bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18079: B-Type Natriuretic Peptide is a Screening Tool to Rule Out Subclinical Left Ventricular Geometry and Diastolic Dysfunction in a Community-Based Population
Authors: Hasegawa Takuya , Asakura Masanori , Kanzaki Hideaki , Kim Jiyoong , Asanuma Hiroshi , Funada Akira , Sugano Yasuo , Ohara Takahiro , Anzai Toshihisa , Kitakaze Masafumi
Published: April 2024

Background:
LV hypertrophy and LV diastolic dysfunction are common and associated with the incidence of cardiac events in the general population. LV systolic and/or diastolic dysfunction and LV hypertrophy are associated with high B-type natriuretic peptide (BNP) levels. Plasma BNP levels have been reported to be a useful biomarker to detect various heart diseases in the general population. However, it has not been investigated whether plasma BNP levels are useful to detect LV hypertrophy and/or diastolic dysfunction in the general population.

Methods:
We studied 1162 community-dwelling subjects without obvious heart diseases (mean age, 63 +/- 11 years; 448 men, 714 women) who participated in annual health checkup in a rural Japanese community, Arita-cho. The population was divided into 5 groups referring to plasma BNP levels. LV diastolic dysfunction was determined with the waves of transmitral flow and mitral annular velocity. LV hypertrophy was defined as the top quintile of LV mass index.

Results:
The prevalence of LV hypertrophy and/or diastolic dysfunction increased along with increases in BNP levels(Table). The area under the receiver operating characteristic curve showed the modest ability of plasma BNP levels for detecting those subjects (0.640 95%CI 0.590-0.690 p<0.001). An optimal threshold for the identification of the subjects with both LV hypertrophy and diastolic dysfunction was a BNP of 22.0 pg/ml with the sensitivity of 61%, the specificity of 58%, positive predictive value of 17%, and negative predictive value of 92%.

Conclusion:
BNP levels seem the useful screening tool to rule out, rather than detect, subclinical LV impairment in the community-based population.
Abstract 18083: Does 6-Minute-Walk Distance Correlate With Right Ventricular Function in Patients With Pulmonary Arterial Hypertension?
Authors: Addetia Karima , Bhave Nicole M , Freed Benjamin H , Gomberg-Maitland Mardi , Mor-Avi Victor , Spencer Kirk T , Dill Karin , Lang Roberto M , Patel Amit R
Published: April 2024

Background:
The majority of treatments available for pulmonary arterial hypertension (PAH) have been approved based on improvement in 6-minute walk distance (6MWD), shown to be an independent predictor of prognosis in these patients. Meanwhile, right ventricular (RV) size and function are also important prognosticators in these patients. We sought to determine whether RV indices on cardiovascular magnetic resonance imaging (CMR) correlated with 6MWD in patients with PAH.

Methods:
Same-day CMR and 6MWD were performed in 35 PAH patients (51±14 yrs, 32 females, BSA=1.8±0.3/m
2
). 22 patients had repeat testing at 7±1 months. Consecutive short-axis cines spanning the entire RV were used to measure ejection fraction (RVEF) and indexed end-diastolic volume (EDVI). Patients who declined to perform the 6MWD test claiming inability were assigned 6MWD=0.

Results:
Mean RVEF, EDVI and 6MWD at baseline were 36±14%, 134±47mL and 349±152m. Four patients were unable to perform 6MWD at baseline and 3 at follow-up. Poor correlation was observed between baseline RV indices and 6MWD (r=0.10 for EDVI and r=0.14 for RVEF; p<0.0001). Patients classified as WHO class III showed significantly worsened mean 6MWD than those classified as WHO class I (296m vs.469m; p<0.01). However, WHO class did not correlate with RVEF or EDVI. Even when 6MWD was categorized into recommended thresholds for predicting prognosis, namely ≤250m (n=7) and >440m (n=8), there was no significant difference in mean RVEF and EDVI between these 2 groups. Finally, when comparing changes in RVEF and 6MWD from baseline to follow-up, 10/24 patients showed concordant changes, while the remaining 12/24 patients showed discordant changes (p=0.59, Figure).

Conclusions:
Since 6MWD does not appear to correlate with RV function in this patient population, further studies are needed to determine the optimal parameters to study disease progression in these patients.
Abstract 18088: Myocardial Delivery of Lipidoid Nanoparticle mRNA Designed for Tailored Expression of Cardiogenic Factors
Authors: Turnbull Irene C , Eltoukhy Ahmed A , Fish Kenneth M , Hajjar Roger J , Anderson Daniel G , Costa Kevin D
Published: April 2024

Introduction:
Nanoparticle-based delivery of mRNA offers a potential alternative to viral vectors for gene therapy, but efficacy has not been demonstrated in the heart. As a proof of concept, we report the first successful lipidoid nanoparticle (LNP) mediated delivery of mRNA to rat myocardium as a novel approach for controlling the timing and distribution of expression of therapeutic factors for cardiac repair.

Methods and Results:
Custom lipidoid formulation yielded functionally stable LNPs containing modified eGFP mRNA. LNP solution (600 uL) was delivered by injection at 8 to 10 sites into adult rat myocardium, followed by recovery. At time of sacrifice, the heart was cut in two: 1) mRNA level was quantified by real time-PCR, and 2) eGFP protein was detected by immunofluorescence of cryosections. To test the dose response (Fig. A), rats received 1, 5 or 10 ug eGFP mRNA (n = 3 per group) and were sacrificed 20 h after injection; compared to saline control, the fold increase in eGFP mRNA in the heart was 142 ± 116, 5628 ± 1292 and 5470 ± 3103 fold, respectively, with higher dosages showing a significant effect (p < 0.05). Fluorescence microscopy confirmed GFP-positive cells in the subepicardium of all treated hearts. Expression kinetics at different time points after injection of 5 ug of eGFP mRNA showed that expression at 6 h (18,380 ± 5457 fold) was significantly higher than at 20 h (p < 0.05), with expression still detectable at 48 h. Biodistribution of eGFP mRNA in harvested lung, liver, spleen, kidney, skeletal muscle, and brain (Fig. B) showed the delivery was cardiac specific, with off-target expression levels less than 1% of that in the heart.

