significantly increases with procedural interventions and is associated with a prolonged hospital course and a 3.2-fold risk of mortality.
Abstract 16905: Relationship Between Cardiac Magnetic Resonance Derived Regional Systolic Strain and Myocardial Tissue Characteristics in Children With Duchenne Muscular Dystrophy
Authors: Gnanappa Ganesh Kumar , Conway Jennifer , Pagano Joseph , Cunningham Chentel , Punithakumar Kumaradevan , Noga Michelle , Tham Edythe
Published: April 2024

Background:
Duchenne Muscular dystrophy (DMD) is an X linked disorder associated with deterioration in cardiac function. Identification of subclinical abnormalities using cardiac magnetic resonance (CMR) may provide an earlier marker to trigger therapy. We aimed to correlate regional left ventricle (LV) myocardial native T1 and extracellular volume (ECV) with regional strain in children with DMD.

Methods:
Fourteen boys with DMD (median 14 years, range 9-18) underwent CMR to measure segmental native T1 and ECV at the basal and mid-ventricular level. Native T1 and ECV were measured from the MOLLI sequence using cvi42 software. Circumferential (CS) and longitudinal (LS) strain values were assessed in the corresponding cine images using an in-house developed, semi-automated deformation technique. Associations of T1 and ECV with strain were examined using Pearson correlation coefficient.

Results:
The majority had LVEF >50% (79%). Median global basal CS (-20.5%) and mid-cavity CS (-18.9%) were normal, but the global LS was reduced (-15.2%). Regions with LGE and CS abnormalities were similar (inferior and inferolateral) but differed from regions with increased T1 & ECV (inferoseptal, anteroseptal) and LS abnormalities (inferoseptal and anteroseptal). CS and LS abnormalities were noted more in mid-cavity than basal segments. There were strong correlations between lower CS and higher native T1 in four segments, and correlations with higher ECV in all segments (Table 1). LS showed no correlations with either native T1 or ECV.

Conclusions:
Native T1 and ECV abnormalities were noted in segments not associated with positive LGE. The relationship between native T1, ECV and CS suggest that regional diffuse fibrosis is associated with subclinical systolic dysfunction and is detectable on CMR prior to global abnormalities. These findings may provide evidence for early medical therapy aimed at delaying cardiac dysfunction in DMD.
Abstract 16909: Anonymity Brings Out the Truth in Social Behavior in Heart Transplantation
Authors: Dimbil Sadia , Velleca Angela , Kittleson Michelle , Patel Jignesh , Levine Ryan , Passano Elizabeth , Kobashigawa Jon A
Published: April 2024

Introduction:
In our heart transplant program, drugs (marijuana) alcohol and smoking are not allowed. Recidivism for drugs, alcohol, and smoking in heart transplant patients is not firmly established as many reported surveys are not anonymous. Anonymity allows patients to freely admit indulgence in these frowned upon activities. We performed an anonymous survey for patients greater than 1 year after transplant to assess their actual use of drugs, alcohol, and smoking.

Methods:
Between December 2016 and May 2018, we administered surveys to 104 patients more than 1-year post transplant. Patients directly entered their answers into a handheld computer so as to maintain anonymity. The survey included questions on use of drugs (marijuana), alcohol and smoking; and whether they quit within 6 months prior to transplant. Other questions included activity/quantity of use after transplant.

Results:
Of 24/104 patients who smoked prior to surgery, only 2 returned to smoking and 1 started smoking after heart transplant. For alcohol use, 48/104 had a history of drinking alcohol prior to transplant. 59/104 patients stated that they drank alcohol after transplant, averaging only 0-3 drinks per week, and usually beginning after 6 months post-transplant. In terms of marijuana, 8/104 smoked prior to heart transplant. Post-transplant, 12 patients used marijuana, mostly due to pain relief and recreation. Most patients (83.3%) began to use marijuana beginning 12 months post-transplant.

Conclusion:
In an anonymous survey of heart transplant patients more than 1-year post-transplant, initiation and recidivism to smoking and marijuana is low with renewal of social drinking post-transplant being common. This survey reveals real-life social activities of heart transplant patients.
Abstract 16910: Complex Heart Failure Phenotypes Differ in Response to Medical Therapy and Exercise Training
Authors: Merrill Miranda , Roeder Christophe , Butler Maggie , Doran Bethany , Stevens Laura , Goerg Carsten , Kao David
Published: April 2024

Background:
Patients with heart failure (HF) are heterogeneous with multiple complex phenotypes across the ejection fraction (EF) spectrum. Phenotype-specific response to various treatments have not been well-described.

Hypothesis:
Clinical response to specific interventions will vary according to HF phenotype.