Conclusion:
Adult rat myocardium was successfully transduced, supporting our hypothesis that lipidoid nanoparticles carrying mRNA allow effective message delivery to cardiac cells in vivo, with potential to optimize gene therapy for enhanced cardiac function and regeneration.
Abstract 18092: Statin Use After an Acute In-Hospital Myocardial Infarction Among Medicare Beneficiaries
Authors: Yun Huifeng , Safford Monika , Brown Todd , Farkouh Michael , Kent Shia , Levitan Emily , Sharma Pradeep , Kilgore Meredith , Bittner Vera , Rosenson Robert , Muntner Paul
Published: April 2024

Background:
American Heart Association (AHA) guidelines recommend all patients are discharged on a statin following a coronary heart disease (CHD) event. Many patients have an acute myocardial infarction (AMI) while hospitalized for another reason but the use of statins upon discharge in this population has not been well studied.

Methods:
Using the Medicare 5% national random sample, we identified beneficiaries who had a hospital discharge diagnosis for AMI or who underwent coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI) in 2007-2009. Medicare requires the primary diagnosis code to represent the initial reason for hospitalization; secondary discharge diagnosis codes capture complications including in-hospital AMI. Beneficiaries taking and not taking statins prior to their hospitalization were analyzed separately. Filling a statin prescription within 90 days after hospital discharge was identified using Medicare Part D claims.

Results:
Of 5,810 and 8,517 Medicare beneficiaries taking and not taking statins prior to their CHD-related hospitalization, 84% and 55% filled a statin within 90 days of discharge, respectively. The proportion of beneficiaries filling a statin following discharge was substantially lower among those with a secondary versus primary discharge diagnosis of AMI, or PCI or CABG (Table). After multivariable adjustment, beneficiaries with a secondary discharge diagnosis of AMI were 41% (risk ratio = 0.59, 95% CI: 0.54 - 0.65) and 11% (risk ratio = 0.89; 95% CI: 0.82 - 0.97) less likely to fill a statin compared to those with a primary discharge diagnosis of AMI.

Conclusion:
A high percentage of Medicare beneficiaries with in-hospital AMIs do not fill statins following hospital discharge. Reasons why patients with in-hospital AMIs do fill statins following discharge need to be identified.
Abstract 18128: Prediction of Elastin Degradation in Aorta Using a Novel Infrared Spectroscopic Methodology
Authors: Cheheltani Rabee , Rao Jayashree , Vorp David A , Pleshko Nancy , Kiani Mohammad F
Published: April 2024

Introduction:
In vivo quantification of elastin degradation has significant implication in advancing diagnosis of abdominal aortic aneurysm (AAA) expansion. We hypothesize that Fourier transform infrared spectroscopy (FTIR) can be used to predict elastin content using a methodology that has the potential for assessing elastin degradation in a clinical setting. Here, a model of AAA was created by varying levels of enzymatic degradation in pig aorta and a multivariate model was developed based on acquired FTIR spectra of the specimens. This model was further validated in human AAA sections.

Methods:
Porcine aorta specimens (n=54) were cut into strips of 100 mg and divided into groups of elastase treated, collagenase treated or untreated by submerging them in enzyme or buffer solutions for different durations. After treatment, samples were cut into half for biochemical assay (Fastin elastin assay) and FTIR. For latter, 9 μm cross sections of frozen tissue were mounted on low-e slides and were scanned with an FTIR spectrometer. Average spectra of specimens were combined with values of elastin content from assay, to develop a partial least squares (PLS) regression model. To further validate, factor-1 matrix of model, was used as reference spectrum in a correlation map to visualize elastin in a section of human AAA wall. This specimen was excised from an aneurysm patient during their elective surgical repair, paraffin embedded, and sectioned on low-e and glass slides, for FTIR analysis and histology.

Results and Conclusion:
The multivariate model predicted elastin content of the specimens (varying between 0% and 80% d/w) with a strong correlation (R
2
=0.81) and could be used to map elastin in human AAA wall sections (Figure). In conclusion, our developed methodology predicts elastin degradation in the imaging modality of FTIR. Expanding this method to fiber optic modality has a potential for clinical assessment of elastin degradation in a minimally invasive fashion.
Abstract 18159: Myocyte Turnover in the Mouse Heart
Authors: Borghetti Giulia , Bai Yingnan , Wybieralska Ewa , Okorek Barbara , Isobe Kazuya , Matsuda Alex , Seymour Mark , Pankratz Todd , Guarin Eric , Goichberg Polina , Leri Annarosa , Rota Marcello , Anversa Piero , Kajstura Jan
Published: April 2024

Despite the identification of cardiac stem cells and their ability to differentiate in the various cardiac cell lineages, the controversy on the turnover rate of myocytes in the adult heart continues. Two independent but complementary protocols were employed to define myocyte renewal in the mouse heart. Mice 2-3 months of age were injected every 12 hours with BrdU (50mg/kg bw) for 6 days prior to sacrifice. A second group of mice received one injection of
14
C-thymidine (300 pCi) and the animals were sacrificed from 1 to 90 days later. The BrdU method allowed us to measure the number of myocytes formed in 6 days. The
14
C-thymidine strategy provided us with an evaluation of myocyte regeneration as a function of time.

In assay 1, BrdU localization in myocytes was determined by immunolabeling and confocal microscopy. After 12 injections of BrdU, 3.1±0.4% or 100,000±13,000 (n=8) left ventricular (LV) myocyte nuclei were labeled, indicating that a significant number of parenchymal cells was added to the LV in 6 days. Given that the number of LV myocytes is constant in the adult mouse heart, myocyte apoptosis and necrosis were measured by hairpin 1 and hairpin 2 in situ ligation, respectively. Myocyte necrosis was also assessed by the incorporation of circulating vitronectin that reflects an irreversible loss of integrity of the plasma-membrane. Apoptosis comprised 186±55 myocyte nuclei/10
6
(n=6) and cell necrosis 316±71/10
6
nuclei. Similarly, vitronectin-positive myocytes were 280±103/10
6
cell profiles (n=4). Since apoptosis last at most 4 hours and necrosis 20 hours, there was a 2.9±0.4% drop out of myocytes in 6 days.

In assay 2, LV myocytes were isolated, purified by differential centrifugation, and the DNA extracted for the measurement of the kinetics of
14
C concentration by Accelerator Mass Spectrometry.
14
C concentration in myocyte DNA increased progressively from 1 to 10 days, and remained essentially constant up to 90 days. These findings indicate that a significant number of new myocytes was formed in 10 days. The regenerated myocytes had a lifespan of at least 90 days as demonstrated by the lack of changes in
14
C from 10 to 90 days. This value is consistent with the rate of myocyte formation and death measured above. Thus, myocyte turnover is high in the adult mouse heart.
Abstract 18254: Pathogenic Role of STIM2 and Orai2 in Pulmonary Arterial Hypertension
Authors: Fernandez Ruby A , Wan Jun , Guo Qiang , Yuan Jason X
Published: April 2024

Pulmonary hypertension (PH) is a fatal disease attributed to increased pulmonary vascular resistance (PVR). Elevated PVR is partially due to sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling. Pulmonary arterial smooth muscle cells (PASMC) in their natural state are plastic and exist in two different phenotypes; a differentiated, contractile phenotype and a dedifferentiated, more proliferative phenotype. An increase in cytosolic free Ca
2+
concentration ([Ca
2+
]
cyt
) is a major stimulus for PASMC proliferation, contributing to pulmonary vascular remodeling. This study characterizes the phenotypic switch observed when freshly dissociated PASMC are cultured from normal male rats or in PASMC isolated from experimental PH rats. Western blot analysis showed freshly isolated pulmonary arteries (PA) express contractile markers that were decreased in cultured PASMC, demonstrating a switch to a proliferative phenotype. Cultured PASMC showed an increase in expression of store-operated and receptor-operated Ca
2+
channels Orai2, STIM2, and TRPC6 compared to freshly dissociated PASMC. Additionally, an increase in store-operated Ca
2+
entry (SOCE) and a decrease in voltage dependent Ca
2+
influx in cultured PASMC was observed when compared to freshly dissociated PASMC, suggesting SOCE plays a greater role in proliferating PASMC. Consistently, isometric force studies showed greater contraction induced by voltage-dependent Ca
2+
channel (VDCC) activation than SOCE induced contraction in freshly isolated pulmonary artery rings. Furthermore, Orai2, STIM2, and TRPC6 were upregulated in proliferative PASMC compared to quiescent PASMC. Knockdown of Orai2 was able to attenuate SOCE in proliferative PASMC demonstrating Orai2 is necessary for SOCE. These data suggest upregulation of STIM2 promotes the phenotypical transition of PASMC from a contractile to a proliferative phenotype by inhibiting VDCC and activating SOC, and that increased expression of Orai2 and TRPC6 channels mediate the increased [Ca
2+
]
cyt
seen in proliferating cells. Understanding the molecular mechanisms which regulate [Ca
2+
]
cyt
and PASMC proliferation is critical for the development of novel therapies for PH.
Abstract 18269: Prognostic Value of Insulin-Like Growth Factor Binding Protein 7 (IGFBP7) in Patients With Heart Failure: Data From CORONA
Authors: Ueland Thor , Nymo Ståle , Kjekshus John , Mcmurray John J , Wikstrand John , Wienhues-Thelen Ulla , Liu Peter , Aukrust Pål , Gullestad Lars
Published: April 2024

Background:
A recent proteomic analyses of cardiac tissue from a transgenic murine model of heart failure (HF) and clinical myocardial samples identified IGFBP7 as a candidate marker of HF. We investigated if serum levels of IGFBP7 were upregulated in human HF, if IGFBP7 provided independent prognostic information in these patients, and potential interactions with statin therapy.

Materials and methods:
Serum IGFBP7 was measured in 187 HF patients and 57 matched healthy controls. The associations of serum IGFBP7 with adverse outcome were assessed in a subset of 1428 patients enrolled in the in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) population, randomly assigned to 10 mg rosuvastatin or placebo, which included patients with HF, aged ≥60 years, in New York Heart Association classes II to IV, who had ischemic heart disease and a reduced left ventricular ejection fraction. Outcome included the primary endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke; n=408), all-cause mortality (n=422), CV mortality (n=344), coronary endpoint (n=330) and CV mortality/hospitalization for worsening of heart failure (n=535).

Results:
Serum IGFBP-7 levels were markedly elevated (p<0.001) in HF patients compared to controls (median [25th, 75th percentile]: 694 [586,874] ng/mL vs. 458 [425,499] ng/mL, p<0.001) and correlated with clinical severity (i.e. NYHA, p=0.002). In univariate analyses, IGFBP7 (continuous variable) was associated with all outcomes [HR ranging from 1.76 (coronary endpoint, p=0.003) to 3.08 (CV death, p<0.001)]. In multi-variable analyses, IGFBP7 remained significant for most endpoints after step 1 adjustment (adjusting for left ventricular ejection fraction, NYHA class, age, body mass index, diabetes, sex, intermittent claudication, heart rate, serum creatinine and apoA1) but the predictive value was markedly attenuated and not significant for any outcome after the addition of CRP and NT-proBNP. No interaction by treatment effects were observed for any outcome.