Methods:
Using latent class analysis, six cluster-based HF phenotypes across the EF spectrum were previously identified using patient data from 2130 patients enrolled in HF-ACTION (LVEF ≤ 35%) and 1767 patients enrolled from the Americas in TOPCAT (LVEF ≥ 45%) based on age, sex, race, CAD, BMI, hyperlipidemia, hypertension, diabetes mellitus, atrial fibrillation, COPD, anemia, and renal function, but not LVEF. Response to aerobic exercise training vs. usual care (HF-ACTION) and spironolactone vs. placebo (TOPCAT) were quantified by phenotype. The primary outcome was a composite of cardiovascular mortality (CVM) or HF hospitalization (HFH). Secondary outcomes included CVM, HFH, and all-cause mortality (ACM). Change in peak VO2 at 3 and 12 months were also analyzed in HF-ACTION.

Results:
Of the established phenotypes, the phenotype composed of elderly non-ischemic patients as well as the non-white/non-ischemic/hypertensive phenotype experienced improvement in combined CVM and HFH, ACM and exercise capacity (28% vs 38%, HR: 0.66 [0.46-0.94], 8% vs 16% HR: 0.49 [0.27-0.91], change in VO2: 1.06±3.01 vs 0.04±3.14, p<0.05). Elderly patients with non-ischemic HFrEF enrolled in HF-ACTION randomized to therapeutic exercise program demonstrated significantly improved exercise capacity compared to usual care (change in VO2: 1.45±2.82 vs -0.09±2.49 and 1.25±3.18 vs 0.66±3.64 respectively, p<0.05). Elderly non-ischemic patients treated with spironolactone in TOPCAT had a lower risk of the primary outcome CVM and HFH (20% vs 27%, HR: 0.67 [0.48-0.95]), driven mostly by reduced CVM (9% vs 17%, HR: 0.52 [0.32-0.84]).

Conclusions:
Response to varied treatments such as exercise training and spironolactone varies among complex HF phenotypes in both HFpEF and HFrEF. Additional investigation which further characterizes phenotype-specific treatments may help select specific interventions most likely to benefit specific phenotypes.
Abstract 16914: Structural and Functional Investigation of Myocardial Fiber Architecture in Genetic Mouse Models of Heterodoxy and Situs Inverses Totalis
Authors: Wu Yijen L , Liu Xiaoqin , Chen Yu , Salamacha Nathan , Han Joyce , Ennis Daniel B , Tadros Sameh , Lo Cecilia
Published: April 2024

Introduction:
Heterotaxy (HTX) patients with congenital heart disease have higher risk of post-surgical complications and increased morbidity and mortality. Given HTX involves disruption of left-right patterning, this suggests laterality disturbance may drive the poor outcome in CHD patients with HTX. To investigate this, we used mouse models with laterality defects. Although HTX mutant mice invariably die prenatally/neonatlly from complex CHD, many mutations causing HTX also giive rise to mice that are adult viable with situs inversus totalis (SIT), or situs solitus (SS) without CHD. Hence, our goal is to delineate myocardial fiber architecture in the SIT and SS mutant mice to gain insights into possible functional deficits associated with HTX.

Hypothesis:
Disturbance in specification of laterality results in abnormal myocardial fiber architecture that can cause cardiac dysfunction and make the heart more vulnerable to stress.

Methods:
Diffusion tensor imaging (DTI) was used to delineate the myocardial fiber organization in SIT and SS mutant mice, and wild-type (WT) control mice. Cardiac MRI and echocardiography were used to evaluate cardiac function with or without dobutamine stress.

Results:
Echocardiography showed no significant differences in global systolic function in the SIT and SS mutant hearts, but they displayed compromised strain rates under dobutamine stress. SIT and SS hearts also exhibited reduced rotation and torsion, suggesting altered myocardial fiber organization. Myocardial tractography by DTI (Fig.A-D) showed less coherent myocardial fiber organization (Fig. G-I) and more diverse helix angles (Fig. K&M) in SIT mutant hearts. Overall, our data showed the mutant SS and SIT hearts have disrupted myocardial fiber architecture resulting in abnormal torsion, rotation, and strain when stressed.

Conclusions:
These findings suggest abnormal myocardial architecture may contribute to the poor clinical outcome in HTX patients with CHD.
Abstract 16922: Accelerated Degeneration and Late Detachment of the Freestyle Aortic Root in Young Adults
Authors: Hosny Hatem , Eldowaik Ahmed , Samaan Amir , Selwanos Peter P , Romeih Soha , Hassan Mohamed , El-Khatib Mohamed , Hebala Muhammed , Bouhout Ismail , El-Hamamsy Ismail , Afifi Ahmed , Yacoub Magdi
Published: April 2024

Introduction:
The ideal valve substitute for the aortic valve in young adults is yet to be identified. The Freestyle stentless aortic root seems to be a viable candidate, but there is not enough data about how it behaves in young patients.