Conclusions:
Serum IGFBP7 levels are elevated in patients with HF but add no predictive information beyond NT-proBNP for adverse outcome in older patients with advanced chronic systolic HF of ischemic aetiology.
Abstract 18274: Under Use of Statins and LDL-C Control Among People With a Framingham 10-Year Coronary Heart Disease Risk > 20%
Authors: Gamboa Christopher , Levitan Emily , Mann Devin , Yun Huifeng , Glasser Stephen , Woolley J. Michael , Rosenson Robert , Farkouh Michael , Safford Monika , Muntner Paul
Published: April 2024

Statins reduce the incidence of coronary heart disease (CHD) in individuals with a history of CHD or risk equivalents. A 10-year CHD risk >20% is considered a CHD risk equivalent but is frequently not estimated. We studied the use of statins and control of LDL-C among participants with a history of CHD or CHD risk equivalents in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study (n=30,239) The 8,812 participants with CHD or risk equivalents were categorized into four mutually exclusive groups: (1) history of CHD, (2) no history of CHD but with a history of stroke and/or aortic aneurysm, (3) no history of CHD, stroke or aortic aneurysm but with diabetes mellitus, or (4) no history of the conditions listed in (1) through (3) but with a Framingham 10-year CHD risk > 20% at baseline. Lipids were measured after an overnight fast, LDL-C was calculated using the Friedewald equation, and statin use was assessed through pill bottle review during an in-home study visit. The mean age of study participants was 65 years (SD=9), 45% were women and 46% were black. In fully adjusted models, compared to those with a history of CHD, the use of statins was statistically significantly lower among people with a history of stroke/aortic aneurysm, history of diabetes, and especially 10-year CHD risk > 20% (Table). Among high risk participants taking statins, the prevalence of LDL-C < 100 mg/dL was similar for those with a history of CHD, a history of stroke/aortic aneurysm and diabetes, but participants with a 10-year CHD risk > 20% were less likely to have an LDL-C < 100 mg/dL. These data suggest many people with high CHD risk, especially those with a FRS >20%, were not receiving guideline-concordant lipid-lowering therapy and quality improvement efforts should focus on this group.
Abstract 18307: Intracoronary Infusion of Allogeneic Cardiosphere Derived Cells, During Acute Myocardial Infarction Delays but Eventually Does Not Limit Remodeling of the Left Ventricle
Authors: Ntalianis Argyrios , Sfakianaki Titika , Sousonis Vassilis , Repasos Evaggelos , Nana Maria , Kontogiannis Chris , Katsaros Lampros , Papalois Apostolos , Nanas John , Terrovitis Ioannis
Published: April 2024

Objective:
In animal models, it has been shown that myocardial cells regenerate even in the adult heart at very slow rates and that regeneration is stimulated after myocardial injury. However the endogenous mechanisms of regeneration are not adequate to limit the damage produced by an acute myocardial infarction.The objective of the study was to demonstrate if remodeling of the left ventricle is attenuated by intracoronary infusion of Allogeneic Cardiosphere Derived Cells (CDCs), at the ischemic phase of acute myocardial infarction, using a chronic ischemia- reperfusion model in swine.

Method:
In twelve pigs, AMI was induced by occlusion of Left Anterior Descending Coronary Artery for 60 minutes. At 60 minutes of ischemia, 6 animals received 5 million allogeneic CDCs (Group 1), and 6 (Group 2) normal saline, using a catheter that crossed the occlusion site. Five minutes after cell infusion, reperfusion was allowed. The follow up period was 30 days. All animals underwent transthoracic echocardiography before and immediately after the AMI, as well as at 15 and 30 days. Left ventricular end diastolic diameter (LVEDD), end-systolic diameter (LVESD) and ejection fraction (LVEF) were measured.

Results:
Group 1 animals did not demonstrate statistical significant increase in LV dimensions or decrease of EF at 15 days (LVEDD from 38mm to 42.6mm, p= 0.149, LVEF from 67.66% to 56.5%, p= 0.335). In contrast, Group 2 animals experienced significant decrease of LV function (LV EF from 56.5% to 48%, p=0.014) and a significant increase of LVESD (from 22.75mm to 28.5mm p=0.005) and LVEDD (from 32 mm to 37.75mm, p=0.009). However, animal in both groups had significant remodeling at 30 days There was an equivalent % reduction of LVEF (8.3% vs 7.6%, p=0.95) and increase of LVEDD and LVESD ( 6.5% vs 9.2 % p=0.3 and 6.3% vs 8.6% p=0.6 ,respectively) in Group 1 compared to Group 2.

Conclusions:
Infusion of allogeneic CDCs during acute AMI was safe and well tolerated hemodynamically, but produced only a transient benefit on LV function. This result may suggest that a re-infusion of cells is necessary at later time points after the index MI, in order to achieve sustained improvement.
Abstract 18322: The Impact of Obesity on Survival in Fontan Conversion Patients
Authors: Freud Lindsay R , Webster Gregory , Tsao Sabrina , Deal Barbara J
Published: April 2024

Introduction:
The negative cardiovascular effects of obesity are well described in adult patients. By increasing both pulmonary and systemic vascular resistance, we hypothesized that obesity would be particularly deleterious in the setting of single ventricle physiology. Our aim was to assess the impact of obesity on mid-term survival in patients following Fontan conversion to extracardiac total cavopulmonary connections.

Methods:
We analyzed the pre-operative body mass index (BMI) of consecutive patients undergoing Fontan conversion at our institution from 1994-2012. Raw BMI values were converted to standardized percentiles and Z-scores to enable comparison to published norms. Overweight and obese were defined as BMI >85%ile and >95%ile for patients <20 years, and BMI 25-30 kg/m
2
and ≥30 kg/m
2
for patients ≥20 years. Transplant-free survival at most recent follow-up was assessed with Kaplan-Meier analyses.

Results:
We evaluated 139 patients with a median age of 24.1 years (3-47) at the time of Fontan conversion surgery. In 49 patients <20 years of age, mean BMI was significantly lower compared to the normal population with a Z-score of -0.5 (p-value 0.02). In the 90 patients ≥20 years, mean BMI was significantly elevated with a Z-score of +0.4 (p-value <0.001). The prevalence of overweight or obese patients rose from 29% among patients <20 years to 40% among those ≥20 years. At median follow-up of 7.6 years following surgery (age 31.8 years), obese patients had significantly lower transplant free-survival compared to non-obese patients (p-value 0.006; see figure).

Conclusion:
During mid-term follow-up of patients following Fontan conversion, obesity is associated with significantly shorter transplant-free survival. While this study is retrospective, it offers a strong negative association between obesity and mortality in single ventricle survivors and underscores the importance of weight management in these patients.
Abstract 18324: Complication Rates of Atrial Fibrillation Ablations: A Comparison of Outcomes From a National Administrative Database to Contemporary Randomized Control Trials
Authors: Pothineni Naga Venkata K , Noheria Amit , Pant Sadip , Patel Nileshkumar J , Chothani Ankit , Shah Neeraj , Mehta Kathan , Savani Ghanshyambhai T , Grover Peeyush , Bhalara Vipulkumar , Rathod Ankit , Deshmukh Abhishek , Viles-Gonzalez Juan , Paydak Hakan
Published: April 2024

Introduction:
The availability, national scope and perceived unbiased nature of administrative data make it the preferred choice for evaluating quality and outcomes. We calculated Atrial Fibrillation ablation complication rates from national administrative data and compared them with data from randomized control trials (RCT).

Methods:
Using the Nationwide Inpatient Sample (NIS) we identified patients treated with AF ablations. We investigated complications described with AF ablation and defined them by validated Clinical Modification (ICD-9-CM) diagnosis codes. We compared them with the complication rates reported from AF ablation from widely quoted RCTs. (AF ablation vs. Antiarrhythmics)

Results:
We analyzed complication rates from 47042 AF ablations performed from the years 2000 to 2008 from the NIS. We also analyzed pooled complication rates from large RCTs. Cardiac tamponade and/or effusion and vascular access complication appear to be the most frequent complications. The NIS data had a higher rate of cardiac tamponade/effusion (21.5 vs. 12.5), vascular access complications (21.2 vs. 19.7) and deaths (4.0 vs. 3.0) when compared to RCTs. Interestingly, RCTs reported a higher rate of stroke/TIA (13.2 vs. 7) when compared to the national administrative data.

Conclusion:
Despite substantial improvement, “real-world” complication rates from administrative data remain higher than those reported in RCTs. The discrepancy may be attributable to differences in operator skills, selection bias and variation in data quality.
Abstract 18328: Neurotrophin 3 Induces the Expression of Osteogenic Proteins in Human Aortic Valve Interstitial Cells via Trk Receptors
Authors: Yao Qingzhou , Song Rui , Zeng Qingchun , Ao Lihua , Yu Xiyong , Fullerton David A , Meng Xianzhong
Published: April 2024

Calcific aortic valve disease affects a large number of elderly people, and progressive aortic valve leaflet calcification ultimately results in heart failure. However, the molecular mechanism that mediates valvular osteogenic responses is incompletely understood. Aortic valve interstitial cells (AVICs) express osteogenic proteins in response to stimulation of Toll-like receptor (TLR) 2 or 4. We recently found that soluble biglycan induces the expression of transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2) in human AVICs via TLR2. The
objective
of this study is to identify novel pro-osteogenic mediators and to elucidate the mechanisms underlying their action in human AVICs.

Methods and results:
We examined gene expression profile in AVICs isolated from 5 normal human aortic valves and 5 diseased human aortic valves using microarray analysis. Among a large group of genes analyzed, mRNA levels of neurotrophin 3 (NT3), a neural growth factor, were markedly up-regulated in AVIC isolates of diseased valves. Immunoblotting analysis confirmed higher levels of NT3 protein in AVICs of diseased valves. Surprisingly, normal human AVICs expressed greater levels of TGF-β1 and BMP-2 when exposed to recombinant human NT3 (0.05 or 0.10 μg/ml) for 3 days. Further, up-regulation of TGF-β1 and BMP-2 expression by NT3 was preceded by phosphorylation of Akt and glycogen synthase kinase 3 beta (GSK3β). The pro-osteogenic effect of NT3 was not affected by blocking antibodies against TLR2 and TLR4, indicating that NT3 is incapable of acting as a danger-associated molecular pattern in human AVICs. However, neural growth factor receptors (TrkA, TrkB, TrkC and p75
NTR
) were detectable in human AVICs. The pan Trk inhibitor K252a (0.2 μmol/L) suppressed Akt and GSK3β phosphorylation, and markedly reduced TGF-β1 and BMP-2 expression following NT3 stimulation.