Methods:
This study reports the mid-term clinical outcome after total aortic root replacement with stentless porcine root (Medtronic Freestyle) for patients younger than 50 years, in a single center, during the period from 2009 to 2017.

Results:
173 patients were enrolled to this study. The median age at operation was 32 years (6-50). 56% were males. 89 patients (51%) had rheumatic heart disease, while 25 patients (14%) had bicuspid aortic valve. 10 patients (6%) had aortic aneurysm. The median valve size was 25 (21-29). 43 patients (25%) had a concomitant procedure during operation, mostly mitral valve surgery. The median bypass time was 180 minutes (82-380). The median follow-up period was 41 months (2-101). In-hospital mortality was 1.2%, while late mortality was 4%. Valve degeneration included virtual disappearance of the walls of the sinuses (encountered in 2 patients after 9 months and 3 years) and late detachment of the valve ring (in 2 patients after 2 and 5 years), resulting in false aneurysms (Figure 1a). Alarmingly, 2 of the patients who developed false aneurysms were discovered by MSCT during routine follow-up, one of them had a normal MSCT 3 years earlier, 2 years after the operation (Figure 1b). 3 patients had re-operation for false aneurysm, with no early mortality. One patient presented in cardiogenic shock caused by severe stenosis due to calcification (Figure 1c) and died after re-operation. Structural valve deterioration (defined as mean aortic gradient > 20 mmHg or aortic regurgitation > 2/4) was 21 ± 8% at 5 years. Freedom from aortic reintervention is 98 ± 3% at 5 years.

Conclusions:
Although the Freestyle aortic root offers excellent hemodynamics, the risk of early degeneration and the development of false aneurysms were found to be major concerns. Freestyle implantation in young patients should be used with caution. We recommend annual screening of those patients with contrast-enhanced imaging for early detection of such complications.
Abstract 16923: Oxidative Mitochondrial Dna Damage - A Potential Link Between Insulin Resistance and Heart Failure in Ageing Obese Mice
Authors: Gorodnya Olena M , McLendon Jared M , Rachek Lyudmila I , Sukhanov Sergiy , Yuzefovych Larysa V , Ruchko Mykhaylo V
Published: April 2024

Introduction:
Obesity and age play a central role in the development of insulin resistance, which is a crucial abnormality driving cardiovascular complications. Chronic diabetes can affect cardiac muscle directly, leading to a decline in cardiac function, known as “diabetic cardiomyopathy”. However, molecular mechanisms underlying the link between insulin resistance and heart failure are not clear.

Hypothesis:
Here, we hypothesize that oxidative mtDNA damage is a linking mechanism between insulin resistance and heart failure, since it contributes to all main pathways distinctive of both processes.

Methods:
In the present study we used 15-month old mice of three genotypes with different levels of mtDNA oxidation because of altered expression of DNA repair glycosylase Ogg1, the first enzyme in the base excision repair pathway in mitochondria. Wild type (WT) mice, Ogg1 knock-out (KO) mice and KO mice transgenically overexpressing mitochondria-targeted Ogg1 (KOTG) were fed a high fat diet for 14 weeks and analyzed for mtDNA damage, bioenergetic and cardiac functions, and blood glucose and insulin levels.

Results:
Our previous results showed that young mice deficient in Ogg1 had increased mtDNA damage, altered mitochondrial respiration and left ventricle hypertrophy, but, despite these abnormalities, their cardiac function remained unchanged. Echocardiography of ageing mice in the present study demonstrated increased left ventricle mass (1.5 fold, p<0.05) and decreased cardiac contractility in KO mice when compared to WT animals (ejection fraction: 54.2±3.1 vs. 71.9±5.2 %, respectively, p<0.05). Compared to hearts from WT mice, KO animals displayed a significant decrease in ATP levels (7.2±0.3 vs. 3.8±0.4 pmole/mcl respectively, p<0.05). These changes in cardiac function and bioenergetics observed in KO mice were accompanied by increase in blood glucose and insulin levels. Interestingly, young (5-month old) KO mice fed a high fat diet also demonstrated increased glucose (KO 256.7±19.9 vs. WT 180.8±22.8 mg/dl, p<0.05) and insulin (5 fold, p<0.05) levels when compared to WT animals. These observations indicate that KO mice fed a high fat diet may develop insulin resistance. All these changes were prevented in KOTG mice, which were not statistically different from WT animals.

Conclusions:
Our results suggest that oxidative mtDNA damage could be a converging point that links both insulin resistance and heart failure in aging obese mice.