Conclusions:
AVICs of diseased human aortic valves express higher levels of NT3. NT3 induces the expression of TGF-β1 and BMP-2 by human AVICs via Trk receptors. Thus, NT3 is a novel pro-osteogenic mediator in human aortic valve, and it may play a role in aortic valve leaflet calcification through up-regulation of the expression of osteogenic proteins by AVICs.
Abstract 18335: Reversing Right Ventricular(RV) and Left Ventricular(LV) Pace Sense(PS) Leads in the Implantable Cardioverter Defibrillator(ICD) Header in Patients With the Medtronic 6949 ICD Lead and Bipolar LV Lead: A Method to Avert Consequences of the Common Failure Modes
Authors: Reeves Rusell
Published: April 2024

Background:
Failure of the ring electrode of an implanted Medtronic Sprint Fidelis (6949 family) ICD lead commonly results in unnecessary shocks and can also lead to failure to pace. Placing a different PS lead will obviate this failure mode. We propose using a bipolar LV lead as the PS lead by connecting it to RV port, and connecting the PS part of the Fidelis lead to the LV port.

Methods:
Between 10/07 and 6/10 we identified 12 patients with Medtronic 6949 ICD leads and a Bipolar LV lead who underwent device procedures. All but one of the LV leads were Medtronic 4194. Criteria for swapping leads include: 1)adequate sensing by the LV lead; 2)no phrenic stimulation when pacing the LV lead; 3)no large T wave on the LV lead; 4) no failure of tip electrode or RV shocking coil of the ICD lead.

The ring pacing electrode is not used, and the SVC coil is rarely needed for defibrillation. The ability to program around phrenic stimulation by reprogramming the LV pacing vector is lost. The LV port is programmed to pace Tip to RV coil. This effectively paces the ICD lead from tip to its coil. The RV port sensing configuration is left bipolar. Any LV-RV timing offset needs to be reversed. We turn off Ventricular Sense Response and LV lead capture management.

Results:
The first patient was not swapped but led to the criteria for future procedures. One patient had an LV R wave of 2.6 mv (threshold 3.5V) and was not swapped. Ten patients underwent the swap. Three had failure of the ring electrode of the Fidelis lead at the time of the procedure. Of the 10 patients, the LV R wave was 18.6 +- 8.2(mean +-SD), pacing threshold 1.26 +- .71, and RV R wave 19.8+-7.0, threshold 0.65+-.15. The patient who had a bipolar lead from another manufacturer developed noise on the LV lead and required reoperation. Another had T wave sensing when BiV paced and received a shock from double counting. This system is functioning after reprogramming. Thus 9 of the 10 have functioned satisfactorily.

Conclusion:
Placing a bipolar LV lead into the RV PS port, and the Fidelis pace/sense connector into the LV port with appropriate reprogramming may be an alternative to either lead extraction or placing a new PS lead or ICD lead in many CRT patients at the time of ICD generator change.
Abstract 18336: Does the Interaction of B-Type Natriuretic Peptide and Depressive Symptom Status Predict Cardiac Mortality and Re-Hospitalization in Rural-Dwelling Heart Failure Patients?
Authors: Miller Pamela S , Moser Debra K , Pelter Michele M , Nesbitt Thomas , Southard Jeffrey , Robinson Susan , Cooper Lawton S , Dracup Kathleen
Published: April 2024

BACKGROUND:
Identification of reduced and preserved left ventricular ejection fraction (LVEF) is a stratification used in heart failure (HF) management and prognosis. Elevated B-type natriuretic peptide (BNP) levels and depressive symptoms are independently associated with poor prognosis; however, their combined risk on cardiac death and re-hospitalization for HF is less clear.

OBJECTIVE:
To assess the combined effect of BNP and depressive symptoms on clinical outcomes in rural-dwelling HF patients with both reduced and preserved LVEF.

METHODS:
Baseline data were collected on 576 patients in the Rural Education to Improve Outcome in Heart Failure (REMOTE) trial. Measures included BNP levels and depressive symptoms (Patient Health Questionnaire [PHQ]-9). Patients were stratified into 4 groups by elevated and normal plasma BNP (>100 pg/ml and ≤100 pg/ml) and with and without depressive symptoms (PHQ-9 ≥ 10 and < 10). Outcomes were defined as composite 2-year endpoint of cardiac death or first HF re-hospitalization.

RESULTS:
There were 199 patients (35%) who had a cardiac event. Kaplan-Meier with log rank test showed the probability of event-free survival differed significantly depending on BNP and depressive symptom status (Figure). In multivariable Cox regression analysis, the risk of the composite endpoint for those with depressive symptoms alone was 0.8 (p = 0.85); with elevated BNP alone, 16.8 (p < 0.001); and combined, 13.1 (p = 0.003) compared to non-depressed patients with normal BNP, independent of other covariates. Composite risk was similar between elevated BNP groups with or without depressive symptoms (p = 0.56). However, LVEF significantly modified the effect (p interaction = 0.03); higher LVEF reduced composite risk in patients with elevated BNP alone (hazard ratio 0.96, p = 0.01).

CONCLUSION:
Combined effect of BNP and depressive symptoms on cardiac event risk may provide useful clinical data in the risk stratification and management of HF outcomes.
Abstract 18338: Biomaterial Delivery Vehicles Improve Acute Retention of Cells in the Infarcted Heart
Authors: Roche Ellen T , Hastings Conn L , Lewin Sarah A , Shvartsman Dmitry , Brudno Yevgeny , Vasilyev Nikolay V , O’Brien Fergal J , Walsh Conor J , Duffy Garry P , Mooney David J
Published: April 2024

Introduction and Hypothesis:
Cell delivery to the infarcted heart has emerged as a promising therapy, but is limited by very low acute retention and engraftment of cells. The hypothesis was that acute retention can be improved with a biomaterial carrier, and the study compared several.

Methods:
Cells were quantified 24 hours post-implantation in a rat myocardial infarct model (Fig. 1a) in five groups (n=8 per group); saline injection (current clinical standard), two injectable gels (alginate and chitosan) and two epicardial patches (alginate and collagen). For injectable groups 60ul of saline or gel containing 400,000 human mesenchymal stem cells was injected intramyocardially in the infarct border zone. 400,000 cells were seeded on alginate or collagen patches, and implanted on the epicardial surface at infarct border zone. At 24 hours, retained cells were quantified with Xenogen imaging system. Hearts were perfused and sectioned to stain for retained cells.

Results:
All biomaterials significantly improved retention compared to a saline control, with 4.1 and 2.6-fold increases for chitosan and alginate injectables, and 14.2 and 19.3-fold increases achieved with collagen and alginate patches, respectively (Fig. 1b-c). Immunohistochemical analysis qualitatively confirmed these findings (Fig. 1d). Encapsulated/seeded cell survival was assessed in hypoxia/ischemia to further compare biomaterials.

Conclusion:
Injectable gels and epicardial patches were demonstrated to improve acute retention of cells when compared to a saline control. Injectable gels enable immediate myocardial delivery while epicardial patches facilitate superior retention and could potentially sustain cell delivery over extended periods. These biomaterial approaches should be considered for future cell therapy applications.

Figure 1: a) Procedural steps b-c) Cell retention after 24 hours d) Ventricle wall showing DAPI and implanted cells with GFP antibody (green) for each group
Abstract 18348: Hoxb13 is a Meis1 Cofactor Involved in Transcriptional Regulation of Cardiomyocyte Cell Cycle
Authors: Muralidhar Shalini , Kimura Wataru , Thet Suwannee , Sadek Hesham A
Published: April 2024

Lower vertebrates, such as newt and zebrafish, retain a robust cardiac regenerative capacity following injury. Although adult mammals lack this cardiac regenerative potential, numerous attempts at unraveling the regenerative potential of the mammalian heart have been pursued to reawaken this process in adult humans. We recently showed that mice are capable of regenerating their hearts shortly after birth following various types of injury. This remarkable regenerative potential appears to be primarily mediated by proliferation of preexisting cardiomyocytes during a brief window of time after birth. However, following arrest of cardiomyocyte proliferation shortly after birth, the mammalian heart loses this regenerative ability. We recently identified Meis1 is a key regulator of postnatal cardiomyocyte cell cycle arrest, where Meis1 deletion in cardiomyocytes results in reactivation of myocyte proliferation in the post-natal heart. However, further the transcriptional networks involved in mediating the postnatal effect of Meis1 in cardiomyocytes remain unclear. The transcriptional activity of Meis1 is known to be tightly linked to a number of Hox genes in various tissues. Therefore, we profiled the expression patterns of entire Hox family of transcription factors by qRT-PCR in the early neonatal window. We found that the only up regulated Hox genes were Hoxa10, Hoxa11, Hoxb13 and Hoxd12, which belonged to the AbdB-like paralogue of Hox genes. Intriguingly, these four transcription factors along with Hoxa9 are the only Hox proteins (out of 37 known mammalian Hox transcription factors) known to interact with Meis1. Detailed analysis of these Hox genes revealed that Hoxb13 mirrors Meis1 expression pattern during normal post-natal development and following injury, shares common cell cycle targets with Meis1, and appears to compensate for loss of Meis1 following its knockout. These findings identify Hoxb13 as a Meis1 cofactor in cardiomyocytes, and an important transcriptional regulator of cardiomyocyte cell cycle.
Abstract 18406: Insulin-Like Growth Factor-1 Increases Synthesis of Mature Type 1 Collagen via Induction of LARP6 Expression and Binding to the 5’ Stem-Loop Structure of Collagen mRNA
Authors: Blackstock Christopher , Higashi Yusuke , Sukhanov Sergiy , Delafontaine Patrice
Published: April 2024

Structural integrity of the fibrous cap of atherosclerotic lesions is a major determinant of plaque stability. We have previously shown that either insulin-like growth factor-1 (IGF-1) -infusion or smooth muscle cell-specific IGF-1-overexpression increases collagen content in atherosclerotic plaque in apoe-/- mice. To identify the mechanism responsible for this increase in collagen, we investigated the effect of IGF-1 on the mRNA-binding protein, la-related protein 6 (LARP6). LARP6 has been shown to bind a conserved stem-loop secondary structure present in the 5’UTR of
Col1a1
and
Col1a2
mRNAs and to coordinate their efficient translation into the heterotrimer of type 1 collagen.

Western blot from primary culture of human aortic smooth muscle cells (hASMCs) or mouse embryonic fibroblasts (mEFs) shows that IGF-1 increased expression of both LARP6 (~2.9-fold, p<0.001) and procollagen-1α (~2.4-fold, p<0.001) within 3 hours. Immunoprecipitation of LARP6, followed by measurement of
Col1a1
and
Col1a2
mRNA via qPCR indicates that IGF-1 increased association of LARP6 with
Col1a1
and
Col1a2
mRNA (p>0.01). Mutation of the 5’stem-loop structure of
Col1a1
mRNA (SL-/-), which inhibits binding of LARP6 but does not affect the coding region of the
Col1a1
gene, abolished the ability of IGF-1 to increase collagen-1α (p<0.001). Moreover, the SL-/- mutation blocked the ability of IGF-1 to increase the rate of pepsin-resistant collagen synthesis, measured via
3
H-proline incorporation assay (p<0.001). Furthermore, western blot of crude aortic lysate from apoe-/- mice suggests that IGF-1-infusion increases LARP6 expression in VSMCs
in vivo
. To assess collagen maturation
in vivo
, aortic valve cross-sections were stained with picro-sirius red and examined using a polarizing microscope. Apoe-/- mice with smooth muscle cell-specific IGF-1-overexpression showed a strikingly amplified ratio of thick mature collagen fibers to thin immature collagen fibers in plaque.

In summary, we show that IGF-1 increases expression of LARP6 in vascular smooth muscle cells leading to increased binding of LARP6 to
Col1a1
and
Col1a2
mRNAs and enhanced synthesis of mature type 1 collagen. These findings uncover a critical cellular mechanism whereby IGF-1 promotes plaque stability.
Abstract 18424: Cardiovascular Death in Student-Athletes and in the General Population: Are Trained Athletes Really at Higher Risk?
Authors: Rutten-Ramos Stephanie , Garberich Ross F , Haas Tammy S , Maron Barry J
Published: April 2024

Background:
Sudden death due to cardiovascular (CV) disease in competitive athletes has become a highly visible concern in the physician and lay communities. Previous studies have reported mortality rates from CV disease in young athletes as 2 to >4/100,000 person-years. However, while CV death rates are believed to be increased for competitive athletes, they have not been placed in the context of normal CV mortality within the general U.S. population.

Methods:
Using 2002 to 2006 cause of death (COD) data from CDC Division of Vital Statistics and population data from U.S. Census Bureau, CV-associated death rates were calculated by gender for populations ages 15-19 and 20-24 years. Comparisons were made to mortality rates obtained for high school athletes in Minnesota and U.S. college athletes.

Results:
Within the general population, CV death rates were 1.9 and 3.5/100,000 person-years for ages 15-19 and 20-24, respectively. When compared to death rates of 0.7/100,000 athlete-years in competitive high school athletes, the rate of CV death in the general population is 2.7 fold higher. Similarly, when compared to the reported death rate of 2.3/100,000 athlete-years, in NCAA athletes the rate of CV death in the general population is 1.5-fold higher. General population CV death rates were 1.9-fold higher for males compared to females in both age groups, and similar to competitive athletes for which male deaths predominate 9:1 (Table). Within the general population, African-American males and females, ages 15-19, had CV death rates 2-fold higher than their white counterparts, and for ages 20-24, African-American men/women had rates 2.3 and 2.7-fold higher than white counterparts, respectively.

Conclusion:
Although high school and college student-athletes are believed to be at increased risk for CV death, comparisons to the general population of similar age suggest otherwise with competitive athletes actually less likely to experience fatal CV events.
Abstract 18435: Normal Body Mass Index Does Not Protect From Coronary Atherosclerosis in the Metabolic Syndrome
Authors: Almandoz Jaime P , Willis Benjamin L , Lambert Jennifer E , Grundy Scott M , DeFina Laura F
Published: April 2024

Background:
Obesity is a known risk factor for coronary atherosclerotic disease, but epidemiological data suggest that it may not additionally contribute to mortality in people with the metabolic syndrome (MetS). We hypothesized that people with normal weight (NW) plus MetS are at greater likelihood for having coronary artery calcium (CAC) than NW without MetS and are as likely to have CAC as those with MetS who are overweight (OW) and/or obese (OB).

Methods:
We evaluated CAC scores (by Agatston units) from computed tomography scans in 11,621 men, age 40-80 years, with no history of CAD from the Cooper Clinic Longitudinal Study. Subjects were divided into 6 groups according to BMI class (NW 18.5-24.9; OW 25-29.9; OB >30 kg/m
2
) and the presence of MetS defined by 3 or 4 metabolic risk factors, exclusive of obesity: BP >130/85 mmHg, glucose >100 mg/dL, triglycerides >150 mg/dL, and HDL-C <40 mg/dL. We summarized levels and prevalence of CAC and tested for trends across obesity levels using multiple logistic regression analyses, adjusting for age and smoking.

Results:
The prevalence CAC >0 in the study population was 55.5%. The table shows median CAC score (Agatston units), CAC >0 prevalence (%), and odds ratios (OR) for CAC >0 and CAC >100 by logistic model, adjusted for age and smoking, in the six groups.

The marginal trend in prevalence of CAC > 0 across BMI groups is significant (p=0.01); however, the trend difference between those with and without MetS is not significant (p=0.773). The group with NW plus MetS has a prevalence of CAC comparable to those with OB plus MetS.

Conclusion:
In persons with or without MetS the likelihood of CAC increases with BMI. Those with MetS are more likely to be OW or OB. However, NW persons with MetS appear as likely to have detectable and clinically significant CAC, or a high odds ratio for CAC, as the OW and OB with MetS. Being NW does not protect against CAC in people with MetS.
Abstract 18465: Human Adipose-Derived Stem Cells for a Vascular Graft
Authors: Arrizabalaga Julien H , Nollert Matthias U
Published: April 2024

The objective of this study is to fabricate a small-diameter tissue engineered blood vessel (TEBV) by using human adipose-derived stem cells (ADSC) in combination with the human amniotic membrane as a mechanically-sound biological substrate. Our technology begins by differentiating adipose-derived stem cells into smooth muscle cells (SMC) and seeding them onto a flat sheet of the amniotic membrane. We assessed our hypothesis that several types of SMC can successfully attach and proliferate on this membrane by fluorescently staining cell nuclei with DAPI and characteristic SMC actin filaments with phallotoxins. The cell-seeded sheet was then wrapped around a 3mm O.D. removable mandrel with 6 revolutions. Human fibrinogen and thrombin were applied to glue the layers together and develop a tubular construct with architecture akin to that of a muscular artery’s tunica media layer. The mechanical integrity of this construct can be further improved upon its exposure to appropriate physiological conditions in a perfusion bioreactor. ADSC can also be differentiated into endothelial cells and seeded into the lumen of this construct to prevent platelet adhesion. The TEBV was characterized for its biochemical and mechanical properties. We examined the vasoactive properties of the vessel in response to agonists such as carbachol, norepinephrine and histamine, and compared our results with porcine coronary arteries. Burst pressure and elastic modulus tests were also performed. In conclusion, adipose-derived stem cells are a viable cell line for differentiation into smooth muscle cells and endothelial cells and may be used in tissue engineering of blood vessels. We have developed a small-diameter TEBV with off-the-shelf availability using a completely biological material seeded with patient-own stem cells.